Medicina y Salud Pública Julio/Agosto by Revista Medicina y Salud Pública (MSP)

EL FUTURO DEL TRATAMIENTO DEL CÁNCER DE

PU L MÓ N EDITORIAL LA IMPORTANCIA DEL RECINTO DE CIENCIAS MÉDICAS CASO MULTIETIOLÓGICO DE PERICARDITIS AGUDA

PRESENTACIÓN INUSUAL DE LINFOMA ANGIOINMUNOBLÁSTICO DE CÉLULAS T

CONFERENCIA DE PRENSA 40 AÑOS DEL SIDA EN PUERTO RICO

EL ROL DE LA GENÉTICA EN EL DESARROLLO Y MANEJO CLÍNICO DEL CÁNCER DE SENO

INCIDENCIA DE CÁNCER DE TIROIDES EN PUERTO RICO Y EE. UU. POR GRUPO RACIAL / ÉTNICO

LA EVOLUCIÓN EN EL TRATAMIENTO DE ARTRITIS REUMATOIDE

Revista Puertorriqueña de Medicina y Salud Pública

The first IL-17A antagonist to achieve the primary endpoint in a head-to-head trial against Humira® (adalimumab) in PsA 1-5

FOR BIOLOGIC-NAIVE PATIENTS WITH PSORIATIC ARTHRITIS

Superiority to Humira in the percentage of patients simultaneously achieving ACR50 and PASI 100 at week 24, with consistency through week 526

SPIRIT-H2H (BIOLOGIC-NAIVE): Simultaneous achievement of ACR50 and PASI 100

PATIENTS ACHIEVING RESPONSE, NRI (%)

SUPERIOR

CONSISTENT

ACR50 & PASI 100 at week 24

through week 52

39%†

36%* 28%

26%

0 0

WEEK

Taltz (n=283)

Humira (n=283)

*P<.05 vs Humira. P≤.001 vs Humira. Nominal P value: Week 52 measure of ACR50 + PASI 100 was not controlled for type-I error; therefore, no statistical comparisons can be made.

†

All patients had BSA ≥3%; patients with BSA ≥10%, PASI ≥12, and sPGA ≥3 followed the dosing for moderate to severe PsO.7 Primary endpoint=simultaneous achievement of ACR50 and PASI 100 at week 24.

SPIRIT-P1 and -P2: ACR response rates at week 24, NRI8

SPIRIT-P1 and -P2: PASI response rates at week 12, NRI

In SPIRIT-P1 (biologic-naive) (Taltz 80 mg every 4 weeks n=107; placebo n=106) and SPIRIT-P2 (TNFi-experienced) (Taltz 80 mg every 4 weeks n=122; placebo n=118), 58% and 53% of Taltz patients, respectively, achieved ACR20 vs 30% and 20% for placebo. Additionally, 40% and 35% of patients receiving Taltz achieved ACR50 vs 15% and 5% for placebo.

In SPIRIT-P1 (biologic-naive) (Taltz 80 mg every 4 weeks n=73; placebo n=67), among PsA patients with plaque psoriasis ≥3% BSA, NRI, 75% of patients receiving Taltz achieved PASI 75 at week 12 vs 8% of patients who received placebo. 32% of patients receiving Taltz achieved PASI 100 at week 12 vs 2% of patients who received placebo.9 In SPIRIT-P2 (TNFi-experienced) (Taltz 80 mg every 4 weeks n=68; placebo n=67), among PsA patients with plaque psoriasis ≥3% BSA, 57% of patients receiving Taltz achieved PASI 75 at week 12 vs 10% for placebo. Additionally, 19% of patients receiving Taltz achieved PASI 100 at week 12 vs 6% for placebo.10 Among patients with sPGA ≥3 at baseline, in SPIRIT-P1 (biologic-naive) (Taltz 80 mg every 4 weeks n=52; placebo n=41), 75% of patients receiving Taltz achieved sPGA 0,1 at week 12 vs 7% for placebo.9 Additionally, in SPIRIT-P2 (TNFi-experienced) (Taltz 80 mg every 4 weeks n=60; placebo n=55), 63% of patients receiving Taltz achieved sPGA 0,1 vs 4% for placebo.10,11

Primary endpoint=ACR20 response at week 24. Inadequate responders (<20% improvement in tender and in swollen joint counts) at week 16 were analyzed as nonresponders after week 16 until the primary endpoint. NRI of intent-to-treat population through week 24.

Taltz has no boxed warning

NRI of intent-to-treat population through week 12. ACR20/50=American College of Rheumatology 20%/50% response; PASI=Psoriasis Area Severity Index; NRI=nonresponder imputation; BSA=body surface area; sPGA=static Physician’s Global Assessment; TNFi=tumor necrosis factor inhibitor; PsA=psoriatic arthritis.

Approved to treat adult patients across the spectrum of axSpA (nr-axSpA, AS) SPIRIT-H2H Trial Design12

SPIRIT-P1 and -P2 Trial Design8,10,13,14

SPIRIT-H2H (N=566) was a phase 4, randomized, open-label, blinded-assessor study evaluating the efficacy and safety of Taltz vs Humira in biologic-naive patients with active psoriatic arthritis and plaque psoriasis BSA ≥3%. The primary efficacy endpoint was the proportion of patients simultaneously achieving ACR50 and PASI 100 at week 24. All patients were ≥18 years of age and had ≥3 swollen and ≥3 tender joints with an inadequate response to ≥1 cDMARD. Patients were randomized (1:1) to Taltz or Humira and allowed to continue a stable dose of concomitant cDMARD during the study. For Taltz patients with psoriatic arthritis only (n=234), the initial dose (160 mg as 2 injections) was followed by 80 mg every 4 weeks. Humira patients (n=231) received 40 mg every other week and no initial dose. Patients who met the trial design criteria for moderate to severe psoriasis (BSA ≥10%, PASI ≥12, and sPGA ≥3) in addition to psoriatic arthritis followed the psoriasis dosing regimen: Taltz patients (n=49) received an initial dose of 160 mg (two 80 mg injections), followed by 80 mg every 2 weeks through week 12, then 80 mg every 4 weeks thereafter. Humira patients (n=52) received an initial dose of 80 mg, then 40 mg every other week starting 1 week after the initial dose.

SPIRIT-P1 (N=417) and SPIRIT-P2 (N=363) were phase 3, randomized, doubleblind, placebo-controlled trials to evaluate the efficacy and safety of Taltz compared with placebo in patients with active psoriatic arthritis. Patients in SPIRIT-P1 were biologic-naive. Patients in SPIRIT-P2 were tumor necrosis factor inhibitor (TNFi)experienced, having had an inadequate response and/or intolerance to 1 or 2 prior TNFis. In both trials, the primary efficacy endpoint was the proportion of patients achieving ACR20 response at week 24. All patients were ≥18 years of age and had ≥3 swollen and ≥3 tender joints. Patients were randomized to placebo or Taltz 80 mg every 2 or 4 weeks following a 160 mg starting dose. In SPIRIT-P1, an active reference arm of Humira 40 mg every 2 weeks was included. Patients in all study arms were allowed to continue taking stable background medications during the trial. Inadequate responders (as defined by blinded criteria of <20% improvement in tender and in swollen joint counts) at week 16 received rescue therapy and were analyzed as nonresponders after week 16 until the primary endpoint. After receiving rescue therapy, inadequate responders in the placebo and Humira arms were re-randomized to Taltz 80 mg every 2 or 4 weeks. NRI methods were used for categorical efficacy analyses during the double-blind treatment period.

cDMARD=conventional disease-modifying antirheumatic drug.

INDICATIONS AND IMPORTANT SAFETY INFORMATION INDICATIONS Taltz is indicated for adults with active psoriatic arthritis (PsA), for adults with active ankylosing spondylitis (AS), and for adults with active non-radiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation. Taltz is also indicated for patients aged 6 years or older with moderate-to-severe plaque psoriasis (PsO) who are candidates for systemic therapy or phototherapy.

CONTRAINDICATIONS

ADVERSE REACTIONS

Taltz is contraindicated in patients with a previous serious hypersensitivity reaction, such as anaphylaxis, to ixekizumab or to any of the excipients.

Most common adverse reactions (≥1%) associated with Taltz treatment are injection site reactions, upper respiratory tract infections, nausea, and tinea infections. Overall, the safety profiles observed in adult patients with psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, and pediatric patients with plaque psoriasis were consistent with the safety profile in adult patients with plaque psoriasis, with the exception of influenza and conjunctivitis in psoriatic arthritis and conjunctivitis, influenza, and urticaria in pediatric psoriasis.

WARNINGS AND PRECAUTIONS Infections Taltz may increase the risk of infection. In clinical trials of adult patients with plaque psoriasis, the Taltz group had a higher rate of infections than the placebo group (27% vs 23%). A similar increase in risk of infection was seen in placebo-controlled trials of adult patients with psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, and pediatric patients with plaque psoriasis. Serious infections have occurred. Instruct patients to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a serious infection develops, discontinue Taltz until the infection resolves.

Pre-Treatment Evaluation for Tuberculosis

Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with Taltz. Do not administer to patients with active TB infection. Initiate treatment of latent TB prior to administering Taltz. Closely monitor patients receiving Taltz for signs and symptoms of active TB during and after treatment.

Hypersensitivity Serious hypersensitivity reactions, including angioedema and urticaria (each ≤0.1%), occurred in the Taltz group in clinical trials. Anaphylaxis, including cases leading to hospitalization, has been reported in post-marketing use with Taltz. If a serious hypersensitivity reaction occurs, discontinue Taltz immediately and initiate appropriate therapy.

Inflammatory Bowel Disease Patients treated with Taltz may be at an increased risk of inflammatory bowel disease. In clinical trials, Crohn’s disease and ulcerative colitis, including exacerbations, occurred at a greater frequency in the Taltz group than the placebo group. During Taltz treatment, monitor patients for onset or exacerbations of inflammatory bowel disease and if IBD occurs, discontinue Taltz and initiate appropriate medical management.

Immunizations Prior to initiating therapy with Taltz, consider completion of all age-appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with Taltz.

Please see Brief Summary of Prescribing Information on next pages. See Instructions for Use included with the device. IX HCP ISI 07MAY2020 References: 1. Data on file. Lilly USA, LLC. DOF-IX-US-0121. 2. Data on file. Lilly USA, LLC. DOF-IX-US-0122. 3. Data on file. Lilly USA, LLC. DOF-IX-US-0123. 4. Data on file. Lilly USA, LLC. DOF-IX-US-0124. 5. Data on file. Lilly USA, LLC. DOF-IX-US-0125. 6. Data on file. Lilly USA, LLC. DOF-IX-US-0190. 7. Mease PJ, Smolen JS, Behrens F, et al. A head-to-head comparison of the efficacy and safety of ixekizumab and adalimumab in biological-naive patients with active psoriatic arthritis: 24-week results of a randomised, open-label, blinded-assessor trial. Ann Rheum Dis. 2020;79:123-131. 8. Taltz [package insert]. Indianapolis, IN: Eli Lilly and Company; 2020. 9. Mease PJ, van der Heijde D, Ritchlin CT, et al; on behalf of SPIRIT-P1 Study Group. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann Rheum Dis. 2017;76:79-87. 10. Nash P, Kirkham B, Okada M, et al; on behalf of SPIRIT-P2 Study Group. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial. Lancet. 2017;389:2317-2327. Supplementary appendix. 11. Data on file. Lilly USA, LLC. TAL20171127A. 12. Data on file. Lilly USA, LLC. DOF-IX-US-0119. 13. Mease PJ, van der Heijde D, Ritchlin CT, et al; on behalf of SPIRIT-P1 Study Group. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase 3 trial SPIRIT-P1. Ann Rheum Dis. 2017;76(suppl):1-30. 14. Nash P, Kirkham B, Okada M, et al; on behalf of SPIRIT-P2 Study Group. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial. Lancet. 2017;389:2317-2327.

For more information, please contact a Lilly representative or visit TaltzPSAH2H.com. Taltz® is a registered trademark owned or licensed by Eli Lilly and Company, its subsidiaries, and affiliates. Humira® is a registered trademark of AbbVie Biotechnology Ltd. PP-IX-US-3933 05/2020 ©LILLY USA, LLC 2020. ALL RIGHTS RESERVED.

Taltz® (ixekizumab) injection Brief Summary: Consult the package insert for complete prescribing information. INDICATIONS AND USAGE Plaque Psoriasis—Taltz is indicated for the treatment of patients aged 6 years and older with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Psoriatic Arthritis—Taltz is indicated for the treatment of adult patients with active psoriatic arthritis. Ankylosing Spondylitis—Taltz is indicated for the treatment of adult patients with active ankylosing spondylitis. Non-radiographic Axial Spondyloarthritis—Taltz is indicated for the treatment of adult patients with active non-radiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation. CONTRAINDICATIONS Taltz is contraindicated in patients with a previous serious hypersensitivity reaction, such as anaphylaxis, to ixekizumab or to any of the excipients (Warnings and Precautions). WARNINGS AND PRECAUTIONS Infections—Taltz may increase the risk of infection. In clinical trials in adult patients with plaque psoriasis, the Taltz group had a higher rate of infections than the placebo group (27% vs 23%). Upper respiratory tract infections, oral candidiasis, conjunctivitis and tinea infections occurred more frequently in the Taltz group than in the placebo group. A similar increase in risk of infection was seen in placebo-controlled trials in patients with pediatric psoriasis, psoriatic arthritis, ankylosing spondylitis, and non-radiographic axial spondyloarthritis (Adverse Reactions). Instruct patients treated with Taltz to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a serious infection or is not responding to standard therapy, monitor the patient closely and discontinue Taltz until the infection resolves. Pre-treatment Evaluation for Tuberculosis—Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with Taltz. Do not administer to patients with active TB infection. Initiate treatment of latent TB prior to administering Taltz. Consider anti-TB therapy prior to initiating Taltz in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Patients receiving Taltz should be monitored closely for signs and symptoms of active TB during and after treatment. Hypersensitivity—Serious hypersensitivity reactions, including angioedema and urticaria (each ≤0.1%), occurred in the Taltz group in clinical trials. Anaphylaxis, including cases leading to hospitalization, has been reported in post-marketing use with Taltz (Adverse Reactions). If a serious hypersensitivity reaction occurs, discontinue Taltz immediately and initiate appropriate therapy. Inflammatory Bowel Disease—Patients treated with Taltz may be at an increased risk of inflammatory bowel disease. In clinical trials, Crohn’s disease and ulcerative colitis, including exacerbations, occurred at a greater frequency in the Taltz group than in the placebo group (Adverse Reactions). During Taltz treatment, monitor for onset or exacerbation of inflammatory bowel disease and if IBD occurs, discontinue Taltz and initiate appropriate medical management. Immunizations—Prior to initiating therapy with Taltz, consider completion of all age-appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with Taltz. No data are available on the response to live vaccines. ADVERSE REACTIONS The following adverse drug reactions are discussed in greater detail in other sections of the label: • Infections (Warnings and Precautions) • Hypersensitivity Reactions (Contraindications and Warnings and Precautions) • Inflammatory Bowel Disease (Warnings and Precautions) Clinical Trials Experience—Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Plaque Psoriasis Weeks 0 to 12: Three placebo-controlled trials in subjects with plaque psoriasis were integrated to evaluate the safety of Taltz compared to placebo for up to 12 weeks. A total of 1167 subjects (mean age 45 years; 66% men; 94% White) with plaque psoriasis received Taltz (160 mg at Week 0, 80 mg every 2 weeks [Q2W] for 12 weeks) subcutaneously. In two of the trials, the safety of Taltz (use up to 12 weeks) was also compared with an active comparator, U.S. approved etanercept. In the 12-week, placebo-controlled period, adverse events occurred in 58% of the Taltz Q2W group (2.5 per subject-year of follow-up) compared with 47% of the placebo group (2.1 per subjectyear of follow-up). Serious adverse events occurred in 2% of the Taltz group (0.07 per subject-year of follow-up), and in 2% of the placebo group (0.07 per subject-year of follow-up). Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the Taltz group than the placebo group during the 12-week placebo-controlled period of the pooled clinical trials. Table 1: Adverse Reactions Occurring in ≥1% of the Taltz Group and More Frequently than in the Placebo Group in the Plaque Psoriasis Clinical Trials through Week 12 Placebo Adverse Reactions Taltz 80 mg Q2W Etanerceptb (N=287) (n%) (N=791) (n%) (N=1167) (n%) Injection site reactions 196 (17) 32 (11) 26 (3) Upper respiratory 163 (14) 23 (8) 101 (13) tract infectionsa Nausea 23 (2) 1 (<1) 5 (1) Tinea infections 17 (2) 0 1 (<1) a Upper respiratory tract infections cluster includes nasopharyngitis and rhinovirus infection. b U.S. approved etanercept.

Adverse reactions that occurred at rates less than 1% in the Taltz group and more frequently than in the placebo group during the 12-week induction period included rhinitis, oral candidiasis, urticaria, influenza, conjunctivitis, inflammatory bowel disease, and angioedema. Weeks 13 to 60: A total of 332 subjects received the recommended maintenance regimen of Taltz 80 mg dosed every 4 weeks. During the maintenance period (Weeks 13 to 60), adverse events occurred in 80% of subjects treated with Taltz (1.0 per subject-year of follow-up) compared to 58% of subjects treated with placebo (1.1 per subject-year of follow-up). Serious adverse events were reported in 4% of subjects treated with Taltz (0.05 per subject-year of follow-up) and none in the subjects treated with placebo. Weeks 0 to 60: Over the entire treatment period (Weeks 0 to 60), adverse events were reported in 67% of subjects treated with Taltz (1.4 per subject-year of follow-up) compared to 48% of subjects treated with placebo (2.0 per subject-year of follow-up). Serious adverse events were reported in 3% of subjects treated with Taltz (0.06 per subject-year of follow-up), and in 2% of subjects treated with placebo (0.06 per subject-year of follow-up). Specific Adverse Drug Reactions: Injection Site Reactions: The most frequent injection site reactions were erythema and pain. Most injection site reactions were mild-to-moderate in severity and did not lead to discontinuation of Taltz. Infections: In the 12-week, placebo-controlled period of the clinical trials in plaque psoriasis, infections occurred in 27% of subjects treated with Taltz (1.2 per subject-year of follow-up) compared to 23% of subjects treated with placebo (1.0 per subject-year of follow-up). Serious infections occurred in 0.4% of subjects treated with Taltz (0.02 per subject-year of follow-up) and in 0.4% of subjects treated with placebo (0.02 per subject-year of follow-up) (Warnings and Precautions). During the maintenance treatment period (Weeks 13 to 60), infections occurred in 57% of subjects treated with Taltz (0.70 per subject-year of follow-up) compared to 32% of subjects treated with placebo (0.61 per subject-year of follow-up). Serious infections occurred in 0.9% of subjects treated with Taltz (0.01 per subject-year of follow-up) and none in the subjects treated with placebo. Over the entire treatment period (Weeks 0 to 60), infections were reported in 38% of subjects treated with Taltz (0.83 per subject-year of follow-up) compared to 23% of subjects treated with placebo (1.0 per subject-year of follow-up). Serious infections occurred in 0.7% of subjects treated with Taltz (0.02 per subject-year of follow-up), and in 0.4% of subject treated with placebo (0.02 per subject-year of follow-up). Inflammatory Bowel Disease: In adult subjects with plaque psoriasis, Crohn’s disease and ulcerative colitis, including exacerbations, occurred at a greater frequency in the TALTZ 80 mg Q2W group (Crohn’s disease 0.1%, ulcerative colitis 0.2%) than the placebo group (0%) during the 12-week, placebo-controlled period in clinical trials (Warnings and Precautions). Laboratory Assessment of Cytopenia: Neutropenia—Over the entire treatment period (Weeks 0 to 60), neutropenia occurred in 11% of subjects treated with Taltz (0.24 per subject-year of follow-up) compared to 3% of subjects treated with placebo (0.14 per subject-year of follow-up). In subjects treated with Taltz, the incidence rate of neutropenia during Weeks 13 to 60 was lower than the incidence rate during Weeks 0 to 12. In the 12-week, placebo-controlled period, neutropenia ≥ Grade 3 (<1,000 cells/mm3) occurred in 0.2% of the Taltz group (0.007 per subject-year of follow-up) compared to 0.1% of the placebo group (0.006 per subject-year of follow-up). The majority of cases of neutropenia were either Grade 2 (2% for Taltz 80 mg Q2W versus 0.3% for placebo; ≥1,000 to <1,500 cells/mm3) or Grade 1 (7% for Taltz 80 mg Q2W versus 3% for placebo; ≥1,500 cells/mm3 to <2,000 cells/mm3). Neutropenia in the Taltz group was not associated with an increased rate of infection compared to the placebo group. Thrombocytopenia—Ninety eight percent of cases of thrombocytopenia were Grade 1 (3% for Taltz 80 mg Q2W versus 1% for placebo; ≥75,000 cells/mm3 to <150,000 cells/mm3). Thrombocytopenia in subjects treated with Taltz was not associated with an increased rate of bleeding compared to subjects treated with placebo. Active Comparator Trials: In the two clinical trials that included an active comparator, the rate of serious adverse events during weeks zero to twelve was 0.7% for U.S.-approved etanercept and 2% for Taltz 80 mg Q2W, and the rate of discontinuation from adverse events was 0.7% for U.S. approved etanercept and 2% for Taltz 80 mg Q2W. The incidence of infections was 18% for U.S. approved etanercept and 26% for Taltz 80 mg Q2W. The rate of serious infections was 0.3% for both Taltz 80 mg Q2W and U.S. approved etanercept. Pediatric Plaque Psoriasis Taltz was evaluated in a placebo-controlled trial in pediatric subjects with moderate-to-severe psoriasis 6 to less than 18 years of age. A total of 171 subjects were studied (115 subjects on Taltz and 56 subjects on placebo). Overall, the safety profile observed in pediatric subjects with plaque psoriasis treated with Taltz every 4 weeks is consistent with the safety profile in adult subjects with plaque psoriasis with the exception of the frequencies of conjunctivitis (2.6%), influenza (1.7%), and urticaria (1.7%). In this clinical trial, Crohn’s disease occurred at a greater frequency in the Taltz group (0.9%) than the placebo group (0%) during the 12-week, placebo-controlled period. Crohn’s disease occurred in a total of 4 Taltz treated subjects (2.0%) in the clinical trial (Warnings and Precautions). Psoriatic Arthritis Taltz was studied in two placebo-controlled trials in patients with psoriatic arthritis. A total of 678 patients were studied (454 patients on Taltz and 224 on placebo). A total of 229 patients in these trials received Taltz 160 mg at Week 0, followed by 80 mg every 4 weeks (Q4W). Overall, the safety profile observed in patients with psoriatic arthritis treated with Taltz Q4W is consistent with the safety profile in adult patients with plaque psoriasis with the exception of the frequencies of influenza (1.3%) and conjunctivitis (1.3%). Ankylosing Spondylitis Taltz was studied in two placebo-controlled trials in patients with ankylosing spondylitis. A total of 566 patients were studied (376 patients on Taltz and 190 on placebo). A total of 195 patients in these trials received Taltz 80 or 160 mg at Week 0, followed by 80 mg every 4 weeks (Q4W). Overall, the

Taltz® (ixekizumab) injection

IX HCP BS 07MAY2020

safety profile observed in patients with ankylosing spondylitis treated with Taltz Q4W is consistent with the safety profile in adult patients with plaque psoriasis. In adult patients with ankylosing spondylitis, Crohn’s disease and ulcerative colitis, including exacerbations, occurred in 2 patients (1.0%) and 1 patient (0.5%), respectively, in the Taltz 80 mg Q4W group and 1 patient (0.5%) and 0%, respectively, in the placebo group during the 16-week, placebo-controlled period in clinical trials. Of these patients, serious events occurred in 1 patient in the Taltz 80 mg Q4W group and 1 patient in the placebo group (Warnings and Precautions). Non-radiographic Axial Spondyloarthritis Taltz was studied in a placebo-controlled trial in patients with non-radiographic axial spondyloarthritis. A total of 303 patients were studied (198 patients on Taltz and 105 on placebo). A total of 96 patients in this trial received Taltz 80 or 160 mg at Week 0, followed by 80 mg every 4 weeks (Q4W). Overall, the safety profile observed in patients with non-radiographic axial spondyloarthritis treated with Taltz 80 mg Q4W up to Week 16 is consistent with the previous experience of Taltz in other indications. Immunogenicity—As with all therapeutic proteins, there is the potential for immunogenicity with Taltz. The assay to test for neutralizing antibodies has limitations detecting neutralizing antibodies in the presence of ixekizumab; therefore, the incidence of neutralizing antibodies development could be underestimated. Plaque Psoriasis Population By Week 12, approximately 9% of adult subjects treated with Taltz every 2 weeks developed antibodies to ixekizumab. Approximately 22% of subjects treated with Taltz at the recommended dosing regimen developed antibodies to ixekizumab during the 60-week treatment period. The clinical effects of antibodies to ixekizumab are dependent on the antibody titer; higher antibody titers were associated with decreasing drug concentration and clinical response. Of the adult subjects who developed antibodies to ixekizumab during the 60-week treatment period, approximately 10%, which equates to 2% of subjects treated with Taltz at the recommended dosing regimen, had antibodies that were classified as neutralizing. Neutralizing antibodies were associated with reduced drug concentrations and loss of efficacy. In pediatric psoriasis subjects treated with ixekizumab at the recommended dosing regimen up to 12 weeks, 21 subjects (18%) developed anti-drug antibodies, 5 subjects (4%) had confirmed neutralizing antibodies associated with low drug concentrations. No conclusive evidence could be obtained on the potential association of neutralizing antibodies and clinical response and/or adverse events due to small number of pediatric subjects in the study. Psoriatic Arthritis Population For subjects treated with Taltz 80 mg every 4 weeks for up to 52 weeks (PsA1), 11% developed anti-drug antibodies, and 8% had confirmed neutralizing antibodies. Ankylosing Spondylitis Population For patients treated with Taltz 80 mg every 4 weeks for up to 16 weeks (AS1, AS2), 5.2% developed anti-drug antibodies, and 1.5% had neutralizing antibodies. Non-radiographic Axial Spondyloarthritis Population Of patients treated with Taltz 80 mg every 4 weeks for up to 52 weeks (nr-axSpA1), 8.9% developed anti-drug antibodies, all of which were low titer. No patient had neutralizing antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to Taltz across indications or with the incidences of antibodies to other products may be misleading. Postmarketing Experience—The following adverse reactions have been identified during postapproval use of Taltz. Because the reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Taltz exposure. Immune system disorders: anaphylaxis (Contraindications and Warnings and Precautions) DRUG INTERACTIONS Cytochrome P450 Substrates—The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation. Thus, Taltz, an antagonist of IL-17A, could normalize the formation of CYP450 enzymes. Therefore, upon initiation or discontinuation of Taltz in patients who are receiving concomitant drugs which are CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) and consider dosage modification of the CYP450 substrate.

Data Animal Data—An embryofetal development study was conducted in cynomolgus monkeys administered ixekizumab. No malformations or embryofetal toxicity were observed in fetuses from pregnant monkeys administered ixekizumab weekly by subcutaneous injection during organogenesis to near parturition at doses up to 19 times the MRHD (on a mg/kg basis of 50 mg/kg/week). Ixekizumab crossed the placenta in monkeys. In a pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered weekly subcutaneous doses of ixekizumab up to 19 times the MRHD from the beginning of organogenesis to parturition. Neonatal deaths occurred in the offspring of two monkeys administered ixekizumab at 1.9 times the MRHD (on a mg/kg basis of 5 mg/kg/week) and two monkeys administered ixekizumab at 19 times the MRHD (on a mg/kg basis of 50 mg/kg/week). These neonatal deaths were attributed to early delivery, trauma, or congenital defect. The clinical significance of these findings is unknown. No ixekizumab-related effects on functional or immunological development were observed in the infants from birth through 6 months of age. Lactation Risk Summary—There are no data on the presence of ixekizumab in human milk, the effects on the breastfed infant, or the effects on milk production. Ixekizumab was detected in the milk of lactating cynomolgus monkeys. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Taltz and any potential adverse effects on the breastfed infant from Taltz or from the underlying maternal condition. Pediatric Use—The safety and effectiveness of Taltz have been established in pediatric subjects aged 6 years to less than 18 years with moderate-to-severe plaque psoriasis. The safety and effectiveness of Taltz in other pediatric indications and for pediatric subjects less than 6 years of age have not been established. Geriatric Use—Of the 4204 psoriasis subjects exposed to Taltz, a total of 301 were 65 years or older, and 36 subjects were 75 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects. OVERDOSAGE—In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and institute appropriate symptomatic treatment immediately. PATIENT COUNSELING INFORMATION—Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use) before the patient starts using Taltz and each time the prescription is renewed, as there may be new information they need to know. Instructions on Self-Administration: Provide guidance to patients and caregivers on proper subcutaneous injection technique, including aseptic technique, and how to use the autoinjector or prefilled syringe correctly (Instructions for Use). Infection: Inform patients that Taltz may lower the ability of their immune system to fight infections. Instruct patients of the importance of communicating any history of infections to the healthcare provider, and contacting their healthcare provider if they develop any symptoms of infection (Warnings and Precautions). Allergic Reactions: Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions (Warnings and Precautions). Additional information can be found at www.Taltz.com.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary—There are no available data on Taltz use in pregnant women to inform any drug associated risks. Human IgG is known to cross the placental barrier; therefore, Taltz may be transmitted from the mother to the developing fetus. An embryofetal development study conducted in pregnant monkeys at doses up to 19 times the maximum recommended human dose (MRHD) revealed no evidence of harm to the developing fetus. When dosing was continued until parturition, neonatal deaths were observed at 1.9 times the MRHD [see Data]. The clinical significance of these nonclinical findings is unknown. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

IX HCP BS 07MAY2020

Taltz® (ixekizumab) injection

IX HCP BS 07MAY2020

FRENTE A LOS DESAFÍOS TRADICIÓN Y FORMACIÓN EXCELENCIA Y COMPROMISO

Revista Puertorriqueña de Medicina y Salud Pública

El Dr. Humberto M. Guiot Martínez es el decano interino de la Escuela de Medicina.

NOMBRAMIENTOS EN EL RECINTO DE CIENCIAS MÉDICAS La Dra. Wanda Maldonado es la nueva rectora interina de la institución. LIXVII - XV

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ANUNCIAN NOMBRAMIENTOS PARA LIDERAR EL RECINTO DE CIENCIAS MÉDICAS La institución informó el nombramiento de la Dra. Wanda Maldonado Dávila como rectora interina de la institución y del Dr. Humberto M. Guiot Martínez como decano interino de la Escuela de Medicina Durante el pasado mes de mayo, el Recinto de Ciencias Médicas (RCM) de la Universidad de Puerto Rico (UPR) anunció el nombramiento de la Dra. Wanda Maldonado Dávila como rectora interina de la institución y del Dr. Humberto M. Guiot Martínez como decano interino de la Escuela de Medicina. La doctora Maldonado Dávila realizó sus estudios de pre-farmacia en Notre Dame of Maryland University en Baltimore, Maryland. A su vez, cuenta con un bachillerato y doctorado en farmacia de la Universidad de Maryland, de la cual en el 2017 recibió un reconocimiento como egresada distinguida. La rectora se ha destacado durante los pasados 10 años como decana de la Escuela de Farmacia del Recinto de Ciencias Médicas, habiendo también presidido el comité de currículo que creó el Programa de Doctorado en Farmacia de la Escuela de Farmacia de la UPR. En el 2019, la doctora Maldonado hizo historia al ser electa mediante votación a nivel nacional como Presidenta Electa del Consejo de Decanos del American Association of Colleges of Pharmacy (AACP). Además de asumir esta posición en julio de 2019, la doctora Maldonado también se convirtió en miembro del Board of Directors del American Association of Colleges of Pharmacy por un término de tres años. La doctora Maldonado Dávila se convirtió así en la primera puertorriqueña en ocupar estos cargos.

Por su parte, el Dr. Humberto M. Guiot Martínez cuenta con un grado de Doctor en Medicina de la Escuela de Medicina de la Universidad de Puerto Rico (UPR), donde también completó su especialidad en Medicina Interna y subespecialidad en Enfermedades Infecciosas. Guiot Martínez está certificado tanto en Enfermedades Infecciosas como en Medicina Interna por el American Board of Internal Medicine. Este ha sido reconocido con el Doctors’ Choice Award durante 10 años consecutivos por el Fellow del American College of Physicians y el Fellow de Infectious Diseases Society of America. Desde el 2019, ocupa la vicepresidencia de la Sociedad de Enfermedades Infecciosas de Puerto Rico. El decano interino ha fungido como Decano Asociado de Asuntos Académicos de la Escuela de Medicina del RCM y como Catedrático Asociado del Departamento de Medicina Interna. El doctor Guiot Martínez ha impartido los cursos de Mecanismo de Enfermedades, Enfermedades Infecciosas y Medicina Interna. Sirvió por 8 años como Director del Curso de Mecanismo de Enfermedades y también fue Coordinador del Bloque Introductorio para Segundo Nivel. Entre los años 2015 y 2019, fue presidente de los Comités de Medicina II y Monitoreo II. Ambos catedráticos se destacan por su trayectoria de compromiso y excelencia profesional y académica con el Recinto de Ciencias Médicas, la UPR y Puerto Rico.

" Ambos catedráticos se destacan por su trayectoria de compromiso y excelencia profesional y académica con el Recinto de Ciencias Médicas, la UPR y Puerto Rico. "

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DR. SANTIAGO CORNIER

ES GALARDONADO POR LA SOCIEDAD DE GENÉTICA HUMANA DE EE.UU. YOLIMARIAN TORRES Medicina y Salud Pública

DR. JUAN ALBERTO SANTIAGO CORNIER, MD, PHD

Editor en Jefe Revista MSP Jefe División Genética del San Jorge Children’s Hospital Director Centro Investigaciones Clínicas del San Jorge Children’s Hospital Catedrático Asociado de la Universidad Central del Caribe en Bayamón Catedrático Asociado del Dpto. de Pediatría de la Ponce HealthSciences University Genetista Sociedad de Educación y Rehabilitación (SER de Puerto Rico)

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APORTE A MSP Con gran alegría y orgullo el sello del Dr. Alberto Santiago Cornier acompañan los 15 años de la Revista de Medicina y Salud Pública, ya que nuestra labor se ha centrado en aportar al gremio médico y de pacientes de la mano de los expertos, tal es el caso del galardonado.

a revista Medicina y Salud Pública (MSP), se enorgullece del nombramiento que la Sociedad Estadounidense de Genética Humana ha hecho al Dr. Alberto Santiago-Cornier, MD, PhD como receptor del Premio de Mentoría 2021. El Dr. Santiago-Cornier es genetista y editor de la Revista MSP, jefe de la Sección de Genética del Hospital de Niños y Mujeres San Jorge en San Juan y es profesor asociado de salud pública en la Universidad de Ciencias de la Salud de Ponce. "El trabajo de Alberto Santiago-Cornier ha sido absolutamente vital para la gente de Puerto Rico contribuyendo al bienestar de los pacientes con enfermedades genéticas y no solo ayudándolos principalmente a través de la educación y los servicios, sino a veces también económicamente", dijo la presidenta de la Sociedad Estadounidense de Genética Humana, Gail Jarvik, MD. Así mismo, en su carta de nominación, Simón Carlo, MD, Profesor Asistente de la Cátedra del IRB, Profesor Asistente de Bioquímica, Pediatría y Psiquiatría Ponce Health Sciences University Ponce expresó, "Creo que, en una isla tan pequeña como Puerto Rico, el hecho de que sus habilidades clínicas, docentes y de mentoría hayan impactado a una proporción tan alta de la población lo convierte en el candidato idóneo para recibir un premio de mentoría". Conmovido ante la entrega del premio, el doctor Simón Carlo, genetista pediátrico y compañero del Dr. Cornier expresó unas sinceras palabras de felicitación y orgullo por este galardón al Dr. Alberto Santiago Cornier. "Puedo decir que fue mi mentor y lo seguirá siendo. Ciertamente espero que sean muchos premios más Alberto, porque son muchos los estudiantes que han pasado por tu oficina aprendiendo y han llegado lejos gracias a tu mentoría", expresó.

Revista Puertorriqueña de Medicina y Salud Pública

Con una efusiva y sincera felicitación la doctora Maribel García, oncóloga pediatra del Hospital San Jorge, expresó su orgullo y el del equipo médico del centro de salud, ante tal premiación para el Dr. Cornier por su valiosa aportación. "Mi querido amigo Alberto, yo recibí ese beneficio de conocerte y tu mentoría, luego dejamos de vernos y nos encontramos aquí en el San Jorge. No se equivocan hoy quienes te reconocen, eres nuestro mentor, nuestro colega. Muchas felicidades", dijo. Por su parte, el doctor Víctor Matos, presidente del Colegio de Cirujanos de Puerto Rico, destacó la labor del Dr. Cornier, "estamos muy contentos con el premio del doctor". AGRADECIMIENTO DEL GALARDONADO Con las emociones a flor de piel y con un sentimiento de gratitud el Dr. Santiago Cornier aseguró que este reconocimiento no es solo suyo, sino de cada persona que se ha involucrado a lo largo de su carrera como profesional de la salud. "Yo solo quiero que sepan que de la misma manera en que yo he dejado un granito de arena en ellos, ellos han puesto su granito de arena en mí", dijo el experimentado médico sobre sus estudiantes. El Dr. Santiago Cornier también resaltó que la labor médica de Puerto Rico ha hecho merecedora a la Isla del retorno de muchos profesionales y espera que en el futuro esto continúe así en beneficio de los pacientes, pero también del prometedor futuro científico de Puerto Rico y sus investigaciones al mundo. Entre los aportes del experto se destacan sus estudios de asociación de todo el genoma, con especial interés en los trastornos genéticos que prevalecen en las poblaciones puertorriqueña / hispana y es reconocido por ser el fundador de la primera investigación genética y de la Asociación de Trastornos Metabólicos en Puerto Rico.

CONTENIDO

RETOS DEL TRATAMIENTO DEL CÁNCER DE PULMÓN METASTÁSICO

TERAPIA DIRIGIDA PARA CÁNCER DE PULMÓN

CASO MULTIETIOLÓGICO DE PERICARDITIS AGUDA

INCIDENCIA DE CÁNCER DE TIROIDES EN PUERTO RICO Y EE. UU. POR GRUPO RACIAL / ÉTNICO, 2011-2015

LA EVOLUCIÓN EN EL TRATAMIENTO DE ARTRITIS REUMATOIDE

EDITOR FUNDADOR Juan Carlos Orengo Valverde, MD, MPH, PhD EDITOR Alberto Santiago Cornier, MD, PhD PRINCIPAL OFICIAL EJECUTIVO Pedro Carlos Lugo Hernández III, P.A PRESIDENTA Y FUNDADORA Glorybelle Hernández Figueroa, MBA VICEPRESIDENTA Y FUNDADORA Laila Paloma Lugo, MBA CONTABILIDAD Julio Soto ADMINISTRACIÓN Marta Ivelisse Vélez Ramos, MBA, MARKETING Y SERVICIOS 360 Alexelena Cayere, Yasmin Morell, Marion Fernández PERIODISTAS Belinda Burgos, Grenda Rivera, Mayra Acevedo, Luis Penchi ARTISTAS GRÁFICOS Natalia Zoé Rivera Torres DIRECTORA AUDIOVISUAL Fabiola Plaza REALIZADORA AUDIOVISIAL Salomé Mateus FOTOS Revista Medicina y Salud Pública DIRECCIÓN GENERAL Carlos Alexis Lugo Marrero DISTRIBUCIÓN OFICINAS Y TORRES MÉDICAS Editorial Mundo ENVÍO DE REVISTAS Y DISTRIBUCIÓN A GRUPOS MÉDICOS Servicio de correo postal/Comunicación Inteligente Para ventas y otros servicios pueden comunicarse al 787.848.3333, msp@editorialmundo.com o www.medicinaysaludpublica.com Revista Puertorriqueña de Medicina y Salud Pública ISSN 1937-8521 COMITÉ EDITORIAL CIENTÍFICO COMITÉ EDITORIAL Olga Rodríguez, MD - Decana Escuela de Medicina de Ponce (Puerto Rico), Vivian Green, LND, MS, PhD, Sub editora y fundadora (Puerto Rico), José Cordero, MD, MPH - Exdecano Escuela Graduada Salud Pública Recinto de Ciencias Médicas UPR (Puerto Rico), Ángeles Rodríguez, MD, MPH (Puerto Rico), Simón Carlo, MD (Puerto Rico), Bárbara Rosado, MD (Puerto Rico), Idhaliz Flores PhD (Puerto Rico), Jesús Cruz-Correa, MD, FACOG (Puerto Rico), Rafael Bredy, MD, LicMTo, MBE, MS (Puerto Rico), David Caseida, MD, FACOG, (Puerto Rico), José Capriles, MD, MHSA (Puerto Rico) Joaquín Laboy, MD, FACOG (Puerto Rico), Luis Adrian Rivera Pomales, MD, PEMBA, MPH, CMQ (Puerto Rico), Juan Fernández, MS, PhD (Puerto Rico), Nuria Sebate, MD (Puerto Rico), Pedro Amador, MD, MPH (Puerto Rico), Nydia Cappas, PsyD (Puerto Rico), Luis Franco, MD (Puerto Rico), Federico Montealegre, DVM, PhD, Msc (Puerto Rico), Nydia Ortiz, PsyD (Puerto Rico), José Pons, PhD, FPPR (Puerto Rico), Esdrás Vélez, JD, MPH (Puerto Rico), Diego Zavala, MSc, PhD, (Puerto Rico), Ana Torres-Martín, MD (Puerto Rico), Julio Cádiz, MD, MPH (Puerto Rico), Rafael Gómez-Cuevas (Colombia), José Javier Orengo, PhD(c) (España), Cesar A. Del Rey, MD (Panamá), Pedro Serrano, MD, PhD (España), Luis Serra-Majem, MD, PhD (España), José Ramón Calvo, MD, PhD (España). Síguenos en www.medicinaysaludpublica.com, www.facebook.com/revistamsp, en Twitter @revistamsp, en LinkedIn como Revista Puertorriqueña de Medicina y Salud Pública. Las normas editoriales de la Revista Puertorriqueña de Medicina y Salud Pública para la publicación de artículos originales y cartas al editor pueden ser accesadas en la página web: www.medicinaysaludpublica.com, y solicitadas a través de msp@editorialmundo.com. Medicina y Salud Pública es propiedad de publicaciones mundo. Medicina es una publicación de la REVISTA PUERTORRIQUEÑA DE MEDICINA Y SALUD PÚBLICA. Medicina y Salud Pública tiene como política corregir y aclarar cualquier información incorrecta que pueda ser publicada en su revista. Medicina y Salud Pública no asume responsabilidad alguna por los anuncios, artículos y otros servicios anunciados en nuestra publicación. Revista Puertorriqueña de Medicina y Salud Pública

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EDITORIAL

LA IMPORTANCIA DEL RECINTO DE CIENCIAS MÉDICAS

DR. ENRIQUE VAZQUEZ-QUINTANA, MD EX- SECRETARIO DEL DEPARTAMENTO DE SALUD

La Universidad de Puerto Rico fue fundada en el 1903. La Ley #1 del 1966 creó los recintos incluyendo el Recinto de Ciencias Médicas (RCM), al igual que la posición del Presidente de la Universidad de Puerto Rico (UPR). En 1967 se nombró al doctor Adán Nigaglioni Loyola, como el primer rector del Recinto de Ciencias Médicas. La Escuela de Farmacia se había establecido en Río Piedras en 1913. La Escuela de Medicina fue fundada en lo que se conocía como la Escuela de Medicina Tropical en San Juan, en el 1950 y la Escuela de Medicina Dental fue creada en el 1960. En el 1972 se construyó el

edificio del Recinto de Ciencias Médicas en el Centro Médico de Puerto Rico y allí convergieron las Escuelas de Medicina, Escuela de Farmacia, Salud Pública y Medicina Dental. En la Escuela de Medicina Tropical ya existía la Escuela de Salud Pública, pero la Escuela de Salud Pública fue establecida oficialmente en el 1970. Posteriormente se crearon las otras dos escuelas, la de Profesiones Relacionadas a la Salud en el 1976 y de Enfermería en 1995. La biblioteca del RCM honra el nombre del doctor Conrado F. Asenjo, quien fuera profesor de bioquímica al comienzo de la Escuela de Medicina. Esta biblioteca es considerada como la más completa de las bibliotecas médicas en la región del Caribe. La Escuela de Medicina de la UPR fue acreditada por el Comité de Enlace en Educación Médica LCME (Liaison Committee on Medical Education) ininterrumpidamente desde el 1954. La última residencia establecida es una combinación de Medicina y Pediatría. Los profesionales egresados del RCM son bilingües, es por eso que son muy solicitados en varios de los estados de Estados Unidos, donde residen muchos puertorriqueños e hispanos. En el RCM se realizan múltiples trabajos de investigación tanto en las ciencias básicas como en ciencias clínicas. Reciben fondos federales para esas investigaciones. Uno de los trabajos clínicos más importantes es el estudio en grupos de familias con más de un miembro con la enfermedad de Alzheimer. Se está experimentando con un nuevo medicamento para el tratamiento de

esa enfermedad, que es la cuarta causa de muerte en Puerto Rico. Mención honorífica para los doctores Jorge Santana y Carmen Zorrilla en sus respectivas líneas de investigación y en la formación de nuevas generaciones de profesionales de la salud en Puerto Rico. Los médicos en adiestramiento en las residencias del RCM atienden a los pacientes que acuden al Centro Médico y a los pacientes que se admiten al Hospital Universitario, el Hospital Pediátrico y al Hospital Oncológico. Los residentes son supervisados por la facultad de la Escuela de Medicina. Igualmente, los residentes de cirugía rotan por el Hospital de Trauma, cuya facultad pertenece al Departamento de Cirugía de la Escuela de Medicina. En el décimo piso del edificio del RCM se encuentra el Laboratorio de Cirugía Experimental creado por el doctor Francisco L. Raffucci en el 1956, en la antigua Escuela de Medicina en San Juan. Allí se realizan estudios experimentales utilizando animales (perros y cerdos). La facultad de la Escuela de Medicina también utiliza el Centro Cardiovascular de Puerto Rico y el Caribe para el adiestramiento de los cardiólogos. Los especialistas del Centro Cardiovascular son en su mayoría egresados de nuestra Escuela de Medicina.

MSP ARTÍCULO / DE REVISIÓN

RETOS DEL TRATAMIENTO DEL CÁNCER DE PULMÓN METASTÁSICO

El manejo de pacientes está evolucionando, como resultado del entendimiento a nivel molecular de las vías que dan origen al cáncer de pulmón de células no pequeñas (NSCLC). Es decir, al sinnúmero de alteraciones moleculares o biomarcadores. Lo cual ha permitido aplicar a este tipo de cáncer el concepto de la medicina personalizada, tal como se ha estado utilizando en otros tumores sólidos como el cáncer de mama y el melanoma.

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MSP ARTÍCULO / DE REVISIÓN

LUIS O NEGRÓN GARCÍA, MD, MS, MT Hematólogo – Oncólogo Hospital La Concepción Hospital Metropolitano de San Germán

PALABRAS CLAVE: Cáncer de pulmón de células no pequeñas, tumor, metástasis, alteraciones moleculares, biomarcadores, medicina personalizada, quimioterapia, inmuno-oncología.

urante los últimos años el tratamiento para el cáncer de pulmón de células no pequeñas (NSCLC) ha consistido en quimioterapia cit o t óxic a sist é mic a c u yo mecanismo de acción es la eliminación de células cancerosas en crecimiento o división. La meta es reducir síntomas, mejorar la calidad de vida y prolongar la vida en algunos pacientes. Debido a los efectos adversos de estas quimioterapias y las pocas opciones de tratamiento, se estima que cerca de un 25 por ciento de los pacientes mueren sin recibir ningún tipo de tratamiento. Sin embargo, la manera en cómo vamos a manejar estos pacientes en la época actual está en evolución. Esto, a raíz del resultado de un mejor entendimiento a nivel

molecular de las vías que dan origen al NSCLC. Nos referimos al sinnúmero de alteraciones moleculares o biomarcadores entre los cuales se encuentran el EGFR, ALK, MET, ROS-1, B-RAF, K-RAS, HER2, RET y la expresión de PD-L1 y el TMB o Tumor Mutational Burden. Lo cual a su vez nos ha permitido aplicar al cáncer de pulmón el concepto de la medicina personalizada como se ha estado utilizando en otros tumores sólidos como el cáncer de mama y el melanoma. Gráfica 1. Cuando evaluamos un paciente con NSCLC y decidimos tratarlo, la histología del tumor sigue siendo importante desde el punto de vista de la quimioterapia que decidamos utilizar aún en la época de los biomarcadores. Nos referimos como ejemplo a

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MSP ARTÍCULO / DE REVISIÓN pemetrexed y bevacizumab cuyo uso está limitado a tumores con histología no escamosa contrario a necitumumab que solo está indicado en tumores de pulmón con este tipo de histología. Luego pasamos a evaluar los biomarcadores o alteraciones genéticas (driver mutations) que puedan ser las responsables del desarrollo del tumor. Es importante señalar que estas alteraciones solo están presentes en el tumor (somáticas) y no en la células normales (células germinales), por lo que no se heredan ni se transfieren a las generaciones futuras. La relevancia de la identificación de estos biomarcadores es que al estar presentes son la vía principal que da origen y promueve el desarrollo del tumor, por lo que suponemos que con tratamiento dirigido a este biomarcador, en teoría, deberíamos detener o controlar el desarrollo de la enfermedad. A continuación mencionamos aquellas alteraciones con tratamiento, fuera de los ensayos clínicos, para el / los oncólogo (s) de la comunidad. Gráfica 2. RECEPTOR DEL FACTOR DE CRECIMIENTO EPIDÉRMICO (EGFR POR SUS SIGLAS EN INGLÉS) Las mutaciones en el EGFR se ven en aproximadamente el 23 por ciento de los casos de los adenocarcinomas de pulmón. Pertenece a la familia de los HER/erbB2 que incluye EGFR (HER1 or erbB1), HER2 or erbB2, HER3 or erbB3 and HER4 or erbB4. Estas son proteínas de la superficie celular con un componente extracelular, una estructura transmembrana y un componente intracelular que contiene el dominio de la kinasa de tirosina,

área donde ocurren las mutaciones que mantienen en modo de “activación” el EGFR. Esta serie de eventos como la proliferación celular, angiogénesis, metástasis y apoptosis una vez iniciadas persisten en ausencia de estímulo lo que se describe como una acción constitutiva. Las alteraciones clásicas ocurren a nivel del exón 19 (aa 747) y 21 (L858R) que constituyen el 90 por ciento de los casos. Estas mutaciones son más comunes en pacientes jóvenes, mujeres, no fumadores, del este de Asia y en adenocarcinoma. Los pacientes con estas alteraciones se tratan con drogas que inhiben la acción de la kinasa de tirosina. De estos hay alrededor de 4 con aprobación de la FDA en Estados Unidos que son erlotinib, gefitinib (ambos primera generación), afatinib (segunda generación) y osimertinib (tercera generación). De todos el más potente, con mejor penetración al SNC y con actividad en paciente con la mutación en el exón 20 (T790M) es osimertinib. Pacientes con mutaciones como G719X, L861Q, S768I pueden ser tratadas con afatinib. (Gráfica 3). LINFOMA QUINASA ANAPLÁSICO (POR SUS SIGLAS EN INGLÉS ALK) El ALK es un gen que codifica una kinasa de tirosina. Esta fue originalmente identificada en ciertos grupos de pacientes con el linfoma anaplásico de células grandes (ALCL) que tenían la translocación (2;5) (p23, q35) (EML4-ALK). Este reordenamiento genético se ha identificado en el 2 al 7 por ciento de los pacientes con NSCLC donde parte del cromosoma se rompe y fusiona con otro o le da la vuelta (inversión) resultando en

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un nuevo gen y una kinasa de tirosina con actividad constitutiva. El término “fusión de ALK”, “reordenamiento de ALK” y “translocación de ALK” son sinónimos y se refieren a la translocación de EML4-ALK. A diferencia de las mutaciones en el EGFR, las translocaciones con ALK no tienen una clara asociación con sexo o raza. Pacientes con esta alteración son tratados con inhibidores de ALK. Hay 4 medicamentos con aprobación de FDA con este mecanismo de acción: crizotinib (primera generación), ceritinib, alectinib y brigatinib (segunda generación). De estos, alectenib parece ser el más potente y con mayor penetración al SNC. El alectinib fue comparado contra crizotinib en el estudio ALEX que demostró un mPFS de 34.8 meses vs. 10.9 meses a favor del primero. ROS-1 ROS-1 es una kinasa de tirosina del receptor de insulina localizado en el cromosoma 6 y con una secuencia homologa al ALK, presente en aproximadamente el 2 % de los NSCLC. Como el ALK y el EGFR su presencia causa una activación constitutiva de la kinasa de tirosina. Tanto el ROS-1, EGFR y el ALK se ven más comúnmente en pacientes jóvenes, no fumadores y adenocarcinomas. Para ROS-1 el único medicamento con aprobación por la FDA es Crizotinib. Tanto EGFR, ALK, ROS-1 y K-RAS se consideran mutuamente excluyentes con raras excepciones de presencias simultáneas de más de una alteración.

MSP ARTÍCULO / DE REVISIÓN BRAF Las mutaciones en el BRAF están presentes del 2 al 4 por ciento de los NSCLC (adenocarcinomas). A diferencia del EGFR y el ALK, las mutaciones en el BRAF se ven principalmente en fumadores. La mutación V600E constituye el 50 por ciento de las mutaciones en el BRAF a diferencia de melanoma donde V600E constituye la mayoría de los casos. Adenocarcinomas con esta mutación responden bien a los inhibidores del BRAF como monoterapia o en combinación con inhibidores del MEK. La combinación de dabrafenib y trametinib está aprobada por la FDA en pacientes con la mutación V600E y es considerado como el tratamiento estándar para esta población de pacientes. RET La alteración en el gene del RET se ha identificado del 1 al 2 % del NSCLC. Estos pacientes pueden responder los inhibidores del RET como Cabozantanib aunque aún no hay resultados disponibles de los ensayos clínicos. Su uso para esta alteración no tiene aprobación por la FDA. MET La mutación del MET en el exón 14 se ha visto en el 2.5 por ciento de los NSCLC (20-30 por ciento en los tumores con histología sarcomatoide). Pacientes con esta mutación pueden responder a inhibidores del MET como crizotinib. Su uso no tiene aprobación por la FDA. INMUNO-ONCOLOGÍA - (IO) A raíz de un mejor entendimiento

del papel que tiene el sistema inmune en la regulación del crecimiento de las células cancerosas han surgido las inmunoterapias como una de las más recientes modalidades para el tratamiento del cáncer. La idea de la relación entre el cáncer y la inmunología viene desde el siglo 19 cuando un cirujano de nombre William Coley reportó cómo un sarcoma disminuyó de tamaño luego de inyectarle bacterias muertas en ciertas áreas del sarcoma. El sistema inmune es educado para reconocer tejido propio y no propio (selección +/-) para poder reaccionar en contra de agentes extraños y evitar daño a nuestro sistema. Parte de este proceso está dado por áreas de control o puntos de cotejo que básicamente desarman el sistema inmune una vez el agresor es eliminado para evitar destrucción del tejido propio. Múltiples tumores, incluyendo el cáncer de pulmón, pueden crear tolerancia del sistema inmune evitando ser reconocidos y atacados, utilizando estos puestos de control. Los bloqueadores de los puntos de control (check point inhibitors) son parte de las nuevas herramientas que tiene el oncólogo hoy en día para tratar el cáncer incluyendo el de pulmón. Estos tratamientos tienen el potencial de restaurar y aumentar la capacidad del sistema inmune para reconocer y eliminar células cancerosas neutralizando los mecanismos utilizados por los tumores para evadir el sistema inmune.De estos medicamentos, existen al menos 5 con aprobación por FDA para su uso en NSCLC. Estas son pembrolizumab, n ivolumab, atezol i z

umab, durvalumab e ipilimumab. Pembrolizumab -es un anticuerpo monoclonal- G4 que se pega al receptor PD-1 (programmed cell death 1) expresado en las células T, B y NK interrumpiendo la unión de este con PD-L1 presente en ciertos tumores y tejido hematopoyético y PD-L2 que está particularmente en tejido hematopoyético. La unión de PD-1: PDL1/2 inhibe la apoptosis de la célula tumoral, promueve la “fatiga” de las células T periféricas, y la conversión de las células T efectoras a células T reguladoras (Treg). Pembrolizumab está aprobado en pacientes con metástasis NSCLC de histología no escamosa en primera línea como monoterapia en tumores con 50 por ciento o más de expresión de PD-L1 [TPS ≥ 50 %] (KEY-NOTE 024) y en combinación con quimioterapia independiente de la expresión del PD-L1 (KEY-NOTE 189) y que estén negativos para la expresión de alteraciones en EGFR y ALK Tiene también una aprobación en segunda línea como monoterapia para pacientes con expresión de 1 por ciento o más de PD-L1 [TPS ≥ 1%] que hayan progresado durante o después de platino. KEY-NOTE 407 busca la aprobación de Pembrolizumab + quimioterapia en primera línea para la paciente metastásicos de histología escamosa.(Gráfica 4). Nivo l u m a b al igu a l que pembrolizumab- es un anti-PD-1 con aprobación para cáncer de pulmón desde marzo del 2015 siendo el primer inhibidor de puntos de control (check

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MSP ARTÍCULO / DE REVISIÓN point inhibitor) en ser aprobado para esta malignidad. Tiene aprobación en segunda línea para NSCLC (ambas histologías) independiente de la expresión del PD-L1 en aquellos pacientes que hayan fallado durante o después de un tratamiento con platino. Los pacientes con alteración del EGFR y AlK tienen que haber recibido el tratamiento correspondiente de acuerdo con el biomarcador. Checkmate 227 combinó nivolumab + ipilimumab (CTL-4 inhibitor) con buenos resultados en aquellos con TMB ≥ a 10 o Tumor Mutational Burden, independiente al nivel de PD-L1. Atezolizumab - es un anti- PD - L1, aprobado como monoterapia en segunda línea para NSCLC- ambas histologías independientes de la expresión del PD-L1 en pacientes que hayan fallado durante o después de tratamiento con platino. Pacientes con alteraciones en EGFR, ALK tiene que haber pasado por la terapia correspondiente. IMpower 150 es un estudio que combinó quimioterapia con bevacizumab +/- atezolizumab en primera línea metastásico en NSCLC con aumento en PFS independiente de la expresión de PD-L1. Este estudio incluyó pacientes con la mutación para EGFR y ALK. Durvalumab - es un anti-PDL1, único con aprobación en estadio no metastásico. Su aprobación es en pacientes con estadio III después de la combinación de platino y radioterapia que hayan progresado luego del tratamiento (Pacific trial). CONCLUSIÓN En los últimos años han surgido una serie de avances en el manejo del paciente con cáncer de pulmón metastásico en comparación con los años pasados donde la mayoría de los pacientes recibían el mismo tratamiento de quimioterapia a base de platino. Con estos nuevos avances, es de suma importancia el tratar de individualizar cada paciente para proveerle el mejor cuidado posible utilizando una secuencia apropiada de estas nuevas terapias. Y sin duda para esto necesitamos un esfuerzo de tipo multidisciplinario. Antes de empezar a tratar un paciente, al igual que hacemos con el cáncer de mama, debemos tener como mínimo 18

EGFR, ALK y ROS-1 y si el tejido es suficiente BRAF. Todos aquellos que se presenten con una alteración molecular, los tratamientos dirigidos a cada biomarcador son la primera y segunda línea de tratamiento. Una vez el paciente progresa a los TKI’s el próximo paso a considerar son las quimioterapias. Los IO se pueden considerar luego de quimioterapias. En los pacientes sin alteraciones moleculares (WT) entonces evaluamos la expresión de PD-L1. En aquellos pacientes con un TPS ≥ 50 %, pembrolizumab como monoterapia debe considerarse la primera línea de tratamiento. En todos los demás pacientes, la combinación de pembrolizumab + quimioterapia es uno de los tratamientos considerado estándar. En los raros casos donde no se incluya un IO, quimioterapia con inhibidores del receptor para el VEGF seguido de mantenimiento (pemetrexed / bevacizumab) se pueden considerar regímenes aceptables. Como vemos el oncólogo de la comunidad tiene un gran reto, dada la diversidad de opciones de tratamientos disponibles para el paciente de cáncer de pulmón, especialmente en estadio metastásico. Todo esto requiere por su puesto un manejo multidisciplinario entre el patólogo, oncólogo, el neumólogo y el radiólogo intervencional. La medicina personalizada llegó al tratamiento del cáncer de pulmón para quedarse. REFERENCIAS: 1. Ganti AK, MD, MS. Newly Diagnosed Lung Cancer: Which Molecular Test are Needed for Optimal Treatment Decision Making?Oncology. June 2018. Vol 32, No 6; 276-280. 2.Horn L, MD, MSC. Molecular Testing for Advance NSCLC. InPractice Oncology. https://w w w.inpractice. c o m >Te x t b o o k s h t t p s : // w w w. accessdata.fda.gov/drugsatfda_docs/ label/2016/202570s017lbl.pdf 3.Kagawuchi T, Koh Y, Ando M, et al. Prospective Analysis of Oncogenic Driver Mutations and Enviromental Factors: Japan Molecular Epidemiology for Lung Cancer Study. J Clin Oncol. 2016: 34(19): 2247.

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4.Leighl NB, Rekhtman N, Biermann WA et al. Molecular testing for selection of patients with lung 5. Cancer for epidermal growth receptors and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of the American Pathologist/ International Association for the study of lung cancer association for molecular pathology guideline. J. Clin Oncol. 2014. Nov 10(32):3673-9. 6. Love N, MD. Cases from Community: Clinical Investigators Provide Their Perspectives on Emerging Research and Actual Patients with Non-Small Cell Lung Cancer. ResearchToPractice. https:// www.researchtopractice.com 7. Riess JW, MD, MS; Gandara DR, MD. Lung Cancer-Stage IV- ASCO-SEP 6th edition ebook version. 1865-1904 8. Sequist LV, Heist RS et al. Implementing multiplexed genotyping of non-small cell lung cancer in to routine clinical practice. Ann Oncol. 2011 Dec: 22(12): 2616-24. Epub 2011 Nov 9.

El oncólogo de hoy tiene un gran reto, dada la diversidad de opciones de tratamientos disponibles y aprobados por la FDA para el manejo de paciente de cáncer de pulmón, especialmente en estadio metastásico. Todo esto requiere de un manejo multidisciplinario entre el patólogo, oncólogo, el neumólogo y el radiólogo inter venciona l. La medicina personalizada llegó al tratamiento del cáncer de pulmón para quedarse.

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INDICATION FOR CYRAMZA CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA. For safety and dosing guidelines for CYRAMZA, see respective Important Safety Information and Brief Summary of Prescribing Information on the following pages.

SELECT IMPORTANT SAFETY INFORMATION FOR CYRAMZA HEMORRHAGE • CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including Grade ≥3 hemorrhagic events. In 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade hemorrhage ranged from 13-55%. Grade 3-5 hemorrhage incidence ranged from 2-5%. • Patients with NSCLC receiving therapeutic anticoagulation or with evidence of major airway invasion by cancer were excluded from REVEL. In addition, patients with NSCLC with a recent history of gross hemoptysis, those receiving chronic therapy with NSAIDs or other anti-platelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from REVEL and RELAY; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown. • Permanently discontinue CYRAMZA in patients who experience severe (Grade 3 or 4) bleeding.

Two trusted brands for treating your thoracic cancer patients. One trusted partner for helping you advance thoracic cancer care. We are committed to delivering options for metastatic non-small cell lung cancer (mNSCLC) so you can choose the right therapy at the right time for your patients. To catch up with our latest advancements in thoracic cancer care, visit: CYRAMZA.com ALIMTA.com Lilly.com

INDICATION FOR ALIMTA ALIMTA is indicated in combination with pembrolizumab (pembro) and platinum chemotherapy for the initial treatment of patients with nonsquamous metastatic non-small cell lung cancer (mNSCLC) with no EGFR or ALK genomic tumor aberrations. Limitation of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

SELECT IMPORTANT SAFETY INFORMATION FOR ALIMTA Contraindication ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed. For safety and dosing guidelines for ALIMTA, see respective Important Safety Information and Brief Summary of Prescribing Information on the following pages.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including Grade ≥3 hemorrhagic events. In 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade hemorrhage ranged from 13-55%. Grade 3-5 hemorrhage incidence ranged from 2-5%. Patients with NSCLC receiving therapeutic anticoagulation or with evidence of major airway invasion by cancer were excluded from REVEL. In addition, patients with NSCLC with a recent history of gross hemoptysis, those receiving chronic therapy with NSAIDs or other anti-platelet therapy other than once daily aspirin or with radiographic evidence of major blood vessel invasion or intratumor cavitation were excluded from REVEL and RELAY; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown. Permanently discontinue CYRAMZA in patients who experience severe (Grade 3 or 4) bleeding. Gastrointestinal Perforations CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. In 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade and Grade 3-5 gastrointestinal perforations ranged from <1-2%. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing CYRAMZA has the potential to adversely affect wound healing. CYRAMZA has not been studied in patients with serious or non-healing wounds. Withhold CYRAMZA for 28 days prior to elective surgery. Do not administer CYRAMZA for at least 2 weeks following a major surgical procedure and until adequate wound healing. The safety of resumption of CYRAMZA after resolution of wound healing complications has not been established. Arterial Thromboembolic Events (ATEs) Serious, sometimes fatal, ATEs, including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia, occurred across clinical trials. In 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade ATE was 1-3%. Grade 3-5 ATE incidence was <1-2%. Permanently discontinue CYRAMZA in patients who experience an ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA. Across five clinical studies, excluding RELAY, in 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade hypertension ranged from 11-26%. Grade 3-5 hypertension incidence ranged from 6-15%. In 221 patients with NSCLC receiving CYRAMZA in combination with erlotinib in the RELAY study, the incidence of new or worsening hypertension was higher (45%), as was the incidence of Grade 3-5 hypertension (24%). Of the patients experiencing new or worsening hypertension in RELAY (N=100 CYRAMZA and erlotinib; N=27 placebo and erlotinib), 13% of those treated with CYRAMZA and erlotinib required initiation of 3 or more antihypertensive medications compared to 4% of patients treated with placebo and erlotinib.

Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Withhold CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA for medically significant hypertension that cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion-Related Reactions (IRR) RR, including severe and life-threatening IRR, occurred in CYRAMZA clinical trials. Symptoms of IRR included rigors/ tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. In 2137 patients with various cancers treated with CYRAMZA in which premedication was recommended or required, the incidence of all Grade IRR ranged from <1- 9%. Grade 3-5 IRR incidence was <1%. Premedicate prior to each CYRAMZA infusion. Monitor patients during the infusion for signs and symptoms of IRR in a setting with available resuscitation equipment. Reduce the infusion rate by 50% for Grade 1-2 IRR. Permanently discontinue CYRAMZA for Grade 3- 4 IRR. Worsening of Pre-existing Hepatic Impairment Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration. Based on safety data from REACH-2, in patients with Child-Pugh A liver cirrhosis, the pooled incidence of hepatic encephalopathy and hepatorenal syndrome was higher for patients who received CYRAMZA (6%) compared to patients who received placebo (0%). Posterior Reversible Encephalopathy Syndrome (PRES) PRES (also known as Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in <0.1% of 2137 patients with various cancers treated with CYRAMZA. Symptoms of PRES include seizure, headache, nausea/vomiting, blindness, or altered consciousness, with or without associated hypertension. Permanently discontinue CYRAMZA in patients who develop PRES. Symptoms may resolve or improve within days, although some patients with PRES can experience ongoing neurologic sequelae or death. Proteinuria Including Nephrotic Syndrome In 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade proteinuria ranged from 3-34%. Grade ≥3 proteinuria (including 4 patients with nephrotic syndrome) incidence ranged from <1-3%. Monitor for proteinuria. Withhold CYRAMZA for urine protein levels that are 2 or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome.

Thyroid Dysfunction In 2137 patients with various cancers treated with CYRAMZA, the incidence of Grade 1-2 hypothyroidism ranged from <1-3%; there were no reports of Grade 3-5 hypothyroidism. Monitor thyroid function during treatment with CYRAMZA. Embryo-Fetal Toxicity CYRAMZA can cause fetal harm when administered to pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for 3 months after the last dose. Lactation Because of the potential risk for serious adverse reactions in breastfed children from ramucirumab, advise women not to breastfeed during treatment with CYRAMZA and for 2 months after the last dose. Adverse Reactions REVEL: The most common adverse reactions (all Grades) observed in patients treated with CYRAMZA with docetaxel at a rate of ≥5% and ≥2% higher than placebo with docetaxel were neutropenia (55% vs 46%), fatigue/asthenia (55% vs 50%), stomatitis/mucosal inflammation (37% vs 19%), epistaxis (19% vs 7%), febrile neutropenia (16% vs 10%), peripheral edema (16% vs 9%), thrombocytopenia (13% vs 5%), lacrimation increased (13% vs 5%), and hypertension (11% vs 5%). The most common serious adverse reactions with CYRAMZA with docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA with docetaxel- treated patients versus 37% in patients who received placebo with docetaxel. Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA with docetaxeltreated patients (9%) than in placebo with docetaxel-treated patients (5%). The most common adverse reactions leading to treatment discontinuation of CYRAMZA were IRR (0.5%) and epistaxis≈(0.3%). For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of Grade ≥3 pulmonary hemorrhage was 1% for CYRAMZA with docetaxel compared to 6% overall incidence and 1% for Grade ≥3 pulmonary hemorrhage for placebo with docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of Grade ≥3 pulmonary hemorrhage was 2% for CYRAMZA with docetaxel compared to 12% overall incidence and 2% for Grade ≥3 pulmonary hemorrhage for placebo with docetaxel. Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA with docetaxel-treated patients in REVEL were hyponatremia (4.8%) and proteinuria (3.3%).

RELAY: The most common adverse reactions (all Grades) observed in patients treated with CYRAMZA with erlotinib at a rate of ≥5% and ≥2% higher than placebo with erlotinib were infections (81% vs 76%), diarrhea (70% vs 71%), hypertension (45% vs 12%), stomatitis (42% vs 36%), alopecia (34% vs 20%), epistaxis (34% vs 12%), proteinuria (34% vs 8%), peripheral edema (23% vs 4%), headache (15% vs 7%), gastrointestinal hemorrhage (10% vs 3%), gingival bleeding (9% vs 1%), and pulmonary hemorrhage (7% vs 2%). The most common serious adverse reactions with CYRAMZA with erlotinib were pneumonia (3.2%), cellulitis (1.8%), and pneumothorax (1.8%). Red blood cell transfusions were given to 3.2% of CYRAMZA-treated patients versus 0 patients who received placebo. Treatment discontinuation of all study drugs due to adverse reactions occurred in 13% of CYRAMZA with erlotinibtreated patients, with increased alanine aminotransferase (1.4%) and paronychia (1.4%) being the most common. The most common adverse reactions leading to treatment discontinuation of CYRAMZA were proteinuria (8.6%) and hyperbilirubinemia (6%). Of the 221 patients who received CYRAMZA with erlotinib, 119 (54%) were 65 and over, while 29 (13%) were 75 and over. Adverse reactions occurring at a 10% or higher incidence in patients receiving CYRAMZA with erlotinib and with a 10% or greater difference between patients aged 65 or older compared to patients aged less than 65 years were: diarrhea (75% versus 65%), hypertension (50% versus 40%), increased ALT (49% versus 35%), increased AST (49% versus 33%), stomatitis (46% versus 36%), decreased appetite (32% versus 19%), dysgeusia (23% versus 12%), and weight loss (19% versus 6%). Please see Brief Summary of Prescribing Information for CYRAMZA on subsequent pages. RB-L HCP ISI 29MAY2020

IMPORTANT SAFETY INFORMATION FOR ALIMTA CONTRAINDICATION

Bullous and Exfoliative Skin Toxicity

ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.

Serious and sometimes fatal, bullous, blistering, and exfoliative skin toxicity, including cases suggestive of Stevens-Johnson Syndrome/toxic epidermal necrolysis, can occur with ALIMTA. Permanently discontinue ALIMTA for severe and life-threatening bullous, blistering, or exfoliating skin toxicity.

WARNINGS AND PRECAUTIONS Myelosuppression and Increased Risk of Myelosuppression Without Vitamin Supplementation ALIMTA can cause severe myelosuppression resulting in a requirement for transfusions and which may lead to neutropenic infection. The risk of myelosuppression is increased in patients who do not receive vitamin supplementation. Prior to treatment with ALIMTA, patients must be instructed to initiate supplementation with oral folic acid. Intramuscular injections of vitamin B12 are also required prior to ALIMTA treatment. Folic acid and vitamin B12 supplementation should be continued during treatment and for 21 days after the last dose of ALIMTA as they may reduce the severity of treatment-related hematologic and gastrointestinal toxicities. Obtain a complete blood count at the beginning of each cycle. Do not administer ALIMTA until the ANC is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3. Permanently reduce ALIMTA in patients with an ANC of less than 500 cells/mm3 or platelet count of less than 50,000 cells/mm3 in previous cycles. In Studies JMDB and JMCH, among patients who received vitamin supplementation, incidence of Grade 3-4 neutropenia was 15% and 23%, the incidence of Grade 3-4 anemia was 6% and 4%, and incidence of Grade 3-4 thrombocytopenia was 4% and 5%, respectively. In Study JMCH, 18% of patients in the ALIMTA arm required red blood cell transfusions compared to 7% of patients in the cisplatin arm. In Studies JMEN, PARAMOUNT, and JMEI, where all patients received vitamin supplementation, incidence of Grade 3-4 neutropenia ranged from 3% to 5%, and incidence of Grade 3-4 anemia ranged from 3% to 5%. Renal Failure ALIMTA can cause severe, and sometimes fatal, renal toxicity. Determine creatinine clearance before each dose and periodically monitor renal function during treatment with ALIMTA. The incidences of renal failure in clinical studies in which patients received ALIMTA with cisplatin were 2.1% in Study JMDB and 2.2% in Study JMCH. The incidence of renal failure in clinical studies in which patients received ALIMTA as a single agent ranged from 0.4% to 0.6% (Studies JMEN, PARAMOUNT, and JMEI). Withhold ALIMTA in patients with a creatinine clearance of less than 45 mL/min.

Interstitial Pneumonitis Serious interstitial pneumonitis, including fatal cases, can occur with ALIMTA treatment. Withhold ALIMTA for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, or fever pending diagnostic evaluation. If pneumonitis is confirmed, permanently discontinue ALIMTA. Radiation Recall Radiation recall can occur with ALIMTA in patients who have received radiation weeks to years previously. Monitor patients for inflammation or blistering in areas of previous radiation treatment. Permanently discontinue ALIMTA for signs of radiation recall. Increased Risk of Toxicity With Ibuprofen in Patients With Renal Impairment Exposure to ALIMTA is increased in patients with mild to moderate renal impairment who take concomitant ibuprofen, increasing the risks of adverse reactions of ALIMTA. In patients with creatinine clearances between 45 mL/min and 79 mL/min, avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of ALIMTA. If concomitant ibuprofen use cannot be avoided, monitor patients more frequently for ALIMTA adverse reactions, including myelosuppression, renal, and gastrointestinal toxicity. Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and increased malformations at doses lower than the recommended human dose of 500 mg/m2. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with ALIMTA and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALIMTA and for 3 months after the final dose.

DRUG INTERACTIONS Ibuprofen increases exposure (AUC) of pemetrexed. In patients with creatinine clearance between 45 mL/min and 79 mL/min: • Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of ALIMTA. • Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided. ADVERSE REACTIONS Severe adverse reactions (Grade 3-4) occurring in ≥20% of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA in combination with pembrolizumab and platinum chemotherapy (carboplatin or cisplatin) versus ALIMTA with platinum chemotherapy + placebo for initial treatment (KEYNOTE-189), respectively, were fatigue (12% vs 6%); diarrhea (5% vs 3%); dyspnea (3.7% vs 5%); vomiting (3.7% vs 3%); nausea (3.5% vs 3.5%); rash (2% vs 2.5%); decreased appetite (1.5% vs 0.5%); constipation (1% vs 0.5%); and pyrexia (0.2% vs 0%). Common adverse reactions (all grades) occurring in ≥20% of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA in combination with pembrolizumab and platinum chemotherapy (carboplatin or cisplatin) versus ALIMTA with platinum chemotherapy + placebo for initial treatment (KEYNOTE-189), respectively, were nausea (56% vs 52%); fatigue (56% vs 58%); constipation (35% vs 32%); diarrhea (31% vs 21%); decreased appetite (28% vs 30%); rash (25% vs 17%); vomiting (24% vs 23%); cough (21% vs 28%); dyspnea (21% vs 26%); and pyrexia (20% vs 15%). USE IN SPECIFIC PATIENT POPULATIONS Lactation: There is no information regarding the presence of pemetrexed or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from ALIMTA, advise women not to breastfeed during treatment with ALIMTA and for one week after the last dose. Males of Reproductive Potential: ALIMTA may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible. Pediatric Use: The safety and effectiveness of ALIMTA in pediatric patients have not been established. Adverse reactions observed in pediatric patients studied were similar to those observed in adults.

Patients with Renal Impairment: ALIMTA is primarily excreted by the kidneys. Decreased renal function results in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function. No dose is recommended for patients with creatinine clearance less than 45 mL/min. Geriatric: The incidences of Grade 3-4 anemia, fatigue, thrombocytopenia, hypertension, and neutropenia were higher in patients 65 years of age and older as compared to younger patients: in at least one of five randomized clinical trials. For safety and dosing guidelines, see Brief Summary of Prescribing Information for ALIMTA on the following pages. PM_HCP_ISI_NSCLC1L_Combo_30 JAN2019

CYRAMZA® (ramucirumab) injection, for intravenous use Brief Summary: Consult the package insert for complete prescribing information. INDICATIONS AND USAGE Non-Small Cell Lung Cancer: CYRAMZA, in combination with erlotinib, is indicated for the treatment of patients with first-line metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) mutations. CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including Grade ≥3 hemorrhagic events. Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade hemorrhage ranged from 13-55%. Grade 3-5 hemorrhage incidence ranged from 2-5%. Patients with NSCLC receiving therapeutic anticoagulation or with evidence of major airway invasion by cancer were excluded from REVEL. In addition, patients with NSCLC with a recent history of gross hemoptysis, those receiving chronic therapy with NSAIDs or other anti-platelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from REVEL and RELAY; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown. Permanently discontinue CYRAMZA in patients who experience severe (Grade 3 or 4) bleeding. Gastrointestinal Perforations CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade and Grade 3-5 gastrointestinal perforations ranged from <1-2%. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF or VEGFR pathway. CYRAMZA, a VEGFR2 antagonist, has the potential to adversely affect wound healing. CYRAMZA has not been studied in patients with serious or non-healing wounds. Withhold CYRAMZA for 28 days prior to elective surgery. Do not administer CYRAMZA for at least 2 weeks following a major surgical procedure and until adequate wound healing. The safety of resumption of CYRAMZA after resolution of wound healing complications has not been established. Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs), including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia, occurred across clinical trials. Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade ATE was 1-3%. Grade 3-5 ATE incidence was <1-2%. Permanently discontinue CYRAMZA in patients who experience an ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA. Across five clinical studies, excluding RELAY, in 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade hypertension ranged from 11-26%. Grade 3-5 hypertension incidence ranged from 6-15%. In 221 patients with NSCLC receiving CYRAMZA in combination with erlotinib in the RELAY study, the incidence of new or worsening hypertension was higher (45%), as was the incidence of Grade 3-5 hypertension (24%). Of the patients experiencing new or worsening hypertension in RELAY (N=100 CYRAMZA and erlotinib; N=27 placebo and erlotinib), 13% of those treated with CYRAMZA and erlotinib required initiation of 3 or more antihypertensive medications compared to 4% of patients treated with placebo and erlotinib. Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Withhold CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA for medically significant hypertension that cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion-Related Reactions Infusion-related reactions (IRR) including severe and life threatening IRR occurred in CYRAMZA clinical trials. The majority of IRR across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRR included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA in which premedication was recommended or required, the incidence of all Grade CYRAMZA® (ramucirumab) injection, for intravenous use

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IRR ranged from <1-9%. Grade 3-5 IRR incidence was <1%. Premedicate prior to each CYRAMZA infusion. Monitor patients during the infusion for signs and symptoms of IRR in a setting with available resuscitation equipment. Reduce the infusion rate by 50% for Grade 1-2 IRR. Permanently discontinue CYRAMZA for Grade 3-4 IRR. Worsening of Pre-existing Hepatic Impairment Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration. Based on safety data from REACH-2, in patients with Child-Pugh A liver cirrhosis, the pooled incidence of hepatic encephalopathy and hepatorenal syndrome was higher for patients who received CYRAMZA (6%) compared to patients who received placebo (0%). Posterior Reversible Encephalopathy Syndrome Posterior Reversible Encephalopathy Syndrome (PRES) (also known as Reversible Posterior Leukoencephalopathy Syndrome [RPLS]) has been reported in <0.1% of 2137 patients enrolled in six clinical studies with CYRAMZA. Symptoms of PRES include seizure, headache, nausea/ vomiting, blindness, or altered consciousness, with or without associated hypertension. Confirm the diagnosis of PRES with magnetic resonance imaging and permanently discontinue CYRAMZA in patients who develop PRES. Symptoms may resolve or improve within days, although some patients with PRES can experience ongoing neurologic sequelae or death. Proteinuria Including Nephrotic Syndrome Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade proteinuria ranged from 3-34%. Grade ≥3 proteinuria (including 4 patients with nephrotic syndrome) incidence ranged from <1-3%. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio. If the result of the urine dipstick is 2+ or greater, perform a 24-hour urine collection for protein measurement. Withhold CYRAMZA for urine protein levels that are 2 or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome. Thyroid Dysfunction Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of Grade 1-2 hypothyroidism ranged from <1-3%; there were no reports of Grade 3-5 hypothyroidism. Monitor thyroid function during treatment with CYRAMZA. Embryo-Fetal Toxicity Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF and VEGFR2 to critical aspects of female reproduction, embryo-fetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for 3 months after the last dose. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. CYRAMZA Administered in Combination with Erlotinib The safety of CYRAMZA was evaluated in RELAY. Patients had previously untreated EGFR exon 19 deletion or exon 21 (L858R) substitution mutation-positive metastatic NSCLC. Patients had ECOG PS 0 or 1. RELAY excluded patients with bilirubin greater than the ULN, central nervous system (CNS) metastases, clinically active interstitial lung disease (ILD), uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major blood vessel invasion or encasement by cancer or intra-tumor cavitation, or gross hemoptysis within the preceding 2 months. The study also excluded patients receiving chronic nonsteroidal anti-inflammatory agents (NSAIDs) or anti-platelet therapy other than once daily aspirin. Patients received either CYRAMZA 10 mg/kg or placebo intravenously every two weeks in combination with erlotinib 150 mg taken orally once daily. Patients randomized to CYRAMZA received a median of 21 doses; the median duration of exposure was 11 months, and 90 (41% of 221) patients received CYRAMZA for at least 12 months. The most common serious adverse reactions in patients who received CYRAMZA with erlotinib were pneumonia (3.2%), cellulitis (1.8%), and pneumothorax (1.8%). Red blood cell transfusions were given to 3.2% of CYRAMZA-treated patients versus 0 patients who received placebo. Treatment discontinuation of all study drugs due to adverse reactions occurred in 13% of CYRAMZA with erlotinib-treated patients, with increased alanine aminotransferase (1.4%) and paronychia (1.4%) being the most common. The most common adverse reactions leading to treatment discontinuation of CYRAMZA were proteinuria (8.6%) and hyperbilirubinemia (6%). The most common adverse reactions (all grades) observed in CYRAMZA with erlotinib-treated patients at a rate of ≥30% of patients and ≥2% higher than placebo with erlotinib-treated patients were infections, hypertension, stomatitis, proteinuria, alopecia, and epistaxis. The most common laboratory abnormalities ≥30% and ≥2% higher than the placebo were increased alanine aminotransferase, increased aspartate aminotransferase, anemia, thrombocytopenia, and neutropenia. Table 4 provides the frequency and severity of adverse reactions (CTCAE, version 4.0) and Table 5 provides the incidence and severity of laboratory abnormalities in RELAY. CYRAMZA® (ramucirumab) injection, for intravenous use

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Table 1: Adverse Reactions Occurring in ≥5% of Patients with a ≥2% Difference Between Arms in RELAY CYRAMZA + Erlotinib Placebo + Erlotinib (N=221) (N=225) Adverse Reactions All Grades Grade ≥3 All Grades Grade ≥3 (%) (%) (%) (%) Infections Infectionsa,b 81 17 76 7 Vascular Hypertension 45 24 12 5 Gastrointestinal Diarrhea 70 7 71 1 Stomatitis 42 2 36 1 Gastrointestinal 10 1 3 <1 hemorrhagec Gingival bleeding 9 0 1 0 Renal and Urinary Proteinuriac 34 3 8 0 Skin and Subcutaneous Tissue Alopecia 34 N/Ad 20 N/Ad Respiratory, Thoracic, and Mediastinal Epistaxis 34 0 12 0 Pulmonary hemorrhagec,e 7 <1 2 <1 General Peripheral edema 23 <1 4 0 Nervous System Headache 15 <1 7 0 Abbreviations: N/A = not applicable. a Includes all preferred terms that are part of the System Organ Class Infections and Infestations. Most common (≥1%) Grade ≥3 infections and frequencies for CYRAMZA with erlotinib compared to placebo with erlotinib, respectively, include pneumonia (3% versus 0%), cellulitis (1% versus 0%), paronychia (4% versus 3%), skin infection (1% versus 0%), and urinary tract infection (1% versus 0%). b Includes 3 fatal events in the CYRAMZA arm. c Gastrointestinal hemorrhage, proteinuria, and pulmonary hemorrhage are consolidated terms. d Grade ≥3 does not exist in CTCAE. e Includes 1 fatal event in the CYRAMZA arm. Table 2: Laboratory Abnormalities Worsening from Baseline in ≥20% (All Grades) of Patients Receiving CYRAMZA with Erlotinib with a Difference Between Arms of ≥2% in RELAY CYRAMZA + Erlotiniba Placebo + Erlotiniba Laboratory Abnormality All Grades Grade ≥3 All Grades Grade ≥3 (%) (%) (%) (%) Chemistry Alanine aminotransferase 74 11 60 13 increased Aspartate aminotransferase 71 6 47 4 increased Alkaline phosphatase 25 <1 16 1 increased Hypokalemia 24 5 18 2 Hematology Anemia 42 5 25 2 Thrombocytopenia 41 3 12 3 Neutropenia 33 7 21 4 a The denominator used to calculate the incidence varied based on the number of patients with a baseline and at least one on-study laboratory measurement: CYRAMZA-treated patients (range 215-218 patients) and placebo-treated patients (range 224-225 patients). CYRAMZA Administered in Combination with Docetaxel The safety of CYRAMZA was evaluated in REVEL. Patients had NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease and ECOG PS 0 or 1. REVEL excluded patients with bilirubin greater than the ULN, uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major airway or blood vessel invasion by cancer, radiographic evidence of intra-tumor cavitation, or gross hemoptysis within the preceding 2 months, and patients receiving therapeutic anticoagulation or chronic antiplatelet therapy other than once daily aspirin. Patients received either CYRAMZA 10 mg/kg or placebo intravenously in combination with docetaxel 75 mg/m2 intravenously every 21 days. Due to an increased incidence of neutropenia and febrile neutropenia in patients enrolled in East Asian sites, REVEL was amended and 24 patients (11 patients receiving CYRAMZA with docetaxel, 13 patients receiving placebo with docetaxel) at East Asian sites received a starting dose of docetaxel at 60 mg/m2 every three weeks. Patients randomized to CYRAMZA received a median of 4.5 doses; the median duration of exposure CYRAMZA® (ramucirumab) injection, for intravenous use

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was 3.5 months, and 195 (31% of 627) patients received CYRAMZA for at least six months. The most common serious adverse reactions in patients who received CYRAMZA with docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA with docetaxel-treated patients versus 37% in patients who received placebo with docetaxel. The most common adverse reactions leading to treatment discontinuation of CYRAMZA were IRR (0.5%) and epistaxis (0.3%). For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of Grade ≥3 pulmonary hemorrhage was 1% for CYRAMZA with docetaxel compared to 6% overall incidence and 1% for Grade ≥3 pulmonary hemorrhage for placebo with docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of Grade ≥3 pulmonary hemorrhage was 2% for CYRAMZA with docetaxel compared to 12% overall incidence and 2% for Grade ≥3 pulmonary hemorrhage for placebo with docetaxel. Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA with docetaxel-treated patients (9%) than in placebo with docetaxel-treated patients (5%). The most common adverse reactions (all grades) observed in CYRAMZA with docetaxel-treated patients at a rate of ≥30% and ≥2% higher than placebo with docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. Table 3 provides the frequency and severity of adverse reactions (NCI CTCAE, version 4.0) in REVEL. Table3: Adverse Reactions Occurring in ≥5% of Patients with a ≥2% Difference Between Arms in REVEL CYRAMZA + Docetaxel Placebo + Docetaxel (N=627) (N=618) Adverse Reactions All Grades Grade 3-4 All Grades Grade 3-4 (%) (%) (%) (%) Hematology Neutropeniaa 55 49 46 40 Febrile neutropenia 16 16 10 10 Thrombocytopeniaa 13 3 5 <1 General Fatigue/Asthenia 55 14 50 11 Peripheral edema 16 0 9 <1 Gastrointestinal Stomatitis/Mucosal 37 7 19 2 inflammation Respiratory, Thoracic, and Mediastinal Epistaxis 19 <1 7 <1 Eye Lacrimation increased 13 <1 5 0 Vascular Hypertensiona 11 6 5 2 a Neutropenia, thrombocytopenia, and hypertension are consolidated terms. Clinically relevant adverse drug reactions reported in ≥1% and <5% of CYRAMZA with docetaxel-treated patients in REVEL were hyponatremia (4.8%) and proteinuria (3.3%). Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading. In clinical trials, 86/2890 (3%) of CYRAMZA-treated patients tested positive for treatment-emergent anti-ramucirumab antibodies by an enzymelinked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 14 of the 86 patients who tested positive for treatment-emergent anti-ramucirumab antibodies. Postmarketing Experience The following adverse reactions have been identified during postapproval use of CYRAMZA. Because such reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Blood and lymphatic system: Thrombotic microangiopathy • Neoplasms benign, malignant and unspecified: Hemangioma • Respiratory, thoracic, and mediastinal: Dysphonia • Vascular: Arterial (including aortic) aneurysms, dissections, and rupture USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to a pregnant woman. There are no available data on CYRAMZA use in pregnant women. Animal models link angiogenesis, VEGF and VEGFR2 to critical aspects of female reproduction, embryo-fetal CYRAMZA® (ramucirumab) injection, for intravenous use

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development, and postnatal development. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise a pregnant woman of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryo-fetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels. Lactation Risk Summary There is no information on the presence of ramucirumab in human milk or its effects on the breastfed child or on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential risk for serious adverse reactions in breastfed children from ramucirumab, advise women not to breastfeed during treatment with CYRAMZA and for 2 months after the last dose. Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating CYRAMZA. Contraception Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to a pregnant woman. Females Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for 3 months after the last dose. Infertility Females Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility. Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. Juvenile Animal Toxicity Data In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent. Geriatric Use Of the 221 patients in RELAY, 119 (54%) were 65 and over, while 29 (13%) were 75 and over. Overall, no clinically meaningful differences in effectiveness were observed between these patients and younger patients. Adverse reactions occurring at a 10% or higher incidence in patients receiving CYRAMZA with erlotinib and with a 10% or greater difference between patients aged 65 or older compared to patients aged less than 65 years were: diarrhea (75% versus 65%), hypertension (50% versus 40%), increased ALT (49% versus 35%), increased AST (49% versus 33%), stomatitis (46% versus 36%), decreased appetite (32% versus 19%), dysgeusia (23% versus 12%) and weight loss (19% versus 6%). Of the 1253 patients in REVEL, 455 (36%) were 65 and over and 84 (7%) were 75 and over. Of the 627 patients who received CYRAMZA with docetaxel in REVEL, 237 (38%) were 65 and over, while 45 (7%) were 75 and over. In an exploratory subgroup analysis of REVEL, the hazard ratio for overall survival in patients less than 65 years old was 0.74 (95% CI: 0.62, 0.87) and in patients 65 years and over was 1.10 (95% CI: 0.89, 1.36). Hepatic Impairment No dose adjustment is recommended for patients with mild (total bilirubin within ULN and aspartate aminotransferase [AST] >ULN or total bilirubin >1 to 1.5 times ULN and any AST) or moderate (total bilirubin >1.5 to 3 times ULN and any AST) hepatic impairment. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single agent CYRAMZA. Rx only Additional information can be found at www.cyramza.com

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ALIMTA® (pemetrexed for injection), for Intravenous Use Initial U.S. Approval: 2004 BRIEF SUMMARY: Consult the package insert for complete prescribing information.

at doses lower than the recommended human dose of 500 mg/m2. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with ALIMTA and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALIMTA and for 3 months after the final dose.

INDICATIONS AND USAGE

ADVERSE REACTIONS

Nonsquamous Non-Small Cell Lung Cancer (NSCLC) ALIMTA (pemetrexed) is indicated: • in combination with pembrolizumab and platinum chemotherapy, for the initial treatment of patients with metastatic non-squamous NSCLC, with no EGFR or ALK genomic tumor aberrations. • in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous, non-small cell lung cancer (NSCLC). • as a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. • as a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy. Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

CONTRAINDICATIONS: ALIMTA is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed. WARNINGS AND PRECAUTIONS Myelosuppression and Increased Risk of Myelosuppression without Vitamin Supplementation ALIMTA can cause severe myelosuppression resulting in a requirement for transfusions and which may lead to neutropenic infection. The risk of myelosuppression is increased in patients who do not receive vitamin supplementation. Prior to treatment with ALIMTA, patients must be instructed to initiate supplementation with oral folic acid. Intramuscular injections of vitamin B12 are also required prior to ALIMTA treatment. Folic acid and vitamin B12 supplementation should be continued during treatment and for 21 days after the last dose of ALIMTA as they may reduce the severity of treatment-related hematologic and gastrointestinal toxicities. Obtain a complete blood count at the beginning of each cycle. Do not administer ALIMTA until the ANC is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3. Permanently reduce ALIMTA in patients with an ANC of less than 500 cells/mm3 or platelet count of less than 50,000 cells/mm3 in previous cycles. In Studies JMDB and JMCH, among patients who received vitamin supplementation, incidence of Grade 3-4 neutropenia was 15% and 23%, the incidence of Grade 3-4 anemia was 6% and 4%, and incidence of Grade 3-4 thrombocytopenia was 4% and 5%, respectively. In Study JMCH, 18% of patients in the ALIMTA arm required red blood cell transfusions compared to 7% of patients in the cisplatin arm. In Studies JMEN, PARAMOUNT, and JMEI, where all patients received vitamin supplementation, incidence of Grade 3-4 neutropenia ranged from 3% to 5%, and incidence of Grade 3-4 anemia ranged from 3% to 5%. Renal Failure ALIMTA can cause severe, and sometimes fatal, renal toxicity. Determine creatinine clearance before each dose and periodically monitor renal function during treatment with ALIMTA. The incidences of renal failure in clinical studies in which patients received ALIMTA with cisplatin were: 2.1% in Study JMDB and 2.2% in Study JMCH. The incidence of renal failure in clinical studies in which patients received ALIMTA as a single agent ranged from 0.4% to 0.6% (Studies JMEN, PARAMOUNT, and JMEI). Withhold ALIMTA in patients with a creatinine clearance of less than 45 mL/min. Bullous and Exfoliative Skin Toxicity Serious and sometimes fatal, bullous, blistering and exfoliative skin toxicity, including cases suggestive of StevensJohnson Syndrome/Toxic epidermal necrolysis can occur with ALIMTA. Permanently discontinue ALIMTA for severe and life-threatening bullous, blistering or exfoliating skin toxicity. Interstitial Pneumonitis Serious interstitial pneumonitis, including fatal cases, can occur with ALIMTA treatment. Withhold ALIMTA for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, or fever pending diagnostic evaluation. If pneumonitis is confirmed, permanently discontinue ALIMTA. Radiation Recall Radiation recall can occur with ALIMTA in patients who have received radiation weeks to years previously. Monitor patients for inflammation or blistering in areas of previous radiation treatment. Permanently discontinue ALIMTA for signs of radiation recall. Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment Exposure to ALIMTA is increased in patients with mild to moderate renal impairment who take concomitant ibuprofen, increasing the risks of adverse reactions of ALIMTA. In patients with creatinine clearances between 45 mL/min and 79 mL/min, avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of ALIMTA. If concomitant ibuprofen use cannot be avoided, monitor patients more frequently for ALIMTA adverse reactions, including myelosuppression, renal, and gastrointestinal toxicity. Embryo-Fetal Toxicity

Non-Squamous NSCLC First-line Treatment of Metastatic Non-squamous NSCLC with Pembrolizumab and Platinum Chemotherapy The safety of ALIMTA in combination with pembrolizumab and investigator’s choice of platinum (either carboplatin or cisplatin) was investigated in Study KEYNOTE-189, a multicenter, double-blind, randomized (2:1), active-controlled trial in patients with previously untreated, metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations. A total of 607 patients received ALIMTA, pembrolizumab, and platinum every 3 weeks for 4 cycles followed by ALIMTA and pembrolizumab (n=405), or placebo, ALIMTA, and platinum every 3 weeks for 4 cycles followed by placebo and ALIMTA (n=202). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. The median duration of exposure to ALIMTA was 7.2 months (range: 1 day to 1.7 years). Seventy-two percent of patients received carboplatin. The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 years or older, 59% male, 94% White and 3% Asian, and 18% with history of brain metastases at baseline. ALIMTA was discontinued for adverse reactions in 23% of patients in the ALIMTA, pembrolizumab, and platinum arm. The most common adverse reactions resulting in discontinuation of ALIMTA in this arm were acute kidney injury (3%) and pneumonitis (2%). Adverse reactions leading to interruption of ALIMTA occurred in 49% of patients in the ALIMTA, pembrolizumab, and platinum arm. The most common adverse reactions or laboratory abnormalities leading to interruption of ALIMTA in this arm (≥2%) were neutropenia (12%), anemia (7%), asthenia (4%), pneumonia (4%), thrombocytopenia (4%), increased blood creatinine (3%), diarrhea (3%), and fatigue (3%). Below summarizes the adverse reactions and laboratory abnormalities that worsened from baseline (graded per NCI CTCAE v4.03) that occurred in ≥20% of patients treated with ALIMTA, pembrolizumab and platinum. Adverse Reactions • Grade 3-4 Adverse Reactions occurring in ≥20% patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA with pembrolizumab and platinum chemotherapy versus ALIMTA and platinum chemotherapy plus placebo for initial treatment (KEYNOTE-189), respectively, were fatigue* (12% vs 6%); diarrhea (5% vs 3%); dyspnea (3.7% vs 5%); vomiting (3.7% vs 3%); nausea (3.5% vs 3.5%); rash† (2% vs 2.5%); decreased appetite (1.5% vs 0.5%); constipation (1% vs 0.5%); and pyrexia (0.2% vs 0%). • All Grades Adverse Reactions occurring in ≥20% of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA with pembrolizumab and platinum chemotherapy versus ALIMTA and platinum chemotherapy plus placebo for initial treatment (KEYNOTE-189), respectively, were nausea (56% vs 52%); fatigue* (56% vs 58%); constipation (35% vs 32%); diarrhea (31% vs 21%); decreased appetite ( 28% vs 30%); rash† (25% vs 17%); vomiting (24% vs 23%); cough (21% vs 28%); dyspnea (21% vs 26%); and pyrexia (20% vs 15%). *Includes asthenia and fatigue Includes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular

†

Laboratory Abnormalities that Worsened from Baseline Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: ALIMTA/pembrolizumab/platinum chemotherapy (range 381-401 patients) and placebo/ ALIMTA/platinum chemotherapy (range 184 to 197 patients). • Grade 3-4 Laboratory Abnormalities that Worsened from Baseline in ≥20% of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA with pembrolizumab and platinum chemotherapy versus ALIMTA and platinum chemotherapy plus placebo for initial treatment (KEYNOTE-189), respectively, were lymphopenia (22% vs 25%); neutropenia (20% vs 19%); anemia (17% vs 18%); thrombocytopenia (12% vs 8%); hypophosphatemia (10% vs 14%); hyperglycemia (9% vs 7%); hyponatremia (7% vs 6%); hypokalemia (5% vs 5%); increased creatinine (4.2% vs 1%); increased ALT (3.8% vs 2.6%); increased AST (2.8% vs 1%); hypoalbuminemia (2.8% vs 1.1%); hypocalcemia (2.8% vs 1.7%); hyperkalemia (2.8% vs 3.1%) and increased alkaline phosphatase (1.8% vs 2.1%). • All Grades Laboratory Abnormalities that Worsened from Baseline in ≥20% of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA with pembrolizumab and platinum chemotherapy versus ALIMTA and platinum chemotherapy plus placebo for initial treatment (KEYNOTE-189), respectively, were anemia (85% vs 81%); lymphopenia (64% vs 64%); hyperglycemia (63% vs 60%); neutropenia (48% vs 41%); increased ALT (47% vs 42%); increased AST (47% vs 40%); hypoalbuminemia (39% vs 39%); increased creatinine (37% vs 25%); hyponatremia (32% vs 23%); hypophosphatemia (30% vs 28%); thrombocytopenia (30% vs 29%); increased alkaline phosphatase (26% vs 29%); hypocalcemia (24% vs 17%); hyperkalemia (24% vs 19%); and hypokalemia (21% vs 20%). Initial Treatment in Combination with Cisplatin The safety of ALIMTA was evaluated in Study JMDB, a randomized (1:1), open-label, multicenter trial conducted in chemotherapy-naive patients with locally advanced or metastatic NSCLC. Patients received either ALIMTA 500 mg/ m2 intravenously and cisplatin 75 mg/ m2 intravenously on Day 1 of each 21-day cycle (n=839) or gemcitabine 1250 mg/m2 intravenously on Days 1 and 8 and cisplatin 75 mg/ m2 intravenously on Day 1 of each 21-day cycle (n=830). All patients were fully supplemented with folic acid and vitamin B12.

Based on findings from animal studies and its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and increased malformations

Study JMDB excluded patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS of 2 or greater), uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study.

ALIMTA® (pemetrexed for injection), for Intravenous Use

PM HCP BS ALLNSCLC 12MAR2019

The data described below reflect exposure to ALIMTA plus cisplatin in 839 patients in Study JMDB. Median age was 61 years (range 26-83 years); 70% of patients were men; 78% were White,16% were Asian, 2.9% were Hispanic or Latino, 2.1% were Black or African American, and <1% were other ethnicities; 36% had an ECOG PS 0. Patients received a median of 5 cycles of ALIMTA. Below shows the frequency and severity of adverse reactions (NCI CTCAE version 2.0) that occurred in ≥5% of 839 patients receiving ALIMTA in combination with cisplatin in Study JMDB. Study JMDB was not designed to demonstrate a statistically significant reduction in adverse reaction rates for ALIMTA, as compared to the control arm, for any specified adverse reaction listed below. • Grade 3-4 Adverse Reactions occurring in ≥5% fully vitamin supplemented patients with locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin for initial treatment (JMDB), respectively, were neutropenia (15% vs 27%); fatigue (7% vs 5%); nausea (7% vs 4%); vomiting (6% vs 6%); anemia (6% vs 10%); thrombocytopenia (4% vs 13%); anorexia (2% vs 1%); creatinine elevation (1% vs 1%); diarrhea (1% vs 2%); stomatitis/pharyngitis (1% vs 0%); constipation (1% vs 0%), sensory neuropathy (0% vs 1%), alopecia (0% vs 1%) and rash/desquamation (0% vs 1%). • All Grades Adverse Reactions occurring in ≥5% fully vitamin supplemented patients with locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin for initial treatment (JMDB), respectively, were nausea (56% vs 53%); fatigue (43% vs 45%); vomiting (40% vs 36%); anemia (33% vs 46%); neutropenia (29% vs 38%); anorexia (27% vs 24%); constipation (21% vs 20%); stomatitis/pharyngitis (14% vs 12%); alopecia (12% vs 21%); diarrhea (12% vs 13%); thrombocytopenia (10% vs 27%); creatinine elevation (10% vs 7%), sensory neuropathy (9% vs 12%); taste disturbance (8% vs 9%); rash/desquamation (7% vs 8%); and dyspepsia/heartburn (5% vs 6%). The following additional adverse reactions of ALIMTA were observed: • Incidence 1% to <5%: febrile neutropenia, infection, pyrexia, dehydration, increased AST, increased ALT, renal failure, conjunctivitis • Incidence <1%: arrhythmia, chest pain, increased GGT, motor neuropathy Maintenance Treatment Following First-Line Non-ALIMTA Containing Platinum-Based Chemotherapy In Study JMEN, the safety of ALIMTA was evaluated in a randomized (2:1), placebo-controlled, multicenter trial conducted in patients with non-progressive locally advanced or metastatic NSCLC following four cycles of a first-line, platinum-based chemotherapy regimen. Patients received either ALIMTA 500 mg/m2 or matching placebo intravenously every 21 days until disease progression or unacceptable toxicity. Patients in both study arms were fully supplemented with folic acid and vitamin B12. Study JMEN excluded patients with an ECOG PS of 2 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study. The data described below reflect exposure to ALIMTA in 438 patients in Study JMEN. Median age was 61 years (range 26-83 years), 73% of patients were men; 65% were White, 31% were Asian, 2.9% were Hispanic or Latino, and <2% were other ethnicities; 39% had an ECOG PS 0. Patients received a median of 5 cycles of ALIMTA and a relative dose intensity of ALIMTA of 96%. Approximately half the patients (48%) completed at least six, 21-day cycles and 23% completed ten or more 21-day cycles of ALIMTA. Below shows the frequency and severity of adverse reactions (NCI CTCAE version 3.0) reported in ≥5% of the 438 ALIMTA-treated patients in Study JMEN. The requirement for transfusions (9.5% versus 3.2%), primarily red blood cell transfusions, and for erythropoiesis stimulating agents (5.9% versus 1.8%) were higher in the ALIMTA arm compared to the placebo arm. • Grade 3-4 Adverse Reactions occurring in ≥5% patients with non-progressive locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA as a single agent versus placebo as maintenance treatment (JMEN), respectively, following non-ALIMTA containing platinum-based induction therapy were anemia (3% vs 1%); neutropenia (3% vs 0%); fatigue (5% vs 1%); nausea (1% vs 1%); anorexia (2% vs 0%); infection (2% vs 0%); mucositis/stomatitis (1% vs 0%); diarrhea (1% vs 0%); and sensory neuropathy (1% vs 0%). • All Grades Adverse Reactions occurring in ≥5% patients with non-progressive locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA as a single agent versus placebo as maintenance treatment (JMEN), respectively, following non-ALIMTA containing platinum-based induction therapy were fatigue (25% vs 11%); nausea (19% vs 6%); anorexia (19% vs 5%); anemia (15% vs 6%); increased rash/desquamation (10% vs 3%); ALT (10% vs 4%); sensory neuropathy (9% vs 4%); vomiting (9% vs 1%); increased AST (8% vs 4%); mucositis/stomatitis (7% vs 2%); neutropenia (6% vs 0%); diarrhea (5% vs 3%); and infection (5% vs 2%). The following additional adverse reactions were observed in patients who received ALIMTA. • Incidence 1% to <5%: alopecia, pruritus/itching, constipation, edema, fever, thrombocytopenia, ocular surface disease (including conjunctivitis), increased lacrimation • Incidence <1%: supraventricular arrhythmia, erythema multiforme, febrile neutropenia, allergic reaction/ hypersensitivity, motor neuropathy, renal failure Maintenance Treatment Following First-line ALIMTA Plus Platinum-Based Chemotherapy The safety of ALIMTA was evaluated in PARAMOUNT, a randomized (2:1), placebo-controlled study conducted in patients with non-squamous NSCLC with non-progressive (stable or responding disease) locally advanced or metastatic NSCLC following four cycles of ALIMTA in combination with cisplatin as first-line therapy for NSCLC. Patients were randomized to receive ALIMTA 500 mg/m2 or matching placebo intravenously on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity. Patients in both study arms received folic acid and vitamin B12 supplementation.

The data described below reflect exposure to ALIMTA in 333 patients in PARAMOUNT. Median age was 61 years (range 32 to 83 years); 58% of patients were men; 94% were White, 4.8% were Asian, and <1% were Black or African American; 36% had an ECOG PS 0. The median number of maintenance cycles was 4 for ALIMTA and placebo arms. Dose reductions for adverse reactions occurred in 3.3% of patients in the ALIMTA arm and 0.6% in the placebo arm. Dose delays for adverse reactions occurred in 22% of patients in the ALIMTA arm and 16% in the placebo arm. Below shows the frequency and severity of adverse reactions (graded per NCI CTCAE version 3.0) reported in ≥5% of the 333 ALIMTA-treated patients in PARAMOUNT. The requirement for red blood cell (13% versus 4.8%) and platelet (1.5% versus 0.6%) transfusions, erythropoiesis stimulating agents (12% versus 7%), and granulocyte colony stimulating factors (6% versus 0%) were higher in the ALIMTA arm compared to the placebo arm. • Grade 3-4 Adverse Reactions occurring in ≥5% patients with non-progressive locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA as a single agent versus placebo as maintenance treatment (PARAMOUNT), respectively, following ALIMTA plus cisplatin induction therapy were anemia (4.8% vs 0.6%); fatigue (4.5% vs 0.6%); neutropenia (3.9% vs 0%); nausea (0.3% vs 0%); and mucositis/stomatitis (0.3% vs 0%). • All Grades Adverse Reactions occurring in ≥5% patients with non-progressive locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA as a single agent versus placebo as maintenance treatment (PARAMOUNT), respectively, following ALIMTA plus cisplatin induction therapy were fatigue (18% vs 11%); anemia (15% vs 4.8%); nausea (12% vs 2.4%); neutropenia (9% vs 0.6%); vomiting (6% vs 1.8%); mucositis/stomatitis (5% vs 2.4%); and edema (5% vs 3.6%). The following additional Grade 3 or 4 adverse reactions were observed more frequently in the ALIMTA arm. • Incidence 1% to <5%: thrombocytopenia, febrile neutropenia • Incidence <1%: ventricular tachycardia, syncope, pain, gastrointestinal obstruction, depression, renal failure, pulmonary embolism Treatment of Recurrent Disease After Prior Chemotherapy The safety of ALIMTA was evaluated in Study JMEI, a randomized (1:1), open-label, active-controlled trial conducted in patients who had progressed following platinum-based chemotherapy. Patients received ALIMTA 500 mg/m2 intravenously or docetaxel 75 mg/m2 intravenously on Day 1 of each 21-day cycle. All patients on the ALIMTA arm received folic acid and vitamin B12 supplementation. Study JMEI excluded patients with an ECOG PS of 3 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to discontinue aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study. The data described below reflect exposure to ALIMTA in 265 patients in Study JMEI. Median age was 58 years (range 22 to 87 years); 73% of patients were men; 70% were White, 24% were Asian, 2.6% were Black or African American, 1.8% were Hispanic or Latino, and <2% were other ethnicities; 19% had an ECOG PS 0. Below shows the frequency and severity of adverse reactions (graded per NCI CTCAE version 2.0) reported in ≥5% of the 265 ALIMTA-treated patients in Study JMEI. Study JMEI is not designed to demonstrate a statistically significant reduction in adverse reaction rates for ALIMTA, as compared to the control arm, for any specified adverse reaction listed below. • Grade 3-4 Adverse Reactions occurring in ≥5% of fully supplemented patients receiving ALIMTA as a single agent versus docetaxel (JMEI), respectively, were neutropenia (5% vs 40%); fatigue (5% vs 5%); anemia (4% vs 4%); nausea (3% vs 2%); anorexia (2% vs 3%); vomiting (2% vs 1%); thrombocytopenia (2% vs 0%); increased ALT (2% vs 0%); alopecia (1% vs 2%); diarrhea (0% vs 3%); stomatitis/ pharyngitis (1% vs 1%); and increased AST (1% vs 0%). • All Grades Adverse Reactions of fully supplemented patients receiving ALIMTA as a single agent versus docetaxel (JMEI), respectively, were fatigue (34% vs 36%); nausea (31% vs 17%); anorexia (22% vs 24%); anemia (19% vs 22%); vomiting (16% vs 12%); stomatitis/pharyngitis (15% vs 17%); rash/desquamation (14% vs 6%); diarrhea (13% vs 24%); neutropenia (11% vs 45%); fever (8% vs 8%); thrombocytopenia (8% vs 1%); increased ALT (8% vs 1%); pruritis (7% vs 2%); increased AST (7% vs 1%); alopecia (6% vs 38%); and constipation (6% vs 4%). The following additional adverse reactions were observed in patients assigned to receive ALIMTA. • Incidence 1% to <5%: abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection, erythema multiforme, motor neuropathy, sensory neuropathy • Incidence <1%: supraventricular arrhythmias, renal failure DRUG INTERACTIONS Effects of Ibuprofen on Pemetrexed Ibuprofen increases exposure (AUC) of pemetrexed. In patients with creatinine clearance between 45 mL/min and 79 mL/min: • Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of ALIMTA. • Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided. USE IN SPECIFIC POPULATIONS Pregnancy

PARAMOUNT excluded patients with an ECOG PS of 2 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study.

Risk Summary Based on findings from animal studies and its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. There are no available data on ALIMTA use in pregnant women. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and malformations at doses lower than the recommended human dose of 500 mg/m2. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

ALIMTA® (pemetrexed for injection), for Intravenous Use

PM HCP BS ALLNSCLC 12MAR2019

Data Animal Data Pemetrexed was teratogenic in mice. Daily dosing of pemetrexed by intravenous injection to pregnant mice during the period of organogenesis increased the incidence of fetal malformations (cleft palate; protruding tongue; enlarged or misshaped kidney; and fused lumbar vertebra) at doses (based on BSA) 0.03 times the human dose of 500 mg/m2. At doses, based on BSA, greater than or equal to 0.0012 times the 500 mg/ m2 human dose, pemetrexed administration resulted in dose-dependent increases in developmental delays (incomplete ossification of talus and skull bone; and decreased fetal weight). Lactation Risk Summary There is no information regarding the presence of pemetrexed or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from ALIMTA, advise women not to breastfeed during treatment with ALIMTA and for one week after last dose. Females and Males of Reproductive Potential Contraception Females ALIMTA can cause fetal harm when administered to a pregnant woman. Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with ALIMTA for at least 6 months after the final dose of ALIMTA. Males Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with ALIMTA and for 3 months after the final dose. Infertility Males ALIMTA may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible. Pediatric Use The safety and effectiveness of ALIMTA in pediatric patients have not been established. The safety and pharmacokinetics of ALIMTA were evaluated in two clinical studies conducted in pediatric patients with recurrent solid tumors. ALIMTA was administered at doses ranging from 400 to 2480 mg/m2 intravenously over 10 minutes on Day 1 of a 21-day cycle to 32 pediatric patients with recurrent solid tumors in a dose-finding study. The maximum tolerated dose (MTD) was determined to be 1910 mg/m2 (60 mg/kg for patients <12 months old). ALIMTA was administered at the MTD every 21 days in an activity-estimating study enrolling 72 patients with relapsed or refractory osteosarcoma, Ewing sarcoma/peripheral primitive neural ectodermal tumor (PNET), rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, or non-brainstem high grade glioma. Patients in both studies received concomitant vitamin B12 and folic acid supplementation and dexamethasone. No tumor responses were observed. Adverse reactions observed in pediatric patients were similar to those observed in adults. Single-dose pharmacokinetics of ALIMTA administered at doses ranging from 400 to 2480 mg/m2 were evaluated in 22 patients (13 males and 9 females) age 4 to 18 years (average age 12 years). Pemetrexed exposure (AUC and Cmax) appeared to increase proportionally with dose. Average clearance (2.30 L/h/m2) and half-life (2.3 hours) were similar in pediatric patients compared to adults. Geriatric Use Of the 3,946 patients enrolled in clinical studies of ALIMTA, 34% were 65 and over and 4% were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. The incidences of Grade 3-4 anemia, fatigue, thrombocytopenia, hypertension, and neutropenia were higher in patients 65 years of age and older as compared to younger patients: in at least one of five randomized clinical trials. Patients with Renal Impairment ALIMTA is primarily excreted by the kidneys. Decreased renal function results in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function. No dose is recommended for patients with creatinine clearance less than 45 mL/min. Additional information can be found at www.Alimta.com

Marketed by: Lilly USA, LLC Indianapolis, IN 46285, USA Copyright © 2004, 2019, Eli Lilly and Company. All rights reserved. PM HCP BS ALLNSCLC 12MAR2019 ALIMTA® (pemetrexed for injection), for Intravenous Use

PM HCP BS ALLNSCLC 12MAR2019

MSP ARTÍCULO / DE REVISIÓN

TERAPIA DIRIGIDA PARA CÁNCER DE PULMÓN

PALABRAS CLAVE Inmunoterapia, cáncer de pulmón, terapias convencionales, inhibidores, tumores

KEYWORDS

Immunotherapy, lung cancer, conventional therapies, inhibitors, tumors

Revista Puertorriqueña de Medicina y Salud Pública

MSP ARTÍCULO / DE REVISIÓN

LUIS DELGADO, MD Hematólogo-Oncólogo Encargado de la Sección de Oncología y de Medicina Interna Hospital Oncológico Dr. Isaac González Martínez

RESUMEN l descubrimiento de los biomarcadores y de los llamados checkpoints en el tejido tumoral nos ha permitido identificar terapias que de acuerdo a diversos estudios están asociadas con un aumento en la sobrevida y mayor calidad en la vida de los pacientes con cáncer de pulmón. Asimismo, la inmunoterapia ha revolucionado nuestros protocolos de tratamientos. Con su llegada hemos logrado fortalecer al sistema inmunológico. Estas medicinas las podemos utilizar como agentes sencillos, en combinación con otras inmunoterapias y con terapias convencionales.

ABSTRACT The discovery of biomarkers and so-called checkpoints in tumor tissue has allowed us to identify therapies that, according to various studies, are associated with an increase in survival and a higher quality of life in patients with lung cancer. Likewise, immunotherapy has revolutionized our treatment protocols. With his arrival we have managed to strengthen the immune system. We can use these medicines as simple agents, in combination with other immunotherapies and with conventional therapies.

Revista Puertorriqueña de Medicina y Salud Pública

MSP ARTÍCULO / DE REVISIÓN Desde la década anterior han llegado grandes avances en el tratamiento en contra el cáncer del pulmón. El descubrimiento de los biomarcadores, EGFR, ALK. ROS1, BRAF y de los llamados checkpoints en el tejido tumoral nos ha permitido identificar terapias que están asociadas con un aumento en la sobrevida y mayor calidad en la vida de los pacientes con esta condición. El descubrimiento de mutaciones del gen EGFR, en el 2004, abrió la puerta a un nuevo mundo de terapias orales mucho más efectivas y más tolerables que la quimioterapia convencional, la cual, en casos avanzados, ofrecía una sobrevida menor a 12 meses. Ver tabla 1. De acuerdo a varios estudios la incidencia de la mutación del gen EGFR, varía de región a región en todo el mundo. Está presente en entre el 15 a 40% de los pacientes con cáncer de pulmón de células no pequeñas. La mayoría de las mutaciones en el EGFR son deleciones en el exón 19 y el exón 21 (L858R)). En estos pacientes con enfermedad avanzada, la terapia con inhibidores de la quinasa de tirosina (TKI), representan la primera línea de tratamiento e incluye medicamentos como gefitinib, erlotinib y afatinib, aunque estudios subsiguientes han demostrado que estas dos mutaciones tienen diferente susceptibilidad a los tratamientos con los TKI. Estudios retrospectivos sugieren que ciertas características, como etnicidad (asiáticos), género (ser mujer), histología (adenocarcinoma y bronquio alveolar) y ser no fumador, son predictores de una mejor respuesta a estas terapias. La primera generación de EGFR TKI incluye al gefitinib, medicamento aprobada en el 2015 y que al compararla con la quimioterapia con regímenes que incluían platino, no demostró una

diferencia significativa en la sobrevida total, (18.8 meses vs. 17,4 meses HR 0.90, 95%), pero si mostró una mejoría en la sobrevida libre de progresión, en aquellos pacientes con adenocarcinoma de pulmón que expresaban la mutación (9.5 vs. 6.3 meses). Los efectos más frecuentes incluyeron diarreas, erupciones en piel y alteración de la función hepática. Un estudio asiático (IPASS), que incluyó 1217 pacientes no fumadores, comparó gefitinib versus Carboplatin/ Paclitaxel y mostró beneficios en términos de progresión de la condición, para el grupo de gefitinib (74% vs. 81.7%), HR 0.74:95%. Al evaluar la respuesta, de acuerdo al status de mutaciones en el EGFR, se vio que los pacientes que recibieron gefitinib y expresaban dicha mutación, tenían un PFS significativamente mejor que aquellos que recibieron Paclitaxel/ Carboplatin (HR:0.48 p<0.0001). Los pacientes que no expresaron la mutación respondieron mejor a la quimioterapia, en comparación con gefitinib. Aunque la respuesta al tratamiento con inhibidores de EGFR es significativamente mayor, se ha detectado el surgimiento de resistencia adquirida y de Novo. Los mecanismos para la resistencia adquirida son variados. El primer mecanismo de resistencia descrito fue una nueva mutación de EGFR (T790M), la cual causa un cambio de treonina a metionina en la posición 790 en el dominio de la kinasa de tirosina EGFR. Este cambio produce una cadena más amplia en esta posición, que impide la interacción con la molécula del erlotinib y crea resistencia al fármaco. La segunda generación de TKI, y que se utiliza en aquellos pacientes que mostraron progresión a los TKI de primera línea, tienen un mecanismo diferente,

Revista Puertorriqueña de Medicina y Salud Pública

dirigido a superar la resistencia a los mecanismos de los TKI de primera línea (bloquea la actividad enzimática de los receptores ErbB). Incluye medicamentos como el Afatinib. Otras generaciones de EGFR TKI han sido incorporadas a nuestro formulario. El osimertinib, mostró en sus estudios iniciales actividad en la resistencia asociada a la mutación T790M. Estudios como el FLAURA reveló una reducción de un 54% en el riesgo de progresión o de muerte vs. la terapia estándar, la cual incluía otros TKI. La mediana en la sobrevida libre de progresión fue de 18.8 vs. 10.2 meses, favoreciendo a osimertinib. La duración de la terapia también fue mejor, 17.2 vs. 8.5 meses. Existe data que sugiere actividad del osimertinib en pacientes con metástasis a cerebro. Existen otras drogas como el Crizonitib, el Cerinitib y el Alectinib que son inhibidores del ALK (Anaplastic Lymphoma Kinase), que han demostrado superioridad sobre quimioterapias con Cisplatino para el tratamiento del cáncer pulmonar (NSCLC). Los genes asociados al ALK juegan un papel muy importante en el desarrollo del cerebro y se encuentran alterados en diferentes malignidades. En el 2007 se relacionó, por vez primera, la presencia de alteraciones ALK y el cáncer de pulmón. Aproximadamente entre un 4-5% de los pacientes con NSCLC presentan dicha alteración, tanto en la población asiática, como en la caucásica. Se han identificado más de 20 alteraciones en los genes ALK asociados al NSCLC. La más frecuentemente asociada es la conocida como EML4-ALK Crizotinib fue inicialmente aprobada por el FDA en el 2011, para el tratamiento de pacientes con NSCLC cuyos tumores fueron positivos para el

MSP ARTÍCULO / DE REVISIÓN

ALK. Varios estudios han demostrado beneficio clínico del crizotinib vs. terapia convencional. El estudio PROFILE 1007 demostró una tasa de respuesta (ORR) de 65% vs. 20% (pemetrexed o docetaxel), en pacientes que habían fallado a terapia con Cisplatin. En otro estudio, el PROFILE 1014, demostró beneficios, en términos de sobrevida libre de progresión y ORR, para los pacientes tratados con crizotinib vs. primera línea en base de platino (mediana de 10.9 vs. 7 meses). Además, se observó el control de las lesiones cerebrales, en aquellos pacientes con metástasis, que fueran positivos para mutaciones en el ALK. En el 2016 la FDA extendió la aprobación de este medicamento para pacientes con NSCLC que fueran ROS-1 positivos. Esta alteración está presente en aproximadamente 1-2% de los pacientes no fumadores, con adenocarcinoma de pulmón. Las terapias dirigidas para esta alteración han demostrado una sobrevida significativamente mejor que la terapia convencional. Se han detectado la coexistencia de diferentes alteraciones cromosómicas en algunos casos de NSCLC, lo cual hace vital, realizar las pruebas para la detección y poder establecer las líneas de tratamientos, de acuerdo a las mismas. Es importante la comunicación con los servicios de patología y con los especialistas que realizarán las biopsias, para obtener material suficiente que nos permita realizar dichas pruebas. Las terapias convencionales han sido de beneficio para los pacientes con NSCLC, pero con la llegada de las terapias dirigidas hemos logrado ofrecer una mejor repuesta clínica, con una calidad de vida superior, aunque no hemos abandonado las terapias convencionales.

En algunas ocasiones, continuamos utilizando combinaciones de estas terapias con anticuerpos monoclonales como el bevacizumab. Este fármaco bloquea los VEGF (vascular endotelial growth factor). Las células cancerosas producen una mayor cantidad de VEGF, lo cual le permite formar vasos sanguíneos que alimenten dichas células y promueven su crecimiento. Este medicamento bloquea ese mecanismo de proliferación tumoral. La FDA le otorgó, en el 2006, la aprobación al bevacizumab para el tratamiento de NSCLC, con histología no escamosa, basado en estudios que demostraron una sobrevida mayor cuando se añadía a las terapias convencionales con paclitaxel, Carboplatino o paclitaxel como agente sencillo. (median OS 12.3 vs. 10.3 meses, HR 0.80). Otros agentes como el Ramucirumab (inhibidor de angiogénesis) y el Necitumumab (afecta las células tumorales EGFR positivas) han sido aprobados por la FDA. Actualmente hemos añadido nuevas alternativas terapéuticas para el cáncer pulmonar. La inmunoterapia ha revolucionado nuestros protocolos de tratamientos. Con su llegada hemos logrado fortalecer al sistema inmunológico. Los inhibidores de los puntos de cotejo han demostrado respuestas clínicas significativas y duraderas en aquellos pacientes con NSCLC avanzado, en primera y segunda línea. Estas medicinas las podemos utilizar como agentes sencillos, en combinación con otras inmunoterapias y con terapias convencionales. Existen varios medicamentos de esta familia (Nivolumab, Pembrolizumab, Atezolizumab, Durvalumab).

El pembrol i z umab en combinación con quimioterapia ha demostrado mayor respuesta que la terapia convencional. Estudios sugieren que aquellos pacientes tratados con pembrolizunab y quimioterapia tenían una disminución de 51% en el riego de muerte que aquellos pacientes que recibieron solamente quimioterapia. Luego de 12 meses, un estimado de 69.2% estaban vivos vs. 49.4% en el grupo que solo recibió quimioterapia. Nivolumab, es un PD-1 inhibidor disponible en el mercado y su aprobación para el tratamiento de NSCLC, se basó en estudios que demostraron respuesta clínica significativa y duradera en pacientes en estadios avanzados como segunda línea de terapia. Su efectividad fue demostrada en estudios comparando su actividad vs. docetaxel. Aquellos pacientes tratados con Nivolumab sobrevivieron un promedio de 12.2 meses vs. 9.9 meses para aquellos tratados con docetaxel. Además 19% de los pacientes tratados experimentaron una respuesta total o parcial que duró un promedio de 17 meses vs. un 12% en aquellos tratados con docetaxel (duración 6 meses). El 17 de agosto de 2018, Nivolumab consiguió la aprobación para el tratamiento de ciertos pacientes de cáncer de pulmón de célula pequeña, previamente tratados. La decisión estuvo basada en los resultados de los estudios que demuestran beneficio clínico en términos de ORR y duración de respuesta. Hemos logrado grandes avances en el tratamiento de esta condición y de otras malignidades. Es cierto que aún nos falta mucho camino que recorrer, pero estamos optimistas y esperamos continuar descubriendo nuevos tratamientos que impacten positivamente la salud y calidad de vida de nuestra población.

Revista Puertorriqueña de Medicina y Salud Pública

MSP CASO CLÍNICO

CASO MULTIETIOLÓGICO DE PERICARDITIS AGUDA

a miopericarditis aguda es una respuesta inespecífica a una amplia variedad de etiologías que se manifiestan con inflamación del pericardio y del saco miocárdico del corazón1. Los criterios diagnósticos son dos de cuatro de estos síntomas, como dolor torácico, cambios en el electrocardiograma, derrame pericárdico y roce2. La prevalencia de pericarditis aguda se ha registrado en el 0,2% de los pacientes hospitalizados y el 5% de los ingresados en urgencias por dolor torácico no isquémico2. Hay muchas causas para la pericarditis, pero se documentan casos raros de pacientes con coxsackie y CMV (0,8%) en un paciente inmunocompetente como etiologías3.

Axel Santiago; 2Luis Acevedo; 3Alexis Otero; Fransciso Lafontaine; 5Ivan Cerezo

1 4

Family Medicine Residency Program, PGY2; Department of Medicine; 3 Department of Family Medicine, 4 Department of Internal Medicine, 5 Department of Cardiology 1 2

This study was approved by the PHSU IRB (Protocol Number 2002028255)

ABSTRACT Acute myopericarditis is a non-specific response to a wide variety of etiologies that manifest with inflammation of the pericardial and myocardial sac of the heart1. Diagnostic criteria are two of four of these symptoms such as chest pain, EKG changes, pericardial effusion and friction rub2. The prevalence of acute pericarditis has been recorded in 0.2% of hospitalized patients and 5% of admitted to the ED for non-ischemic chest pain2. There are many causes to pericarditis, but rare cases are documented of patients with both coxsackie and CMV (0.8%) in an immunocompetent patient as etiologies3.

Revista Puertorriqueña de Medicina y Salud Pública

MSP CASO CLÍNICO

Caso clínico: HPI: Un varón de 23 años acude al servicio de urgencias con consulta de dolor torácico súbito, opresivo, no irradiado en reposo, 10/10, acompañado de vómitos, SOB, diaforesis y escalofríos. Durante el examen físico, estuvo alerta y con dolor agudo. El examen fue anodino. Los laboratorios mostraron niveles elevados de troponina y CK-MB con un electrocardiograma que mostró elevaciones de ST difusas. El paciente fue llevado a cateterismo cardíaco de urgencia, el cual fue negativo y luego de los laboratorios correspondientes se realizó ecocardiograma, TAC abdominopélvico y colonoscopia con biopsia. Los laboratorios fueron compatibles con virus coxsackie tipo B y biopsia con citomegalovirus positivo. Historial médico anterior: Denegado. Condiciones Generales: Alerta, orientado y gravemente enfermo. Cardiovascular: RRR, ritmo regular, normal S1 y S2, sin fricción pericárdica Pulmones: CTAx2 Extremidades: Fuerza muscular 5/5 en extremidades superiores e inferiores. Troponinas: 20.400 ng / mL Tomografía computarizada de la cabeza del tórax sin contraste: Negativo TC abdominal con y sin contraste: Ganglios linfáticos perirrectales de tamaño patológico, eje corto posterolateral derecho de 1,2 cm, eje corto presacro izquierdo de 1,3 cm

e ilíaco común de 0,9 cm. Ganglios linfáticos retroperitoneales superficiales al eje corto de la VCI proximal que miden 0,8 cm y menores en la región retroaórtica retroperitoneal izquierda. Cateterismo cardíaco: Negativo, sin signos de CAD Ecocardiograma: No se observaron anomalías en el movimiento de la pared en reposo. El tamaño de la aurícula izquierda está en los límites superiores de lo normal. La fracción de eyección del ventrículo izquierdo es 65-70%. Panel viral: Coxsackie Tipo B + Informe de biopsia: Células reactivas al CMV con inflamación y necrosis focal Discusión del caso: Nuestro paciente tuvo una presentación compatible con miopericarditis, dolor torácico y elevaciones difusas del ST acompañadas de fiebre y síntomas gastrointestinales, con un cateterismo cardíaco negativo que motivó una TAC abdominopélvica más detallada en la que presentaba múltiples ganglios reactivos. Se realizó colonoscopia con biopsia y se observó masa de 10 cm. Los resultados de laboratorio revelaron coxsackie y los resultados de las biopsias fueron compatibles con la infección por CMV. En una persona joven competente, la infección por CMV implica un curso típico de la enfermedad similar a un síndrome similar a la mononucleosis autolimitada.

Revista Puertorriqueña de Medicina y Salud Pública

La infección rara vez ocasiona complicaciones graves de órganos específicos como gastrointestinales y cardiovasculares, se han reportado neurológicas2. Nuestro caso entra en una categoría aún más rara, debido a múltiples etiologías como coxsackie y CMV, en las que muy pocos casos se han reportado 0,8%. Un seguimiento multidisciplinario es importante porque los síntomas residuales pueden persistir en los pacientes. Ocasionalmente se pueden descubrir neoplasias malignas ocultas y se han descrito otras complicaciones graves asociadas a la infección por CMV, como shock cardiogénico, taponamiento o insuficiencia cardíaca aguda3. etiologías virales como diagnóstico diferencial de la miocarditis aguda3. Puntos de aprendizaje: . Se necesita un alto índice de sospecha para realizar el diagnóstico con prontitud e iniciar el tratamiento para disminuir las secuelas, la morbilidad y la mortalidad. . El tratamiento de la miopericarditis por CMV debe realizarse junto con la educación y el apoyo adecuados de otros proveedores de atención médica, como Cardiología y Oncología. . Como Médicos de Familia, el aspecto más importante es monitorear y tener un seguimiento periódico de este joven paciente y tener un enfoque multidisciplinario de manejo. Referencias: Kyto Villae (2005) from the source: h t t p s : //a c a d e m i c . o u p . c o m /c i d / article/40/5/683/3645472 Imazio, Massimo (2020) from the source: https://www.uptodate.com/contents/ clinical-manifestations-and-diagnosis-ofmyocarditis-in-adults Magno, Moacyr. (2016) from the source: https://bmcresnotes.biomedcentral.com/ articles/10.1186/s13104-016-2181-5 M T Kearney from the source: https:// pmj.bmj.com/content/77/903/4

Revista Puertorriqueña de Medicina y Salud Pública

MSP ARTÍCULO / ORIGINAL

INCIDENCIA DE CÁNCER DE TIROIDES EN PUERTO RICO Y EE. UU. POR GRUPO RACIAL / ÉTNICO

ABSTRACT Background: Puerto Rico has the highest incidence rate of thyroid cancer (TC) in the Americas and the third highest rate worldwide. The purpose of this study was to compare the burden of TC between the population of PR and United States (US) non-Hispanic Whites (NHW), non-Hispanic Blacks (NHB), and US Hispanics (USH) during the period 2011–2015.

papillary carcinoma (PTC), and other TC histologic types. Data was analyzed by sex, age groups, and histologic type. Racial/ethnic differences by sex, age, and histologic types were assessed using the Standardized Rate Ratio (SRR) and its 95% CI. Results: During the period 2011–2015 there were 5175 and 65,528 cases of TC diagnosed in PR and the US, respectively. The overall age-adjusted incidence rate of PTC was almost two-fold higher in PR than in the US (25.8/100,000 vs. 12.9/100,000). Among PR women, the incidence rate of PTC was 40.0/100,000 compared to 19.4/100,000 in US. PR women had 83% increased risk of being diagnosed with PTC than NHW women,

Methods: TC data for the period 2011–2015 was obtained from the Puerto Rico Central Cancer Registry (PRCCR) and the Surveillance Epidemiology and Ends Results Program (SEER) 18 Registries Research Data. TC was categorized in: Revista Puertorriqueña de Medicina y Salud Pública 40

a 2.25-fold increased risk than USH, and 3.45-fold increased risk than NHB women. For men, PR had 34% increased risk of being diagnosed with PTC than NHW men, 2.2- fold increased risk than USH men, and 3.2-fold higher risk than in NHB men. Conclusion: Further research is needed to understand this disparity in the island. This research should address the extent of overdiagnosis in PR, the role of health insurance status and insurance type, characteristics of the healthcare delivery system as well as the role of patient and environmental factors. Keywords: Puerto Rico, Hispanic, Thyroid Cancer, Overdiagnosis, Health disparities

ARTÍCULO / ORIGINAL

Guillermo Tortolero-Luna1,2* , Carlos R. Torres-Cintrón1, Mariela Alvarado-Ortiz1,3, Karen J. Ortiz-Ortiz1,2, Diego E. Zavala-Zegarra1 and Edna Mora-Piñero2,4 Afiliaciones:

Puerto Rico Central Cancer Registry, University of Puerto Rico Comprehensive Cancer Center, San Juan, Puerto Rico. guillermo.tortolero@upr.edu. 2 Division of Cancer Control and Population Sciences, University of Puerto Rico, Comprehensive Cancer Center, PO Box 70344, San Juan, PR, 00936-8344, Puerto Rico. guillermo.tortolero@upr.edu. 3 Puerto Rico Central Cancer Registry, University of Puerto Rico Comprehensive Cancer Center, San Juan, Puerto Rico. 4 Department of Social Sciences, Graduate School of 1

RESUMEN Background: Puerto Rico has Antecedentes: Puerto Rico tiene la tasa de incidencia más alta de cáncer de tiroides (CT) en las Américas y la tercera tasa más alta a nivel mundial. El propósito de este estudio fue comparar la carga de CT entre la población de Puerto Rico y los blancos no hispanos (NHW) de los Estados Unidos (EE. UU.), los negros no hispanos (NHB) y los hispanos de los EE. UU. (USH) durante el período 2011- 2015. Métodos: Los datos de CT para el período 2011-2015 se obtuvieron del Registro Central de Cáncer de Puerto Rico (PRCCR) y del Programa de Vigilancia de Epidemiología y Resultados Finales (SEER) 18 Registros de Datos de Investigación. El CT se clasificó en: carcinoma papilar (PTC) y otros

Public Health, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico. 5 Division of Cancer Control and Population Sciences, University of Puerto Rico, Comprehensive Cancer Center, PO Box 70344, San Juan, PR, 00936-8344, Puerto Rico. 6 Department of Surgery, School of Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico. PMID: 31253133 PMCID: PMC6599344 DOI: 10.1186/s12885-019-5854-3

tipos histológicos de CT. Los datos se analizaron por sexo, grupos de edad y tipo histológico. Las diferencias raciales / étnicas por sexo, edad y tipos histológicos se evaluaron utilizando la Razón de Tasas Estandarizadas (SRR) y su IC del 95%. Resultados: Durante el período 2011-2015 hubo 5175 y 65,528 casos de CT diagnosticados en PR y EE. UU., respectivamente. La tasa de incidencia global de PTC ajustada por edad fue casi dos veces mayor en PR que en los EE. UU. (25,8 / 100.000 frente a 12,9 / 100.000). Entre las mujeres de RP, la tasa de incidencia de PTC fue de 40,0 / 100.000 en comparación con 19,4 / 100.000 en EE. UU. Las mujeres con PR tenían un 83% más de riesgo de ser diagnosticadas con PTC que las mujeres NHW,

egún GLOBOCAN 2018 [1], Puerto Rico (PR) tiene la tasa de incidencia más alta de cáncer de tiroides (CT) en las Américas y la cuarta tasa más alta en todo el mundo, justo por debajo de la República de Corea, Chipre y Canadá. Considerando que, los Estados Unidos continentales (EE. UU.) ocupa el segundo lugar en las Américas y el séptimo en todo el mundo. En PR, el TC es el tercer cáncer principal en mujeres y el decimotercero en hombres, representando el 11,5 y el 2,5% de todos los cánceres diagnosticados en mujeres y hombres, respectivamente [2]. La tasa de incidencia general ajustada por edad de CT invasiva en los EE. UU. Para el período 2011-2015 fue de 14,4 / 100.000; mientras que en PR fue 27,3 / 100.000. Al igual que en otras poblaciones, en PR las tasas de mortalidad por cáncer de tiroides son muy bajas. La mortalidad general ajustada por edad de CT en PR para el

un riesgo 2,25 veces mayor que las mujeres USH y un riesgo 3,45 veces mayor que las mujeres NHB. Para los hombres, PR tenía un 34% más de riesgo de ser diagnosticado con PTC que los hombres NHW, un riesgo 2,2 veces mayor que los hombres USH y un riesgo 3,2 veces mayor que en los hombres NHB. Conclusión:se necesitan más investigaciones para comprender esta disparidad en la isla. Esta investigación debe abordar el alcance del sobrediagnóstico en las relaciones públicas, el papel del estado del seguro médico y el tipo de seguro, las características del sistema de prestación de atención médica, así como el papel del paciente y los factores ambientales. Palabras clave: disparidades en salud; Hispano; Sobrediagnóstico; Puerto Rico; Cáncer de tiroides

período 2011-2015 fue de 0,3 / 100.000. Además, durante el período de 1987 a 2015, las tasas de mortalidad por cáncer de tiroides disminuyeron un 1,2% por año en las mujeres y un 1,6% por año en los hombres. Un rápido aumento de la incidencia de CT en las últimas décadas está bien documentado en todo el mundo [3-7]. Esta tendencia se ha observado tanto en hombres como en mujeres; sin embargo, las tasas de incidencia de CT han sido consistentemente más altas en mujeres que en hombres y el aumento se ha restringido al cáncer papilar de tiroides (PTC) [5, 8-10]. En los EE. UU., CT es el cáncer que aumenta más rápidamente tanto en mujeres como en hombres. La incidencia de CT en los EE. UU. aumentó de 10,9 / 100.000 en 2000 a 21,6 / 100.000 en 2015 en mujeres y de 3,8 / 100.000 a 7,5 / 100.000 en hombres (Programa de Vigilancia, Epidemiología y Resultados Finales (SEER) SEER * Stat Database: Revista Puertorriqueña de Medicina y Salud Pública

MSP ARTÍCULO / ORIGINAL Incidence - SEER 18 Regs). De manera similar, en PR, CT fue el cáncer que aumentó más rápidamente durante el período 2000 a 2015; Las tasas de CT aumentaron de 7,7 a 50,7 / 100.000 en mujeres y de 2,4 a 13,7 / 100.000 en hombres (PRCCR, 2018). La tendencia creciente en la incidencia de CT invasiva se atribuye en parte al sobrediagnóstico de lesiones pequeñas debido a: el uso cada vez mayor de nuevas modalidades de diagnóstico [11-17]; aumentar la vigilancia médica [11-13, 18]; y aumentar el acceso a los servicios de salud [19-21]. Vaccarella et al. [22] estimaron que durante el período 2003-2007, en países industrializados seleccionados, del 51 al 83% de los casos diagnosticados en mujeres y del 3 al 59% de los casos diagnosticados en hombres, podrían atribuirse a un sobrediagnóstico. Además del sobrediagnóstico, otros factores que se encuentran asociados con el riesgo de CT incluyen: exposición a la radiación por tomografías computarizadas; factores nutricionales, menstruales y reproductivos; obesidad [23]; resistencia a la insulina; inactividad física [24]; y un nivel socioeconómico alto [19, 21, 25]. Se informan diferencias raciales / étnicas en la incidencia de CT en los EE. UU. y otras poblaciones [26-31]. En los EE. UU., se observan tasas de incidencia más altas de CT entre los blancos no hispanos (NHW); tasas intermedias entre los hispanos de EE. UU. (USH); y el más bajo entre los negros no hispanos (NHB). Los puertorriqueños constituyen la segunda población hispana más grande de los EE. UU. Con más de 4 millones que viven en los EE. UU. continentales y 3,5 millones en el Estado Libre Asociado de PR. En Puerto Rico, el 99% de la población se auto identifican como hispanos de los cuales el 97% son

nacidos en PR; las mujeres representan el 52,5% de la población; y la edad media de la población es de 40 años [32, 33]. El cuarenta y cinco por ciento de la población de PR vive por debajo de la línea de pobreza federal, en comparación con el 16% en EE. UU. Esto es dos veces más alto que el porcentaje reportado en el estado más pobre de los EE. UU., Mississippi (22%). El ingreso anual medio en PR es de $19.630 (US $ 51.915) y el 60% (US $ 17%) tiene un ingreso familiar de <$ 25.000 [32, 33]. Hasta donde sabemos, ningún estudio ha comparado la incidencia de CT entre los residentes de PR y los grupos raciales / étnicos de EE. UU. Por lo tanto, el propósito de este análisis es comparar por primera vez la incidencia de CT en Puerto Rico con la observada en NHW, NHB y USH por edad y sexo, utilizando datos del Registro Central de Cáncer de Puerto Rico (PRCCR) y el Programa de Vigilancia, Epidemiología y Resultados Finales (SEER) para el período 2011-2015, el último período disponible para ambas fuentes de datos. Métodos Obtuvimos datos de incidencia de CT para el período 2011-2015 del PRCCR [2] y la base de datos de registros SEER 18 [34]. El Programa de Vigilancia, Epidemiología y Resultados Finales-18 (SEER-18) del Instituto Nacional del Cáncer (NCI) recopila datos de incidencia de cáncer de registros basados en la población. El archivo incluye información de 18 registros poblacionales de alta calidad (SEER-18: Alaska, Connecticut, Detroit, Atlanta, Greater Georgia, Rural Georgia, San Francisco-Oakland y San Jose-Monterey California, Greater California, Hawaii, Iowa, Kentucky , Los Ángeles California, Luisiana, Nuevo México, Nueva

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Jersey, Washington [región de Seattle y Puget Sound] y Utah) que cubren aproximadamente el 34,6% de la población de EE. UU. (31,9% de blancos, 30,0% de afroamericanos, 44,0% hispanos, 49,3% de los indios americanos y nativos de Alaska, el 57,5% de los asiáticos y el 68,5% de los hawaianos / isleños del Pacífico). Los casos de cáncer de tiroides diagnosticados durante 2011-2015 se determinaron a partir del archivo de incidencia de cáncer SEER, que proporciona información demográfica y de diagnóstico de cáncer para cada caso. Los datos se extraen de los registros médicos en los centros de atención médica, incluyendo hospitales, consultorios médicos y laboratorios de patología, siguiendo los estándares de datos de la Asociación Norteamericana de Registros Centrales del Cáncer (NAACCR) [1]. Desde 1997, el PRCCR está financiado por el Programa Nacional de Registros de Cáncer (NPCR) de los CDC. Los datos de este análisis incluyen solamente casos c o n f ir m a d o s microscópicamente con edad y sexo conocidos. El PRCCR tiene la certificación de oro de la NAACCR y está reconocido como Registro de vigilancia por el NPCR. El PRCCR utiliza los estándares de codificación del programa SEER y NAACCR. Se utilizaron los criterios especificados en la tercera revisión de la Clasificación Internacional de Enfermedades para Oncología (CIE-O-3) para seleccionar los casos de CT invasores para el período 2011 a 2015. A los efectos del estudio, clasificamos los casos de CT invasivos en dos subgrupos histológicos: carcinoma papilar de tiroides (PTC; códigos ICD-O-3 8050, 8260, 8340–8341, 8343–8344, 8350) y “otros” tipos histológicos de CT. (Otros TC; incluidos todos los demás códigos

ARTÍCULO / ORIGINAL de TC ICD-O-3). Las tasas de incidencia brutas y ajustadas por edad se calcularon utilizando el software SEER * - Stat v.8.3.5. [35]. Los datos se analizaron por sexo, grupos de edad, grupo racial / étnico y tipo histológico. Se compararon las tasas de incidencia de CT invasiva para el período 2011-2015 en Puerto Rico y EE. UU. Los denominadores de las tasas de incidencia de PR fueron estimaciones de población específicas por sexo, basadas en la población de cosecha de 2016 de la Oficina del Censo de EE. UU. [36]. Las tasas de incidencia anual por 100.000 habitantes se ajustaron por edad mediante el método directo a la población estándar de los EE. UU. de 2000, utilizando 19 categorías de edad. Evaluamos las diferencias raciales / étnicas por sexo, utilizando la Razón de Tasas Estandarizadas (SRR) y su IC del 95%. Los SRR se calcularon utilizando el software Stata v.15 [37]. Cuando se notificaron menos de 6 casos, las cifras y las tasas no se presentan debido a la posibilidad de estimaciones estadísticamente poco fiables y para proteger la confidencialidad [1]. La Junta de Revisión Institucional del Recinto de Ciencias Médicas de la Universidad de Puerto Rico aprobó el estudio. Resultados Durante el período 2011-2015, se notificaron 5175 casos incidentes de cáncer de tiroides al PRCCR. El 81% (n = 4208) de los casos fueron mujeres y solo el 19% (n = 967) fueron hombres; El 45% de los casos se diagnosticaron en la población de 40 a 59 años; y el 94% de los casos (n = 4.877) fueron carcinomas papilares de tiroides (PTC). En comparación, durante el mismo período, se diagnosticaron 65.528 casos de CT en los EE. UU., 75% (n = 49.373) de los cuales se diagnosticaron

en mujeres, 44% se diagnosticaron en hombres y mujeres de 40 a 59 años y 90% (n = 58.665) se clasificaron como PTC. Dada la pequeña proporción de casos clasificados como “otros” tipos histológicos de CT, nuestro análisis se enfoca solo en PTC. La figura 1 muestra las tasas de incidencia de CPT ajustadas por edad en Puerto Rico y EE.UU. (población estándar de EE.UU. de 2000) estratificadas por sexo. La tasa de incidencia general ajustada por edad del PTC fue casi dos veces mayor en Puerto Rico que en EE.UU. (25,8/100.000 frente a 12,9/100.000). Entre las mujeres de Puerto Rico , la tasa de incidencia de CPT fue de 40,0/100.000 frente a 19,4/100.000 en EE.UU.; mientras que en los hombres fue de 9,8 y 6,2/100.000, respectivamente. Entre las mujeres de Puerto Rico y de EE.UU., las tasas de incidencia de CTP específicas por edad aumentaron rápidamente con la edad, alcanzando un máximo a la edad de 40-59 años (PR: 75,5 frente a EE.UU.: 33,7/100.000 mujeres), disminuyendo bruscamente a partir de entonces (Fig. 2). Entre los hombres de la RP y de EE.UU., las tasas específicas de CPT por edad alcanzaron su máximo a una edad una década mayor que en las mujeres, 60-79 años (PR: 20,7 vs. EE.UU.: 14,8 /100.000). Las tasas de incidencia de CPT en mujeres y hombres que viven en Puerto Rico fueron superiores a las registradas en otros grupos raciales/étnicos de EE.UU. Entre las mujeres, la Puerto Rico tuvo la mayor tasa de incidencia de CPT ajustada por edad (40,0/100.000), seguida de la NHW (21,8/100.000), la USH (17,8/100.000) y la NHB (11,6/100.000) (Fig. 3). Del mismo modo, entre los hombres, Puerto Rico tuvo la mayor tasa de incidencia de PTC (9,8/100.000), seguida por la RSH

(7,3/100.000), la USH (4,5/100.000) y el BNH (3,1/100.000) (Fig. 3). Las tasas de incidencia de CPT ajustadas a la edad por sexo, grupo de edad y raza/etnia se presentan en las Figs. 4 y 5. En comparación con las mujeres de otros grupos raciales/étnicos, las mujeres de Puerto Rico tuvieron las tasas de incidencia más altas; mientras que las mujeres de la NHB tuvieron las tasas de incidencia más bajas de PTC. Estas diferencias raciales/étnicas se observaron en todos los grupos de edad. Entre las mujeres PR, NHW y USH, las tasas aumentaron rápidamente con la edad, alcanzando un máximo a la edad de 40-59 años (75,5, 37,1 y 30,7/100.000, respectivamente) disminuyendo rápidamente a partir de entonces. Mientras que entre las mujeres NHB, las tasas aumentaron de forma constante con la edad, alcanzando un máximo a la edad de 60-79 años (22,2/100.000), disminuyendo a partir de entonces (Fig. 4a). Al igual que las mujeres de Puerto Rico , los hombres de Puerto Rico tuvieron las tasas de incidencia más altas de PTC; mientras que los hombres de la NHB tuvieron la tasa más baja. Estas diferencias raciales/ étnicas se observaron en todos los grupos de edad. En los hombres, todos los grupos raciales/étnicos mostraron un patrón similar con las tasas de incidencia de CTP que aumentaron con la edad, alcanzaron su máximo a los 60-79 años y disminuyeron en los grupos de mayor edad (Fig. 4b). La tabla 1 muestra la razón de tasas estandarizada (SRR) y sus intervalos de confianza del 95% que evalúan la diferencia en el riesgo de ser diagnosticado de PCT entre los grupos de raza/etnia Puerto Rico y USA por sexo y grupo de edad. Las mujeres de Puerto Rico tenían un riesgo un 83%

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MSP ARTÍCULO / ORIGINAL mayor de ser diagnosticadas de PCT que las mujeres de NHW (SRR = 1,83; IC 95% 1,77-1,90), un riesgo 2,25 veces mayor que las de USH (SRR = 2,25; IC 95% 2,17- 2,34), y un riesgo 3,45 veces mayor que las de NHB (SRR = 3,45; IC 95% 3,29-3,62) (Tabla 1). Se observaron diferencias similares en los hombres: donde los de Puerto Rico tenían un riesgo un 34% mayor de ser diagnosticados de CPT que los de la NHW (SRR = 1,34; IC del 95%: 1,25-1,44), un riesgo 2,2 veces mayor que el de la USH (SRR = 2,19; IC del 95%: 2,01-2,38) y un riesgo 3,2 veces mayor que el de la NHB (SRR = 3,22; IC del 95%: 2,90-3,57) (Cuadro 1). Discusión Hasta donde sabemos, este es el primer estudio que compara las tasas de incidencia de CTP entre la población de Puerto Rico y los grupos raciales/étnicos de EE.UU. (NHW, NHB y USH). En Puerto Rico, en consonancia con los estudios realizados en todo el mundo, la mayoría de los casos de CT se clasificaron como PTC (94% de los casos). Nuestro estudio mostró diferencias significativas en la incidencia de CTP entre la población de la isla y los grupos raciales/étnicos de EE.UU. Las tasas de incidencia de CTP ajustadas a la edad fueron más altas en los residentes de Puerto Rico, seguidos de NHW, USH y NHB; más altas en las mujeres que en los hombres; y más altas entre los que tenían entre 40 y 59 años. Las diferencias entre los residentes de Puerto Rico y los grupos raciales/ étnicos de EE.UU. (NHW, USH y NHB), fueron estadísticamente significativas (p < 0,05). Estas diferencias se observaron tanto en mujeres como en hombres, y persistieron en todos los grupos de edad. Aunque no se presentaron los resultados sobre "otros" tipos histológicos de CT, nuestros datos no mostraron diferencias

en la incidencia global de todos los "otros" tipos histológicos de CT entre Puerto Rico y EE.UU. (1,5/ 100.000 frente a 1,5/100.000), respectivamente. Asimismo, no se observaron diferencias de sexo o edad en la incidencia de "otros" tipos histológicos de CT entre Puerto Rico y EE.UU. Se desconocen las razones de las diferencias observadas en las tasas de incidencia de CPT entre los residentes de Puerto Rico y los grupos raciales/étnicos de EE.UU. y es probable que sean multifactoriales. Puerto Rico comparte una alta carga de algunos de los estilos de vida y factores ambientales que se han asociado con el CT. Con base en los datos del Sistema de Vigilancia de Factores de Riesgo del Comportamiento de 2016 y el Sistema de Vigilancia de la Diabetes de 2015 de los Estados Unidos, los residentes de Puerto Rico tienen mayores tasas de prevalencia de diabetes (PR 14,7% vs. US 9,1%); sobrepeso y obesidad (PR 66. 5% vs. US 65.2%); menores tasas de actividad física (150 min/semana: PR 34.1% vs. US 51.3%); bajo consumo de frutas (< 1 por día: PR 55.6% vs. US 39.7%) y bajo consumo de vegetales (< 1 por día PR 24.5% vs. US 22.1%) [38]. Además, un estudio realizado entre adultos de 21 a 79 años residentes en el área metropolitana de San Juan mostró una alta prevalencia de síndrome metabólico (43,3%) entre la población de estudio [39]. La tasa de prevalencia del síndrome metabólico fue sólo ligeramente superior en los hombres (45,3%) que en las mujeres (42,2%) y ligeramente superior en los residentes de Puerto Rico que en la población adulta de EE.UU. [39]. Sin embargo, la relación entre estos factores y el riesgo de CPT no está clara. No obstante, al igual que en otras poblaciones, es poco probable que estos factores puedan explicar

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el rápido aumento observado en las últimas tres décadas en la incidencia del PTC en Puerto Rico y en todo el mundo. Tampoco, estos factores explican las diferencias de sexo y edad observadas en la isla y en todo el mundo. Al igual que en otras poblaciones, las elevadas tasas de incidencia de CPT observadas en mujeres y hombres de Puerto Rico, podrían atribuirse a un mejor acceso a la atención médica, a la introducción de nuevas tecnologías de diagnóstico y al aumento de la vigilancia médica, lo que da lugar a un sobrediagnóstico y a un tratamiento excesivo de las lesiones indolentes subclínicas [15, 18, 22, 40]. Para el periodo 2003-2007, Vaccarella et al. estimaron que el sobrediagnóstico representaba el 90% de los casos en Corea del Sur de los casos diagnosticados en mujeres; entre el 70 y el 80% de los casos en Estados Unidos, Italia, Francia y Australia; y el 50% de los casos en Japón, los países nórdicos, Inglaterra y Escocia; mientras que, en los hombres, el sobrediagnóstico representaba el 70% de los casos en Francia, Italia y Corea del Sur; el 45% en Estados Unidos y Australia; y menos del 25% en los demás países analizados [16]. El sobrediagnóstico es el resultado de múltiples factores, como el paciente, el proveedor, el sistema sanitario y el entorno. Estos factores incluyen las características sociodemográficas del paciente, el acceso a la asistencia sanitaria, la calidad del registro del cáncer, la influencia de los medios de comunicación, los incentivos económicos y médico-legales y la educación médica, entre otros; sin embargo, la mayoría de las investigaciones se han centrado en los factores individuales [41]. Si el sobrediagnóstico fuera el principal impulsor de las diferencias observadas

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en la incidencia del CPT entre la población de Puerto Rico, y la población de grupos raciales/étnicos de EE.UU., esperaríamos observar una mayor prevalencia de aquellos factores que conducen al sobrediagnóstico en Puerto Rico, que en EE.UU. La contribución de la cobertura del seguro médico y del acceso a la asistencia sanitaria al sobrediagnóstico y al sobretratamiento está bien documentada [42]. Massachusetts tiene una de las coberturas de seguro médico más altas de los Estados Unidos. El gobierno de Puerto Rico, al igual que el Estado de Massachusetts, implementó un Plan de Salud del Gobierno (GHP) en 1994 como un programa administrado por el gobierno que proporciona servicios de salud a los ciudadanos indigentes y empobrecidos de Puerto Rico que viven por debajo o en el 250% del nivel de pobreza federal. En 2016, el 94% de la población de la isla y el 97% de la población de Massachusetts tenían cobertura de seguro médico [42, 43]. En Puerto Rico, aproximadamente, el 49% de la población asegurada recibe cobertura sanitaria a través de Medicaid (Medicaid/CHIP y GHP) [32]. Massachusetts, el estado con la mayor cobertura de seguro médico en los EE.UU., tenía la tasa global más alta de CT (20,4/100.000) y la tasa de CT masculina (10,7/100.000) y la segunda tasa más alta de CT femenina (30,2/100.000) en los EE.UU. [44]. La expansión de Medicaid se ha asociado a un mayor acceso a la asistencia sanitaria y a la utilización de los servicios. Massachusetts experimentó un aumento en la utilización de servicios y procedimientos quirúrgicos [42, 45-48], incluyendo un aumento del 26% en la tasa de pacientes sometidos a

tiroidectomía, un aumento del 22% en la tasa de disección de cuello, un aumento del 15% en la tasa de ingresos por cáncer de páncreas y un aumento del 67% en la tasa de resecciones quirúrgicas por cáncer de páncreas [42, 47]. El aumento a lo largo del tiempo en la utilización de estos procedimientos se observó tanto en pacientes blancos como no blancos, pero el aumento fue más rápido en los pacientes no blancos, lo que apoya el papel del estado del seguro médico en el sobrediagnóstico y el sobretratamiento y en la reducción de las diferencias raciales/étnicas y socioeconómicas en el acceso a la atención [42]. Otros factores potenciales que apoyan el papel del sobrediagnóstico para explicar las diferencias en la incidencia del PTC entre la población de Puerto Rico y los grupos raciales/étnicos de EE.UU., incluyen: 1) el mayor porcentaje de lesiones de PTC diagnosticadas en una etapa localizada en Puerto Rico (76,3%) en comparación con los Estados Unidos (69,8%); 2) el gran porcentaje de lesiones pequeñas reportadas al PRCCR entre 2008 y 2015 (53% de las lesiones ≤1 cm y 33% de las lesiones de 1,1 a 4 cm); y la gran proporción de casos diagnosticados mediante procedimientos guiados por ultrasonido (> 47%) (SEER 18 Regs, Puerto Rico Central Cancer Registry 2018). Se ha encontrado que una mayor posición socioeconómica (PSE) está asociada con el riesgo de CT, lo que sugiere que la PSE podría ser una medida sustitutiva de la situación de seguro, el acceso a la atención sanitaria, el nivel educativo y otros comportamientos saludables [19, 49]. Sin embargo, utilizando el índice de posición socioeconómica (SEP) desarrollado por el PRCCR [50], observamos una relación en

forma de "U" entre el SES y la incidencia de CT en Puerto Rico, observándose mayores tasas de incidencia en los niveles más bajos (I) y más altos (IV y V) del índice SEP (Fig. 5). Sin embargo, estas diferencias no fueron estadísticamente significativas (p > 0,05). La falta de relación entre el NSE y la incidencia de CPT entre los residentes de Puerto Rico podría explicarse por la cobertura casi universal del seguro de salud en la isla, que conduce a un mayor acceso a la atención sanitaria que aumenta la oportunidad de un diagnóstico de CPT y resulta en el sobrediagnóstico y el sobretratamiento. Además, entre los sobrevivientes de cáncer en Puerto Rico, el CT fue el cuarto tipo de cáncer más común, con un 7,21% (4723 casos). Aproximadamente, el 83% (3905) de los sobrevivientes de cáncer de tiroides eran mujeres [51]. Entre las mujeres, el cáncer de tiroides representó el 12,3% de todos los sobrevivientes de cáncer femenino [51]. Del mismo modo, en los Estados Unidos, los sobrevivientes de CT representaron el 14,6% de todos los supervivientes de cáncer. Las mujeres representaron el 78,3% (n = 630.660) de los supervivientes de cáncer femeninos y representaron el 7,7% de todos los supervivientes de cáncer femeninos [52]. Por último, se estima que el coste de la atención al CT en los Estados Unidos alcanzará los 18.000-21.000 millones de dólares en 2019 [53]. Los datos recientes sugieren que el aumento de la incidencia y el sobrediagnóstico de la CT pueden estar empezando a frenar. Desde aproximadamente 2015, se han realizado diversos esfuerzos para reducir el papel del sobrediagnóstico en la tendencia al aumento de la CT. Estos esfuerzos abarcan desde la educación pública hasta los cambios en las directrices y el diagnóstico [54]. En 2015, la Asociación Americana de Tiroides (ATA) recomendó un enfoque de estratificación de riesgos para el uso de biopsias por aspiración con aguja fina de nódulos tiroideos. Estas directrices desaconsejan la biopsia de nódulos de menos de 1 cm de tamaño y, por primera vez, las directrices de la ATA reconocen la vigilancia activa como una estrategia de gestión alternativa para los pacientes con cáncer de tiroides de bajo riesgo [54]. No obstante, se reconoce que es probable que el cambio de las conductas Revista Puertorriqueña de Medicina y Salud Pública

MSP ARTÍCULO / ORIGINAL clínicas de los médicos sea difícil y lento; por lo tanto, estos esfuerzos requerirán el desarrollo y la implementación de intervenciones multinivel basadas en la evidencia para continuar con esta tendencia invertida de manera más rápida [55]. Además, en 2017 el Grupo de Trabajo de Servicios Preventivos de los Estados Unidos (USPSTF) recomendó no realizar el cribado de CT en individuos asintomáticos, una recomendación de grado "D" [54]. Dos estudios recientes concluyeron que, desde el punto de vista del valor, la vigilancia activa era superior a la cirugía; mientras que un tercer estudio descubrió que la rentabilidad depende de la variabilidad de la perspectiva del paciente sobre la calidad de vida [54]. Conclusión Este es el primer estudio que compara las tasas de incidencia de CTP entre la población de Puerto Rico y los grupos raciales/étnicos de EE.UU. (NHW, NHB y USH). En Puerto Rico, en consonancia con otros estudios realizados, la mayoría de los casos de CT fueron categorizados como PTC (94% de los casos). Nuestros hallazgos mostraron diferencias significativas en la incidencia de CTP entre la población de Puerto Rico y los grupos raciales/ étnicos de EE.UU. Al igual que otros estudios, el sobrediagnóstico parece explicar las altas tasas de incidencia. Es necesario realizar más investigaciones para abordar los posibles factores de riesgo del PTC/TC que podrían explicar esta disparidad en la isla, incluyendo: la evaluación del alcance del sobrediagnóstico en Puerto Rico, el papel del estado del seguro de salud y el tipo de seguro (GHP, seguro privado y no asegurado), las características del sistema de prestación de servicios de salud y los factores ambientales e individuales. Abreviaturas ATA: American Thyroid Association; GHP: Government Health Plan; ICD-O3: International Classification of Diseases for Oncology 3rd Edition; NAACCR: North American Association of Central Cancer Registries; NHB: NonHispanic Blacks; NHW: Non-Hispanic Whites; NPCR: Programa Nacional de Registros de Cáncer; PR: Puerto Rico; PRCCR: Puerto Rico Central Cancer Registry; 46

PTC: Papillary thyroid cancer; SEER: Sur veillance Epidemiolo gy and End Results Program; SES: Estatus socioeconómico; SRR: Standardized rate ratio; CT: Thyroid cancer; US: Estados Unidos; USH: US Hispanics; USPSTF: United States Preventive Services Task Force. Agradecimientos Ninguno. Contribuciones de los autores GTL contribuyó sustancialmente a la concepción y el diseño de este estudio, a la recopilación, el análisis y la interpretación de los datos, y redactó el manuscrito. CTC ha hecho contribuciones sustanciales a la concepción y el diseño de este estudio, a la recogida, análisis e interpretación de los datos, y revisado críticamente el manuscrito. MAO participó en la concepción y el diseño de este estudio, en la recogida, el análisis y la interpretación de los datos, y revisó críticamente el manuscrito. KJO participó en la concepción y el diseño de este estudio, en la recopilación, el análisis y la interpretación de los datos, y revisó críticamente el manuscrito. DZZ participó en la concepción y el diseño de este estudio, la interpretación de los datos y la revisión crítica del manuscrito. EMP participó en la interpretación de los datos, aportó una visión clínica médica y revisó críticamente el manuscrito. Todos los autores leyeron y aprobaron el manuscrito final. Financiamiento Este trabajo fue apoyado por fondos federales del Programa Nacional de Registros de Cáncer (NPCR número de concesión 6NU58DP006318) al Registro Central de Cáncer de Puerto Rico en el Centro Integral de Cáncer de la Universidad de Puerto Rico y del Instituto Nacional de Salud al Programa de Investigación de Oncología Comunitaria del Instituto Nacional de Cáncer (NCORP) en Puerto Rico (número de concesión 5UG1CA189862). El NPCR apoya la recopilación y el análisis de datos. El NCORP apoya el análisis de datos. Disponibilidad de datos y materiales Los conjuntos de datos generados y analizados durante el presente estudio

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no están disponibles al público debido a la política de confidencialidad del Registro Central de Cáncer de Puerto Rico, pero están disponibles a través del autor correspondiente si se solicita razonablemente. Aprobación ética y consentimiento para participar La Junta de Revisión Institucional del Recinto de Ciencias Médicas de la Universidad de Puerto Rico ha aprobado la realización de este análisis. El consentimiento de participación se considera innecesario debido al análisis retrospectivo de los datos. Consentimiento para la publicación No procede. Intereses contrapuestos Los autores declaran que no tienen intereses contrapuestos. Detalles del autor 1 Registro Central de Cáncer de Puerto Rico, Centro Oncológico Integral de la Universidad de Puerto Rico, San Juan, Puerto Rico. 2 División de Control del Cáncer y Ciencias de la Población, Universidad de Puerto Rico, Centro Oncológico Integral, PO Box 70344, San Juan, PR 00936-8344, Puerto Rico. 3 Depar tamento de Ciencias Sociales, Escuela Graduada de Salud Pública, Recinto de Ciencias Médicas, Universidad de Puerto Rico, San Juan, Puerto Rico. 4 Departamento de Cirugía, Escuela de Medicina, Recinto de Ciencias Médicas, Universidad de Puerto Rico, San Juan, Puerto Rico. Recibido: 4 de enero de 2019 Aceptado: 19 de junio de 2019 Publicado en línea: 28 de junio de 2019 Nota del editor Springer Nature se mantiene neutral con respecto a las reclamaciones jurisdiccionales en los mapas publicados y las afiliaciones institucionales.

ARTÍCULO / ORIGINAL Referencias 1. Ferlay JS, Bray HR, Forman F, Mathers D, C. Parkin D. GLOBOCAN 2018: estimated cancer incidence, mortality, prevalence and disabilityadjusted life years (DALYs) worldwide in; 2018. 2. Puerto Rico Central Cancer Registry. Incidence Case File (April 2, 2018). 2018. 3. Pellegriti G, Frasca F, Regalbuto C, Squatrito S, Vigneri R. Worldwide increasing incidence of thyroid cancer: update on epidemiology and risk factors. J Cancer Epidemiol. 2013. 4. Reitzel LR, Nguyen N, Li N, Xu L, Regan SD, Sturgis EM. Trends in thyroid Cancer incidence in Texas from 1995 to 2008 by socioeconomic status and race/ethnicit y. Thyroid [Internet]. 2014;24(3):556–67. Available from:. ht tps:// doi.org/10.1089/ thy.2013.0284. 5. La Vecchia C, Malvezzi M, Bosetti C, Garavello W, Bertuccio P, Levi F, et al. Thyroid cancer mortality and incidence: A global overview. Int J Cancer. 2015;136(9):2187–95. 6. Horn-Ross, Pamela L. Lichtensztajn, Daphne Y. Clarke, Cristina A. Dosiou, Chr ysoula. Oakley- Girvan, Ingrid. Reynolds, Peggy. Gomez, Scarlett L. Nelson DO. Continued rapid increase in thyroid cancer incidence in California: trends by patient, tumor, and neighborhood characteristics. Cancer Epidemiol Biomark Prev 2014;23(6):1067–1079. 7. Davies L, Welch HG. Current thyroid cancer trends in the United States. JAMA Otolaryngol Head Neck Surg [Internet]. 2014 Apr [cited 2015 Oct 3]; 140(4):317–322. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 24557566. 8. Pandeya N, M c Le o d DS, Balasubramaniam K, Baade PD, Youl PH, Bain CJ, et al. Increasing thyroid cancer incidence in Queensland, Australia 1982-2008 - true increase or overdiagnosis. Clin Endocrinol. 2016;84(2):257–64. 9. Davies L, Welch HG. Increasing Incidence of Thyroid Cancer in the United States, 1973-2002. JAMA [Internet]. 2006 May 10 [cited 2015 Oct 20];295(18): 2164. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/16684987. 10. Bray F, Ferlay J, Soerjomataram

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MSP ARTÍCULO / ORIGINAL Available from: http://www.ncbi.nlm. nih.gov/pubmed/23336663. 28. Weeks KS, Kahl AR, Lynch CF, Charlton ME. Racial/ethnic differences in thyroid cancer incidence in the United States, 2007-2014. Cancer. 2018; 124(7):1483–91. 29. Merrill RM, Harris JD, Merrill JG. Differences in incidence rates and early detection of Cancer among non-Hispanics and Hispanics whites in the United States. Ethn Dis. 2013;23:349–55. 30. Pinheiro PS, Sherman RL, Trapido EJ, Fleming LE, Huang Y, Gomez-Marin O, et al. Cancer incidence in first generation U.S. Hispanics: Cubans, Mexicans, Puerto Ricans, and new Latinos. Cancer Epidemiol Biomarkers Prev [Internet]. 2009 Aug [cited 2015 Oct 20];18(8):2162–2169. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/19661072. 31. Finlayson A, Barnes I, Sayeed S, McIver B, Beral V, Ali R. Incidence of thyroid cancer in England by ethnic group, 2001–2007. Br J Cancer [Internet]. Nature Publishing Group; 2014;110(5):1322–1327. Available from: https://doi.org/10.1038/bjc.2014.4 32. US Census Bureau. American Community Survey 1-Year Estimates. 2015. 33. US Census Bureau. American Community Survey 5-Year Estimates. 2015. 34. Surveillance, Epidemiology, and End Results (SEER) Program (www.seer. cancer.gov) SEER*Stat Database: Incidence - SEER 18 Regs Research Data +Hurricane Katrina Impacted Louisiana Cases, Nov 2017 Sub (2000–2015) − Linke based on the N 2017 submission. SEER 18 Registries. 2018. 35. Surveillance Research Program NCIS software (www.seer.cancer.gov/ seerstat). SEER*Stat software. 36. United States Census. Vintage 2016 estimates series from the Population Division of the United States Census Bureau. 2016. 37. StataCorp. Stata: Release 15. Statistical Software. College Station TSL. STATA; 2017. 38. US Department of Health and Human Services C for DC and P. Behavioral Risk Factor Surveillance System Survey Data [Internet]. 2016. Available from: https://www.cdc.gov/ diabetes/data/index.html. 48

39. Pérez CM, Guzmán M, Ortiz AP, Estrella M, Valle Y, Pérez N, Haddock L, Suárez E. NIH Public Access. Ethn Dis 2008;18(4):434–41. 40. Morris LG, Tuttle RM, Davies L. Changing trends in the incidence of thyroid cancer in the United States. JAMA Otolaryngol - Head Neck Surg. 2016; 142(7):709–11. 41. Sanabria A, Kowalski LP, Shah JP, Nixon IJ, Angelos P, Williams MD, et al. Growing incidence of thyroid carcinoma in recent years: factors underlying overdiagnosis. Head Neck. 2018;40(4):855–66. 42. Loehrer AP, Murthy SS, Song Z, Lubitz CC, James BC. Association of insurance expansion with surgical management of thyroid cancer. JAMA Surg. 2017;152(8):734–40. 43. Henry J Kaiser Family Foundation. Disparities Policy-Puerto Rico: Fast Facts [Internet]. KFF. 2017. Available from: https://www.kff.org/disparities-policy/ fact-sheet/puerto-rico-fast-facts/ 44. US Cancer Statistics Working Group. US Cancer Statistics Data Visualizations Tool, based on November 2017 submission data (1999-2015): US Department of Health and Human Services, Centers for Disease Control andPrevention and National Cancer Institute [Internet] 2018. Available from: www.cdc.gov/cancer/dataviz. 45. Ellimoottil C, Miller S, Ayanian JZ, Miller DC. Effect of insurance expansion on utilization of inpatient surgery. JAMA Surg. 2014;149(8):829–36. 46. Loehrer AP, Song Z, Auchincloss HG, Hut ter M M. Massachuset ts health carereform and reduced racial disparities in minimally invasive surgery. JAMA Surg. 2013;148(12):1116–22. 47. Loehrer AP, Chang DC, Hutter MM, Song Z, Lillemoe KD, Warshaw A, Ferrone CR. Health insurance expansion and treatment of pancreatic cancer: does increased access lead to improved care? J Am Coll Surg. 2015;221(6): 1015–22. 48. Loehrer AP, Hawkins AT, Auchincloss HG, Song Z, Hutter MM, Patel VI. Impact of expanded insurance coverage on racial disparities in vascular disease: insights from Massachusetts. Ann Surg. 2016;263(4):705–11. 49. Altekruse S, Das A, Cho H, Petkov V, Yu M. Do US thyroid cancer incidence rates increase with socioeconomic status among people with health

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insurance? An observational study using SEER population-based data. BMJ Open [Internet]. 2015;5(12):e009843. Available from: http://bmjopen.bmj. c o m/c o n t e n t/5/12/e 0 0 98 4 3.f u l l. pdf#page=1&view=FitH. 50. Torres- Cintrón M, Ortiz AP, Ortiz-Ortiz K J, Figueroa-Vallés NR, Pérez-Irizarry J, Díaz-Medina G, et al. Using a socioeconomic position index to assess disparities in cancer incidence and mor talit y, Puer to Rico, 1995–2004. Prev Chronic Dis [Internet]. 2012;9:E15. Available from: http://w w w.pubmedcentral.nih.gov/ articlerender.fcgi?artid=3298767&tool= pmcentrez&rendertype=abstract. [cited 2015 Oct 16]. 51. Estrada-Merly N, Ramos-Cartagena JM, Agosto-Rosa H, Zayas-Martínez LM, Rodríguez-Reyes LE, Torres-Cintrón CR, Alvarado-Ortiz M, Zavala D, TortoleroLuna G, Ortiz AP. Sobrevivientes de Cáncer en Puerto Rico: 1987–2014. Puerto Rico: San Juan; 2017. 52. American Cancer Society. Cancer Treatment & Survivorship Facts & Figures 2016–2017 [Internet]. Atlanta; 2016. Available from: https://www.cancer. org/ content/dam/cancer-org/research/ cancer-facts-and-statistics/cancertreatmentand - sur vivorship - facts - and - figures/ cancer-treatment-andsurvivorship-factsand-figures-2016-2017.pdf. 53. Aschebrook-Kilfoy B, Schechter RB, Shih Y-CT, Kaplan EL, Chiu BC-H, Angelos P, et al. The clinical and economic burden of a sustained increase in thyroid cancer incidence. Cancer Epidemiol Biomarkers Prev [Internet]. ;22(7):1252–9. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/23677575. [cited 2015 Sep 14]. 54. Roman BR, Morris LG, Davies L. The thyroid cancer epidemic, 2017 perspective. Curr Opin Endocrinol Diabetes Obes. 2017;24(5):332–6. 55. Reschovsky JD, Rich EC, Lake TK. Factors contributing to variations in physicians’ use of evidence at the point of care: A conceptual model. J Gen Intern Med. 2015;30:555–61. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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MSP CASO CLÍNICO

PRESENTACIÓN INUSUAL DE LINFOMA ANGIOINMUNOBLÁSTICO DE CÉLULAS T Biopsia: linfoma angioinmunoblástico de células T, patrón 1, con células similares a Reed Sternberg (RS) mezcladas.

RESUMEN l linfoma angioinmunoblástico de células T (AITL) es un tipo poco común de linfoma no Hodgkin agresivo. Se cree que surge de un subconjunto de linfocitos T auxiliares CD4 positivos periféricos. Este tipo de linfoma es más prominente en los países occidentales, pero con una incidencia extremadamente baja en los Estados Unidos. En los Estados Unidos, la incidencia es de aproximadamente 0,05 casos por 100.000 personas al año. Suele presentarse en adultos mayores con una mediana de más de 60 años y un ligero predominio masculino.

ABSTRACT Angioimmunoblastic T cell lymphoma (AITL) is rare type of aggressive non - Hodgkin lymphoma. It is thought to arise from a subset of peripheral CD4 positive helper T cells. This type of lymphoma is more prominent in western countries but with an extremely low incidence in the United States. In the United States the incidence is approximately 0.05 cases per 100,000 person years. Usually occurs in older adults with a median over 60 years of age and slight male predominance.

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Presentación del caso: Un varón de 62 años acudió a nuestra sala de urgencias quejándose de exantema maculopapular generalizado progresivo, asociado a prurito que había comenzado dos semanas antes en extremidades superiores y abdomen. La larva migrans de Cutanea se encontró en el examen y se desarrolló 6 días antes de la visita al hospital con Linfadenopatía de cuello presente desde septiembre de 2020 y biopsiada. Antecedentes médicos: Hipertensión, enfermedad de las arterias coronarias y arritmias cardíacas (PVC) tratadas con terapia médica, diabetes mellitus II, apnea obstructiva del sueño, enfermedad pulmonar obstructiva crónica, trastorno depresivo mayor, trastorno de ansiedad, cavernoma cerebral, enfermedad del túnel carpiano, linfoide reactivo al VEB hiperplasia. Historial social: No consumo de alcohol, tabaco o drogas ilícitas. Testigo de Jehová.

MSP CASO CLÍNICO

Carlos A. Colón Guzmán, PGY-2, Julissa Jaca Castro, MS4; 3 Aracelis Nieves Rodríguez, 3 Judianys Santiago Delgado, MD, 4 Caroline Rivera Olmo, MD. 1 2

Manatí Medical Center: 1 Family Medicine Residency, 2 Autonumus University of Guadalajara, 3 Family Medicine Department, 4 Internal Medicine/Hematology-Oncology. Manatí Medical Center, PO Box 1142 Manatí, PR 00674

Estado general: Alerta, activo y orientado, gravemente enfermo, sin signos de angustia aguda. Piel: Erupción maculopapular con vesículas hemorrágicas, costras y marcas de arañazos. Múltiples larvas migratorias cutáneas pequeñas. Cabeza y cuello: Normocefálico, atraumático, mucosa oral húmeda, adenopatías cervicales, cicatriz de cuello derecho. Extremidades: Adenopatía axilar grande derecha, sin adenopatías inguinales, sin presencia de edema ni cianosis. Estudios e intervenciones: En base a las características atípicas observadas en la revisión inicial, se realizaron estudios de PCR para los reordenamientos del gen del receptor de células T y del IG. Estos confirman la presencia de una población de células T clonales. De igual modo células T atípicas, también positivas para PD1 e ICOS rodeadas de folículos reactivos. La revisión de las secciones teñidas para CD30, CD15 y PAX5, muestra células atípicas fuertemente positivas para CD30, parcialmente positivas para CD15 y débilmente positivas para PAX5, que se asemejan a células RS. Algunas de estas células muestran expresión parcial de CD20. Estas células se encuentran dispersas en la paracorteza y aumentan en los senos linfoides. Los estudios de reordenamiento de IG muestran un patrón anormal con picos de mayor intensidad, pero no diagnósticos de un

proceso clonal de células B. Como se informó anteriormente, hay un aumento de células positivas para EBER, pero las células similares a RS son negativas para EBER. Estas características respaldan el diagnóstico de linfoma angioinmunoblástico de células T (AITL), Patrón 1. En el AITL se pueden ver células que se asemejan a las células HRS y pueden confundirse con el linfoma de Hodgkin clásico. Discusión del caso: . La infección crónica por VEB con hiperplasia linfoide es un trastorno poco común que pone en peligro la vida y tiene un mayor riesgo de desarrollar linfoma de células T. . Nuestro caso tuvo una infección por VEB tratada con éxito con Rituxan en 2018 y con remisión completa. La linfadenopatía mejoró y la PET no mostró enfermedad activa. . La linfadenopatía de cuello reapareció en 2020 y la biopsia FNA no mostró proceso linfoproliferativo agudo. La biopsia por escisión completa del ganglio linfático del cuello fue inicialmente negativa, pero después de pruebas rigurosas aparecieron células binucleadas que se asemejan a Reed-Sternberg (RS), se encuentran células de apariencia similar en los linfomas de Hodgkin. Todos los síntomas se resolvieron con Brentuximab (BV) más ciclofosfamida,

doxorrubicina y prednisona (CHP). . Un enfoque multidisciplinario en la terapia es importante y el monitoreo periódico es esencial para evitar el proceso linfoproliferativo y la recaída. Puntos de aprendizaje: . Los médicos deben evaluar los factores de riesgo de cada paciente con linfadenopatía persistente y en desarrollo. . La progresión de la enfermedad a pesar de un tratamiento adecuado o una rápida evolución de los síntomas debe llevar al médico a reevaluar el diagnóstico. . La presentación poco común de este linfoma, que puede simular etiologías infecciosas a autoinmunes, hace que el diagnóstico sea extremadamente desafiante. Referencias: 1. Grogg KL, Attygalle AD, Macon WR, et al. Angioimmunoblastic T-cell lymphoma: a neoplasm of germinal-enter T-helper cells? Blood 2005; 106:1501. 2. Siegert W, Nerl C, Agthe A, et al. Angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma: prognostic impact of clinical observations and laboratory findings at presentation. The Kiel Lymphoma Study Group. Ann Oncol 1995; 6:659. 3. Straus SE. The chronic mononucleosis syndrome. J Infect Dis 1988; 157:405. Este estudio fue aprobado por el PHSU IRB (número de protocolo XXXXXXXX.)

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For adults with CLL/SLL

CHOOSE A FUTURE FREE FROM CONTINUOUS CLL TREATMENT: Only VENCLEXTA regimens are CHEMO-FREE and designed to be COMPLETED IN

12 MONTHS

For previously untreated CLL/SLL with VENCLEXTA + GAZYVA® (obinutuzumab)

COMPLETED IN

24 MONTHS* For previously treated CLL/SLL with VENCLEXTA + rituximab

Ask your doctor if VENCLEXTA is right for you. *From Cycle 1, Day 1 of rituximab, after 5-week VENCLEXTA dose ramp-up.

Use VENCLEXTA is a prescription medicine used to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). It is not known if VENCLEXTA is safe and effective in children.

Important Safety Information What is the most important information I should know about VENCLEXTA? VENCLEXTA can cause serious side effects, including: Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and may lead to death. Your healthcare provider will do tests to check your risk of getting TLS before you start taking VENCLEXTA. You will receive other medicines before starting and during treatment with VENCLEXTA to help reduce your risk of TLS. You may also need to receive intravenous (IV) fluids into your vein. Your healthcare provider will do blood tests to check for TLS when you first start treatment and during treatment with VENCLEXTA. It is important to keep your appointments for blood tests. Tell your healthcare provider right away if you have any symptoms of TLS during treatment with VENCLEXTA, including fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.

Revista Puertorriqueña de Medicina y Salud Pública

Visit VENCLEXTA.com to learn more

Drink plenty of water during treatment with VENCLEXTA to help reduce your risk of getting TLS. Drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before your first dose, on the day of your first dose of VENCLEXTA, and each time your dose is increased. Your healthcare provider may delay, decrease your dose, or stop treatment with VENCLEXTA if you have side effects. When restarting VENCLEXTA after stopping for 1 week or longer, your healthcare provider may again check for your risk of TLS and change your dose. Who should not take VENCLEXTA? Certain medicines must not be taken when you first start taking VENCLEXTA and while your dose is being slowly increased because of the risk of increased TLS. • Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VENCLEXTA and other medicines may affect each other causing serious side effects. • Do not start new medicines during treatment with VENCLEXTA without first talking with your healthcare provider. Before taking VENCLEXTA, tell your healthcare provider about all of your medical conditions, including if you: • have kidney or liver problems. • have problems with your body salts or electrolytes, such as potassium, phosphorus, or calcium. • have a history of high uric acid levels in your blood or gout. • are scheduled to receive a vaccine. You should not receive a “live vaccine” before, during, or after treatment with

Actor portrayal VENCLEXTA, until your healthcare provider tells you it is okay. If you are not sure about the type of immunization or vaccine, ask your healthcare provider. These vaccines may not be safe or may not work as well during treatment with VENCLEXTA. • are pregnant or plan to become pregnant. VENCLEXTA may harm your unborn baby. If you are able to become pregnant, your healthcare provider should do a pregnancy test before you start treatment with VENCLEXTA, and you should use effective birth control during treatment and for at least 30 days after the last dose of VENCLEXTA. If you become pregnant or think you are pregnant, tell your healthcare provider right away. • are breastfeeding or plan to breastfeed. It is not known if VENCLEXTA passes into your breast milk. Do not breastfeed during treatment with VENCLEXTA and for 1 week after the last dose. What should I avoid while taking VENCLEXTA? You should not drink grapefruit juice or eat grapefruit, Seville oranges (often used in marmalades), or starfruit while you are taking VENCLEXTA. These products may increase the amount of VENCLEXTA in your blood. What are the possible side effects of VENCLEXTA? VENCLEXTA can cause serious side effects, including: • Low white blood cell counts (neutropenia). Low white blood cell counts are common with VENCLEXTA, but can also be severe. Your healthcare provider will do blood tests to check your blood counts during treatment with VENCLEXTA and may pause dosing. • Infections. Death and serious infections such as pneumonia and blood infection (sepsis) have happened during treatment with VENCLEXTA. Your healthcare provider will closely monitor and treat you right away if you have a fever or any signs of infection during treatment with VENCLEXTA.

Tell your healthcare provider right away if you have a fever or any signs of an infection during treatment with VENCLEXTA. The most common side effects of VENCLEXTA when used in combination with obinutuzumab or rituximab or alone in people with CLL or SLL include low white blood cell counts; low platelet counts; low red blood cell counts; diarrhea; nausea; upper respiratory tract infection; cough; muscle and joint pain; tiredness; and swelling of your arms, legs, hands, and feet. VENCLEXTA may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare provider if you have concerns about fertility. These are not all the possible side effects of VENCLEXTA. For more information, ask your healthcare provider or pharmacist. You are encouraged to report side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. If you cannot afford your medication, contact genentechaccess.com/patient/brands/venclexta for assistance. Please see Brief Summary of full Prescribing Information on following pages. VENCLEXTA® is a registered trademark of AbbVie Inc. GAZYVA® is a registered trademark of Genentech, Inc. Distributed and marketed by AbbVie Inc., 1 North Waukegan Road, North Chicago, IL 60064. Marketed by Genentech USA, Inc., 1 DNA Way, South San Francisco, CA 94080-4990. ©2021 AbbVie Inc. and Genentech USA, Inc. Revista2021 Puertorriqueña de Medicina y Salud Pública 57 US-VENC-200401 February

DO NOT RE-SIZE US-VENC-200401

VENCLEXTA® (ven-KLEKS-tuh) (venetoclax tablets)

CONSUMER BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

Patient Information

Read the Medication Guide that comes with VENCLEXTA before you start taking it and each time you get a refill. There may be new information. This brief summary does not take the place of talking with your doctor about your medical condition or treatment.

What is the most important information I should know about VENCLEXTA?

• Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VENCLEXTA and other medicines may affect each other causing serious side effects. • Do not start new medicines during treatment with VENCLEXTA without first talking with your healthcare provider. Before taking VENCLEXTA, tell your healthcare provider about all of your medical conditions, including if you: • have kidney problems • have liver problems • have problems with your body salts or electrolytes, such as potassium, phosphorus, or calcium • have a history of high uric acid levels in your blood or gout • are scheduled to receive a vaccine. You should not receive a “live vaccine” before, during, or after treatment with VENCLEXTA, until your healthcare provider tells you it is okay. If you are not sure about the type of immunization or vaccine, ask your healthcare provider. These vaccines may not be safe or may not work as well during treatment with VENCLEXTA. • are pregnant or plan to become pregnant. VENCLEXTA may harm your unborn baby. • If you are able to become pregnant, your healthcare provider should do a pregnancy test before you start treatment with VENCLEXTA. • Females who are able to become pregnant should use effective birth control during treatment and for at least 30 days after the last dose of VENCLEXTA. • If you become pregnant or think you are pregnant, tell your healthcare provider right away. • are breastfeeding or plan to breastfeed. It is not known if VENCLEXTA passes into your breast milk. Do not breastfeed during treatment and for 1 week after the last dose of VENCLEXTA. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VENCLEXTA and other medicines may affect each other causing serious side effects. See “Who should not take VENCLEXTA?”

VENCLEXTA can cause serious side effects, including: • Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and may lead to death. Your healthcare provider will do tests to check your risk of getting TLS before you start taking VENCLEXTA. You will receive other medicines before starting and during treatment with VENCLEXTA to help reduce your risk of TLS. You may also need to receive intravenous (IV) fluids into your vein. Your healthcare provider will do blood tests to check for TLS when you first start treatment and during treatment with VENCLEXTA. It is important to keep your appointments for blood tests. Tell your healthcare provider right away if you have any symptoms of TLS during treatment with VENCLEXTA, including: • fever • seizures • chills • irregular heartbeat • nausea • dark or cloudy urine • vomiting • unusual tiredness • confusion • muscle or joint pain • shortness of breath Drink plenty of water during treatment with VENCLEXTA to help reduce your risk of getting TLS. Drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before your first dose, on the day of your first dose of VENCLEXTA, and each time your dose is increased. Your healthcare provider may delay, decrease your dose, or stop treatment with VENCLEXTA if you have side effects. When restarting VENCLEXTA after stopping for 1 week or longer, your healthcare provider may again check for your risk of TLS and change your dose. See “What are the possible side effects of VENCLEXTA?” for more information about side effects. What is VENCLEXTA? VENCLEXTA is a prescription medicine used: • to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). • in combination with azacitidine, or decitabine, or low-dose cytarabine to treat adults with newly diagnosed acute myeloid leukemia (AML) who: • are 75 years of age or older, or • have other medical conditions that prevent the use of standard chemotherapy. It is not known if VENCLEXTA is safe and effective in children. Who should not take VENCLEXTA? Certain medicines must not be taken when you first start taking VENCLEXTA and while your dose is being slowly increased because of the risk of increased tumor lysis syndrome (TLS).

20065599 Venclexta CB - 7.625 x 10.5 (2).indd 1

How should I take VENCLEXTA? • Take VENCLEXTA exactly as your healthcare provider tells you to take it. Do not change your dose of VENCLEXTA or stop taking VENCLEXTA unless your healthcare provider tells you to. • When you first take VENCLEXTA: • You may need to take VENCLEXTA at a hospital or clinic to be monitored for TLS. • If you are taking VENCLEXTA for CLL or SLL, your healthcare provider will start VENCLEXTA at a low dose. Your dose will be slowly increased weekly over 5 weeks up to the full dose. Read the Quick Start Guide that comes with VENCLEXTA before your first dose.

• If you are taking VENCLEXTA for AML, your healthcare provider will start VENCLEXTA at a low dose. Your dose will be slowly increased daily up to the full dose. Follow your healthcare provider’s instructions carefully while increasing to the full dose. • Follow the instructions about drinking water described in the section of this Brief Summary about TLS called “What is the most important information I should know about VENCLEXTA?” and also in the Quick Start Guide. • Take VENCLEXTA 1 time a day with a meal and water at about the same time each day. • Swallow VENCLEXTA tablets whole. Do not chew, crush, or break the tablets. • If you miss a dose of VENCLEXTA and it has been less than 8 hours, take your dose as soon as possible. If you miss a dose of VENCLEXTA and it has been more than 8 hours, skip the missed dose and take the next dose at your usual time. • If you vomit after taking VENCLEXTA, do not take an extra dose. Take the next dose at your usual time the next day. What should I avoid while taking VENCLEXTA? You should not drink grapefruit juice, eat grapefruit, Seville oranges (often used in marmalades), or starfruit while you are taking VENCLEXTA. These products may increase the amount of VENCLEXTA in your blood. What are the possible side effects of VENCLEXTA? VENCLEXTA can cause serious side effects, including: • See “What is the most important information I should know about VENCLEXTA?” • Low white blood cell count (neutropenia). Low white blood cell counts are common with VENCLEXTA but can also be severe. Your healthcare provider will do blood tests to check your blood counts during treatment with VENCLEXTA and may pause dosing. • Infections. Death and serious infections such as pneumonia and blood infection (sepsis) have happened during treatment with VENCLEXTA. Your healthcare provider will closely monitor and treat you right away if you have fever or any signs of infection during treatment with VENCLEXTA. Tell your healthcare provider right away if you have a fever or any signs of an infection during treatment with VENCLEXTA. The most common side effects of VENCLEXTA when used in combination with obinutuzumab, or rituximab, or alone in people with CLL or SLL include: • low platelet counts • cough • low red blood cell counts • muscle and joint pain • diarrhea • tiredness • nausea • swelling of your arms, • upper respiratory tract legs, hands, and feet infection

18 Dec 2020 9:28 PM

DO NOT RE-SIZE US-VENC-200401

The most common side effects of VENCLEXTA in combination with azacitidine, or decitabine, or low-dose cytarabine in people with AML include: • nausea • shortness of breath • diarrhea • bleeding • low platelet count • low red blood cell • constipation count • low white blood cell • rash count • stomach (abdominal) • fever with low white pain blood cell count • infection in your • tiredness blood • vomiting • muscle and joint pain • swelling of arms, • dizziness legs, hands, or feet • cough • fever • sore throat • infection in lungs • low blood pressure VENCLEXTA may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare provider if you have concerns about fertility. These are not all the possible side effects of VENCLEXTA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

20065599 Venclexta CB - 7.625 x 10.5 (2).indd 2

How should I store VENCLEXTA? • Store VENCLEXTA at or below 86°F (30°C). • For people with CLL or SLL, keep VENCLEXTA tablets in the original package during the first 4 weeks of treatment. Do not transfer the tablets to a different container. Keep VENCLEXTA and all medicines out of reach of children. General information about the safe and effective use of VENCLEXTA. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use VENCLEXTA for a condition for which it was not prescribed. Do not give VENCLEXTA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about VENCLEXTA that is written for health professionals. What are the ingredients in VENCLEXTA? Active ingredient: venetoclax Inactive ingredients: copovidone, colloidal silicon dioxide, polysorbate 80, sodium stearyl fumarate, and calcium phosphate dibasic. The 10 mg and 100 mg coated tablets also include: iron oxide yellow, polyvinyl alcohol, polyethylene glycol, talc, and titanium dioxide. The 50 mg

coated tablets also include: iron oxide yellow, iron oxide red, iron oxide black, polyvinyl alcohol, talc, polyethylene glycol, and titanium dioxide. Manufactured and Marketed by: AbbVie Inc. North Chicago, IL 60064 © 2016-2020 AbbVie Inc.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. If you cannot afford your medication, contact genentech-access.com/patient/brands/ venclexta for assistance. Ref: 20065599 Revised November, 2020 LAB-4396 MASTER

US-VENC-200401

18 Dec 2020 9:28 PM

MSP ARTÍCULO ORIGINAL MSP ARTÍCULO / ORIGINAL

El rol de la genética en el desarrollo y manejo clínico del cáncer de seno Por: Julie Dutil, PhD, Profesora Asociada Ponce Health Sciences University Department of Biochemistry Member, Advisory Board of the Tampa Bay Community Cancer Network's (TBCCN) initiative on bioethics and biobanking Member, American Society for Human Genetics Reviewer, American Journal of Medical Genetics Part A Reviewer, US Pakistan Scientific Exchange Program of the National Academies of Science Collaborator, US-Latin America Cancer Research Network Member, American Association for Cancer Research Reviewer, Molecular Carcinogenesis

Los genomas ancestrales dibujan el rostro del cáncer de seno en la isla y dan indicadores de menos sobreprotección de las mujeres puertorriqueñas sobre el tumor de la mortal afección Resumen En Puerto Rico, aproximadamente 1,540 mujeres son diagnosticadas con cáncer de seno invasivo cada año, representando el 32% de todos los cánceres y el 16% de las muertes por cáncer. Entre 5 a 10% de todos los cánceres de mama se producen debido a la herencia de raras mutaciones deletéreas en genes de predisposición muy penetrantes como BRCA1 y BRCA2. Las mujeres portadoras de una mutación deletérea en los genes de BRCA están en un riesgo substancialmente más alto de desarrollar cáncer de mama (hasta 87% en la vida) e, inclusive, otros tipos de cáncer.

Abstract About 1,540 women are diagnosed with invasive breast cancer each year in Puerto Rico, representing 32% of all cancers and 16% of cancer deaths. Approximately 5–10% of all breast cancers occur due to the inheritance of rare deleterious mutations in highly penetrating predisposition genes, such as BRCA1 and BRCA2. Women carrying a deleterious mutation in BRCA genes are at a substantially higher risk for developing breast cancer (up to 87% in their lifetime) and even other cancers.

Palabras claves: Keywords: cáncer hereditario, cáncer de mama, mutaciones inherited cancer, breast cancer, deleterious mutadeletéreas, genes BRCA, genética, prueba de tions, BRCA genes, genetics, genetic testing genética

Para obtener alguna información sobre nuestra investigación o sobre los cánceres hereditarios en general, se puede comunicar a través del correo electrónico: jdutil@psm.edu con la Profesora Asociada Julie Dutil, en la Ponce Health Sciences University. Revista Puertorriqueña de Medicina y Salúd Pública

Revista Puertorriqueña de Medicina y Salud Pública

MSP ARTÍCULO ORIGINAL ARTÍCULO / ORIGINAL

Introducción En Puerto Rico, aproximadamente 1,540 mujeres son diagnosticadas con cáncer de seno invasivo cada año, representando el 32% de todos los cánceres y el 16% de las muertes por cáncer. Los factores de riesgo para el cáncer de mama incluyen edad, ubicación geográfica, estatus socioeconómico, eventos reproductivos, hormonas exógenas, factores de estilo de vida, densidad de la mama y antecedentes familiares de mama y otros cánceres. Entre 5 a 10% de todos los cánceres de mama se producen debido a la herencia de raras mutaciones deletéreas en genes de predisposición muy penetrante como BRCA1/2. Se ha demostrado que mutaciones hereditarias en genes como PTEN, p53, CHEK2, ATM, NBS1, RAD50, BRIP1 y PALB2 también confieren un riesgo moderado a alto de cáncer de mama. Proporción del cáncer de mama con causas genéticas o ambientales Las mujeres portadoras de una mutación deletérea en los genes de BRCA están en un riesgo substancialmente más alto de desarrollar cáncer de mama (hasta 87% en la vida) u ovario (hasta 44%) en comparación con la población en general. También, han demostrado estar en mayor riesgo de otros cánceres, entre ellos el melanoma, cáncer de la próstata y del

páncreas. Además, las mutaciones de BRCA dominante se asocian al diagnóstico a temprana edad y a una probabilidad más alta que el tumor sea de tipo triple negativo. El único método para el diagnóstico de un cáncer hereditario es hacer una prueba de genética, donde se hace la secuenciación de los genes de BRCA u otros. Manejo clínico de las familias con una predisposición genética al cáncer de seno Las pruebas genéticas para los cánceres hereditarios sirven para educar a las personas con predisposición sobre los riesgos de desarrollar cáncer de mamas y otros tipos de cáncer. La asesoría genética y pruebas típicamente se ofrecen a pacientes con cáncer de mama o sus familiares basados en el riesgo de portar una mutación de cáncer hereditario estimada por antecedentes personales y familiares de cáncer. Esto se considera el estándar de atención, según lineamientos nacionales de múltiples médicos profesionales organizaciones de Estados Unidos, incluyendo la Sociedad Americana de Oncología Clínica (ASCO) y la Red Nacional Integral de Cáncer (NCCN). Las personas con un alto riesgo de tener mutaciones de cáncer de seno hereditario son reconocidas por una historia personal de cáncer de ovario o seno, inicio temprano (< 50 años de

edad) del cáncer de mama o antecedentes familiares de cáncer de mama, cáncer de mama bilateral, el cáncer de mama masculino o el cáncer de ovario. La mayor vigilancia, la cirugía profiláctica e intervenciones de quimiopreventivo son, entre las opciones disponibles, para los portadores de mutaciones de BRCA para gestionar el riesgo de mama y otros cánceres. Investigaciones han demostrado que quienes son educados acerca de su riesgo de cáncer de mama son más propensos a participar en riesgo, reducir comportamientos y estrategias de detección temprana -como examen mensual automática de mama-, visitas a médicos, mamografía y proyección de imagen por resonancia magnética (MRI) de mama. Además, el uso de la quimioterapia y/o quirúrgica preventiva tienen un impacto positivo en la supervivencia en portadoras de mutaciones de cáncer hereditario. En pacientes con cáncer recién diagnosticado, los resultados de prueba genética de BRCA afecta también las decisiones quirúrgicas. Los beneficios de la evaluación del riesgo de cáncer y pruebas de BRCA también se extienden a otros miembros de la familia, como portador de detección se puede distinguir entre los de alto riesgo y aquellos con riesgo promedio, escasamente algunos individuos de opciones de reducción de riesgos innecesarias. 11 Revista Puertorriqueña de Medicina y Salúd Pública

Revista Puertorriqueña de Medicina y Salud Pública

MSP ARTÍCULO ORIGINAL MSP ARTÍCULO / ORIGINAL

Investigaciones sobre la genética de los cánceres de mama en Puerto Rico Desde 2007, nuestro grupo en la Ponce Health Sciences University se dedica a identificar los factores genéticos involucrados en el riesgo de cáncer en la población puertorriqueña. Esta investigación es financiada por el Instituto Nacional de Cáncer (NCI, por siglas en inglés), del Instituto Nacional de Salud de Estados Unidos (NIH). Los proyectos y cursos incluyen la identificación de las mutaciones frecuentes en la población de Puerto Rico en los genes de BRCA y otros genes de susceptibilidad, usando la secuenciación de próxima generación. Además, tenemos proyectos dedicados a determinar el rol de la ancestría genética en el desarrollo de los tumores de cáncer de seno agresivo de tipo triple negativo. Mientras que la mayoría de las poblaciones hispanas son una mezcla de 3 razas ancestrales (africana, europea y taína), la proporción relativa de cada una dentro y a través de las poblaciones del Caribe y América del Sur. Por ejemplo, estudios utilizando marcadores genéticos informativos sobre la ascendencia genética han

demostrado que los puertorriqueños llevan más ascendencia europea y africana, pero significativamente menos ascendencia taína que las poblaciones de México. Las mujeres hispanas tienen menos riesgo de desarrollar cáncer de seno, pero el pronóstico es peor que para las mujeres europeas o de Estados Unidos. Nuestros estudios muestran que las mujeres puertorriqueñas con más ascendencia genética africana tienen más probabilidad de desarrollar un cáncer de seno de tipo triple negativo, conocido como más agresivo y con menos opciones de tratamiento. En el espectro de la mutación subyacente a los cánceres de seno hereditarios en Puerto Rico, tres mutaciones recurrentes cuentan para más del 70% de todas las mutaciones BRCA observado en este estudio poblacional. Las mutaciones frecuentes en Puerto Rico son diferentes de las que se encuentran en otros países de American Latina y del Caribe. Estos resultados indican la importancia de seguir la investigación dirigida a la población de Puerto Rico para entender bien las causas genéticas de los cánceres de seno en la Isla.

12 Revista Puertorriqueña de Medicina y Salúd Pública

Revista Puertorriqueña de Medicina y Salud Pública

"Nuestros estudios muestran que las mujeres puertorriqueñas con más ascendencia genética africana tienen más probabilidad de desarrollar un cáncer de seno de tipo triple negativo, conocido como el más agresivo y con menos opciones de tratamiento" Conclusión Una historia familiar de cán-cer de seno desempeña un rol muy importante en el riesgo de padecerlo, por lo que las pruebas genéticas para los cánceres hereditarios pueden educar a las personas con predisposición a desarrollar cáncer de mamas y otros tipos de cáncer. A través de la historia médica y fami-liar, se puede identificar a pacientes y familiares para recibir educación sobre los riesgos de cáncer.

In HR+, HER2– MBC

A SIGNIFICANT SURVIVAL IMPROVEMENT

With consistent results even in women likely to do worse1-6* Verzenio + fulvestrant helps to raise the bar of what is possible for pre/peri- and postmenopausal women with disease recurrence or progression following endocrine therapy (ET)

46.7-month mOS with Verzenio + fulvestrant (n=446) (95% CI: 39.2-52.2) vs 37.3-month mOS with fulvestrant alone (n=223) (95% CI: 34.4-43.2); HR=0.757 (95% CI: 0.606-0.945), P=.01372,7 *Visceral disease and primary ET resistance were studied in the clinical trial and could confer a less favorable prognosis. For more information on trial design, see below. MONARCH 2 was a phase III, randomized, double-blind, placebo-controlled trial that enrolled 669 patients with HR+, HER2− MBC who progressed on or after ET. Pre/perimenopausal women (17%) were rendered postmenopausal prior to the study. Patients had received no chemotherapy and no more than 1 prior ET in the metastatic setting. Patients were randomized 2:1 to Verzenio + fulvestrant (n=446) or placebo + fulvestrant (n=223). Verzenio and placebo were dosed PO BID on a continuous dosing schedule until disease progression or unacceptable toxicity. 500 mg fulvestrant was administered by IM injection on days 1, 15, and 29 of the first month and once monthly thereafter. The primary endpoint was PFS. Key secondary endpoints were ORR, OS, and DoR.1,8 BID=twice a day; CI=confidence interval; DoR=duration of response; HR=hazard ratio; IM=intramuscular; mOS=median overall survival; ORR=objective response rate; OS=overall survival; PO=orally; PFS=progression-free survival.

Verzenio is indicated for the treatment of hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) advanced or metastatic breast cancer (MBC)¹: • In combination with fulvestrant for women with disease progression following endocrine therapy SELECT IMPORTANT SAFETY INFORMATION Diarrhea occurred in 81% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 86% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and 90% of patients receiving Verzenio alone in MONARCH 1. Grade 3 diarrhea occurred in 9% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 13% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and in 20% of patients receiving Verzenio alone in MONARCH 1. Episodes of diarrhea have been associated with dehydration and infection. Diarrhea incidence was greatest during the first month of Verzenio dosing. In MONARCH 3, the median time to onset of the first diarrhea event was 8 days, and the median duration of diarrhea for Grades 2 and 3 were 11 and 8 days, respectively. In MONARCH 2, the median time to onset of the first diarrhea event was 6 days, and the median duration of diarrhea for Grades 2 and 3 were 9 days and 6 days, respectively. In MONARCH 3, 19% of patients with diarrhea required a dose omission and 13% required a dose reduction. In MONARCH 2, 22% of patients with diarrhea required a dose omission and 22% required a dose reduction. The time to onset and resolution for diarrhea were similar across MONARCH 3, MONARCH 2, and MONARCH 1. Instruct patients that at the first sign of loose stools, they should start antidiarrheal therapy such as loperamide, increase oral fluids, and notify their healthcare provider for further instructions and appropriate follow-up. For Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization, discontinue Verzenio until toxicity resolves to ≤Grade 1, and then resume Verzenio at the next lower dose. Please see Select Important Safety Information throughout and Brief Summary of full Prescribing Information for Verzenio on the following pages.

Revista Puertorriqueña de Medicina y Salud Pública

For women with HR+, HER2− MBC with disease recurrence or progression on or after ET

9.4-month statistically significant mOS benefit2 Definitive OS results2,7

ENDPOINT: OS IN ITT POPULATION σSECONDARY SECONDARY ENDPOINT: OS IN ITT POPULATION2,7

• Results are based on a preplanned interim analysis and considered to be definitive, due to the observation of 77% (338/441) of the planned OS events needed for the final analysis

Verzenio + fulvestrant (n=446) Placebo + fulvestrant (n=223)

46.7

100

SURVIVAL PROBABILITY (%)

months

0.757

median OS with Verzenio + fulvestrant (95% CI: 39.2-52.2)

(95% CI: 0.606-0.945)

– The percentage of events at the time of analysis was 47.3% (n=211) and 57.0% (n=127) in the Verzenio + fulvestrant and fulvestrant alone arms, respectively

P=.0137

Primary endpoint: PFS in the ITT population1,2 • 16.4-month mPFS with Verzenio + fulvestrant (n=446) (95% Cl: 14.4-19.3) vs 9.3-month mPFS with fulvestrant alone (n=223) (95% Cl: 7.4-12.7); HR=0.553 (95% CI: 0.449-0.681), P<.0001

37.3 months

median OS with placebo + fulvestrant (95% CI: 34.4-43.2)

• The percentage of PFS events at the time of analysis was 49.8% (n=222) and 70.4% (n=157) in the Verzenio + fulvestrant and fulvestrant alone arms, respectively

TIME (MONTHS)

446

410

384

339

302

265

234

202

101

223

201

191

170

148

122

The only CDK4 & 6 inhibitor to significantly improve OS regardless of menopausal status in combination with fulvestrant2,9

CDK4 & 6=cyclin-dependent kinases 4 and 6; ITT=intent-to-treat; mPFS=median progression-free survival.

SELECT IMPORTANT SAFETY INFORMATION Neutropenia occurred in 41% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 46% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and 37% of patients receiving Verzenio alone in MONARCH 1. A Grade ≥3 decrease in neutrophil count (based on laboratory findings) occurred in 22% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 32% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and in 27% of patients receiving Verzenio alone in MONARCH 1. In MONARCH 3, the median time to first episode of Grade ≥3 neutropenia was 33 days, and in MONARCH 2 and MONARCH 1, was 29 days. In MONARCH 3, median duration of Grade ≥3 neutropenia was 11 days, and for MONARCH 2 and MONARCH 1 was 15 days. Monitor complete blood counts prior to the start of Verzenio therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia. Febrile neutropenia has been reported in <1% of patients exposed to Verzenio in the MONARCH studies. Two deaths due to neutropenic sepsis were observed in MONARCH 2. Inform patients to promptly report any episodes of fever to their healthcare provider. Severe, life-threatening, or fatal interstitial lung disease (ILD) and/ or pneumonitis can occur in patients treated with Verzenio and other CDK4/6 inhibitors. Across clinical trials (MONARCH 1, MONARCH 2, MONARCH 3), 3.3% of Verzenio-treated patients had ILD/pneumonitis of any grade, 0.6% had Grade 3 or 4, and 0.4% had fatal outcomes. Additional cases of ILD/pneumonitis have been observed in the post-marketing setting, with fatalities reported.

Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded by means of appropriate investigations. Dose interruption or dose reduction is recommended in patients who develop persistent or recurrent Grade 2 ILD/pneumonitis. Permanently discontinue Verzenio in all patients with grade 3 or 4 ILD/pneumonitis. Grade ≥3 increases in alanine aminotransferase (ALT) (6% versus 2%) and aspartate aminotransferase (AST) (3% versus 1%) were reported in the Verzenio and placebo arms, respectively, in MONARCH 3. Grade ≥3 increases in ALT (4% versus 2%) and AST (2% versus 3%) were reported in the Verzenio and placebo arms respectively, in MONARCH 2. In MONARCH 3, for patients receiving Verzenio plus an aromatase inhibitor with Grade ≥3 increases in ALT or AST, median time to onset was 61 and 71 days, respectively, and median time to resolution to Grade <3 was 14 and 15 days, respectively. In MONARCH 2, for patients receiving Verzenio plus fulvestrant with Grade ≥3 increases in ALT or AST, median time to onset was 57 and 185 days, respectively, and median time to resolution to Grade <3 was 14 and 13 days, respectively. For assessment of potential hepatotoxicity, monitor liver function tests (LFTs) prior to the start of Verzenio therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, dose discontinuation, or delay in starting treatment cycles is recommended for patients who develop persistent or recurrent Grade 2, or Grade 3 or 4, hepatic transaminase elevation.

Puertorriqueña MedicinaInformation y Salud Públicathroughout and Brief Please seeRevista Select ImportantdeSafety 64 Summary of full Prescribing Information for Verzenio on the following pages.

In preplanned subgroup analyses

Consistent results in women with visceral disease and primary ET resistance1-6* *Visceral disease and primary ET resistance were studied in the clinical trial and could confer a less favorable prognosis. σ 8.1-MONTH mOS INCREASE IN WOMEN WITH VISCERAL DISEASE2

σ 7.2-MONTH mOS INCREASE IN WOMEN WITH PRIMARY ET RESISTANCE2

Verzenio + fulvestrant (n=245) Placebo + fulvestrant (n=128)

40.3

100

0.675

median OS with Verzenio + fulvestrant

(95% CI: 0.511-0.891)

0.686

median OS with Verzenio + fulvestrant

(95% CI: 0.451-1.043)

32.2 months median OS with placebo + fulvestrant

months

38.7

100

months

80 SURVIVAL PROBABILITY (%)

SURVIVAL PROBABILITY (%)

Verzenio + fulvestrant (n=112) Placebo + fulvestrant (n=60)

31.5 months

median OS with placebo + fulvestrant

TIME (MONTHS)

245

228

217

184

162

141

124

102

112

101

128

111

105

• Visceral disease: ≥1 lesion on an internal organ or in the third space (eg, lung, liver, pleural, or peritoneal metastatic involvement)10

• Primary ET resistance: relapse within 2 years of starting adjuvant ET or progressive disease within the first 6 months of first-line ET for MBC1

Preplanned subgroup analyses of OS were performed for stratification factors of disease site (including visceral disease) and endocrine resistance (including primary ET resistance). Analyses were not adjusted for multiplicity, and the study was not powered to test the effect of Verzenio + fulvestrant among subgroups.11

Verzenio + fulvestrant delayed time to chemotherapy2 • Exploratory analysis: 50.2-month median time to chemotherapy with Verzenio + fulvestrant (n/N=200/446) vs 22.1-month median time to chemotherapy with fulvestrant alone (n/N=135/223); HR=0.625 (95% CI: 0.501-0.779) – 37.5% reduction in risk of progressing to chemotherapy • Time to chemotherapy is defined as time from randomization to initiation of first post-discontinuation chemotherapy. Patients who died prior to receiving chemotherapy (n=111) did not contribute an event to this analysis • This exploratory analysis was not controlled for type 1 error, and the study was not powered to test this endpoint

n=number of events; N=total number of patients.

SELECT IMPORTANT SAFETY INFORMATION Venous thromboembolic events were reported in 5% of patients treated with Verzenio plus an aromatase inhibitor as compared to 0.6% of patients treated with an aromatase inhibitor plus placebo in MONARCH 3. Venous thromboembolic events were reported in 5% of patients treated with Verzenio plus fulvestrant in MONARCH 2 as compared to 0.9% of patients treated with fulvestrant plus placebo. Venous thromboembolic events included deep vein thrombosis, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary vein thrombosis, and inferior vena cava thrombosis. Across the

clinical development program, deaths due to venous thromboembolism have been reported. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate.

Please see Select Important Safety Information throughout and Brief Summary of full Prescribing Information for Verzenio on the following pages.

Revista Puertorriqueña de Medicina y Salud Pública

Redefining survival expectations for women with HR+, HER2− MBC2

OS was a key secondary endpoint of MONARCH 2.2 Results are based on a preplanned interim analysis and considered to be definitive.2

See the difference Verzenio can make for patients at www.verzenio.com/hcp SELECT IMPORTANT SAFETY INFORMATION Verzenio can cause fetal harm when administered to a pregnant woman based on findings from animal studies and the mechanism of action. In animal reproduction studies, administration of abemaciclib to pregnant rats during the period of organogenesis caused teratogenicity and decreased fetal weight at maternal exposures that were similar to the human clinical exposure based on area under the curve (AUC) at the maximum recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Verzenio and for at least 3 weeks after the last dose. There are no data on the presence of Verzenio in human milk or its effects on the breastfed child or on milk production. Advise lactating women not to breastfeed during Verzenio treatment and for at least 3 weeks after the last dose because of the potential for serious adverse reactions in breastfed infants. Based on findings in animals, Verzenio may impair fertility in males of reproductive potential. The most common adverse reactions (all grades, ≥10%) observed in MONARCH 2 for Verzenio plus fulvestrant and ≥2% higher than placebo plus fulvestrant vs placebo plus fulvestrant were diarrhea (86% vs 25%), neutropenia (46% vs 4%), fatigue (46% vs 32%), nausea (45% vs 23%), infections (43% vs 25%), abdominal pain (35% vs 16%), anemia (29% vs 4%), leukopenia (28% vs 2%), decreased appetite (27% vs 12%), vomiting (26% vs 10%), headache (20% vs 15%), dysgeusia (18% vs 3%), thrombocytopenia (16% vs 3%), alopecia (16% vs 2%), stomatitis (15% vs 10%), ALT increased (13% vs 5%), pruritus (13% vs 6%), cough (13% vs 11%), dizziness (12% vs 6%), AST increased (12% vs 7%), peripheral edema (12% vs 7%), creatinine increased (12% vs <1%), rash (11% vs 4%), pyrexia (11% vs 6%), and weight decreased (10% vs 2%). The most frequently reported ≥5% Grade 3 or 4 adverse reactions that occurred in the Verzenio arm vs the placebo arm of MONARCH 2 were neutropenia (27% vs 2%), diarrhea (13% vs <1%), leukopenia (9% vs 0%), anemia (7% vs 1%), and infections (6% vs 3%). Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 2 in ≥10% for Verzenio plus fulvestrant and ≥2% higher than placebo plus fulvestrant vs placebo plus fulvestrant were increased serum creatinine (98% vs 74%; 1% vs 0%), decreased white blood cells (90% vs 33%; 23% vs 1%), decreased neutrophil count (87% vs 30%; 33% vs 4%), anemia (84% vs 33%; 3% vs <1%), decreased lymphocyte count (63% vs 32%; 12% vs 2%), decreased platelet count (53% vs 15%; 2% vs 0%), increased ALT (41% vs 32%; 5% vs 1%), and increased AST (37% vs 25%; 4% vs 4%). Strong and moderate CYP3A inhibitors increased the exposure of abemaciclib plus its active metabolites to a clinically meaningful extent and may lead to increased toxicity. Avoid concomitant use of the strong CYP3A inhibitor ketoconazole. Ketoconazole is predicted to increase the AUC of abemaciclib by up to 16-fold. In patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the Verzenio dose to 100 mg twice daily with concomitant use of strong Revista Puertorriqueña Medicina y Salud 01/2020 ©Lilly USA,deLLC 2020. All rightsPública reserved. Verzenio® is a registered 66PP-AL-US-2070 trademark owned or licensed by Eli Lilly and Company, its subsidiaries or affiliates.

CYP3A inhibitors other than ketoconazole. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the Verzenio dose to 50 mg twice daily with concomitant use of strong CYP3A inhibitors. If a patient taking Verzenio discontinues a strong CYP3A inhibitor, increase the Verzenio dose (after 3 to 5 half-lives of the inhibitor) to the dose that was used before starting the inhibitor. With concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the Verzenio dose in 50 mg decrements. Patients should avoid grapefruit products. Avoid concomitant use of strong or moderate CYP3A inducers and consider alternative agents. Coadministration of strong or moderate CYP3A inducers decreased the plasma concentrations of abemaciclib plus its active metabolites and may lead to reduced activity. With severe hepatic impairment (Child-Pugh Class C), reduce the Verzenio dosing frequency to once daily. The pharmacokinetics of Verzenio in patients with severe renal impairment (CLcr <30 mL/min), end stage renal disease, or in patients on dialysis is unknown. No dosage adjustments are necessary in patients with mild or moderate hepatic (Child-Pugh A or B) and/or renal impairment (CLcr ≥30-89 mL/min). Please see Select Important Safety Information throughout and Brief Summary of full Prescribing Information for Verzenio on the following pages. AL HCP ISI_M2 23OCT2019 References: 1. Verzenio [package insert]. Indianapolis, IN: Eli Lilly and Company; 2019. 2. Sledge GW Jr, Toi M, Neven P, et al. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor–positive, ERBB2-negative breast cancer that progressed on endocrine therapy—MONARCH 2: a randomized clinical trial [published online September 29, 2019]. JAMA Oncol. doi:10.1001/jamaoncol.2019.4782. 3. Imkampe A, Bendall S, Bates T. The significance of the site of recurrence to subsequent breast cancer survival. Eur J Surg Oncol. 2007;33:420-423. 4. Largillier R, Ferrero JM, Doyen J, et al. Prognostic factors in 1038 women with metastatic breast cancer. Ann Oncol. 2008;19:2012-2019. 5. Solomayer EF, Diel IJ, Meyberg GC, Gollan C, Bastert G. Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis. Breast Cancer Res Treat. 2000;59:271-278. 6. Cardoso F, Senkus E, Costa A, et al. 4th ESO–ESMO international consensus guidelines for advanced breast cancer (ABC 4). Annals of Oncology. 2018;29(8):1634-1657. 7. Data on file. Lilly USA, LLC. DOF-AL-US-0088. 8. Sledge GW Jr, Toi M, Neven P, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2− advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35:2875-2884. 9. Turner NC, Slamon DJ, Ro J, et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med. 2018;379:1926-1936. 10. Data on file. Lilly USA, LLC. ONC20171128a. 11. Data on file. Lilly USA, LLC. ONC20180103a.

VERZENIO® (abemaciclib) tablets, for oral use Initial U.S. Approval: 2017 BRIEF SUMMARY: Consult the package insert for complete prescribing information. INDICATIONS AND USAGE VERZENIO® (abemaciclib) is indicated: • in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. • in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. • as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS Diarrhea Diarrhea occurred in 81% of patients receiving VERZENIO plus an aromatase inhibitor in MONARCH 3, 86% of patients receiving VERZENIO plus fulvestrant in MONARCH 2, and 90% of patients receiving VERZENIO alone in MONARCH 1. Grade 3 diarrhea occurred in 9% of patients receiving VERZENIO plus an aromatase inhibitor in MONARCH 3, 13% of patients receiving VERZENIO plus fulvestrant in MONARCH 2, and in 20% of patients receiving VERZENIO alone in MONARCH 1. Episodes of diarrhea have been associated with dehydration and infection. Diarrhea incidence was greatest during the first month of VERZENIO dosing. In MONARCH 3, the median time to onset of the first diarrhea event was 8 days, and the median duration of diarrhea for Grades 2 and 3 were 11 and 8 days, respectively. In MONARCH 2, the median time to onset of the first diarrhea event was 6 days, and the median duration of diarrhea for Grades 2 and 3 were 9 days and 6 days, respectively. In MONARCH 3, 19% of patients with diarrhea required a dose omission and 13% required a dose reduction. In MONARCH 2, 22% of patients with diarrhea required a dose omission and 22% required a dose reduction. The time to onset and resolution for diarrhea were similar across MONARCH 3, MONARCH 2, and MONARCH 1.

Dose interruption or dose reduction is recommended for patients who develop persistent or recurrent Grade 2 ILD/pneumonitis. Permanently discontinue VERZENIO in all patients with Grade 3 or 4 ILD or pneumonitis. Hepatotoxicity In MONARCH 3, Grade ≥3 increases in ALT (6% versus 2%) and AST (3% versus 1%) were reported in the VERZENIO and placebo arms, respectively. In MONARCH 2, Grade ≥3 increases in ALT (4% versus 2%) and AST (2% versus 3%) were reported in the VERZENIO and placebo arms, respectively. In MONARCH 3, for patients receiving VERZENIO plus an aromatase inhibitor with Grade ≥3 ALT increased, median time to onset was 61 days, and median time to resolution to Grade <3 was 14 days. In MONARCH 2, for patients receiving VERZENIO plus fulvestrant with Grade ≥3 ALT increased, median time to onset was 57 days, and median time to resolution to Grade <3 was 14 days. In MONARCH 3, for patients receiving VERZENIO plus an aromatase inhibitor with Grade ≥3 AST increased, median time to onset was 71 days, and median time to resolution was 15 days. In MONARCH 2, for patients receiving VERZENIO plus fulvestrant with Grade ≥3 AST increased, median time to onset was 185 days, and median time to resolution was 13 days. Monitor liver function tests (LFTs) prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, dose discontinuation, or delay in starting treatment cycles is recommended for patients who develop persistent or recurrent Grade 2, or Grade 3 or 4, hepatic transaminase elevation. Venous Thromboembolism In MONARCH 3, venous thromboembolic events were reported in 5% of patients treated with VERZENIO plus an aromatase inhibitor as compared to 0.6% of patients treated with an aromatase inhibitor plus placebo. In MONARCH 2, venous thromboembolic events were reported in 5% of patients treated with VERZENIO plus fulvestrant as compared to 0.9% of patients treated with fulvestrant plus placebo. Venous thromboembolic events included deep vein thrombosis, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary vein thrombosis, and inferior vena cava thrombosis. Across the clinical development program, deaths due to venous thromboembolism have been reported. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate. Embryo-Fetal Toxicity

Instruct patients that at the first sign of loose stools, they should start antidiarrheal therapy such as loperamide, increase oral fluids, and notify their healthcare provider for further instructions and appropriate follow up. For Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization, discontinue VERZENIO until toxicity resolves to ≤Grade 1, and then resume VERZENIO at the next lower dose.

Based on findings from animal studies and the mechanism of action, VERZENIO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of abemaciclib to pregnant rats during the period of organogenesis caused teratogenicity and decreased fetal weight at maternal exposures that were similar to the human clinical exposure based on area under the curve (AUC) at the maximum recommended human dose.

Neutropenia Neutropenia occurred in 41% of patients receiving VERZENIO plus an aromatase inhibitor in MONARCH 3, 46% of patients receiving VERZENIO plus fulvestrant in MONARCH 2, and 37% of patients receiving VERZENIO alone in MONARCH 1. A Grade ≥3 decrease in neutrophil count (based on laboratory findings) occurred in 22% of patients receiving VERZENIO plus an aromatase inhibitor in MONARCH 3, 32% of patients receiving VERZENIO plus fulvestrant in MONARCH 2, and in 27% of patients receiving VERZENIO in MONARCH 1. In MONARCH 3, the median time to first episode of Grade ≥3 neutropenia was 33 days, and in MONARCH 2 and MONARCH 1 was 29 days. In MONARCH 3, median duration of Grade ≥3 neutropenia was 11 days, and for MONARCH 2 and MONARCH 1 was 15 days.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with VERZENIO and for at least 3 weeks after the last dose.

Monitor complete blood counts prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia. Febrile neutropenia has been reported in <1% of patients exposed to VERZENIO in the MONARCH studies. Two deaths due to neutropenic sepsis were observed in MONARCH 2. Inform patients to promptly report any episodes of fever to their healthcare provider. Interstitial Lung Disease (ILD)/Pneumonitis Severe, life-threatening, or fatal lung disease (ILD) and/or pneumonitis can occur in patients treated with VERZENIO and other CDK 4/6 inhibitors. Across clinical trials (MONARCH 1, MONARCH 2, and MONARCH 3), 3.3% of VERZENIO-treated patients had ILD/pneumonitis of any grade, 0.6% had Grade 3 or 4, and 0.4% had fatal outcomes. Additional cases of ILD/pneumonitis have been observed in the postmarketing setting, with fatalities reported.

ADVERSE REACTIONS Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. MONARCH 3: VERZENIO in Combination with an Aromatase Inhibitor (Anastrozole or Letrozole) as Initial Endocrine-Based Therapy Postmenopausal Women with HR-positive, HER2-negative locoregionally recurrent or metastatic breast cancer with no prior systemic therapy in this disease setting MONARCH 3 was a study of 488 women receiving VERZENIO plus an aromatase inhibitor or placebo plus an aromatase inhibitor. Patients were randomly assigned to receive 150 mg of VERZENIO or placebo orally twice daily, plus physician’s choice of anastrozole or letrozole once daily. Median duration of treatment was 15.1 months for the VERZENIO arm and 13.9 months for the placebo arm. Median dose compliance was 98% for the VERZENIO arm and 99% for the placebo arm.

Dose reductions due to an adverse reaction occurred in 43% of patients receiving VERZENIO plus anastrozole or letrozole. Adverse reactions leading to dose reductions in ≥5% of patients were diarrhea and neutropenia. VERZENIO dose reductions due to diarrhea of any grade occurred in 13% of patients receiving VERZENIO plus an aromatase inhibitor compared to 2% of patients receiving placebo plus an aromatase inhibitor. VERZENIO dose reductions due to neutropenia of any grade occurred in 11% of patients receiving VERZENIO plus an aromatase inhibitor compared to 0.6% of patients receiving placebo plus an aromatase inhibitor.

VERZENIO® (abemaciclib) tablets, for oral use

AL HCP BS 19SEP2019

Table 1: Adverse Reactions ≥10% of Patients Receiving VERZENIO Plus Anastrozole or Letrozole and ≥2% Higher Than Placebo Plus Anastrozole or Letrozole in MONARCH 3 (Cont.)

Permanent treatment discontinuation due to an adverse event was reported in 13% of patients receiving VERZENIO plus an aromatase inhibitor and in 3% placebo plus an aromatase inhibitor. Adverse reactions leading to permanent discontinuation for patients receiving VERZENIO plus an aromatase inhibitor were diarrhea (2%), ALT increased (2%), infection (1%), venous thromboembolic events (VTE) (1%), neutropenia (0.9%), renal impairment (0.9%), AST increased (0.6%), dyspnea (0.6%), pulmonary fibrosis (0.6%) and anemia, rash, weight decreased and thrombocytopenia (each 0.3%). Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 11 cases (3%) of VERZENIO plus an aromatase inhibitor treated patients versus 3 cases (2%) of placebo plus an aromatase inhibitor treated patients. Causes of death for patients receiving VERZENIO plus an aromatase inhibitor included: 3 (1%) patient deaths due to underlying disease, 3 (0.9%) due to lung infection, 3 (0.9%) due to VTE event, 1 (0.3%) due to pneumonitis, and 1 (0.3%) due to cerebral infarction. The most common adverse reactions reported (≥20%) in the VERZENIO arm and ≥2% than the placebo arm were diarrhea, neutropenia, fatigue, infections, nausea, abdominal pain, anemia, vomiting, alopecia, decreased appetite, and leukopenia (Table 1). The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, diarrhea, leukopenia, increased ALT, and anemia. Diarrhea incidence was greatest during the first month of VERZENIO dosing. The median time to onset of the first diarrhea event was 8 days, and the median durations of diarrhea for Grades 2 and for Grade 3 were 11 days and 8 days, respectively. Most diarrhea events recovered or resolved (88%) with supportive treatment and/or dose reductions. Nineteen percent of patients with diarrhea required a dose omission and 13% required a dose reduction. The median time to the first dose reduction due to diarrhea was 38 days. Table 1: Adverse Reactions ≥10% of Patients Receiving VERZENIO Plus Anastrozole or Letrozole and ≥2% Higher Than Placebo Plus Anastrozole or Letrozole in MONARCH 3 Placebo plus VERZENIO plus Anastrozole or Letrozole Anastrozole or Letrozole N=161 N=327 All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 % % % % % % Gastrointestinal Disorders Diarrhea 81 9 0 Nausea 39 <1 0 Abdominal pain 29 1 0 Vomiting 28 1 0 Constipation 16 <1 0 Infections and Infestations Infectionsa 39 4 <1 Blood and Lymphatic System Disorders Neutropenia 41 20 2 Anemia 28 6 0 Leukopenia 21 7 <1 Thrombocytopenia 10 2 <1 General Disorders and Administration Site Conditions Fatigue 40 2 0 Influenza like illness 10 0 0 Skin and Subcutaneous Tissue Disorders Alopecia 27 0 0 Rash 14 <1 0 Pruritus 13 0 0 Metabolism and Nutrition Disorders Decreased appetite 24 1 0 Investigations Blood creatinine 19 2 0 increased 16 6 <1 Alanine aminotransferase increased 15 3 0 Aspartate aminotransferase increased Weight decreased 10 <1 0 VERZENIO® (abemaciclib) tablets, for oral use

30 20 12 12 12

1 1 1 2 0

0 0 0 0 0

2 5 2 2

<1 1 0 <1

<1 0 <1 0

32 8

0 0

11 5 9

0 0 0

AL HCP BS 19SEP2019

Placebo plus VERZENIO plus Anastrozole or Letrozole Anastrozole or Letrozole N=161 N=327 All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 % % % % % % Respiratory, Thoracic, and Mediastinal Disorders Cough 13 0 0 Dyspnea 12 <1 <1 Nervous System Disorders Dizziness 11 <1 0 a

9 6

0 <1

0 0

Includes all reported preferred terms that are part of the Infections and Infestations system organ class. Most common infections (>1%) include upper respiratory tract infection, lung infection, and pharyngitis.

Additional adverse reactions in MONARCH 3 include venous thromboembolic events (deep vein thrombosis, pulmonary embolism, and pelvic venous thrombosis), which were reported in 5% of patients treated with VERZENIO plus anastrozole or letrozole as compared to 0.6% of patients treated with anastrozole or letrozole plus placebo. Table 2: Laboratory Abnormalities ≥10% in Patients Receiving VERZENIO Plus Anastrozole or Letrozole and ≥2% Higher Than Placebo Plus Anastrozole or Letrozole in MONARCH 3

Laboratory Abnormality Creatinine increased White blood cell decreased Anemia Neutrophil count decreased Lymphocyte count decreased Platelet count decreased Alanine aminotransferase increased Aspartate aminotransferase increased

VERZENIO plus Placebo plus Anastrozole or Letrozole Anastrozole or Letrozole N=327 N=161 All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 % % % % % % 98 2 0 84 0 0 82 13 0 27 <1 0 82 80

2 19

0 3

28 21

0 3

0 0

36 48

1 6

<1 <1

12 25

<1 2

0 0

Creatinine Increased Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function. Across the clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of VERZENIO dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated GFR, which are not based on creatinine, may be considered to determine whether renal function is impaired. MONARCH 2: VERZENIO in Combination with Fulvestrant Women with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression on or after prior adjuvant or metastatic endocrine therapy The safety of VERZENIO (150 mg twice daily) plus fulvestrant (500 mg) versus placebo plus fulvestrant was evaluated in MONARCH 2. The data described below reflect exposure to VERZENIO in 441 patients with HR-positive, HER2-negative advanced breast cancer who received at least one dose of VERZENIO plus fulvestrant in MONARCH 2. Median duration of treatment was 12 months for patients receiving VERZENIO plus fulvestrant and 8 months for patients receiving placebo plus fulvestrant. Dose reductions due to an adverse reaction occurred in 43% of patients receiving VERZENIO plus fulvestrant. Adverse reactions leading to dose reductions in ≥5% of patients were diarrhea and neutropenia. VERZENIO dose reductions due to diarrhea of any grade occurred in 19% of patients receiving VERZENIO plus fulvestrant compared to 0.4% of patients receiving placebo and fulvestrant. VERZENIO dose reductions due to neutropenia of any grade occurred in 10% of patients receiving VERZENIO plus fulvestrant compared to no patients receiving placebo plus fulvestrant. VERZENIO® (abemaciclib) tablets, for oral use

AL HCP BS 19SEP2019

Permanent study treatment discontinuation due to an adverse event was reported in 9% of patients receiving VERZENIO plus fulvestrant and in 3% of patients receiving placebo plus fulvestrant. Adverse reactions leading to permanent discontinuation for patients receiving VERZENIO plus fulvestrant were infection (2%), diarrhea (1%), hepatotoxicity (1%), fatigue (0.7%), nausea (0.2%), abdominal pain (0.2%), acute kidney injury (0.2%), and cerebral infarction (0.2%). Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 18 cases (4%) of VERZENIO plus fulvestrant treated patients versus 10 cases (5%) of placebo plus fulvestrant treated patients. Causes of death for patients receiving VERZENIO plus fulvestrant included: 7 (2%) patient deaths due to underlying disease, 4 (0.9%) due to sepsis, 2 (0.5%) due to pneumonitis, 2 (0.5%) due to hepatotoxicity, and one (0.2%) due to cerebral infarction. The most common adverse reactions reported (≥20%) in the VERZENIO arm were diarrhea, fatigue, neutropenia, nausea, infections, abdominal pain, anemia, leukopenia, decreased appetite, vomiting, and headache (Table 3). The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, diarrhea, leukopenia, anemia, and infections.

c d

e f g

Includes upper respiratory tract infection, urinary tract infection, lung infection, pharyngitis, conjunctivitis, sinusitis, vaginal infection, sepsis. Includes neutropenia, neutrophil count decreased. Includes anemia, hematocrit decreased, hemoglobin decreased, red blood cell count decreased. Includes leukopenia, white blood cell count decreased. Includes platelet count decreased, thrombocytopenia. Includes asthenia, fatigue.

Additional adverse reactions in MONARCH 2 include venous thromboembolic events (deep vein thrombosis, pulmonary embolism, cerebral venous sinus thrombosis, subclavian vein thrombosis, axillary vein thrombosis, and DVT inferior vena cava), which were reported in 5% of patients treated with VERZENIO plus fulvestrant as compared to 0.9% of patients treated with fulvestrant plus placebo. Table 4: Laboratory Abnormalities ≥10% in Patients Receiving VERZENIO Plus Fulvestrant and ≥2% Higher Than Placebo Plus Fulvestrant in MONARCH 2 VERZENIO plus Fulvestrant N=441

Table 3: Adverse Reactions ≥10% in Patients Receiving VERZENIO Plus Fulvestrant and ≥2% Higher Than Placebo Plus Fulvestrant in MONARCH 2 VERZENIO plus Fulvestrant Placebo plus Fulvestrant N=441 N=223 All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 % % % % % % Gastrointestinal Disorders Diarrhea 86 13 0 25 <1 0 Nausea 45 3 0 23 1 0 a Abdominal Pain 35 2 0 16 1 0 Vomiting 26 <1 0 10 2 0 Stomatitis 15 <1 0 10 0 0 Infections and Infestations 43 5 <1 25 3 <1 Infectionsb Blood and Lymphatic System Disorders 46 24 3 4 1 <1 Neutropeniac Anemiad 29 7 <1 4 1 0 28 9 <1 2 0 0 Leukopeniae 16 2 1 3 0 <1 Thrombocytopeniaf General Disorders and Administration Site Conditions 46 3 0 32 <1 0 Fatigueg Edema peripheral 12 0 0 7 0 0 Pyrexia 11 <1 <1 6 <1 0 Metabolism and Nutrition Disorders Decreased appetite 27 1 0 12 <1 0 Respiratory, Thoracic and Mediastinal Disorders Cough 13 0 0 11 0 0 Skin and Subcutaneous Tissue Disorders Alopecia 16 0 0 2 0 0 Pruritus 13 0 0 6 0 0 Rash 11 1 0 4 0 0 Nervous System Disorders Headache 20 1 0 15 <1 0 Dysgeusia 18 0 0 3 0 0 Dizziness 12 1 0 6 0 0 Investigations 13 4 <1 5 2 0 Alanine aminotransferase increased 12 2 0 7 3 0 Aspartate aminotransferase increased Creatinine increased 12 <1 0 <1 0 0 Weight decreased 10 <1 0 2 <1 0 a

Includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, abdominal tenderness.

VERZENIO® (abemaciclib) tablets, for oral use

AL HCP BS 19SEP2019

Placebo plus Fulvestrant N=223

All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 % % % % % % Creatinine increased

White blood cell decreased

Neutrophil count decreased

Anemia

Lymphocyte count decreased

Platelet count decreased

Alanine aminotransferase increased

Aspartate aminotransferase increased

Creatinine Increased Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function. In clinical studies, increases in serum creatinine (mean increase, 0.2 mg/dL) occurred within the first 28-day cycle of VERZENIO dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated glomerular filtration rate (GFR), which are not based on creatinine, may be considered to determine whether renal function is impaired. VERZENIO Administered as a Monotherapy in Metastatic Breast Cancer (MONARCH 1) Patients with HR-positive, HER2-negative breast cancer who received prior endocrine therapy and 1-2 chemotherapy regimens in the metastatic setting Safety data below are based on MONARCH 1, a single-arm, open-label, multicenter study in 132 women with measurable HR+, HER2- metastatic breast cancer. Patients received 200 mg VERZENIO orally twice daily until development of progressive disease or unmanageable toxicity. Median duration of treatment was 4.5 months. Ten patients (8%) discontinued study treatment from adverse reactions due to (1 patient each) abdominal pain, arterial thrombosis, aspartate aminotransferase (AST) increased, blood creatinine increased, chronic kidney disease, diarrhea, ECG QT prolonged, fatigue, hip fracture, and lymphopenia. Forty-nine percent of patients had dose reductions due to an adverse reaction. The most frequent adverse reactions that led to dose reductions were diarrhea (20%), neutropenia (11%), and fatigue (9%). Deaths due to adverse events during treatment or during the 30-day follow up were reported in 2% of patients. Cause of death in these patients was due to infection (2 patients) or pneumonitis (1 patient). The most common reported adverse reactions (≥20%) were diarrhea, fatigue, nausea, decreased appetite, abdominal pain, neutropenia, vomiting, infections, anemia, headache, and thrombocytopenia (Table 5). Severe (Grade 3 and 4) neutropenia was observed in patients receiving abemaciclib. VERZENIO® (abemaciclib) tablets, for oral use

AL HCP BS 19SEP2019

Table 5: Adverse Reactions (≥10% of Patients) in MONARCH 1

All Grades %

VERZENIO N=132 Grade 3 %

Gastrointestinal Disorders Diarrhea 90 Nausea 64 Abdominal pain 39 Vomiting 35 Constipation 17 Dry mouth 14 Stomatitis 14 Infections and Infestations Infections 31 General Disorders and Administration Site Conditions Fatiguea 65 Pyrexia 11 Blood and Lymphatic System Disorders Neutropeniab 37 Anemiac 25 Thrombocytopeniad 20 Leukopeniae 17 Metabolism and Nutrition Disorders Decreased appetite 45 Dehydration 10 Respiratory, Thoracic and Mediastinal Disorders Cough 19 Musculoskeletal and Connective Tissue Disorders Arthralgia 15 Nervous System Disorders Headache 20 Dysgeusia 12 Dizziness 11 Skin and Subcutaneous Tissue Disorders Alopecia 12 Investigations Creatinine increased 13 Weight decreased 14 a b c

d e

Grade 4 % 0 0 0 0 0 0 0

Effect of Other Drugs on VERZENIO

13 0

0 0

19 5 4 5

5 0 0 <1

Other Strong CYP3A Inhibitors In patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the VERZENIO dose to 100 mg twice daily with concomitant use of strong CYP3A inhibitors other than ketoconazole. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the VERZENIO dose to 50 mg twice daily with concomitant use of strong CYP3A inhibitors. If a patient taking VERZENIO discontinues a strong CYP3A inhibitor, increase the VERZENIO dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the inhibitor. Patients should avoid grapefruit products.

3 2

0 0

0 0 0

<1 0

0 0

Table 6: Laboratory Abnormalities for Patients Receiving VERZENIO in MONARCH 1

Creatinine increased White blood cell decreased Neutrophil count decreased Anemia Lymphocyte count decreased Platelet count decreased ALT increased AST increased

DRUG INTERACTIONS

20 5 2 2 <1 0 0

Includes asthenia, fatigue. Includes neutropenia, neutrophil count decreased. Includes anemia, hematocrit decreased, hemoglobin decreased, red blood cell count decreased. Includes platelet count decreased, thrombocytopenia. Includes leukopenia, white blood cell count decreased.

All Grades % 98 91 88 68 42 41 31 30

VERZENIO dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated GFR, which are not based on creatinine, may be considered to determine whether renal function is impaired.

VERZENIO N=132 Grade 3 % <1 28 22 0 13 2 3 4

Grade 4 % 0 0 5 0 <1 0 0 0

CYP3A Inhibitors Strong and moderate CYP3A inhibitors increased the exposure of abemaciclib plus its active metabolites to a clinically meaningful extent and may lead to increased toxicity. Ketoconazole Avoid concomitant use of ketoconazole. Ketoconazole is predicted to increase the AUC of abemaciclib by up to 16-fold.

Moderate CYP3A Inhibitors With concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the VERZENIO dose in 50 mg decrements, if necessary. Strong and Moderate CYP3A Inducers Coadministration of strong or moderate CYP3A inducers decreased the plasma concentrations of abemaciclib plus its active metabolites and may lead to reduced activity. Avoid concomitant use of strong or moderate CYP3A inducers and consider alternative agents. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on findings in animals and its mechanism of action, VERZENIO can cause fetal harm when administered to a pregnant woman. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. In animal reproduction studies, administration of abemaciclib during organogenesis was teratogenic and caused decreased fetal weight at maternal exposures that were similar to human clinical exposure based on AUC at the maximum recommended human dose (see Data). Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. Data Animal Data In an embryo-fetal development study, pregnant rats received oral doses of abemaciclib up to 15 mg/kg/day during the period of organogenesis. Doses ≥4 mg/kg/day caused decreased fetal body weights and increased incidence of cardiovascular and skeletal malformations and variations. These findings included absent innominate artery and aortic arch, malpositioned subclavian artery, unossified sternebra, bipartite ossification of thoracic centrum, and rudimentary or nodulated ribs. At 4 mg/kg/day in rats, the maternal systemic exposures were approximately equal to the human exposure (AUC) at the recommended dose. Lactation Risk Summary There are no data on the presence of abemaciclib in human milk, or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed infants from VERZENIO, advise lactating women not to breastfeed during VERZENIO treatment and for at least 3 weeks after the last dose. Females and Males of Reproductive Potential

Pregnancy Testing Based on animal studies, VERZENIO can cause fetal harm when administered to a pregnant woman. Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with VERZENIO.

VERZENIO® (abemaciclib) tablets, for oral use

AL HCP BS 19SEP2019

Contraception Females VERZENIO can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during VERZENIO treatment and for at least 3 weeks after the last dose. Infertility Males Based on findings in animals, VERZENIO may impair fertility in males of reproductive potential. Pediatric Use The safety and effectiveness of VERZENIO have not been established in pediatric patients. Geriatric Use Of the 900 patients who received VERZENIO in MONARCH 1, MONARCH 2, and MONARCH 3, 38% were 65 years of age or older and 10% were 75 years of age or older. The most common adverse reactions (≥5%) Grade 3 or 4 in patients ≥65 years of age across MONARCH 1, 2, and 3 were neutropenia, diarrhea, fatigue, nausea, dehydration, leukopenia, anemia, infections, and ALT increased. No overall differences in safety or effectiveness of VERZENIO were observed between these patients and younger patients. Renal Impairment No dosage adjustment is required for patients with mild or moderate renal impairment (CLcr ≥30-89 mL/min, estimated by Cockcroft-Gault [C-G]). The pharmacokinetics of abemaciclib in patients with severe renal impairment (CLcr <30 mL/min, C-G), end stage renal disease, or in patients on dialysis is unknown. Hepatic Impairment No dosage adjustments are necessary in patients with mild or moderate hepatic impairment (Child-Pugh A or B). Reduce the dosing frequency when administering VERZENIO to patients with severe hepatic impairment (Child-Pugh C). OVERDOSAGE There is no known antidote for VERZENIO. The treatment of overdose of VERZENIO should consist of general supportive measures. Rx only. Additional information can be found at www.verzenio.com.

AL HCP BS 19SEP2019

CARTA AL EDITOR Resumen La organización FER fue creada con el propósito de ser un ente que facilite la canalización de servicios y educación para pacientes con condiciones reumáticas y para promover la investigación que redunden en el desarrollo de nuevos tratamientos que aporten al bienestar general del paciente con condiciones reumáticas para que alcancen una vida más saludable, activa y productiva. Palabras clave FER, condiciones reumáticas, investigación

esde el nacimiento de FER en el 2009, se ha evidenciado que en la unión está la fuerza, partiendo de los derechos del paciente. Son pocos los que se atreven a hablar de la condición que le aqueja, y más aquella que toma la decisión de que un día no se levante de la cama, no pueda abrocharse los botones de su camisa y padezca de dolor crónico. Precisamente es lo que ha promovido FER desde entonces, el que los pacientes se unan y estén mano a mano con los médicos especialistas y que logren liberarse de tabúes y se empoderen de su condición, según ha sido enfático del Dr. Oscar Soto Raíces, quien preside la Junta de la organización. Junto a la directora ejecutiva de la organización, Griselle Lugo, han logrado educar no solo a los pacientes, sino a un país entero de que existen más de 100 condiciones reumáticas de las que hay que generar conciencia porque pudieran pasar desapercibidas tanto a nivel médico como a nivel del apoyo familiar tan trascendental para el control de las mismas. Por lo tanto, por segundo año consecutivo la Fundación de Enfermedades Reumáticas 72

(FER) logró aglutinar a los principales reumatólogos del país al servicio de ciento pacientes que se conectaron al evento de manera virtual para tener acceso directo a estos especialistas y expresarle sus principales dudas. Precisamente el logro surge de la constante necesidad de mantener a los pacientes educados para que puedan sobrellevar la enfermedad, sobre todo en tiempo donde el miedo y el estrés por los contagios ocasionados por el virus COVID19 son parte del día a día. Como colateral a esto se le ha unido el retraso en la atención médica que han sufrido muchos pacientes, lo que a su vez ha provocado la exacerbación de sus enfermedades, obligando a los médicos a utilizar medidas clínicas más agresivas en búsqueda del control de la salud de esta población y ofrecer herramientas adicionales para manejar el estrés, factor de riesgo que funge como catalítico de las enfermedades autoinmunes. Debido a estas necesidades, la actividad incluyó a especialistas de los Estados Unidos, entre ellos, el Dr. Daniel Hernández, director médico y enlace de la comunidad de habla hispana de Creaky Joints y el Dr. Guillermo Valenzuela,

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director del Instituto de Medicinas Alternativas (IRIS). Adicional a estos conferenciantes, fueron el Dr. Ramón Ortega, Dra. Noemí Varela, Dra. Elivette Zambrana, entre otros especialistas en reumatología. El evento contó con cuatro horas de transmisión en vivo ininterrumpidas a través de las plataformas de redes sociales tanto de FER, la Revista Medicina y Salud Pública y la emisora Radio Isla 1320. Además se presentaron cápsulas informativas animadas y con intermedios musicales y de comedia, para el deleite y educación de todos los pacientes conectados. El evento culminó con un mensaje del Presidente de FER, el Dr. Soto Raíces, sobre la continuación de esta actividad el próximo año y que la misma podrá ser presencial, dependiendo del estatus y regulaciones relacionadas a la pandemia de Covid 19. Pero lo más importante, es que sin importar las limitaciones, FER ha logrado romper los paradigmas y demostrar que la unión médico paciente puede ser real. Referencia Revista de Medicina y Salud Pública. MSP Pacientes.

MSP ARTÍCULO / MÉDICO

LA EVOLUCIÓN EN EL TRATAMIENTO DE ARTRITIS REUMATOIDE

a artritis Reumatoide (AR), es una condición autoinmune, crónica y sistémica. Proviene de una falla en el sistema inmune en donde el sistema pierde su capacidad para regularse. Esto produce inflamación descontrolada y persistente en la membrana sinovial de las articulaciones, así como en otros tejidos como pulmón, ojos y vasos sanguíneos entre otros. La artritis reumatoide es la artritis inflamatoria crónica más prevalente. La sinovitis crónica que resulta de esta inflamación puede llevar a la destrucción del cartílago y hueso, causando subluxación y deformidad, así como pérdida de 74

espacio en la articulación lo que lleva a la disminución de rango de movimiento de la articulación afectada. Esto se traduce en pérdida de función e incapacidad. Es una condición heterogénea que requiere el uso de múltiples terapias con diferentes modos de acción para lograr la remisión o al menos una actividad baja de la inflamación. No hay biomarcadores específicos disponibles o de fácil uso hoy en día que permitan decidir cuál es la mejor droga para cada individuo que padece de la condición excepto una prueba para predecir la respuesta de los pacientes a un anti-TNF (PrismRA).

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Si usamos otros biomarcadores como el anti-CCP Ab y RF para predecir severidad y prognosis y ayudarnos a dirigir el tratamiento. En las últimas dos décadas, el tratamiento de la artritis ha evolucionado significativamente y han cambiado los algoritmos de terapia con estrategias de tratamiento dirigido conocido como “treat to target” con metas mas especificas con la remisión como meta final. La introducción de tratamiento con biológicos y antirreumáticos no biológicos ha cambiado de forma significativa las expectativas y prognosis en el tratamiento. Con el fin de prevenir

ARTÍCULO / MÉDICO DR. ÓSCAR SOTO RAÍCES, Reumatólogo y Presidente de la Fundación de Enfermedades Reumáticas (FER)

el daño estructural a las articulaciones, la pérdida de función y mantener la calidad de vida, los pacientes con artritis reumatoide se tratan más temprano y de forma más agresiva. Para lograr esto es necesario utilizar medicamentos modificadores de la condición temprano en el tratamiento. Metotrexato como medicamento modificador de la condición de base. El metotrexato (MTX) sigue siendo la primera opción en el tratamiento de la artritis reumatoide, ya que es eficaz en la mayoría de los pacientes y aproximadamente una cuarta parte podrían lograr remisión. Por esta razón se considera un medicamento modificador de la condición. Tiene un perfil de toxicidad aceptable y bajos costos. En el manejo de la AR temprana, MTX es recomendado como un fármaco de primera línea por el Colegio Americano de Reumatología (ACR) y la Liga Europea contra el Reumatismo (EULAR). Ha demostrado ser eficaz en monoterapia y también es medicamento de base para las terapias combinadas. Cuando el metrotexato no logra controlar la artritis de forma efectiva y/o no se alcanza la remisión se recurre al uso de biológicos modificadores u otros modificadores sintéticos específicos que actúan como inmuno moduladores. Ambos grupos de medicamentos se pueden usar como monoterapia o en combinación con metrotexato para lograr el mejor control y la remisión de la condición. Los agentes biológicos modificadores de la condición son mayormente anticuerpos monoclonales o receptores que atacan específicamente una molécula en la superficie de la célula soluble ya sea una citosina, un receptor de citosinas o algún antígeno en la membrana celular. Deben ser administrados de forma intravenosa

o subcutánea ya que son proteínas. No entran a la célula, pero ejercen su función a través de receptores extracelulares o en la superficie de la célula. Los inhibidores sintéticos específicos como los inhibidores de JAK. Son moléculas orales pequeñas que actúan de forma intracelular y de forma reversible previniendo la fosforilación de enzimas quinasas conocidas como JAK. Estas enzimas actúan activando de forma intracelular los receptores de citosinas no dependientes de quinasas de tirosina causando forsforilación del receptor y activando a su vez otras proteínas intracelulares que penetran el núcleo para activar la transcripción genética. Existen varias familias de medicamentos con distintos objetivos (targets) moleculares disponibles para el tratamiento de la AR: Agentes inhibidores de TNF-alpha El factor de necrosis de tumor (TNF) es un citosina pro-inflamatoria que desempeña un papel importante en la inflamación crónica en AR. La inhibición de TNF mejora las manifestaciones clínicas del RA y reduce la progresión radiográfica. Existen agentes biológicos dirigidos al TNF aprobados para el tratamiento de la AR: infliximab (INF), etanercept (ETN), adalimumab (ADA), certolizumab (CMZ) y golimumab (GLM). Varios ensayos clínicos de estos compuestos mostraron eficacia excelente en RA von disminucion de síntomas clínicos y retardo o arresto de la progresión radiografica y un perfil de riesgo aceptable al usarlos en combinación con metotrexato. Infliximab fue el primer inhibidor alfa de TNF (TNFi) desarrollado. Es un anticuerpo monoclonal quimérico y requiere aplicación intravenosa cada 4-8 semanas. Etanercept es una proteína de fusión del receptor soluble de TNF y la porción fc de inmunoglobu-

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MSP ARTÍCULO / MÉDICO lina, tiene la vida media más corta de TNFi disponible y se administra por vía subcutánea. Adalimumab es un anticuerpo monoclonal completamente humano que se une al TNF. Certolizumab pegol es un fragmento de Fab anti-TNF pegilado y humanizado. Su estructura lo hace diferente de otros TNFi. Porque tiene mínima a ninguna transferencia placentaria activa, el análisis de los resultados del embarazo favorece a esta droga con respecto a efecto teratogénico y al riesgo de muerte fetal. Golimumab es un anticuerpo monoclonal totalmente humanizado. Las comparaciones basadas en análisis de datos indirectos y retrospectivos han demostrado que la eficacia del anti-TNF parece ampliamente similar entre los cinco fármacos. Sin embargo, las características de algunos pacientes podrían sugerir que un inhibidor de TNF es más favorable sobre el otro. Los datos relativos a la seguridad también parecen comparables entre ellos. Un meta análisis de ensayos clínicos de control aleatorios de pacientes con AR tratados con anti-TNF demostró un mayor riesgo de infección grave y de interrupción del tratamiento debido a eventos adversos en comparación con placebo y los tratamientos farmacológicos antirreumáticos modificadores de la enfermedad tradicionales. Bloqueo co-estimulatorio de células T (CD80/86) Abatacept es una proteína de fusión completamente humana que inhibe la segunda señal requerida para la activación de las células T (al unirse a los antígenos co - estimulatorios CD80 y CD86). Primero fue desarrollado en la formulación intravenosa y luego subcutánea. Abatacept reduce la actividad de la enfermedad en pacientes con respuesta inadecuada a y a inhibidores de TNF. Varios estudios reducción del daño articular radiográfico en pacientes tratados con Abatacept. El estudio ATTEST evaluó abatacept e infliximab frente a placebo en pacientes con AR con respuesta inadecuada al MTX. Después de un año, los eventos adversos, las infecciones graves y las interrupciones debidas al AE fueron menores con abatacept que con infliximab, mostrando

un perfil de seguridad y tolerabilidad más aceptable para este fármaco. El ensayo AMPLE (cabeza a cabeza que comparó abatacept y adalimumab ambos combinados con MTX) mostró una eficacia similar basada en el resultado clínico funcional y radiográfico. A pesar de que la frecuencia de AE fue similar en ambos grupos, hubo menos interrupciones debido a AEs e infecciones graves y menos reacciones locales en el sitio de inyección con abatacept, favoreciendo este fármaco. Inhibidores de interleucina 6 (IL-6) Hay dos fármacos antagonistas de los receptores de interleucina 6 (anti-IL6) aprobados para el tratamiento de la AR. El tocilizumab (TCZ) es un anticuerpo monoclonal completamente humanizado dirigido contra el receptor de IL-6 que se puede administrar por vía intravenosa o subcutánea, y sarilumab, un anticuerpo monoclonal humano dirigido contra la subunidad alfa del complejo receptor de IL-6. Ambas drogas demostraron ser eficaces para los pacientes con respuesta inadecuada a los csDMARDs (drogas antirreumáticas de modificación de la enfermedad sintética convencional) y a los inhibidores de TNF. El estudio ACT-RAY mostró que no había superioridad relevante de TCZ + MTX en comparación con la monoterapia TCZ con respecto a las respuestas clínicas y radiográficas en pacientes con MTX-IR. Como consecuencia, los anti-IL6 han sido recomendados por las guías EULAR en pacientes en monoterapia. Ambas drogas se han comparado con un tratamiento anti-TNF en monoterapia con resultados que favorecen el uso de anti-IL6 como monoterapia ara el tratamiento de la AR. Rituximab (anti-CD20) Rituximab es un anticuerpo monoclonal quimérico dirigido contra CD20 que produce el agotamiento o depleción de células B. Su eficacia se ha demostrado en pacientes que no respondieron a los otros medicamentos modicadores de la condición no biológico. Los pacientes seropositivos tienden a responder mejor a Rituximab que los pacientes seronegativos. El evento adverso más frecuente con Rituximab es la reacción a la

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infusión. Aunque esta droga produce un agotamiento prolongado de células B, el riesgo para la infección seria era similar entre el placebo y los grupos de RXT. Moléculas pequeñas: Inhibidores de la quinasa de Janus Los inhibidores de la quinasa de Janus (JAKi) son la clase más nueva de medicamentos para el tratamiento del RA. Hay cuatro tipos diferentes de proteínas JAKs: JAK1, JAK2, JAK3 y Tyk2 (tirosina quinasa) y hasta ahora, 3 inhibidores diferentes de JAKs están aprobados por la FDA para el tratamiento de la AR: Tofacitinib, Baricitinib y Upadacitinib. Todos estos medicamentos han probado ser útiles en le tratamiento de AR y en retardar o detener la progresión de la condición. Terapias emergentes Existen terapias con mecanismos de acción prometedores en proceso de investigación para ser aprobados para el tratamiento de AR. Otilimab es un anticuerpo monoclonal que inhibe GM-CSF (granulocyte-macrophage colony-stimulating factor), un mediador importante de la respuesta inmune en condiciones inflamatorias. En un estudio fase 2, Otilimab con metotrexate fue bien tolerado y a pesar de no haber alcanzado su objetivo primario, DAS28-CRP remisión, si hubo mejoría al compararlo con placebo en distintas medidas de actividad física como dolor y función física. Esto llevo a un estudio fase 3 el cual se esta llevando a cabo en estos momentos en donde se compara el compuesto vs placebo y otros dos protocolos en donde se compara con tofacitinib y contra sarilumab. ABX464 es una molécula pequeña que produce una inducción selectiva y específica de miR-124. Un crucial modulador de inflamación en las células del sistema inmune innato que puede proveer una regulacion terapéutica de los tractos fisiológicos afectados en las condiciones inflamatorias. Un estudio fase 2 investiga la seguridad y tolerabilidad de este compuesto en combinación con metotrexato en pacientes con artritis reumatoide de moderada a severa. Iscalimab (CFZ533) es un anticuerpo monoclonal que bloquea el tracto de

ARTÍCULO / MÉDICO activación de CD154-CD40 ya está haciendo desarrollado como un agente inmuno-suspresivo. El tracto de co-estimulación de CD40-CD154 es esencial para la generación de respuesta de anticuerpos dependientes de células T, formación de centros germinales y diferenciación de células B de memoria. En los macrófagos y células dendríticas regula la activación y diferenciación, así como la presentación de antígenos a células T. Debido al mecanismo de acción Iscalimab presenta una terapia prometedora en rechazo de trasplante y desórdenes autoinmunes. Esta terapia se encuentra en etapa fase 1 de investigación para enfermedades como artritis reumatoide, nefritis lúpica y syndrome de Sjogren’s entre otros. Olokizumab es un anticuerpo monoclonal que bloquea interleucina 6. Cuatro estudios clínicos en el momento evalúan su efectividad en artritis reumatoide de moderada a severa en adultos para los cuales Metotrexato no es adecuado o han presentado una respuesta inadecuada a un inhibidor de TNF. Los tratamientos aquí discutidos aumentan la probabilidad de manejar la condición de manera exitosa. La evolución de medicamentos que modulan áreas específicas del sistema inmune ofrece opciones de tratamiento que nos ayudan a individualizar el tratamiento y tener más probabilidades de lograr remisión. Es importante de recordar que el diagnóstico temprano de la AR es sumamente importante, así como el tratamiento adecuado para lograr la remisión clínica y mantener al paciente funcionando sin ninguna o con las menores limitaciones posibles. Las opciones de tratamientos de artritis reumatoide continúan evolucionando y ofrecen mas herramientas para ofrecer una terapia mas dirigida, especifica e individualizada. Con la excelente respuesta que se logra hoy día al usar estos tratamientos podríamos entonces preguntarnos... ¿Estamos cerca de encontrar la cura para la AR? No tenemos una cura en el futuro cercano para AR pero ciertamente estamos mas cerca y los avances no cesan en la identificación de células y

proteínas del sistema inmune que son importantes en la pato fisiología de esta enfermedad. Esto lleva a seguir desarrollando nuevos objetivos para regular el sistema inmune y reducir la inflamación que afecta las articulaciones y el sistema en general en pacientes con AR. En el futuro esperamos tener disponibles mas biomarcadores que nos ayuden a escoger el medicamento apropiado para el paciente que padece de artritis reumatoide. Referencias Caporali R, Fakhouri WKH, Nicolay C, Longley HJ, Losi S, Rogai V. New Rheumatoid Arthritis Treatments for 'Old' Patients: Results of a Systematic Review. Adv Ther. 2020 Sep;37(9):3676-3691. doi: 10.1007/s12325- 020 - 01435- 6. Epub 2020 Jul 23. PMID: 32705531; PMCID: PMC7444401. Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020;79(6):685–699. doi:10.1136/annrheumdis-2019-216655 Smolen JS, Breedveld FC, Burmester GR, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis. 2016;75(1):3–15. doi:10.1136/annrheumdis-2015-207524 Jasvinder AS, Kenneth GS, Louis Bridges JR, et al. 2015 American college of rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res. 2016;68(1):1–25. doi:10.1002/ acr.22783 van Vollenhoven RF, Geborek P, Forslind K, et al. Conventional combination treatment versus biological treatment in methotrexate - refrac tory early rheumatoid arthritis: 2 years follow-up of the randomised, non-blinded, parallel-group Swefot trial. Lancet. 2012;379(9827):1712–1720. doi:10.1016/S0140-6736(12)60027-0 Katchamart W, Trudeau J, Phumethum V, et al. Efficacy and toxicity of methotrexate (MTX) monotherapy versus MTX combination therapy with non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systematic review and meta-analysis. Ann Rheum

Dis. 2009;68(7):1105–1112. doi:10.1136/ ard.2008.099861 Bucley CD. Efficacy, patient-reported outcomes, and safety of the anti-granulocyte macrophage colony-stimulating factor antibody otilimab (GSK3196165) in patients with rheumatoid arthritis: a Randomised, Phase 2b, Dose-Ranging Study. Lancet. 2020;2:E677–E688. Genovese MC, Fleischmann R, Furst D, et al. Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a Randomised Phase IIb Study. Ann Rheum Dis. 2014;73(9):1607–1615. doi:10.1136/ annrheumdis-2013-204760 Begon-Pescia C, Campos N, Apolit C, Garcel A, Scherrer D. Specific and selective induction of miR-124 in immune cells by the quinoline ABX464: a transformative therapy for inflammatory diseases. Drug Discov Today. 2021. Espié P, He Y, Koo P, et al. First-inhuman clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody. Am J Transplant. 2020;20(2):463– 473. doi:10.1111/ ajt.15661 Mellors T, et al. Clinical validation of a blood-based predictive test for stratification of response to tumor necrosis factor inhibitor therapies in rheumatoid arthritis patients. Netw Syst Med. 2020; 3(1):91104.

Revista Puertorriqueña de Medicina y Salud Pública

ADAPTEMOS NUESTROS SERVICIOS Y CONSTRUYAMOS UNA SOCIEDAD MÁS RESPONSIVA A LAS NECESIDADES DEL ADULTO MAYOR

Revista Puertorriqueña de Medicina y Salud Pública

ada etapa de vida tiene sus retos y experiencias que la distinguen. Los adultos mayores podrían presentar necesidades particulares tanto físicas, emocionales y sociales. Ante cada una de estas situaciones, es importante adaptar los servicios, accesos y programas, garantizándoles una mejor calidad de vida. Firme en su compromiso con la población de adultos mayores en Puerto Rico, MCS Classicare (OSS) cuenta con programas dedicados a atender las necesidades de esta población y que enfocan cada uno de los esfuerzos en coordinar y facilitar los accesos a los servicios médicos, clínicos y sociales que necesitan. A través del programa de Alcance Comunitario, MCS identifica las necesidades no clínicas y sociales de sus afiliados para así ayudarles a mantener un estado de salud optimo y mejorar su calidad de vida. Tras identificar las necesidades de estos afiliados, el programa de Alcance Comunitario trabaja mano a mano en la coordinación de servicios con agencias públicas y privadas, los municipios y las entidades sin fines de lucro dedicadas a apoyarlos. De este

modo junto a otros programas de MCS, se complementa la atención del cuidado holístico de la salud de sus afiliados. Internamente, Alcance Comunitario trabaja de manera integrada con el personal de los programas clínicos y de servicio al cliente, así como con los médicos, proveedores de servicios de salud física y mental, entre otros. Esto contribuye a que se minimice la fragmentación de servicios, a la vez que aumenta la efectividad en el cuidado de salud del afiliado. Entre tanto, MCS Classicare ofrece a sus afiliados programas de bienestar con intervenciones multidimensionales enfocadas en educarlos, motivarlos y brindarles experiencias que les ayuden a mantener su salud mental y emocional en buen estado, así como a prevenir la ocurrencia o el progreso de condiciones crónicas. A través de material escrito y charlas educativas, talleres de jardinería y nutrición, y actividades virtuales para fortalecer su condición física a través del Club Te Paga, entre otras iniciativas; se les apoya para que mantengan su calidad de vida y continúen viviendo un estilo de vida saludable.

El espectro de necesidades de cuidado que presenta la población del adulto mayor es amplio. Es responsabilidad de todos como sociedad facilitarle a esta población las herramientas y el acceso a los servicios que requieren para atender todas sus necesidades. A través de sus programas de bienestar y manejo clínico, MCS Classicare ha reiterado por años su compromiso con atender las diversas necesidades de la población Medicare en Puerto Rico. De esta forma, la compañía cumple su misión de proveer cuidado genuino a sus afiliados y aporta a la construcción de una sociedad más responsiva a las necesidades de una población envejeciente. Para recibir información y material educativo de los programas de bienestar de MCS Classicare y ser parte de MCS Club Te Paga, visita www.mcsclassicare.com o a través de la página de Facebook en MCSPuertoRico.

MCS Classicare es un plan OSS suscrito por MCS Advantage, Inc.

Revista Puertorriqueña de Medicina y Salud Pública

DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj): subcutaneous administration in ~3 to 5 minutes1

SAME POWERFUL EFFICACY. FASTER ADMINISTRATION. * 1,2

Approved across 6 indications spanning a wide range of multiple myeloma patients1

INDICATIONS DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) is indicated for the treatment of adult patients with multiple myeloma: ®

• In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant • In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy • In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant • In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy • As monotherapy in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS DARZALEX FASPRO ® is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase, or any of the components of the formulation.

WARNINGS AND PRECAUTIONS Hypersensitivity and Other Administration Reactions Both systemic administration-related reactions, including severe or life-threatening reactions, and local injection-site reactions can occur with DARZALEX FASPRO ®.

Systemic Reactions In a pooled safety population of 683 patients with multiple myeloma (N=490) or light chain (AL) amyloidosis (N=193) who received DARZALEX FASPRO® as monotherapy or in combination, 10% of patients experienced a systemic administration-related reaction (Grade 2: 3.5%, Grade 3: 1%). Systemic administration-related reactions occurred in 9% of patients with the first injection, 0.4% with the second injection, and cumulatively 0.8% with subsequent injections. The median time to onset was 3.2 hours (range: 9 minutes to 3.5 days). Of the 117 systemic administration-related reactions that occurred in 66 patients, 100 (85%) occurred on the day of DARZALEX FASPRO® administration. Delayed systemic administrationrelated reactions have occurred in less than 1% of the patients. Severe reactions included hypoxia, dyspnea, hypertension, and tachycardia. Other signs and symptoms of systemic administrationrelated reactions may include respiratory symptoms, such as bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis, and wheezing, as well as anaphylactic reaction, pyrexia, chest pain, pruritus, chills, vomiting, nausea, and hypotension. Pre-medicate patients with histamine-1 receptor antagonist, acetaminophen, and corticosteroids. Monitor patients for systemic administration-related reactions, especially following the first and second injections. For anaphylactic reaction or life-threatening (Grade 4) administration-related reactions, immediately and permanently discontinue DARZALEX FASPRO®. Consider administering corticosteroids and other medications after the administration of DARZALEX FASPRO® depending on dosing regimen and medical history to minimize the risk of delayed (defined as occurring the day after administration) systemic administration-related reactions. Local Reactions In this pooled safety population, injection-site reactions occurred in 9% of patients, including Grade 2 reactions in 0.7%. The most frequent (>1%) injection-site reaction was injection-site erythema. These local reactions occurred a median of 5 minutes (range: 0 minutes to 4.7 days) after starting administration of DARZALEX FASPRO®. Monitor for local reactions and consider symptomatic management.

DARZALEX FASPRO®: For a strong start to their treatment journey ~3 to 5 minute administration • Subcutaneous injection is substantially faster than intravenous daratumumab1,2 The recommended dose of DARZALEX FASPRO® is 1,800 mg daratumumab and 30,000 units hyaluronidase administered subcutaneously over ~3 to 5 minutes. DARZALEX FASPRO® is for subcutaneous use only. Do not administer intravenously.1 See the Dosage and Administration section of the Prescribing Information for dosing considerations and dosing schedules for approved regimens. See Important Safety Information below for hypersensitivity and administration reactions, pre-medication and post-medication requirements, and other important considerations for use of DARZALEX FASPRO®.

Get the latest data and information at darzalexhcp.com/faspro Contact your Oncology Specialist to learn more about DARZALEX FASPRO ®

Efficacy consistent with intravenous daratumumab

Fewer systemic ARRs vs intravenous daratumumab

• DARZALEX FASPRO® demonstrated a non-inferior overall response rate (ORR) vs intravenous daratumumab in an open-label, randomized study assessing monotherapy in 522 patients1

• Nearly 3x reduction in systemic administration-related reactions† (ARRs) with DARZALEX FASPRO® vs intravenous daratumumab observed in the COLUMBA trial (13% of patients on DARZALEX FASPRO® had a systemic ARR of any grade vs 34% with intravenous daratumumab)1,3

– ORR was 41% (95% CI: 35%, 47%) for DARZALEX FASPRO® (n=263) and 37% (95% CI: 31%, 43%) for intravenous daratumumab (n=259)1 – Eligible patients were required to have relapsed or refractory multiple myeloma who had received ≥3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who were double-refractory to a PI and an immunomodulatory agent1 • In a single arm of a multicohort, open-label trial, DARZALEX FASPRO® with lenalidomide and dexamethasone (DRd) was evaluated in 65 patients with multiple myeloma who had received ≥1 prior multiple myeloma therapy. The ORR was 91% (95% CI: 81%, 97%)1

• Both systemic ARRs, including severe or life-threatening reactions, and local injection-site reactions can occur with DARZALEX FASPRO®. See Important Safety Information for more details1 *For intravenous daratumumab, median durations of 16 mg/kg infusions for the first, second, and subsequent infusions were approximately 7, 4, and 3 hours, respectively.2 In clinical trials of DARZALEX FASPRO ®, DARZALEX® (daratumumab), and the Prescribing Information for DARZALEX®, the term “infusion reactions” was used instead of “systemic administration-related reactions.”

†

• In a single arm of a multicohort, open-label trial, DARZALEX FASPRO® with bortezomib, melphalan, and prednisone (DVMP) was evaluated in 67 patients with newly diagnosed multiple myeloma who were ineligible for a transplant. The ORR was 88% (95% CI: 78%, 95%)1

Neutropenia Daratumumab may increase neutropenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX FASPRO® until recovery of neutrophils. In lower body weight patients receiving DARZALEX FASPRO®, higher rates of Grade 3-4 neutropenia were observed. Thrombocytopenia Daratumumab may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Consider withholding DARZALEX FASPRO® until recovery of platelets. Embryo-Fetal Toxicity Based on the mechanism of action, DARZALEX FASPRO ® can cause fetal harm when administered to a pregnant woman. DARZALEX FASPRO ® may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX FASPRO ® and for 3 months after the last dose. The combination of DARZALEX FASPRO® with lenalidomide or thalidomide is contraindicated in pregnant women because lenalidomide and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide or thalidomide prescribing information on use during pregnancy. Interference With Serological Testing Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab administration. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type are not impacted.

Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX FASPRO®. Type and screen patients prior to starting DARZALEX FASPRO®. Interference With Determination of Complete Response Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some DARZALEX FASPRO® -treated patients with IgG kappa myeloma protein.

ADVERSE REACTIONS In multiple myeloma, the most common adverse reaction (≥20%) with DARZALEX FASPRO® monotherapy is upper respiratory tract infection. The most common adverse reactions with combination therapy (≥20% for any combination) include fatigue, nausea, diarrhea, dyspnea, insomnia, pyrexia, cough, muscle spasms, back pain, vomiting, upper respiratory tract infection, peripheral sensory neuropathy, constipation, and pneumonia. The most common hematology laboratory abnormalities (≥40%) with DARZALEX FASPRO® are decreased leukocytes, decreased lymphocytes, decreased neutrophils, decreased platelets, and decreased hemoglobin. Please see Brief Summary on adjacent pages. cp-143279v2 References: 1. DARZALEX FASPRO® [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc. 2. DARZALEX® [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc. 3. Mateos M-V, Nahi H, Legiec W, et al. Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial. Lancet Haematol. 2020. doi: 10.1016/S2352-3026(20)30070-3. [Epub ahead of print]

DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) injection, for subcutaneous use Brief Summary of Full Prescribing Information INDICATIONS AND USAGE Multiple Myeloma DARZALEX FASPRO is indicated for the treatment of adult patients with multiple myeloma: • in combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant. • in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy. • in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant. • in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy. • as monotherapy, in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent. Light Chain Amyloidosis DARZALEX FASPRO in combination with bortezomib, cyclophosphamide and dexamethasone is indicated for the treatment of adult patients with newly diagnosed light chain (AL) amyloidosis. This indication is approved under accelerated approval based on response rate [see Clinical Studies (14.1) in Full Prescribing Information]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). Limitations of Use DARZALEX FASPRO is not indicated and is not recommended for the treatment of patients with light chain (AL) amyloidosis who have NYHA Class IIIB or Class IV cardiac disease or Mayo Stage IIIB outside of controlled clinical trials [see Warnings and Precautions]. CONTRAINDICATIONS DARZALEX FASPRO is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase or any of the components of the formulation [see Warnings and Precautions and Adverse Reactions]. WARNINGS AND PRECAUTIONS Hypersensitivity and Other Administration Reactions Both systemic administration-related reactions, including severe or lifethreatening reactions, and local injection-site reactions can occur with DARZALEX FASPRO. Systemic Reactions In a pooled safety population of 683 patients with multiple myeloma (N=490) or light chain (AL) amyloidosis (N=193) who received DARZALEX FASPRO as monotherapy or as part of a combination therapy, 10% of patients experienced a systemic administration-related reaction (Grade 2: 3.5%, Grade 3: 1%). Systemic administration-related reactions occurred in 9% of patients with the first injection, 0.4% with the second injection, and cumulatively 1% with subsequent injections. The median time to onset was 3.2 hours (range: 9 minutes to 3.5 days). Of the 117 systemic administration-related reactions that occurred in 66 patients, 100 (85%) occurred on the day of DARZALEX FASPRO administration. Delayed systemic administration-related reactions have occurred in 1% of the patients. Severe reactions included hypoxia, dyspnea, hypertension and tachycardia. Other signs and symptoms of systemic administration-related reactions may include respiratory symptoms, such as bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis, and wheezing, as well as anaphylactic reaction, pyrexia, chest pain, pruritus, chills, vomiting, nausea, and hypotension. Pre-medicate patients with histamine-1 receptor antagonist, acetaminophen and corticosteroids [see Dosage and Administration (2.5) in Full Prescribing Information]. Monitor patients for systemic administration-related reactions, especially following the first and second injections. For anaphylactic reaction or life-threatening (Grade 4) administration-related reactions, immediately and permanently discontinue DARZALEX FASPRO. Consider administering corticosteroids and other medications after the administration of DARZALEX FASPRO depending on dosing regimen and medical history to minimize the risk of delayed (defined as occurring the day after administration) systemic administration-related reactions [see Dosage and Administration (2.5) in Full Prescribing Information]. Local Reactions In this pooled safety population, injection-site reactions occurred in 9% of patients, including Grade 2 reactions in 0.7%. The most frequent (>1%) injection-site reaction was injection site erythema. These local reactions occurred a median of 5 minutes (range: 0 minutes to 4.7 days) after starting administration of DARZALEX FASPRO. Monitor for local reactions and consider symptomatic management.

DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) injection Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis Serious or fatal cardiac adverse reactions occurred in patients with light chain (AL) amyloidosis who received DARZALEX FASPRO in combination with bortezomib, cyclophosphamide and dexamethasone [see Adverse Reactions]. Serious cardiac disorders occurred in 16% and fatal cardiac disorders occurred in 10% of patients. Patients with NYHA Class IIIA or Mayo Stage IIIA disease may be at greater risk. Patients with NYHA Class IIIB or IV disease were not studied. Monitor patients with cardiac involvement of light chain (AL) amyloidosis more frequently for cardiac adverse reactions and administer supportive care as appropriate. Neutropenia Daratumumab may increase neutropenia induced by background therapy [see Adverse Reactions]. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX FASPRO until recovery of neutrophils. In lower body weight patients receiving DARZALEX FASPRO, higher rates of Grade 3-4 neutropenia were observed. Thrombocytopenia Daratumumab may increase thrombocytopenia induced by background therapy [see Adverse Reactions]. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Consider withholding DARZALEX FASPRO until recovery of platelets. Embryo-Fetal Toxicity Based on the mechanism of action, DARZALEX FASPRO can cause fetal harm when administered to a pregnant woman. DARZALEX FASPRO may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX FASPRO and for 3 months after the last dose [see Use in Specific Populations]. The combination of DARZALEX FASPRO with lenalidomide or thalidomide is contraindicated in pregnant women, because lenalidomide and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide or thalidomide prescribing information on use during pregnancy. Interference with Serological Testing Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab administration. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum [see References]. The determination of a patient’s ABO and Rh blood type are not impacted [see Drug Interactions]. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX FASPRO. Type and screen patients prior to starting DARZALEX FASPRO [see Dosage and Administration (2.1) in Full Prescribing Information]. Interference with Determination of Complete Response Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein [see Drug Interactions]. This interference can impact the determination of complete response and of disease progression in some DARZALEX FASPRO-treated patients with IgG kappa myeloma protein. ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hypersensitivity and Other Administration Reactions [see Warning and Precautions]. • Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis [see Warning and Precautions]. • Neutropenia [see Warning and Precautions]. • Thrombocytopenia [see Warning and Precautions]. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Newly Diagnosed Multiple Myeloma In Combination with Bortezomib, Melphalan and Prednisone The safety of DARZALEX FASPRO with bortezomib, melphalan and prednisone (D-VMP) was evaluated in a single-arm cohort of PLEIADES [see Clinical Studies (14.1)]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to 6, once every 3 weeks from weeks 7 to 54 and once every 4 weeks starting with week 55 until disease progression or unacceptable toxicity (N=67) in combination with bortezomib, melphalan and prednisone. Among these patients, 93% were exposed for 6 months or longer and 19% were exposed for greater than one year.

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DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) injection

Serious adverse reactions occurred in 39% of patients who received DARZALEX FASPRO. Serious adverse reactions in >5% of patients included pneumonia and pyrexia. Fatal adverse reactions occurred in 3% of patients. Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 4.5% of patients. The adverse reaction resulting in permanent discontinuation of DARZALEX FASPRO in more than 1 patient was neutropenic sepsis. Dosage interruptions (defined as dose delays or skipped doses) due to an adverse reaction occurred in 51% of patients who received DARZALEX FASPRO. Adverse reactions requiring dosage interruptions in >5% of patients included thrombocytopenia, neutropenia, anemia, and pneumonia. The most common adverse reactions (≥20%) were upper respiratory tract infection, constipation, nausea, fatigue, pyrexia, peripheral sensory neuropathy, diarrhea, cough, insomnia, vomiting, and back pain. Table 1 summarizes the adverse reactions in patients who received DARZALEX FASPRO with bortezomib, melphalan and prednisone (D-VMP) in PLEIADES. Table 1: Adverse Reactions (≥10%) in Patients Who Received DARZALEX FASPRO with Bortezomib, Melphalan and Prednisone (D-VMP) in PLEIADES DARZALEX FASPRO with Bortezomib, Melphalan and Prednisone (N=67) Adverse Reaction All Grades (%) Grades ≥3 (%) Infections 39 0 Upper respiratory tract infectiona Bronchitis 16 0 Pneumoniab 15 7# Gastrointestinal disorders Constipation 37 0 Nausea 36 0 Diarrhea 33 3# Vomiting 21 0 Abdominal painc 13 0 General disorders and administration site conditions 36 3 Fatigued Pyrexia 34 0 Edema peripherale 13 1# Nervous system disorders Peripheral sensory neuropathy 34 1# Dizziness 10 0 Respiratory, thoracic and mediastinal disorders Coughf 24 0 Psychiatric disorders Insomnia 22 3# Musculoskeletal and connective tissue disorders Back pain 21 3# Musculoskeletal chest pain 12 0 Metabolism and nutrition disorders Decreased appetite 15 1# Skin and subcutaneous tissue disorders Rash 13 0 Pruritus 12 0 Vascular disorders Hypertension 13 6# Hypotension 10 3# a Upper respiratory tract infection includes nasopharyngitis, respiratory syncytial virus infection, respiratory tract infection, rhinitis, tonsillitis, upper respiratory tract infection, and viral pharyngitis. b Pneumonia includes lower respiratory tract infection, lung infection, pneumocystis jirovecii pneumonia, pneumonia, and pneumonia bacterial. c Abdominal pain includes abdominal pain, and abdominal pain upper. d Fatigue includes asthenia, and fatigue. e Edema peripheral includes edema, edema peripheral, and peripheral swelling. f Cough includes cough, and productive cough. # Only grade 3 adverse reactions occurred.

Table 2 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO with bortezomib, melphalan and prednisone (D-VMP) in PLEIADES.

Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO with bortezomib, melphalan and prednisone (D-VMP) included: • General disorders and administration site conditions: infusion reaction, injection site reaction, chills • Infections: herpes zoster, urinary tract infection, influenza, sepsis • Musculoskeletal and connective tissue disorders: arthralgia, muscle spasms • Nervous system disorders: headache, paresthesia • Metabolism and nutrition disorders: hypocalcemia, hyperglycemia • Respiratory, thoracic and mediastinal disorders: dyspnea, pulmonary edema • Cardiac disorders: atrial fibrillation

Table 2: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO with Bortezomib, Melphalan and Prednisone (D-VMP) in PLEIADES DARZALEX FASPRO with Bortezomib, Melphalan and Prednisonea Laboratory Abnormality All Grades (%) Grades 3-4 (%) Decreased leukocytes 96 52 Decreased lymphocytes 93 84 Decreased platelets 93 42 Decreased neutrophils 88 49 Decreased hemoglobin 48 19 a Denominator is based on the safety population treated with D-VMP (N=67). Relapsed/Refractory Multiple Myeloma In Combination with Lenalidomide and Dexamethasone The safety of DARZALEX FASPRO with lenalidomide and dexamethasone (D-Rd) was evaluated in a single-arm cohort of PLEIADES [see Clinical Studies (14.2) in Full Prescribing Information]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity (N=65) in combination with lenalidomide and dexamethasone. Among these patients, 92% were exposed for 6 months or longer and 20% were exposed for greater than one year. Serious adverse reactions occurred in 48% of patients who received DARZALEX FASPRO. Serious adverse reactions in >5% of patients included pneumonia, influenza and diarrhea. Fatal adverse reactions occurred in 3.1% of patients. Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 11% of patients who received DARZALEX FASPRO. Adverse reactions resulting in permanent discontinuation of DARZALEX FASPRO in more than 1 patient were pneumonia and anemia. Dosage interruptions due to an adverse reaction occurred in 63% of patients who received DARZALEX FASPRO. Adverse reactions requiring dosage interruptions in >5% of patients included neutropenia, pneumonia, upper respiratory tract infection, influenza, dyspnea, and blood creatinine increased. The most common adverse reactions (≥20%) were fatigue, diarrhea, upper respiratory tract infection, muscle spasms, constipation, pyrexia, pneumonia, and dyspnea. Table 3 summarizes the adverse reactions in patients who received DARZALEX FASPRO with lenalidomide and dexamethasone (D-Rd) in PLEIADES. Table 3: Adverse Reactions (≥10%) in Patients Who Received DARZALEX FASPRO with Lenalidomide and Dexamethasone (D-Rd) in PLEIADES DARZALEX FASPRO with Lenalidomide and Dexamethasone (N=65) All Grades (%) Grades ≥3 (%) Adverse Reaction General disorders and administration site conditions Fatiguea 52 5# Pyrexia 23 2# Edema peripheral 18 3# Gastrointestinal disorders Diarrhea 45 5# Constipation 26 2# Nausea 12 0 Vomiting 11 0 Infections 43 3# Upper respiratory tract infectionb Pneumoniac 23 17 Bronchitisd 14 2# Urinary tract infection 11 0 Musculoskeletal and connective tissue disorders Muscle spasms 31 2# Back pain 14 0 Respiratory, thoracic and mediastinal disorders Dyspneae 22 3 Coughf 14 0 Nervous system disorders Peripheral sensory neuropathy 17 2# Psychiatric disorders Insomnia 17 5# Metabolism and nutrition disorders Hyperglycemia 12 9# Hypocalcemia 11 0

DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) injection a b

c d e f #

Fatigue includes asthenia, and fatigue. Upper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection viral, rhinitis, sinusitis, upper respiratory tract infection, and upper respiratory tract infection bacterial. Pneumonia includes lower respiratory tract infection, lung infection, and pneumonia. Bronchitis includes bronchitis, and bronchitis viral. Dyspnea includes dyspnea, and dyspnea exertional. Cough includes cough, and productive cough. Only grade 3 adverse reactions occurred.

Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO with lenalidomide and dexamethasone (D-Rd) included: • Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal chest pain • Nervous system disorders: dizziness, headache, paresthesia • Skin and subcutaneous tissue disorders: rash, pruritus • Gastrointestinal disorders: abdominal pain • Infections: influenza, sepsis, herpes zoster • Metabolism and nutrition disorders: decreased appetite • Cardiac disorders: atrial fibrillation • General disorders and administration site conditions: chills, infusion reaction, injection site reaction • Vascular disorders: hypotension, hypertension Table 4 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO with lenalidomide and dexamethasone (D-Rd) in PLEIADES.

Monotherapy The safety of DARZALEX FASPRO as monotherapy was evaluated in COLUMBA [see Clinical Trials (14.2) in Full Prescribing Information]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously or daratumumab 16 mg/kg administered intravenously; each administered once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity. Among patients receiving DARZALEX FASPRO, 37% were exposed for 6 months or longer and 1% were exposed for greater than one year. Serious adverse reactions occurred in 26% of patients who received DARZALEX FASPRO. Fatal adverse reactions occurred in 5% of patients. Fatal adverse reactions occurring in more than 1 patient were general physical health deterioration, septic shock, and respiratory failure. Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received DARZALEX FASPRO. Adverse reactions resulting in permanent discontinuation of DARZALEX FASPRO in more than 2 patients were thrombocytopenia and hypercalcemia. Dosage interruptions due to an adverse reaction occurred in 26% of patients who received DARZALEX FASPRO. Adverse reactions requiring dosage interruption in >5% of patients included thrombocytopenia. The most common adverse reaction (≥20%) was upper respiratory tract infection. Table 5 summarizes the adverse reactions in COLUMBA. Table 5: Adverse Reactions (≥10%) in Patients Who Received DARZALEX FASPRO or Intravenous Daratumumab in COLUMBA DARZALEX FASPRO Intravenous Daratumumab (N=260) (N=258) All Grades Grade ≥3 All Grades Grade ≥3 (%) (%) (%) (%) Adverse Reaction Infections Upper respiratory 24 1# 22 1# tract infectiona Pneumoniab 8 5 10 6@ Gastrointestinal disorders 11 0.4# Diarrhea 15 1# # Nausea 8 0.4 11 0.4#

Table 5: Adverse Reactions (≥10%) in Patients Who Received DARZALEX FASPRO or Intravenous Daratumumab in COLUMBA (continued) DARZALEX FASPRO Intravenous Daratumumab (N=260) (N=258) All Grades Grade ≥3 All Grades Grade ≥3 (%) (%) (%) (%) Adverse Reaction General disorders and administration site conditions Fatiguec 15 1# 16 2# Infusion reactionsd 13 2# 34 5# Pyrexia 13 0 13 1# Chills 6 0.4# 12 1# Musculoskeletal and connective tissue disorders Back pain 10 2# 12 3# Respiratory, thoracic and mediastinal disorders 9 1# 14 0 Coughe 6 1# 11 1# Dyspneaf a Upper respiratory tract infection includes acute sinusitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, rhinitis, rhinovirus infection, sinusitis, and upper respiratory tract infection. b Pneumonia includes lower respiratory tract infection, lung infection, pneumocystis jirovecii pneumonia, and pneumonia. c Fatigue includes asthenia, and fatigue. d Infusion reactions includes terms determined by investigators to be related to infusion. e Cough includes cough, and productive cough. f Dyspnea includes dyspnea, and dyspnea exertional. # Only grade 3 adverse reactions occurred. @ Grade 5 adverse reactions occurred. Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO included: • General disorders and administration site conditions: injection site reaction, peripheral edema • Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal chest pain, muscle spasms • Gastrointestinal disorders: constipation, vomiting, abdominal pain • Metabolism and nutrition disorders: decreased appetite, hyperglycemia, hypocalcemia, dehydration • Psychiatric disorders: insomnia • Vascular disorders: hypertension, hypotension • Nervous system disorders: dizziness, peripheral sensory neuropathy, paresthesia • Infections: bronchitis, influenza, urinary tract infection, herpes zoster, sepsis, hepatitis B virus reactivation • Skin and subcutaneous tissue disorders: pruritus, rash • Cardiac disorders: atrial fibrillation • Respiratory, thoracic and mediastinal disorders: pulmonary edema Table 6 summarizes the laboratory abnormalities in COLUMBA. Table 6: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Receiving DARZALEX FASPRO or Intravenous Daratumumab in COLUMBA DARZALEX Intravenous FASPROa Daratumumaba Grades All Grades All 3-4 Grades 3-4 Grades (%) (%) (%) Laboratory Abnormality (%) Decreased leukocytes 65 19 57 14 Decreased lymphocytes 59 36 56 36 Decreased neutrophils 55 19 43 11 Decreased platelets 43 16 45 14 Decreased hemoglobin 42 14 39 16 a Denominator is based on the safety population treated with DARZALEX FASPRO (N=260) and Intravenous Daratumumab (N=258). Light Chain Amyloidosis In Combination with Bortezomib, Cyclophosphamide and Dexamethasone The safety of DARZALEX FASPRO with bortezomib, cyclophosphamide and dexamethasone (D-VCd) was evaluated in ANDROMEDA [see Clinical Studies (14.2) in Full Prescribing Information]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity or a maximum of 2 years. Among patients who received D-VCd, 74% were exposed for 6 months or longer and 32% were exposed for greater than one year. Serious adverse reactions occurred in 43% of patients who received DARZALEX FASPRO in combination with VCd. Serious adverse reactions that occurred in at least 5% of patients in the D-VCd arm were pneumonia (9%), cardiac failure (8%), and sepsis (5%). Fatal adverse reactions occurred in 11% of

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Table 4: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO with Lenalidomide and Dexamethasone (D-Rd) in PLEIADES DARZALEX FASPRO with Lenalidomide and Dexamethasonea All Grades Grades 3-4 Laboratory Abnormality (%) (%) Decreased leukocytes 94 34 Decreased lymphocytes 82 58 Decreased platelets 86 9 Decreased neutrophils 89 52 Decreased hemoglobin 45 8 a Denominator is based on the safety population treated with D-Rd (N=65).

DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) injection

patients. Fatal adverse reactions that occurred in more than one patient included cardiac arrest (4%), sudden death (3%), cardiac failure (3%), and sepsis (1%). Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 5% of patients. Adverse reactions resulting in permanent discontinuation of DARZALEX FASPRO in more than one patient were pneumonia, sepsis, and cardiac failure. Dosage interruptions (defined as dose delays or skipped doses) due to an adverse reaction occurred in 36% of patients who received DARZALEX FASPRO. Adverse reactions which required a dosage interruption in ≥3% of patients included upper respiratory tract infection (9%), pneumonia (6%), cardiac failure (4%), fatigue (3%), herpes zoster (3%), dyspnea (3%), and neutropenia (3%). The most common adverse reactions (≥20%) were upper respiratory tract infection, diarrhea, peripheral edema, constipation, fatigue, peripheral sensory neuropathy, nausea, insomnia, dyspnea, and cough. Table 7 below summarizes the adverse reactions in patients who received DARZALEX FASPRO with VCd in ANDROMEDA.

Table 8 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO with VCd in ANDROMEDA.

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Table 7: Adverse Reactions (≥10%) in Patients with AL Amyloidosis Who Received DARZALEX FASPRO with Bortezomib, Cyclophosphamide and Dexamethasone (D-VCd) with a Difference Between Arms of >5% Compared to VCd in ANDROMEDA D-VCd VCd (N=193) (N=188) All Grades Grades 3-4 All Grades Grades 3-4 (%) (%) (%) (%) Adverse Reaction Infections Upper respiratory 40 1# 21 1# tract infectiona b Pneumonia 15 10 9 5 Gastrointestinal disorders Diarrhea 36 6# 30 4 29 0 Constipation 34 2# Nervous system disorders Peripheral sensory 31 3# 20 2# neuropathy Respiratory, thoracic and mediastinal disorders Dyspneac 26 4 20 4# Coughd 20 1# 11 0 Musculoskeletal and connective tissue disorders Back pain 12 2# 6 0 Arthralgia 10 0 5 0 5 0 Muscle spasms 10 1# Cardiac disorders Arrhythmiae 11 4 5 2 General disorders and administration site conditions Injection site 11 0 0 0 reactionsf # a

b c d e

Only grade 3 adverse reactions occurred. Upper respiratory tract infection includes laryngitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, rhinovirus infection, sinusitis, tonsillitis, tracheitis, upper respiratory tract infection, upper respiratory tract infection bacterial, and viral upper respiratory tract infection. Pneumonia includes lower respiratory tract infection, pneumonia, pneumonia aspiration, and pneumonia pneumococcal. Dyspnea includes dyspnea, and dyspnea exertional. Cough includes cough, and productive cough. Arrhythmia includes atrial flutter, atrial fibrillation, supraventricular tachycardia, bradycardia, arrhythmia, bradyarrhythmia, cardiac flutter, extrasystoles, supraventricular extrasystoles, ventricular arrhythmia, ventricular extrasystoles, atrial tachycardia, ventricular tachycardia Injection site reactions includes terms determined by investigators to be related to daratumumab injection.

Clinically relevant adverse reactions not included in Table 7 and occurred in patients who received DARZALEX FASPRO with bortezomib, cyclophosphamide and dexamethasone (D-VCd) included: • Skin and subcutaneous tissue disorders: rash, pruritus • Nervous system disorders: paresthesia • General disorders and administration site conditions: infusion reaction, chills • Cardiac disorders: cardiac failurea, cardiac arrest • Metabolism and nutrition disorders: hyperglycemia, hypocalcemia, dehydration • Infections: bronchitis, herpes zoster, sepsis, urinary tract infection, influenza • Vascular disorders: hypertension • Musculoskeletal and connective tissue disorders: musculoskeletal chest pain • Gastrointestinal disorders: pancreatitis • Respiratory, thoracic and mediastinal disorders: pulmonary edema a Cardiac failure includes cardiac dysfunction, cardiac failure, cardiac failure congestive, cardiovascular insufficiency, diastolic dysfunction, pulmonary edema, and left ventricular dysfunction occurred in 11% of patients.

Table 8: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO with Bortezomib, Cyclophosphamide and Dexamethasone (D-VCd) in ANDROMEDA D-VCd VCd All Grades Grades 3-4 All Grades Grades 3-4 (%) (%) (%) (%) Laboratory Abnormality Decreased lymphocytes 81 54 71 46 Decreased hemoglobin 66 6 70 6 Decreased leukocytes 60 7 46 4 Decreased platelets 46 3 40 4 Decreased neutrophils 30 6 18 4 Denominator is based on the number of patients with a baseline and post-baseline laboratory value for each laboratory test, N=188 for D-VCd and N=186 for VCd. Cardiac Adverse Reactions in Light Chain (AL) Amyloidosis Among patients who received DARZALEX FASPRO in combination with VCd, 72% of patients had baseline cardiac involvement with Mayo Cardiac Stage I (3%), Stage II (46%) and Stage III (51%). Serious cardiac disorders occurred in 16% of patients (8% of patients with Mayo Cardiac Stage I and II and 28% of patients with Stage III). Serious cardiac disorders in >2% of patients included cardiac failure (8%), cardiac arrest (4%) and arrhythmia (4%). Fatal cardiac disorders occurred in 10% of patients (5% of patients with Mayo Cardiac Stage I and II and 19% of patients with Stage III) who received DARZALEX FASPRO in combination with VCd. Fatal cardiac disorders that occurred in more than one patient in the D-VCd arm included cardiac arrest (4%), sudden death (3%), and cardiac failure (3%). Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other daratumumab products or other hyaluronidase products may be misleading. In patients with multiple myeloma and light chain (AL) amyloidosis who received DARZALEX FASPRO as monotherapy or as part of a combination therapy, less than 1% of 633 patients developed treatment-emergent antidaratumumab antibodies. In patients with multiple myeloma and light chain (AL) amyloidosis who received DARZALEX FASPRO as monotherapy or as part of a combination therapy, 7% of 628 patients developed treatment-emergent anti-rHuPH20 antibodies. The anti-rHuPH20 antibodies did not appear to affect daratumumab exposure. None of the patients who tested positive for anti-rHuPH20 antibodies tested positive for neutralizing antibodies. Postmarketing Experience The following adverse reactions have been identified with post-approval use of daratumumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System: Anaphylactic reaction Gastrointestinal: Pancreatitis Infections: Cytomegalovirus, Listeriosis DRUG INTERACTIONS Effects of Daratumumab on Laboratory Tests Interference with Indirect Antiglobulin Tests (Indirect Coombs Test) Daratumumab binds to CD38 on RBCs and interferes with compatibility testing, including antibody screening and cross matching. Daratumumab interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding [see References] or genotyping. Since the Kell blood group system is also sensitive to DTT treatment, supply K-negative units after ruling out or identifying alloantibodies using DTT-treated RBCs. If an emergency transfusion is required, administer non-cross-matched ABO/ RhD-compatible RBCs per local blood bank practices. Interference with Serum Protein Electrophoresis and Immunofixation Tests Daratumumab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M protein). False positive SPE and IFE assay results may occur for patients with IgG kappa myeloma protein impacting initial assessment of complete responses by International Myeloma Working Group (IMWG) criteria. In DARZALEX FASPRO-treated patients with persistent very good partial response, where daratumumab interference is suspected, consider using a FDA-approved daratumumab-specific IFE assay to distinguish daratumumab from any remaining endogenous M protein in the patient’s serum, to facilitate determination of a complete response.

DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) injection

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary DARZALEX FASPRO can cause fetal harm when administered to a pregnant woman. The assessment of associated risks with daratumumab products is based on the mechanism of action and data from target antigen CD38 knockout animal models (see Data). There are no available data on the use of DARZALEX FASPRO in pregnant women to evaluate drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The combination of DARZALEX FASPRO and lenalidomide or thalidomide is contraindicated in pregnant women, because lenalidomide and thalidomide may cause birth defects and death of the unborn child. Lenalidomide and thalidomide are only available through a REMS program. Refer to the lenalidomide or thalidomide prescribing information on use during pregnancy. Clinical Considerations Fetal/Neonatal Adverse Reactions Immunoglobulin G1 (IgG1) monoclonal antibodies are transferred across the placenta. Based on its mechanism of action, DARZALEX FASPRO may cause depletion of fetal CD38 positive immune cells and decreased bone density. Defer administering live vaccines to neonates and infants exposed to daratumumab in utero until a hematology evaluation is completed. Data Animal Data DARZALEX FASPRO for subcutaneous injection contains daratumumab and hyaluronidase. Mice that were genetically modified to eliminate all CD38 expression (CD38 knockout mice) had reduced bone density at birth that recovered by 5 months of age. Data from studies using CD38 knockout animal models also suggest the involvement of CD38 in the regulation of humoral immune responses (mice), feto-maternal immune tolerance (mice), and early embryonic development (frogs). No systemic exposure of hyaluronidase was detected in monkeys given 22,000 U/kg subcutaneously (12 times higher than the human dose) and there were no effects on embryo-fetal development in pregnant mice given 330,000 U/kg hyaluronidase subcutaneously daily during organogenesis, which is 45 times higher than the human dose. There were no effects on pre- and post-natal development through sexual maturity in offspring of mice treated daily from implantation through lactation with 990,000 U/kg hyaluronidase subcutaneously, which is 134 times higher than the human doses. Lactation Risk Summary There is no data on the presence of daratumumab and hyaluronidase in human milk, the effects on the breastfed child, or the effects on milk production. Maternal immunoglobulin G is known to be present in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. Because of the potential for serious adverse reactions in the breastfed child when DARZALEX FASPRO is administered with lenalidomide or thalidomide and dexamethasone, advise women not to breastfeed during treatment with DARZALEX FASPRO. Refer to lenalidomide or thalidomide prescribing information for additional information. Data Animal Data No systemic exposure of hyaluronidase was detected in monkeys given 22,000 U/kg subcutaneously (12 times higher than the human dose) and there were no effects on post-natal development through sexual maturity in offspring of mice treated daily during lactation with 990,000 U/kg hyaluronidase subcutaneously, which is 134 times higher than the human doses. Females and Males of Reproductive Potential DARZALEX FASPRO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations]. Pregnancy Testing With the combination of DARZALEX FASPRO with lenalidomide or thalidomide, refer to the lenalidomide or thalidomide labeling for pregnancy testing requirements prior to initiating treatment in females of reproductive potential. Contraception Advise females of reproductive potential to use effective contraception during treatment with DARZALEX FASPRO and for 3 months after the last dose. Additionally, refer to the lenalidomide or thalidomide labeling for additional recommendations for contraception. Pediatric Use Safety and effectiveness of DARZALEX FASPRO in pediatric patients have not been established.

Geriatric Use Of the 291 patients who received DARZALEX FASPRO as monotherapy for relapsed and refractory multiple myeloma, 37% were 65 to <75 years of age, and 19% were 75 years of age or older. No overall differences in effectiveness of DARZALEX FASPRO have been observed between patients ≥65 years of age and younger patients. Adverse reactions that occurred at a higher frequency (≥5% difference) in patients ≥65 years of age included upper respiratory tract infection, urinary tract infection, dizziness, cough, dyspnea, diarrhea, nausea, fatigue, and peripheral edema. Serious adverse reactions that occurred at a higher frequency (≥2% difference) in patients ≥65 years of age included pneumonia. Clinical studies of DARZALEX FASPRO as part of a combination therapy for patients with multiple myeloma did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. Of the 193 patients who received DARZALEX FASPRO as part of a combination therapy for light chain (AL) amyloidosis, 35% were 65 to <75 years of age, and 10% were 75 years of age or older. Clinical studies of DARZALEX FASPRO as part of a combination therapy for patients with light chain (AL) amyloidosis did not include sufficient numbers of patients aged 65 and older to determine whether effectiveness differs from that of younger patients. Adverse reactions that occurred at a higher frequency in patients ≥65 years of age were peripheral edema, asthenia, pneumonia and hypotension. No clinically meaningful differences in the pharmacokinetics of daratumumab were observed in geriatric patients compared to younger adult patients [see Clinical Pharmacology (12.3) in Full Prescribing Information]. REFERENCES 1. Chapuy, CI, RT Nicholson, MD Aguad, et al., 2015, Resolving the daratumumab interference with blood compatibility testing, Transfusion, 55:1545-1554 (accessible at http://onlinelibrary.wiley.com/doi/10.1111/trf.13069/epdf). PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Hypersensitivity and Other Administration Reactions Advise patients to seek immediate medical attention for any of the following signs and symptoms of systemic administration-related reactions: itchy, runny or blocked nose; chills, nausea, throat irritation, cough, headache, shortness of breath or difficulty breathing [see Warnings and Precautions].

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Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis Advise patients to immediately contact their healthcare provider if they have signs or symptoms of cardiac adverse reactions [see Warnings and Precautions]. Neutropenia Advise patients to contact their healthcare provider if they have a fever [see Warnings and Precautions]. Thrombocytopenia Advise patients to contact their healthcare provider if they have bruising or bleeding [see Warnings and Precautions]. Embryo-Fetal Toxicity Advise pregnant women of the potential hazard to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions, Use in Specific Populations]. Advise females of reproductive potential to avoid becoming pregnant during treatment with DARZALEX FASPRO and for at least 3 months after the last dose [see Use in Specific Populations]. Advise patients that lenalidomide and thalidomide have the potential to cause fetal harm and have specific requirements regarding contraception, pregnancy testing, blood and sperm donation, and transmission in sperm. Lenalidomide and thalidomide are only available through a REMS program [see Use in Specific Populations]. Interference with Laboratory Tests Advise patients to inform their healthcare provider, including personnel at blood transfusion centers, that they are taking DARZALEX FASPRO, in the event of a planned transfusion [see Warnings and Precautions]. Advise patients that DARZALEX FASPRO can affect the results of some tests used to determine complete response in some patients and additional tests may be needed to evaluate response [see Warnings and Precautions]. Hepatitis B Virus (HBV) Reactivation Advise patients to inform healthcare providers if they have ever had or might have a hepatitis B infection and that DARZALEX FASPRO could cause hepatitis B virus to become active again [see Adverse Reactions].

CATEDRÁTICA DE CIENCIAS MÉDICAS ES NOMBRADA PRESIDENTA DE LA ASSOCIATION FOR CLINICAL AND TRANSLATIONAL

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Dra. Karen Martínez González, catedrática y directora del Departamento de Psiquiatría del RCM.

a Escuela de Medicina del Recinto de Ciencias Médicas (RCM) de la Universidad de Puerto Rico (UPR), anunció hoy que la Dra. Karen Martínez González, Catedrática y directora del Departamento de Psiquiatría del RCM, fue nombrada como presidenta de la Association for Clinical and Translational Science (ACTS) para el período 2021-2022. El nombramiento fue otorgado durante el anuncio de la nueva Junta Directiva del ACTS para el período 2021-2022, el cual se realizó en días recientes. "Me complace liderar un grupo de líderes que son representativos de la amplitud de nuestra profesión y las personas que la integran. Con el creciente interés en la ciencia clínica y traslacional, nuestro objetivo es identificar y evaluar tendencias nuevas y emergentes de desarrollo de investigación en los que ACTS pueda aportar y tener un impacto positivo", expresó la Dra. Martínez González. El presidente de la Universidad de Puerto Rico, el doctor Jorge Haddock, elogió el

nombramiento y sus repercusiones para la academia, así como para la investigación y la ciencia. "El nombramiento de la doctora Karen Martínez González como líder de una entidad prestigiosa y cuyo trabajo tiene un impacto significativo en el quehacer científico e investigativo nos llena de orgullo. Su nombramiento engrandece esta institución que, por décadas, ha formado a profesionales que se han destacado a nivel nacional e internacional. Confío en que su liderazgo frente a la organización nos permita desarrollar, desde la UPR, nuevos proyectos en beneficio de la comunidad universitaria y de la sociedad.!¡Enhorabuena!", señaló Haddock. La Association for Clinical and Translational Science (ACTS) es una asociación nacional que incluye a todas las universidades de Estados Unidos que tienen centros de investigación clínica-traslacional. "Para mí es un verdadero honor poder representar a la Universidad de Puerto Rico y espero poder inspirar a muchos otros estudiantes y facultativos a

integrarse a asociaciones profesionales y educativas de relevancia a nivel nacional e internacional como lo es ACTS", concluyó la doctora Martínez. Según el Dr. Humberto M. Guiot, Decano Interino de la Escuela de Medicina del RCM, "la trayectoria de la Dra. Karen G. Martínez se caracteriza tanto por sus aportaciones a la ciencia clínica-traslacional como por su liderazgo y compromiso con la academia. Su nombramiento a tan prestigiosa asociación demuestra la excelencia de nuestros egresados y nuestra facultad. Estamos convencidos de que durante la presidencia la doctora Martínez González el ACTS alcanzará todas sus metas." De su parte, el director ejecutivo de ACTS, Kim Wiatr afirmó que "la Junta Directiva de ACTS sigue comprometida con aportar al optimizar la ciencia. Asimismo, continuarán acrecentando el apoyo de la Asociación en la financiación de la investigación clínica y traslacional, así como su diversidad y esfuerzos de inclusión". Revista Puertorriqueña de Medicina y Salud Pública

ELECCIÓN DE LA DIRECTORA EJECUTIVA DEL CENTRO COMPRENSIVO DE CÁNCER UPR COMO MIEMBRO DE LA JUNTA DE DIRECTORES DEL “ASSOCIATION OF AMERICAN CANCER INSTITUTES” (AACI)

a doctora Marcia Cruz – Correa, directora ejecutiva del Centro Comprensivo de Cáncer de la Universidad de Puerto Rico fue electa mediante votación como nuevo miembro de la Junta de Directores de la “Association of American Cancer Institutes” (AACI) junto con otros líderes de centros oncológicos de los Estados Unidos.

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AACI es una prestigiosa asociación que representa a los 102 centros de cáncer en Estados Unidos y Canadá, cuya misión es acelerar el progreso contra el cáncer empoderando a estos centros oncológicos a aliviar el sufrimiento y la carga causada por el cáncer. El Centro Comprensivo de Cáncer UPR ha sido miembro de esta asociación desde marzo del 2020. Los miembros del AACI eligieron al Dr. Robert Winn, director del VCU Massey Cancer Center como vice-presidente/ presidente electo de su Junta de Directores y a la Dra. Marcia Cruz-Correa, del Centro Comprensivo de Cáncer UPR, al Dr. Rubén Mesa del Mays Cancer Center, al Dr. Robert H. Vonderheide del Abramson Cancer Center y a la Dra. Joann Sweasy del University of Arizona Cancer Center como nuevos miembros de dicha Junta. “Es un honor y orgullo ser parte de esta nueva Junta de Directores del AACI 2021 y sobre todo representar al Centro Comprensivo de Cáncer UPR para colaborar y aportar en el mejoramiento de la lucha contra el cáncer a nivel nacional. Ser miembro de la Junta solidifica las relaciones con los líderes de otros centros oncológicos y permite conocer y estar a la vanguardia de los avances clínicos, de investigación y tratamientos de esta condición, causa principal de muertes en Puerto Rico” indicó la Dra. Marcia Cruz-Correa, gastroenteróloga oncóloga, investigadora y profesora de la Escuela de Medicina del Recinto de Ciencias Médicas de la Universidad de Puerto Rico. La Dra. Cruz–Correa también se desempeña como investigadora principal de la Alianza Hispana para la Investigación Clínica y Translacional (AACR), es catedrática en oncología quirúrgica del MD Anderson Cancer Center de la Universidad de Texas y catedrática asociada en medicina de la Escuela de Medicina de la Universidad de Johns Hopkins.

Educación +auto-cuidado +Excelencia Profesional +Adherencia Terapéutica =Salud y Cardiología

Salud y Cardiología Revista Puertorriqueña de Medicina y Salud Pública

REUMAEXPO INTERNACIONAL 2021 COMPLETAMENTE VIRTUAL LLEGÓ PARA QUEDARSE

El grupo de trabajo de FER estuvo encabezado por el médico- reumatólogo, Dr. Oscar Soto-Raíces, Presidente de FER; la Directora Ejecutiva, Profesora Griselle Lugo, William Borges y la señora Marta González-Alonso, ambos pacientes y miembros de la Junta Directiva FER, Lic. Lilyana Figueroa- Román, Dr. Ramón Ortega, Dra. Elivette Zambrana, Dra. Amarilis Pérez-De Jesús, Dra. Noemí Varela-Rosario, Dr. Ricardo Gago, M.D., pasado Presidente de la Asociación de Reumatólogos de Puerto Rico, la Dra. Paloma Alejandro-Silva y el Dr. Rodolfo Concepción.

l pasado sábado, 26 de junio de 2021, la Fundación Puertorriqueña de Enfermedades Reumáticas conocida por sus siglas (FER), celebró su evento anual, ReumaExpo 2021 Internacional, Edición Digital de manera interactiva nuevamente, donde proveyeron una experiencia interesante y atractiva para la comunidad puertorriqueña de pacientes con condiciones reumáticas y la comunidad en general, a través de Facebook Live, YouTube Live, Radio Isla 1320, radioisla.tv y Facebook Live de Radio Isla 1320AM y todas las plataformas de la Revista Medicina y Salud Pública. Este año, la Fundación tuvo como objetivo principal continuar informando 90

sobre lo más reciente en tratamientos para condiciones reumáticas, así como las tendencias y las nuevas soluciones del mercado. La Fundación FER es una entidad sin fines de lucro dedicada a aportar al bienestar general del paciente con condiciones reumáticas para que alcancen una vida más saludable, activa y productiva ante la existencia de más de 200 condiciones reumáticas. Un nutrido grupo de interesados en los temas y galenos conocedores en la materia, se dieron cita para orientar y contestar numerosas preguntas a los visitantes, participantes y público general concentrando todos los espacios necesarios para orientar, responder y recomendar a los pacientes para que

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tengan una vida más saludable, activa y productiva. La Fundación FER contó con un grupo de colaboradores médicos e invitados, tales como: Dr. Oscar Soto-Raíces, Presidente de FER; Dr. Ramón Ortega, Dra. Elivette Zambrana, Dra. Amarilis Pérez-De Jesús, Dra. Noemí Varela-Rosario, Dr. Ricardo Gago, M.D., pasado Presidente de la Asociación de Reumatólogos de Puerto Rico, la Dra. Paloma Alejandro-Silva y el Dr. Rodolfo Concepción, contestando las preguntas de los participantes que se unieron a la transmisión. El Dr. Daniel Hernández, Director de Asuntos Médicos y Alcance Hispano de Global Healthy Living Foundation y el prestigioso reumatólogo de Miami, FL, el

Dr. Guillermo Valenzuela fueron nuestros invitados especiales en vivo via SKYPE. También de estuvieron el señor William Borges y la señora Marta GonzálezAlonso, ambos pacientes y miembros de la Junta Directiva FER. A ellos se unió la Lic. Lilyana Figueroa-Román, nutricionista y también paciente de LUPUS, para aportar su testimonio como paciente y sus conocimientos sobre nutrición para beneficio de los pacientes con estas condiciones. Además, se ofrecieron cápsulas educativas enfocadas con el propósito de orientarlos en las alternativas para poder manejar las condiciones más comunes tales como: Artritis Reumatoide, Artritis Psoriásica, Artritis Idiopática Juvenil,

Gota, Osteoartritis, LUPUS, Espondilitis Anquilosante y Fibromialgia. Actualmente FER continúa ofreciendo su programa radial “Hablemos de Reumatología con Fundación FER", todos los sábados de 8:30 a 9:00 a.m. por Radio Isla 1320, Radioisla.tv y Radio Isla 1320 Facebook Live, con el propósito de educar y apoyar a los pacientes. El programa se ha estado ofreciendo durante la pandemia del Covid-19 en vivo. "Estamos muy satisfechos con la acogida que han tenido nuestras presentaciones virtuales de ReumaExpo Internacional porque hemos podido llegar a miles de pacientes de habla hispana en todo el mundo.", indicó el reumatólogo, Dr. Oscar Soto Raíces, presidente de FER.

“Esperamos que los pacientes que no pudieron ver la transmisión en vivo puedan disfrutarla cuantas veces deseen por medio de todas nuestras plataformas sociales. ReumaExpo Internacional 2021 es una herramienta útil y amena para aprender a manejar sus condiciones.”, indicó la Directora Ejecutiva de FER, Griselle Lugo. Para más información pueden acceder a www.fundacionfer. org o comunicarse con Griselle Lugo, Directora Ejecutiva vía correo electrónico glugo@fundacionfer. org. Estamos en las redes sociales Facebook, Instagram, Twitter y YouTube (Fundación FER) http:// www.youtube.com/c/FundaciónFER Revista Puertorriqueña de Medicina y Salud Pública

JAVIER MORALES, MD

INFETÓLOGO, INVESTIGADOR Y MÉDICO QUE IDENTIFICÓ AL PRIMER PACIENTE CON VIH EN PUERTO RICO Y DIRECTOR DE CLINICAL RESEARCH PUERTO RICO

CARMEN ZORRILLA, MD

GINECÓLOGA OBSTETRA E INVESTIGADORA PRINCIPAL EN EL CENTRO DE ESTUDIOS MATERNO-INFANTILES (CEMI) DECANA DE INVESTIGACIÓN DEL RCM

JORGE SANTANA BAGUR, MD, FIDSA INFECTÓLOGO Y DIRECTOR DE LA UNIDAD DE INVESTIGACIONES CLÍNICAS SOBRE EL SIDA (ACTU)

EQUIPO EDITORIAL Y GERENCIAL DE LA REVISTA DE MEDICINA Y SALUD PÚBLICA JUNTO A LOS PANELISTAS DEL FORO "A 40 AÑOS DEL SIDA" EN PUERTO RICO, COMO PARTE DE UNA ALIANZA DE MSP Y EL RECINTO DE CIENCIAS MÉDICAS.

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HUMBERTO GUIOT, MD, FACP, FIDSAINFECTÓLOGO Y DECANO INTERINO DE LA ESCUELA DE MEDICINA DEL RECINTO DE CIENCIAS MÉDICAS

PARTE DE LOS ESTUDIANTES DE MEDICINA QUE SE DIERON CITA AL FORO PARA APRENDER SOBRE EL PRECEDENTE QUE MARCARON LOS MÉDICOS INVESTIGADORES AL INICIO DE LA PANDEMIA DEL VIH EN PUERTO RICO.

PARTE DE LA NUEVA CEPA DE MÉDICOS PUERTORRIQUEÑOS QUE TUVIERON LA OPORTUNIDAD DE PREGUNTAR SOBRE LA EVOLUCIÓN DE LOS TRATAMIENTOS PARA MUJERES EMBARAZADAS DIAGNOSTICADAS CON VIH EN PUERTO RICO.

LA MAYORÍA DE LOS ESTUDIANTES DE MEDICINA FUERON AQUELLOS INTERESADOS EN PRACTICAR LA INFECTOLOGÍA, GINECOLOGÍA Y OBSTRETICIA, MEDICINA DE FAMILIA, ENTRE OTRAS DISCIPLINAS MÉDICAS.

EL FORO CULMINÓ CON LA HISTORIA DE LA PRIMERA PACIENTE EMBARAZADA CON VIH EN PUERTO RICO Y EL COCTEL DE MÁS DE 20 PASTILLAS QUE HACE MÁS DE UNA DÉCADA DEBÍAN INGERIR COMO PARTE DE SU TRATAMIENTO Y EL ESFUERZO DE EVITAR LA TRANSMISIÓN DEL VIRUS AL NEONATO.

Revista Puertorriqueña de Medicina y Salud Pública

Puerto Rico no se rinde ante la Hepatitis C y aspira al mismo deseo de la Organización Mundial de la Salud a erradicarla para el 2030. Por tal razón Medicina y Salud Pública se unió a la organización VOCES y la Coalición Nacional de Hepatitis C de Puerto Rico y un destacado equipo de especialistas y protagonistas de los principales logros contra la enfermedad se unieron en una conferencia de prensa para anunciar la realización de pruebas masivas gratuitas alrededor de toda la isla.

HON. JOSÉ LUIS DALMAU

HON. RUBÉN SOTO RIVERA PRESIDENTE COMISIÓN DE SALUD SENADO DE PUERTO RICO

PRESIDENTE COLEGIO DE MÉDICOS CIRUJANOS DE PUERTO RICO

LILLIAM RODRÍGUEZ CAPÓ

DR. GINÉS MARTÍNEZ MANGUAL

DR. LEMUEL MARTÍNEZ

PRESIDENTE SENADO DE PUERTO RICO

CEO Y FUNDADORA DE VOCES COALICIÓN DE INMUNIZACIÓN Y PROMOCIÓN DE LA SALUD DE P.R.

Entre los presentes estuvieron: el Dr. Jorge Santana, infectólogo y director de la Unidad de Investigaciones Clínicas contra el SIDA (ACTU), el Dr. Lemuel Martínez, presidente de la Sociedad de Enfermedades Infecciosas de Puerto Rico, Dr. Víctor Ramos, presidente del Colegio Médico Cirujanos de Puerto Rico, Dr.Gines Martínez, gastroenterólogo del Centro Comprensivo de Cáncer de Puerto Rico, Lilly Rodríguez, directora ejecutiva de VOCES, Luis Dalmau, presidente del Senado, entre otros.

DIRECTOR UNIDAD DE ENDOSCOPÍA CENTRO COMPRENSIVO DE CÁNCER DE PR

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DR. VÍCTOR RAMOS

PRESIDENTE SOCIEDAD DE ENFERMEDADES INFECCIOSAS DE PR (SEIPR)

DR. JORGE SANTANA BAGUR DIRECTOR UNIDAD DE INVESTIGACIONES CLÍNICAS (ACTU) ESCUELA DE MEDICINA RCM

PARTE DE LOS RECURSOS QUE SE DIERON CITA A LA CONFERENCIA DE PRENSA SOBRE EL INICIO DE PRUEBAS MASIVAS DE HEPATITIS C, JUNTO CON EL EQUIPO DE TRABAJO DE LA REVISTA MSP.

DE IZQUIERDA A DERECHA: ARRIBA: DR. JORGE SANTANA BAGUR, DR. LEMUEL MARTÍNEZ, DR. GINÉS MARTÍNEZ MANGUAL Y DR. VÍCTOR RAMOS. ABAJO: HON. JOSÉ LUIS DALMAU, LILLIAM RODRÍGUEZ CAPÓ Y HON. RUBÉN SOTO RIVERA.

REPRESENTANTES DE ABBVIE DE IZQUIERDA A DERECHA: RODRIGO RUEDA, ANNETTE RODRÍGUEZ, EDUARDO BARREIRO, DR. FERNANDO APONTE, LANESSA CINTRON, Y NÉSTOR ORTIZ.

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AGENDA MÉDICA 2021 EVENTOS Y CONVENCIONES www.medicinaysaludpublica.com

Puerto Rico

Fecha

Actividad

Lugar

Contacto

TIPO DE EVENTO

7 al 21 de agosto de 2021

Compulsory Courses Regarding

Virtual

High Education Health 787-964-6394 heh@hehpr.com/www.hehpr.com

Curso

13 al 15 de agosto de 2021

24 th Convención anual de la Sociedad Radiológica de Puerto Rico

Sheraton Convention Center Hotel San Juan, PR

info@socrad.com info@serrayserra.com 787 406-4571/787 640-5776

Convención

19 al 22 de agosto de 2021

Convención anual del Colegio de Farmacéuticos de PR

Wyndham Grand Rio Mar Río Grande, PR

Colegio de Farmacéuticos de PR 787-753-7157

Convención

27 al 29 de agosto 2021

Congreso anual Coalición de Asma de PR

Sheraton Convention Center Hotel San Juan, PR

IC Planners ivettecolon@icplannerspr.com 787-504-3655

Congreso

28 de agosto de 2021

Advances in Gastroenterology & Hepatology Conference 5 CME Asociación Puertorriqueña de Gastroenterología

Modalidad: Hibrida

RiVS Marketing 787-548-0047 info@rivsmarketing.com

Conferencia

11 de septiembre de 2021

Update in Liver Diseases 2021 5CME Asociación Puertorriqueña de Gastroenterologia

Modalidad: Virtual (ZOOM webinar)

RiVS Marketing 787-548-0047 info@rivsmarketing.com

Conferencia

25 de septiembre de 2021

Palliative Medicine: Beyond End-of-Life Care 7CME Centro Comprensivo de Cáncer de la UPR

Sonesta Hotel (Intercontinental), San Juan, PR

RiVS Marketing 787-548-0047 info@rivsmarketing.com

Conferencia

8 al 11 de octubre de 2021

Convención anual de la Asociación de Hematología y Oncología Médica de PR (AHOMPR)

Ponce Hilton Hotel & Casino Ponce, PR

Germaine Quiñones caribegyn2015@gmail.com 787-608-1477

Convención

9 de Octubre de 2021

Excellence in GI Nursing 5 CE (Nurses Only) Sociedad Puertorriqueña de Asistentes de Gastroenterología

La Concha Hotel, San Juan, PR

RiVS Marketing 787-548-0047 info@rivsmarketing.com

Conferencia

9 de octubre de 2021

Sociedad Radiológica de Puerto Rico Breast Imaging Annual Summit

Sheraton Puerto Rico Hotel

info@socrad.com info@serrayserra.com 787 406-4571/787 640-5776

Seminario

AGENDA MÉDICA 2021 EVENTOS Y CONVENCIONES www.medicinaysaludpublica.com

Puerto Rico

Fecha

Actividad

Lugar

Contacto

TIPO DE EVENTO

9 de octubre de 2021

Cursos Obligatorios de Telemedicina para Médicos

Virtual

High Education Health 787-964-6394 heh@hehpr.com/www.hehpr.com

Curso

13 al 15 de octubre de 2021

Convención anual de la Asociación de Hospitales de PR

Distrito de Convenciones San Juan, PR

AHPR 787-764-0290 www.hospitalepr.com

Convención

14 al 17 de octubre de 2021

Convención anual Sociedad Puertorriqueña de Cardiología

Virtual

Sociedad Puertorriqueña de Cardiología 787-620-2228 socprcardio@gmail.com

Convención

21 al 24 de octubre de 2021

Convención Caribe Gyn 2021

Ponce Hilton Hotel & Casino Ponce, PR

Germaine Quiñones caribegyn2015@gmail.com 787-608-1477

Convención

La Concha Hotel, San Juan, PR

RiVS Marketing 787-548-0047 info@rivsmarketing.com

Conferencia

30 de octubre de 2021

Reducing the Risk of Cardiovascular Events, Heart Failure and Progression of Chronic Kidney Disease 3 CME/MOC

American College of Physician

Octubre de 2021

Convención anual Puerto Rico Urological Association

Por confirmar**

Aixa Vélez genteinc@gmail.com 787-649-7681

Convención

5 al 7 de noviembre de 2021

Convención anual PR HIV Treaters Association

Virtual

Educational Partners & Coaching 787-646-0780 perez.vilma@gmail.com

Convención

Noviembre de 2021

Convención anual American College of Cardiology, PR Chapter

Por confirmar**

Aixa Vélez genteinc@gmail.com 787-649-7681

Convención

10 al 12 de diciembre de 2021

Convención Sociedad Puertorriqueña de Endocrinología y Diabetología (SPED)

Hotel San Juan San Juan, PR

Educational Partners & Coaching 787-646-0780 perez.vilma@gmail.com

Convención

Revista Puertorriqueña de Medicina y Salud Pública

A CIENCIA CIERTA

DR. ÓSCAR SOTO RAÍCES, Reumatólogo y Presidente de la Fundación de Enfermedades Reumáticas (FER)

n los últimos años, gracias a la atención esmerada, permanente y priorizada de la salud por parte de Soto Raíces y la Fundación de Enfermedades Reumáticas, los pacientes con esta condición han presentado un notable avance en su calidad de vida. Entre sus logros más significativos se encuentra mantener activa a la principal organización de ayuda a pacientes con enfermedades reumáticas en medio de una de las peores pandemias que ha experimentado la humanidad y la creación de un centro de estudio e investigación de alto nivel, como los es el Mindful Rheumatix y el centro de investigación clínica Mindful Medical Research de donde es su director médico. El Dr. Soto hizo su grado en medicina en la Universidad Central del Caribe en Puerto Rico y en Medicina Interna de la University of South

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Florida, Tampa, Florida. Realizó su Subespecialidad en Reumatología de Emory University School of Medicine en Atlanta, Georgia donde también se desarrolló como facultativo en donde obtiene grado de Catedrático Auxiliar en el año 2000. Se ha desempañado con éxito como Catedrático Auxiliar de la Escuela de Medicina de Ponce y Profesor Adjunto de la Escuela de Medicina del Recinto de Ciencias Médicas de la Universidad de Puerto Rico. La contribución del Dr. Soto a la salud pública se manifiesta a través de sus múltiples escritos para publicaciones dirigidas al público, así como publicaciones para médicos. Ha contribuido como autor para libros de texto médico en Medicina Interna y Reumatología, siendo protagonista de congresos y conferencias médicas. A Ciencia Cierta podemos decir que el Dr.

Soto Raíces, un padre de familia e hijo ejemplar, un ciudadano de primer orden y un profesional con altos valores éticos y sentido de humanidad ha sido uno de los principales y más destacados Presidentes de la Asociación de Reumatólogos de PR, teniendo como uno de los momentos más relevantes de su fructífera carrera la creación de la Fundación Puertorriqueña de Enfermedades Reumáticas (FER). El interés por este campo de este insigne médico puertorriqueño se fundamenta en el legítimo deseo de curar una enfermedad, o, al menos, de limitar su propagación. La medicina, como toda ciencia, necesita de la investigación, pero también de médicos como el Dr. Óscar Soto Raíces, pues sólo así se puede asegurar su avance en el conocimiento de la salud y de los procesos patológicos del ser humano.

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AbbVie Aquí. Ahora.

Desarrollando las medicinas del futuro, a la vez que ayudamos a millones a vivir mejor hoy. En AbbVie, trabajamos hacia avances médicos del futuro, a la vez que nos enfocamos en las necesidades diarias de las personas. Porque nunca nos daremos por vencidos ayudando a las personas a vivir sus mejores vidas hoy y mañana. Conozca acerca de nuestro trabajo: herenow.abbvie

Prisca Honore, PhD Científica en inmunología de AbbVie

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