IASLC Lung Cancer News - V3, N6 by IASLC

LUNG CANCER

V3 / N6 / DECEMBER 2018

FOR THORACIC SPECIALISTS Read online at LungCancerNews.org & Visit IASLC.org

INSIDE 6

Dr. Fred R. Hirsch Departs IASLC CEO Role, Joins Mount Sinai Hospital

Scientific Highlights from the IASLC Latin America Conference on Lung Cancer

Neoadjuvant Nivolumab Shows Unprecedented Pathologic Complete Response for Stage III NSCLC

James P. Allison and Tasuku Honjo Jointly Awarded the Nobel Prize

Prophylactic Cranial Irradiation in Locally Advanced NSCLC Falls Flat

NCI Corner: Racial Differences in the Transcriptomes of Lung Tumors

The Future Is Now: Pathology Is Going Digital

Fighting the Tobacco Scourge: Implementation of TobaccoControl Measures Begets Public Health Success

FDA Approval Processes in the Era of Targeted Therapies: A Conversation with Dr. Richard Pazdur

The State of Lung Cancer in Egypt: Progress Is at Hand

NEWS

I N T E R N AT I O N A L A S S O C I AT I O N F O R T H E S T U D Y O F L U N G C A N C E R IMMUNOTHERAPY

Explaining IMpower132: An Interview with Dr. Vassiliki A. Papadimitrakopoulou In the following interview, Vassiliki A. Papadimitrakopoulou, MD, Jay and Lori Eisenberg Distinguished Professor of Medicine and section chief of Thoracic Medical Oncology at the University of Texas MD Anderson Cancer Center, discusses the findings and implications of IMpower132.

Q: Please explain the findings of IMpower132. A: IMpower132 was a global, randomized, open-label, phase III study of 578 patients with stage IV nonsquamous NSCLC who were chemotherapy naive. Eligibility criteria included measurable disease by Response Evaluation Criteria in Solid Tumors guidelines v1.1 and Eastern Cooperative Oncology Group Performance Status 0-1. Exclusion criteria

included tumors known to harbor EGFR driver mutations or ALK translocations, untreated central nervous system metastases, autoimmune disease, and prior exposure to immunotherapy. Patients were randomly assigned 1:1 to receive four or six cycles of carboplatin at a dose of AUC 6 mg/mL/min or to 75 mg/m2 of cisplatin plus 500 mg/m2 of pemetrexed every 3 weeks, followed by pemetrexed as maintenance therapy (Arm B) or to carboplatin/pemetrexed or cisplatin/pemetrexed plus 1,200 mg of atezolizumab, followed by combination pemetrexed and atezolizumab as maintenance therapy (Arm A). Results of the study showed that the atezolizumab plus platinum pemetrexed– based chemotherapy (Arm A) resulted in improved progression-free survival (PFS; median 7.6 months versus 5.2 months for the control group) and was associated with a 40% reduction in risk

for disease progression (hazard ratio [HR] 0.60, 95 CI [0.49, 072]) in all patients and Vassiliki A. across key clini- Dr. Papadimitrakopoulou cal subgroups, including Asian patients (HR 0.42, 95% CI [0.28, 0.63]), never smokers (HR 0.49; 95% CI [0.28, 0.87]), and current and former smokers (HR 0.61, 95% CI [0.50, 0.74]). Also, at the interim overall survival (OS) analysis, atezolizumab plus pemetrexed–based chemotherapy demonstrated a numerical improvement in OS of 4.5 months over pemetrexed-based chemotherapy alone (HR: 0.81, 95% CI [0.64, 1.03]; p = 0.0797).

Q: Does IMpower132 change the therapeutic playing field in any way? continued on page 6

IMMUNOTHERAPY

Targeted Therapy Plus Immune Checkpoint Inhibitors: Research Opportunities, But No Improvement in Activity to Date by targeted therapy (Table 1).1 In pre-clinical studies, oncogenic EGFR and ALK The treatment of patients with advanced signaling was reported to induce immune NSCLC harbouring an actionable oncoescape via the PD-1/PD-L1 axis.2,3 Some gene with tyrosine kinase inhibitors retrospective studies suggested an asso(TKIs) directed at its oncogenic molecuciation between EGFR-positive or ALKlar alteration represents one of the most positive NSCLC and PD-L1 expression.3 significant advances in lung cancer manHowever, other studies have reported agement. Another area of achievement in an inverse relationship between PD-L1 the treatment of advanced Table 1. Modulation of Immune Cell Function by Selected Molecular Targeted Agents1 expression and EGFR NSCLC has been the use mutations and no assoAgent Effect of immune checkpoint ciation between PD-L1 Bevacizumab Reduces regulatory T cells; increases DC maturation/priming and expression and ALK inhibitors targeting proT cell tumor infiltration grammed death receptor-1 rearrangement, as well EGFR-targeting mAb Promotes immunogenic cell death (PD-1) and programmed as an uninflamed tumor Erlotinib Upregulates NKG2D ligands death receptor ligand-1 microenvironment.5-7 Ibrutinib Promotes immunogenic cell death (PD-L1). Although EGFR Imatinib Promotes expansion of circulating natural killer cells and ALK TKIs can induce Existing Data JAK2 inhibitors Increases DC maturation, decreases STAT3, decreases tumor PD-L1 rapid responses in a large Early-phase studLapatinib Promotes tumor infiltration by cytotoxic T cells ies of combination number of patients with MAPK inhibitors Upregulates expression of MHC class I molecules advanced oncogene-driven targeted therapy and Sorafenib Reduces regulatory T cells immune checkpoint NSCLC, the duration Sunitinib Reduces regulatory T cells inhibitors in patients of response is generally Abbreviations: DC, dendritic cell; MHC, major histocompatibility complex. By Ross Soo, MB BS, PhD, FRACP

modest. In contrast, immune checkpoint inhibitors have the potential for durable disease control; however, the response rates are lower. Given this situation, research must address whether molecular targeted agents and immune checkpoint inhibitors can be combined safely to improve antitumor activity. Immune cell function can be modulated

with pretreated or treatment-naive EGFR-positive or with EML4ALK–positive NSCLC have been Dr. Ross Soo reported (Table 2, page 8). Response rates for combination EGFR TKIs or ALK TKIs plus immune checkpoint inhibitors are, at best, similar to previously reported response rates with EGFR TKIs/ALK TKIs alone, suggesting no synergistic effect. This observation has also been seen in preclinical studies of EGFR TKIs and immune checkpoint inhibitors8 as well as ALK TKIs and immune checkpoint inhibitors.9 Unfortunately, in some studies of combination EGFR/ALK TKIs plus immune checkpoint inhibitors, grade 3 to 4 treatment-related adverse events were unexpectedly higher than previously reported continued on page 8

FOR THE TREATMENT OF METASTATIC EGFRm NSCLC

FIRST-LINE TAGRISSO DELIVERED ®

AN UNPRECEDENTED

18.9 vs 10.2 months median PFS vs erlotinib/gefitinib in the FLAURA study

Hazard ratio=0.46 (95% CI: 0.37, 0.57), P<0.0001

Randomized, double-blind, active-controlled trial in 556 patients with metastatic EGFRm NSCLC who had not received prior systemic treatment for advanced disease. Patients were randomized 1:1 to either TAGRISSO (n=279; 80 mg orally, once daily) or EGFR TKI comparator (n=277; gefitinib 250 mg or erlotinib 150 mg, once daily). Crossover was allowed for patients in the EGFR TKI comparator arm at confirmed progression if positive for the EGFR T790M resistance mutation. Patients with CNS metastases not requiring steroids and with stable neurologic status were included in the study. The primary endpoint of the study was PFS based on investigator assessment (according to RECIST v.1.1). Secondary endpoints included OS, ORR, and DOR.1,2

INDICATION

TAGRISSO is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.

SELECT SAFETY INFORMATION

• There are no contraindications for TAGRISSO • Interstitial lung disease (ILD)/pneumonitis occurred in 3.9% of the 1142 TAGRISSO-treated patients; 0.4% of cases were fatal. Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (eg, dyspnea, cough and fever). Permanently discontinue TAGRISSO if ILD is confirmed • Heart rate-corrected QT (QTc) interval prolongation occurred in TAGRISSO-treated patients. Of the 1142 TAGRISSO-treated patients in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. No QTc-related arrhythmias were reported.

GROUNDBREAKING EFFICACY DOSING

ALL SUBGROUPS

First-line TAGRISSO offers convenient, once-daily dosing, with or without food1

Delivered consistent PFS results across all subgroups, including patients with or without CNS metastases2 First-line osimertinib (TAGRISSO) is a National Comprehensive Cancer Network® (NCCN®) Category 1* option3 *Category 1 means NCCN has uniform consensus based upon high-level evidence.3

SELECT SAFETY INFORMATION

Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia • Cardiomyopathy occurred in 2.6% of the 1142 TAGRISSO-treated patients; 0.1% of cardiomyopathy cases were fatal. A decline in left ventricular ejection fraction (LVEF) ≥10% from baseline and to <50% LVEF occurred in 3.9% of 908 patients who had baseline and at least one follow-up LVEF assessment. Conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in patients with cardiac risk factors. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure, permanently discontinue TAGRISSO • Keratitis was reported in 0.7% of 1142 patients treated with TAGRISSO in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist • Verify pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose • Most common adverse reactions (≥20%) were diarrhea, rash, dry skin, nail toxicity, stomatitis, fatigue and decreased appetite

Abbreviations: CNS, central nervous system; DOR, duration of response; EGFRm, epidermal growth factor receptor mutation-positive; NSCLC, non-small cell lung cancer; ORR, overall response rates; OS, Overall Survival; PFS, progression-free survival; RECIST, Response Evaluation Criteria In Solid Tumors; TKI, tyrosine kinase inhibitor. REFERENCES: 1. TAGRISSO [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2018. 2. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. 3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NSCLC V.5.2018. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed June 29, 2018. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. To view the most recent and complete version of the guideline, go online to NCCN.org.

Please see Brief Summary of Prescribing Information on adjacent pages.

LEARN MORE AT TagrissoHCP.com

TAGRISSO® (osimertinib) tablets, for oral use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. INDICATIONS AND USAGE First-line Treatment of EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC) TAGRISSO is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test [see Dosage and Administration (2.1) in the full Prescribing Information]. DOSAGE AND ADMINISTRATION Patient Selection Select patients for the first-line treatment of metastatic EGFR-positive NSCLC with TAGRISSO based on the presence of EGFR exon 19 deletions or exon 21 L858R mutations in tumor or plasma specimens [see Clinical Studies (14) in the full Prescribing Information]. If these mutations are not detected in a plasma specimen, test tumor tissue if feasible. Information on FDA-approved tests for the detection of EGFR mutations is available at http://www.fda.gov/ companiondiagnostics. Recommended Dosage Regimen The recommended dosage of TAGRISSO is 80 mg tablet once a day until disease progression or unacceptable toxicity. TAGRISSO can be taken with or without food. If a dose of TAGRISSO is missed, do not make up the missed dose and take the next dose as scheduled. Administration to Patients Who Have Difficulty Swallowing Solids Disperse tablet in 60 mL (2 ounces) of non-carbonated water only. Stir until tablet is dispersed into small pieces (the tablet will not completely dissolve) and swallow immediately. Do not crush, heat, or ultrasonicate during preparation. Rinse the container with 120 mL to 240 mL (4 to 8 ounces) of water and immediately drink. If administration via nasogastric tube is required, disperse the tablet as above in 15 mL of non-carbonated water, and then use an additional 15 mL of water to transfer any residues to the syringe. The resulting 30 mL liquid should be administered as per the nasogastric tube instructions with appropriate water flushes (approximately 30 mL). Dosage Modifications Adverse Reactions Table 1. Recommended Dosage Modifications for TAGRISSO Target Organ

Adverse Reactiona

Pulmonary Interstitial lung disease (ILD)/Pneumonitis QTc† interval greater than 500 msec on at least 2 separate ECGsb Cardiac QTc interval prolongation with signs/ symptoms of life-threatening arrhythmia

Other

b †

Withhold TAGRISSO until QTc interval is less than 481 msec or recovery to baseline if baseline QTc is greater than or equal to 481 msec, then resume at 40 mg dose. Permanently discontinue TAGRISSO.

Symptomatic congestive heart failure

Permanently discontinue TAGRISSO.

Adverse reaction of Grade 3 or greater severity

Withhold TAGRISSO for up to 3 weeks.

If improvement to Grade 0-2 within 3 weeks Resume at 80 mg or 40 mg daily. If no improvement within 3 weeks

Dosage Modiﬁcation Permanently discontinue TAGRISSO.

Embryo-Fetal Toxicity Based on data from animal studies and its mechanism of action, TAGRISSO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, osimertinib caused post-implantation fetal loss when administered during early development at a dose exposure 1.5 times the exposure at the recommended clinical dose. When males were treated prior to mating with untreated females, there was an increase in preimplantation embryonic loss at plasma exposures of approximately 0.5 times those observed at the recommended dose of 80 mg once daily. Verify pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose [see Use in Specific Populations (8.1, 8.3) in the full Prescribing Information]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1) in the full Prescribing Information] QTc Interval Prolongation [see Warnings and Precautions (5.2) in the full Prescribing Information] Cardiomyopathy [see Warnings and Precautions (5.3) in the full Prescribing Information] Keratitis [see Warnings and Precautions (5.4) in the full Prescribing Information] 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. The data in the Warnings and Precautions section reflect exposure to TAGRISSO in 1142 patients with EGFR mutation-positive NSCLC who received TAGRISSO at the recommended dose of 80 mg once daily in two randomized, active-controlled trials [FLAURA (n=279) and AURA3 (n=279)], two single arm trials [AURA Extension (n=201) and AURA2 (n=210)], and one dose-finding study, AURA1 (n=173) [see Warnings and Precautions (5) in the full Prescribing Information]. The data described below reflect exposure to TAGRISSO (80 mg daily) in 558 patients with EGFR mutationpositive, metastatic NSCLC in two randomized, active-controlled trials [FLAURA (n=279) and AURA3 (n=279)]. Patients with a history of interstitial lung disease, drug induced interstitial disease or radiation pneumonitis that required steroid treatment, serious arrhythmia or baseline QTc interval greater than 470 msec on electrocardiogram were excluded from enrollment in these studies. Previously Untreated EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer The safety of TAGRISSO was evaluated in FLAURA, a multicenter international double-blind randomized (1:1) active controlled trial conducted in 556 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive, unresectable or metastatic NSCLC who had not received previous systemic treatment for advanced disease. The median duration of exposure to TAGRISSO was 16.2 months. The most common adverse reactions (≥20%) in patients treated with TAGRISSO were diarrhea (58%), rash (58%), dry skin (36%), nail toxicity (35%), stomatitis (29%), and decreased appetite (20%). Serious adverse reactions were reported in 4% of patients treated with TAGRISSO; the most common serious adverse reactions (≥1%) were pneumonia (2.9%), ILD/pneumonitis (2.1%), and pulmonary embolism (1.8%). Dose reductions occurred in 2.9% of patients treated with TAGRISSO. The most frequent adverse reactions leading to dose reductions or interruptions were prolongation of the QT interval as assessed by ECG (4.3%), diarrhea (2.5%), and lymphopenia (1.1%). Adverse reactions leading to permanent discontinuation occurred in 13% of patients treated with TAGRISSO. The most frequent adverse reaction leading to discontinuation of TAGRISSO was ILD/pneumonitis (3.9%). Tables 2 and 3 summarize common adverse reactions and laboratory abnormalities which occurred in FLAURA. FLAURA was not designed to demonstrate a statistically significant reduction in adverse reaction rates for TAGRISSO, or for the control arm, for any adverse reaction listed in Tables 2 and 3. Table 2. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in FLAURA* Adverse Reaction

Permanently discontinue TAGRISSO.

Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0). ECGs = Electrocardiograms QTc = QT interval corrected for heart rate

Any Grade (%)

EGFR TKI comparator (geﬁtinib or erlotinib) (N=277)

Grade 3 or higher (%)

Any Grade (%)

Grade 3 or higher (%)

Gastrointestinal Disorders

Drug Interactions Strong CYP3A4 Inducers If concurrent use is unavoidable, increase TAGRISSO dosage to 160 mg daily when co-administering with a strong CYP3A inducer. Resume TAGRISSO at 80 mg 3 weeks after discontinuation of the strong CYP3A4 inducer [see Drug Interactions (7) and Clinical Pharmacology (12.3) in the full Prescribing Information]. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Interstitial Lung Disease/Pneumonitis Interstitial lung disease (ILD)/pneumonitis occurred in 3.9% of the 1142 TAGRISSO-treated patients; 0.4% of cases were fatal. Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough and fever). Permanently discontinue TAGRISSO if ILD is confirmed [see Dosage and Administration (2.4) and Adverse Reactions (6) in the full Prescribing Information]. QTc Interval Prolongation Heart rate-corrected QT (QTc) interval prolongation occurs in patients treated with TAGRISSO. Of the 1142 patients treated with TAGRISSO in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec [see Clinical Pharmacology (12.2) in the full Prescribing Information]. No QTc-related arrhythmias were reported. Clinical trials of TAGRISSO did not enroll patients with baseline QTc of > 470 msec. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia [see Dosage and Administration (2.4) in the full Prescribing Information]. Cardiomyopathy Across clinical trials, cardiomyopathy (defined as cardiac failure, chronic cardiac failure, congestive heart failure, pulmonary edema or decreased ejection fraction) occurred in 2.6% of the 1142 TAGRISSO-treated patients; 0.1% of cardiomyopathy cases were fatal. A decline in left ventricular ejection fraction (LVEF) ≥ 10% from baseline and to less than 50% LVEF occurred in 3.9% of 908 patients who had baseline and at least one follow-up LVEF assessment. Conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in patients with cardiac risk factors. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure, permanently discontinue TAGRISSO [see Dosage and Administration (2.4) in the full Prescribing Information]. Keratitis Keratitis was reported in 0.7% of 1142 patients treated with TAGRISSO in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist.

TAGRISSO (N=279)

Diarrheaa

2.2

2.5

Stomatitis

0.7

0.4

Nausea

Constipation

Vomiting

1.4

Rashb

1.1

6.9

Dry skinc

0.4

1.1

Nail toxicityd

0.4

0.7

0.4

2.5

1.8

Skin Disorders

Pruritus

Metabolism and Nutrition Disorders Decreased appetite

Respiratory, Thoracic and Mediastinal Disorders Cough

0.4

Dyspnea

0.4

1.4

0.4

2.2

0.7

Neurologic Disorders Headache Cardiac Disorders Prolonged QT Intervalf

General Disorders and Administration Site Conditions Fatigueg

1.4

Pyrexia

0.4

Infection and Infestation Disorders Upper Respiratory Tract Infection * NCI CTCAE v4.0 a b c d e f g

One grade 5 (fatal) event was reported (diarrhea) for EGFR TKI comparator Includes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, rash pruritic, rash vesicular, rash follicular, erythema, folliculitis, acne, dermatitis, dermatitis acneiform, drug eruption, skin erosion. Includes dry skin, skin ﬁssures, xerosis, eczema, xeroderma. Includes nail bed disorder, nail bed inﬂammation, nail bed infection, nail discoloration, nail pigmentation, nail disorder, nail toxicity, nail dystrophy, nail infection, nail ridging, onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia. Includes pruritus, pruritus generalized, eyelid pruritus. The frequency of “Prolonged QT Interval” represents reported adverse events in the FLAURA study. Frequencies of QTc intervals of >500 ms or >60 ms are presented in Section 5.2. Includes fatigue, asthenia.

TAGRISSO® (osimertinib) tablets, for oral use Table 3. Laboratory Abnormalities Worsening from Baseline in ≥ 20% of Patients in FLAURA TAGRISSO (N=279) Laboratory Abnormalitya,b

Change from Baseline All Grades (%)

EGFR TKI comparator (geﬁtinib or erlotinib) (N=277)

Change from Baseline to Grade 3 or Grade 4 (%)

Change from Baseline All Grades (%)

Change from Baseline to Grade 3 or Grade 4 (%)

Hematology Lymphopenia

5.6

4.2

Anemia

0.7

0.4

Thrombocytopenia

0.7

0.4

Neutropenia

3.0

Chemistry

a b

Hyperglycemiac

0.5

Hypermagnesemia

0.7

0.4

Hyponatremia

1.1

1.5

Increased AST

1.1

4.1

Increased ALT

0.7

Hypokalemia

0.4

1.1

Hyperbilirubinemia

1.1

NCI CTCAE v4.0 Each test incidence, except for hyperglycemia, is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO range: 267 - 273 and EGFR TKI comparator range: 256 - 268) Hyperglycemia is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TAGRISSO (179) and EGFR comparator (191)

DRUG INTERACTIONS Effect of Other Drugs on Osimertinib Strong CYP3A Inducers Co-administering TAGRISSO with a strong CYP3A4 inducer decreased the exposure of osimertinib compared to administering TAGRISSO alone [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Decreased osimertinib exposure may lead to reduced efﬁcacy. Avoid co-administering TAGRISSO with strong CYP3A inducers. Increase the TAGRISSO dosage when co-administering with a strong CYP3A4 inducer if concurrent use is unavoidable [see Dosage and Administration (2.4) in the full Prescribing Information]. No dose adjustments are required when TAGRISSO is used with moderate and/or weak CYP3A inducers. Effect of Osimertinib on Other Drugs Co-administering TAGRISSO with a breast cancer resistant protein (BCRP) or P-glycoprotein (P-gp) substrate increased the exposure of the substrate compared to administering it alone [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Increased BCRP or P-gp substrate exposure may increase the risk of exposure-related toxicity. Monitor for adverse reactions of the BCRP or P-gp substrate, unless otherwise instructed in its approved labeling, when co-administered with TAGRISSO. Drugs That Prolong the QTc Interval The effect of co-administering medicinal products known to prolong the QTc interval with TAGRISSO is unknown. When feasible, avoid concomitant administration of drugs known to prolong the QTc interval with known risk of Torsades de pointes. If not feasible to avoid concomitant administration of such drugs, conduct periodic ECG monitoring [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) in the full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on data from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) in the full Prescribing Information], TAGRISSO can cause fetal harm when administered to a pregnant woman. There are no available data on TAGRISSO use in pregnant women. Administration of osimertinib to pregnant rats was associated with embryolethality and reduced fetal growth at plasma exposures 1.5 times the exposure at the recommended clinical dose (see Data). 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.

Data Animal Data When administered to pregnant rats prior to embryonic implantation through the end of organogenesis (gestation days 2-20) at a dose of 20 mg/kg/day, which produced plasma exposures of approximately 1.5 times the clinical exposure, osimertinib caused post-implantation loss and early embryonic death. When administered to pregnant rats from implantation through the closure of the hard palate (gestation days 6 to 16) at doses of 1 mg/kg/day and above (0.1 times the AUC observed at the recommended clinical dose of 80 mg once daily), an equivocal increase in the rate of fetal malformations and variations was observed in treated litters relative to those of concurrent controls. When administered to pregnant dams at doses of 30 mg/kg/day during organogenesis through lactation Day 6, osimertinib caused an increase in total litter loss and postnatal death. At a dose of 20 mg/kg/day, osimertinib administration during the same period resulted in increased postnatal death as well as a slight reduction in mean pup weight at birth that increased in magnitude between lactation days 4 and 6. Lactation Risk Summary There are no data on the presence of osimertinib or its active metabolites in human milk, the effects of osimertinib on the breastfed infant or on milk production. Administration to rats during gestation and early lactation was associated with adverse effects, including reduced growth rates and neonatal death [see Use in Specific Populations (8.1) in the full Prescribing Information]. Because of the potential for serious adverse reactions in breastfed infants from osimertinib, advise women not to breastfeed during treatment with TAGRISSO and for 2 weeks after the final dose. Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Contraception TAGRISSO can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) in the full Prescribing Information]. Females Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose [see Use in Specific Populations (8.1) in the full Prescribing Information]. Males Advise male patients with female partners of reproductive potential to use effective contraception during and for 4 months following the final dose of TAGRISSO [see Nonclinical Toxicology (13.1) in the full Prescribing Information]. Infertility Based on animal studies, TAGRISSO may impair fertility in females and males of reproductive potential. The effects on female fertility showed a trend toward reversibility. It is not known whether the effects on male fertility are reversible [see Nonclinical Toxicology (13.1) in the full Prescribing Information]. Pediatric Use The safety and effectiveness of TAGRISSO in pediatric patients have not been established. Geriatric Use Forty-three percent (43%) of the 1142 patients in FLAURA (n=279), AURA3 (n=279), AURA Extension (n=201), AURA2 (n=210), and AURA1, (n=173) were 65 years of age and older. No overall differences in effectiveness were observed based on age. Exploratory analysis suggests a higher incidence of Grade 3 and 4 adverse reactions (13.4% versus 9.3%) and more frequent dose modifications for adverse reactions (13.4% versus 7.6%) in patients 65 years or older as compared to those younger than 65 years. Renal Impairment No dose adjustment is recommended in patients with creatinine clearance (CLcr) 15 - 89 mL/min, as estimated by Cockcroft-Gault. There is no recommended dose of TAGRISSO for patients with end-stage renal disease (CLcr < 15 mL/min) [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Hepatic Impairment No dose adjustment is recommended in patients with mild to moderate hepatic impairment (Child-Pugh A and B or total bilirubin ≤ ULN and AST > ULN or total bilirubin 1 to 3 times ULN and any AST). There is no recommended dose for TAGRISSO for patients with severe hepatic impairment (total bilirubin between 3 to 10 times ULN and any AST) [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 TAGRISSO is a registered trademark of the AstraZeneca group of companies. ©AstraZeneca 2018 Rev. 08/18 US-23593 9/18

IASLC LUNG CANCER NEWS / DECEMBER 2018

Names and News Dr. Fred R. Hirsch Departs IASLC CEO Role, Joins Mount Sinai Hospital Fred R. Hirsch, MD, resigned from his position of IASLC CEO at the end of October and has joined Mount Sinai Hospital in New York City as the executive director for the Clinical Lung Cancer Institute and Endowed Professor at the Icahn Medical School, Mount Sinai, where he will be facilitating basic and translational lung cancer research and clinical studies. Dr. Hirsch has a sincere passion for the IASLC and its multidisciplinary mission that will not lessen after his transition. “I myself received an IASLC Fellowship

when I was younger that was crucial to my career,” he said. “I will personally continue to be an active IASLC member and advocate for this wonderful organization; hopefully, I can contribute to its future in a different capacity.” Since joining the IASLC 41 years ago, Dr. Hirsch has been an engaged member who has served the organization in a number of capacities. He served as chair of the Prevention, Screening, and Early Detection Committee, as well as the Pathology Committee. Dr. Hirsch also was associate editor of the IASLC journal,

the Journal of Thoracic Oncology (JTO). He served on the Board of Directors for the IASLC from 2005-2013 and was editor of the IASLC newsletter from 2000-2013. In 2007, Dr. Hirsch received the Mary J. Matthews Pathology/Translational Research Award for lifetime achievements in pathology and translational research of thoracic malignancies. Dr. Hirsch created and led numerous IASLC workshops and scientific meetings, particularly in Europe and Latin America—furthering the IASLC’s mission of providing global education to thoracic oncology specialists.

IMpower132 from page 1

Fig. 1. PFS Improvement Across Key Patient Subgroups

Since becoming CEO in 2013, Dr. Hirsch helped to transition JTO to a new publisher and has watched the impact factor skyrocket, going from 6.4 to 10.336. The organization itself Dr. Fred R. Hirsch has also witnessed marked growth, having added approximately 4,000 new members—bringing the continued on page 15

A: These IMpower132 study results are significant because they further support the use of atezolizumab plus chemotherapy in chemotherap-naive NSCLC. Changes in routine clinical practice might have to be considered after final reporting of the OS analysis in 2019. In addition, this study has the largest Asian subpopulation in a global checkpoint inhibitor combination trial in first line, treatment-naive NSCLC presented to date, with a remarkable HR of 0.42 in this group of patients. Therefore, further analysis of the significance of these findings is warranted. Additionally, the lack of increased benefit in patients with baseline liver metastases further supports the hypothesis that Socinski, Reck, and IMpower150 colleagues have presented, suggesting that the combination of bevacizumab and atezolizumab is required to confer clinical benefit in these patients.1

Q: Please explain the paradoxical results in those with lower levels of PD-L1 expression: The PFS confidence intervals crossed unity and there was no apparent survival benefit in this group, whereas benefits were more pro-

Data cutoff : May 22, 2018. Abbreviations: APP, atezolizumab + carboplatin/cisplatin + pemetrexed; PP, carboplatin/cisplatin + pemetrexed. a Stratified HR for ITT; unstratified for all other subgroups. b Patients with other/unknown race (n = 46) and unknown baseline ECOG PS (n = 2) not included.

nounced in those with higher levels of expression and in those with no expression. Why do you suppose the group of patients with no PD-L1 expression would have benefited more? A: For this study, PD-L1 testing was not required, and approximately 60% of all patients had PD-L1 testing performed.

Fig. 2. Atezolizumab Combination Reduced the Risk of Disease Worsening or Death (PFS) by 40%

Additionally, multiple factors could have affected these analyses including relatively small sample size, underperformance of the immunohistochemical assay, and potential enrichment of the PD-L1–low expression group with patients whose tumors harbored adverse genomic alterations (such as LKB1 loss). In addition, similar trends were previously seen in the analyses of KEYNOTE-0212 and IMpower131.3

Q: Do you think the PD-1/PD-L1

Data cutoff : May 22, 2018. Abbreviations: APP, atezolizumab + carboplatin/cisplatin + pemetrexed; CR, complete response; DOR, duration of response; HR, hazard ratio; IRF, independent review facility; ORR, objective response rate; PP, carboplatin/cisplatin + pemetrexed; PR, partial response.

inhibitors are largely interchangeable? Or does pembrolizumab (in light of the positive results of KEYNOTE-1894) hold some advantage over atezolizumab? A: Cross-trial comparisons are not feasible because of differences in patient populations included, including distribution and prevalence of PD-L1 expression (in particular PD-L1 high), dose intensity of chemotherapy delivered, and differences

in crossover to subsequent therapy. As such, definitive conclusions regarding the advantage of one checkpoint inhibitor versus another cannot be drawn. ✦ References: 1. Socinski MA, Jotte RM, Cappuzzo F, et al., for the IMpower150 Study Group. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med. 2018;378:2288-2301. 2. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17:1497-1508. Presented at ESMO Immuno-Oncology Congress. Geneva, Switzerland: 2017. 3. Jotte RM, Cappuzzo F, Vynnychenko I, et al. IMpower131: Primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. Presented at: American Society of Clinical Oncology Annual Meeting; Chicago, Illinois: June 4, 2018. 4. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378(22):2078-2092.

LUNGCANCERNEWS.ORG / DECEMBER 2018

MEETING HIGHLIGHTS

Scientific Highlights from the IASLC Latin America Conference on Lung Cancer The top five abstracts from year’s conference, held in Córdoba, Argentina, dealt with PD-1 inhibitors, immunotherapy, and biomarkers. By Edgardo S. Santos Castillero, MD, FACP

Five abstracts were presented at the Presidential Symposium of the 2018 IASLC Latin America Conference on Lung Cancer, held in August in Córdoba, Argentina. All of the presentations cen-

tered on immunotherapy, with the following themes: (1) defining best treatment options as first-line therapy, (2) novel immunotherapy combinations, (3) novel biomarkers to assess immuneoncology response, and (4) possible differences among ethnic groups. The KEYNOTE-024 trial featured prolonged follow-up (data cutoff July 10, 2017) and demonstrated that first-line pembrolizumab monotherapy remains superior to platinum-based chemotherapy in patients with greater than 50% PD-L1 expression, despite crossover from chemotherapy to an anti–PD-1 drug. The hazard ratio for overall survival (OS) was 0.63, 95% CI (0.47, 0.86).1 The authors of KEYNOTE-042 empha-

sized that this study, with a primary endpoint of OS, demonstrated superiority of pembrolizumab over platinum-based chemotherapy in chemotherapy-naive patients with locally advanced or metastatic NSCLC without sensitizing EGFR or ALK abnormalities and PD-L1 expression of 1% or greater.2 From the authors’ perspectives, this trial may extend the role of pembrolizumab monotherapy as a firstline therapy option for patients with lung cancer expressing any degree of PD-L1 expression, although its use in those with less than 50% PD-L1 expression remains controversial. Part 1 of the complex CheckMate 227 study was also presented during the Presidential Symposium.3 With a minimum followup of 11.2 months, PFS was significantly longer for nivolumab plus ipilimumab compared with standard platinum-based chemotherapy in patients with high TMB, defined as 10 or more mutations per megabase (HR 0.58, 97.5% CI [0.41, 0.81]; p = 0.0002). These results held up regardless of PD-L1 expression or histology across all subgroups. The side effects of nivolumab/low-dose ipilimumab were manageable. Finally, Saravia et al.4 presented data on immunotherapy in Hispanic patients. Of note, none of the phase III immunotherapy studies in lung cancer explicitly sought out Hispanic patients. This group of authors presented the largest

series to date (216 patients) of immunotherapy outcomes in Hispanic patients, showing that the overall response rate (ORR) s eems to b e lower compared Dr. Edgardo S. Santos to their non- Castillero Hispanic white counterparts. This study was conducted at Memorial Cancer Institute in collaboration with Sylvester Comprehensive Cancer Center, H. Lee Moffitt Cancer Center and Research Institute (all in Florida, US), and the National Cancer Institute in Peru. The same group, led by Luis E. Raez, MD, FACP, FCCP, looked for new biomarkers to assess immunotherapy response. In this presentation, investigators focused on use of cfRNA isolated from the plasma of patients with lung cancer.5 The study showed that the changes in cfRNA correlated very well with ORR, as demonstrated by CT scans in patients with lung cancer undergoing immunotherapy. Also, PD-L1 measured in plasma RNA correlated well with tissue PD-L1 testing, making it another promising biomarker to assess immunotherapy response. ✦ About the Author: Dr. Santos Castillero is a thoracic oncologist at the Center for HematologyOncology and is a clinical associate professor at Florida Atlantic University. He is also chair of the IASLC Publications Committee.

INDUSTRY AND REGULATORY NEWS Lorlatinib Approved for Second- or Third-Line Management of ALK-positive Metastatic NSCLC November 2, 2018—The U.S. Food and Drug Administration granted accelerated approval to lorlatinib for patients with, ALK (+) metastatic or recurrent NSCLC with disease progression on crizotinib and at least one other ALK inhibitor or on alectinib or ceritinib as first ALK inhibitor therapy for metastatic or recurrent disease. The accelerated approval was based on data from a nonrandomized, dose-ranging multicohort, multicenter study evaluating a subgroup of 215 patients with ALK-positive metastatic NSCLC who received prior treatment with one or more ALK kinase inhibitors (Study B7461001; NCT01970865). The major efficacy measures were overall response rate (ORR) and intracranial ORR, according to RECIST 1.1, as assessed by an independent central review committee. The ORR was 48% (95% CI: 42-55), and the estimated median response duration was 12.5 months (95% CI: 8.4-23.7. Response rates were 4% for complete and 44% for partial responses. Of 89 patients with measurable CNS lesions (according to RECIST 1.1), the intracranial ORR was 60% (95% CI: 49-70), with 21% complete and 38% partial responses. The estimated median response duration was 19.5 months for those with measurable CNS lesions (95% CI: 12.4-not reached). The most common adverse reactions (incidence ≥ 20%) were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea. ✦

References: 1. Brahmer J, Rodríguez-Abreu D, Robinson A, et al. KEYNOTE-024 Update: Pembrolizumab vs Platinum-Based Chemotherapy for Advanced NSCLC with PD-L1 Tumor Proportion Score ≥50%. Presented at: IASLC Latin America Conference on Lung Cancer 2018; August 17, 2018; Córdoba, Argentenia. 2. Lopes G, Wu Y, Kudaba I, et al. Phase 3 KEYNOTE-042 Study: Pembrolizumab vs Platinum-Based Chemotherapy as 1l Therapy for Advanced NSCLC with a PD-L1 TPS ≥1%. Presented at: IASLC Latin America Conference on Lung Cancer 2018; August 17, 2018; Córdoba, Argentenia. 3. Mathias C, Reck M, Hellmann M, et al. CheckMate 227: Nivolumab + Ipilimumab vs Chemotherapy as 1L Treatment for Advanced NSCLC With High Tumor Mutational Burden. Presented at: IASLC Latin America Conference on Lung Cancer 2018; August 17, 2018; Córdoba, Argentenia. 4. Saravia D, Raez L, Ruiz R, et al. Clinical Outcomes in Hispanic Patients Treated with Checkpoint Inhibitors. Presented at: IASLC Latin America Conference on Lung Cancer 2018; August 17, 2018; Córdoba, Argentenia. 5. Raez L, Usher J, Danenberg K, et al. New Biomarkers to Follow Therapy Response in Plasma of NSCLC Patients. Presented at: IASLC Latin America Conference on Lung Cancer 2018; August 17, 2018; Córdoba, Argentenia.

MEETING HIGHLIGHTS

Inaugural LATAM Awards The IASLC Latin America Conference on Lung Cancer in August featured a new awards presentation. The awards, sponsored by the IASLC Latin America Group (LATAM) were, in the words of LATAM Chair Luis E. Raez, MD, “for people who have not only moved forward the mission and vision of the IASLC glob- Dr. Luis E. Raez ally but who have also had a significant contribution to the IASLC LATAM.” The awardees included Paul A. Bunn Jr., MD; David R. Gandara, MD; David P. Carbone, MD, PhD; and Fred R. Hirsch, MD, PhD. A special award was also given to Pia Hirsch for all of her years of support to the LATAM region. The LATAM plans to continue giving out the awards at future IASLC Latin America conferences. ✦

IASLC LUNG CANCER NEWS / DECEMBER 2018

IMMUNOTHERAPY

Neoadjuvant Nivolumab Shows Unprecedented Pathologic Complete Response for Stage III NSCLC By Mariano Provencio-Pulla, MD, PhD

Patients with stage IIIA NSCLC with clinically evident N2 nodal spread have an overall 5-year survival rate of only 10% to 15%. The aims of therapy in stage III disease are to increase both locoregional and systemic control of the disease. Because distant metastases remain the major reason for treatment failure, it is likely that more effective cytotoxic or other antitumor agents will be required to further improve levels of response and survival.1

Targeted Therapy Plus Immune Checkpoint Inhibitors from page 1

Fig. 1. NADIM: Study Design and Flowchart

Adjuvant treatment

Neoadjuvant treatment NSCLC IIIA patients with resectable disease

Nivolumab 360 mg + Paclitaxel 200 mg/m2 + Carboplatine AUC 6

SURGERY (In the 3rd or 4th week from day 21 cycle 3 of neoadjuvant treatment)

IV, Q3W 3 Cycles

(N2 or T4N0/N1)

Blood extraction (C1)

Blood extraction (C3)

Tumor block

Nivolumab 240 mg Q2W for 4 months and Nivolumab 480 mg Q4W for 8 months

FOLLOW UP (3 years)

IV (1 year)

Blood extraction (every 6 months)

Tumor block

Neoadjuvant administration of two doses of nivolumab to patients with earlystage lung cancer has been shown to lead to a major pathologic response—defined as less than 10% of viable tumor cells remaining in the resected specimen—in 45% of tumors.2 Neoadjuvant therapy has theoretical advantages: in vivo assessment of response to chemotherapy helps identify patients who will potentially benefit from adjuvant chemotherapy; early treatment of micrometastatic disease is optimized; a reduction in drug resistance continued on page 9

Table 2. Studies of EGFR and ALK TKIs and Immune Checkpoint Inhibitors Author

Key Patient Criteria

Patients TKI treatment

IO treatment

Grade 3-4 TRAE ORR

EGFR TKI + IO

with TKIs or immune checkpoint inhibitors alone (Table 2).10-12 For example, in a phase I study of osimertinib and durvalumab (TATTON), an unexpectedly increased frequency of treatment-related adverse toxicity was reported, with 38% of patients developing interstitial lung disease (ILD) with grade 3 to 4 toxicity seen in 16% of cases. To place this in context, the incidence of ILD with single-agent osimertinib and durvalumab is 2.9% and 2%, respectively.10 Because of the high frequency of ILD observed, this treatment arm has been discontinued. In a phase I/II study of crizotinib and nivolumab, severe hepatic toxicities leading to the discontinuation of the combination treatment were seen in 38% of patients. In contrast, the discontinuation rates due to hepatic toxicities from singleagent crizotinib and nivolumab are about 2.3% and 0.3% to 1.5%, respectively.12 Current studies of combination molecular targeted therapy and immune checkpoint inhibitors in EGFR-positive or EML4-ALK–positive NSCLC are often associated with increased toxicities but not with greater activity; these combinations should not be administered in routine clinical practice. These findings highlight the importance of conducting well-designed phase I studies and also provide an opportunity to evaluate for biomarkers of efficacy and safety. Further studies on safety and activity of immune checkpoint inhibitors plus targeted agents are required in other oncogene-driven lung tumors such as KRAS, BRAF, or ROS1 NSCLC. Other research avenues being pursued include the characterization of the tumor microenvironment in oncogene-driven NSCLC, use of preclinical models and clinical studies for optimal treatment dosing, and sequencing and development of biomarkers to

Gettinger13 EGFR+, TKI treated or naive

Erlotinib 150mg qd

Nivolumab 3mg/kg q2w

10% diarrhea

Rudin14

EGFR+, TKI naive or one prior non-EGFR TKI Tx

Erlotinib 150mg qd 1w run in

Atezolizumab 1200mg q3w

7% ALT, 7% rash, 75% 7% fever

Gibbons11

EGFR+, TKI naive

Gefitinib 250mg qd: concurrent or 4w lead-in

Durvalumab 10mg/kg q2w

55% hepatic

79%

Ahn10

EGFR+, TKI treated or naive

Osimertinib 80mg qd

Durvalumab 3-10mg/kg q2w

16% ILD

70% (TKI naive)

Gefitinib 250mg qd 2 week run in

Tremelimumab 3-10mg/kg q4w

27% diarrhea

Planchard15 EGFR+, TKI treated

15%

ALK TKI + IO Spigel12

ALK+, treatment naive

Crizotinib 250mg bd

Nivolumab 240mg q2w

38% hepatic

38%

Felip16

ALK+, treatment naive/ prior Tx

Ceritinib 450mg bd or 300mg bd

Nivolumab 240mg q2w

25% ALT 22% GGT

69%

Kim17

ALK+, treatment naive

Alectinib 600mg bd (C1: 7 day lead-in)

Atezolizumab 1200mg q3w

18.9% rash 9.5% ALT

86%

Shaw18

ALK+, treatment naive

Lorlatinib 100mg qd

Avelumab 10mg/kg q2w

18.9% rash 9.5% ALT

86%

Shaw18

ALK/ROS1/MET-ve, >1 treatment

Crizotinib 250mg bd

Avelumab 10mg/kg q2w

16.7% ALT

17%

Abbreviations: TKI, tyrosine kinase inhibitor; IO, immuno-oncology; TRAE, treatment-related adverse event; ORR, overall response rate; Tx, treatment; qd, daily; bd, 2 times a day; q2w, every other week; q3w, every 3 weeks; q4w, every 4 weeks; ALT, alanine transaminase elevation; GGT, gamma-glutamyl transferase elevation; ILD, interstitial lung disease.

identify immunotherapeutic activity in early-phase trials. ✦ About the Author: Dr. Soo is a senior consultant, Department of Haematology-Oncology, National University Cancer Institute, Singapore, and an adjunct senior research fellow, Cancer Science Institute, National University of Singapore. References: 1. Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G. Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. Cancer Cell. 2015;28(6):690-714. 2. Akbay EA, Koyama S, Carretero J, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov. 2013;3(12):1355-1363. 3. Ota K, Azuma K, Kawahara A, et al. Induction of PD-L1 expression by the EML4-ALK oncoprotein and down stream signaling pathways in non-small cell lung cancer. Clin Cancer Res. 2015;21(17):4014-4021. 4. Azuma K, Ota K, Kawahara A, Hattori S, Iwama E, Harada T. Association of PD-L1 overexpression with activating EGFR mutations in surgically resected non-small cell lung cancer. Ann Oncol. 2014;25(10):1935-1940. 5. Soo RA, Lim SM, Syn NL, et al. Immune checkpoint inhibitors in epidermal growth factor receptor mutant non-small cell lung cancer: Current controversies and future directions. Lung Cancer. 2018;115:12-20. 6. Dong ZY, Zhang JT, Liu SY, et al. EGFR mutation

correlates with uninflamed phenotype and weak immunogenicity, causing impaired response to PD-1 blockade in non-small cell lung cancer. Oncoimmunology. 2017;6(11):e1356145. 7. Toki MI, Mani N, Smithy JW, et al. Immune marker profiling and PD-L1 expression across Non-Small Cell Lung Cancer mutations. J Thorac Oncol. 2018 Sep 26. pii: S1556-0864(18)331243311. [Epub ahead of print] 8. Chen N, Fang W, Zhan J, et al. Upregulation of PD-L1 by EGFR activation mediates the immune escape in EGFR-driven NSCLC: Implication for optional immune targeted therapy for NSCLC patients with EGFR mutation. J Thorac Oncol. 2015;10(6):910-923. 9. Hong S, Chen N, Fang W, et al. Upregulation of PD-L1 by EML4-ALK fusion protein mediates the immune escape in ALK positive NSCLC: Implication for optional anti-PD-1/PD-L1 immune therapy for ALK-TKIs sensitive and resistant NSCLC patients. Oncoimmunology. 2015;5(3):e1094598. 10. Ahn M-J, Yang J, Yu H, et al. 136O. Osimertinib combined with durvalumab in EGFR-mutant non-small cell lung cancer: Results from the TATTON phase Ib trial. J Thorac Oncol. 2016 Apr;11(4 Suppl):S115. 11. Gibbons DL, Chow LQ, Kim DW, et al. 57O Efficacy, safety and tolerability of MEDI4736 (durvalumab [D]), a human IgG1 anti-programmed cell death-ligand-1 (PD-L1) antibody, combined with gefitinib (G): A phase I expansion in TKI-naive patients (pts) with EGFR mutant NSCLC. J Thorac Oncol. 2016;11(4 Suppl):S115. 12. Spigel DR, Reynolds C, Waterhouse D, et al. Phase 1/2 Study of the Safety and Tolerability of Nivolumab Plus Crizotinib for the First-Line

13.

14.

15.

16.

17.

18.

Treatment of Anaplastic Lymphoma Kinase Translocation — Positive Advanced Non–Small Cell Lung Cancer (CheckMate 370). J Thorac Oncol. 2018 May;13(5):682-688. Gettinger S, Hellmann MD, Chow LQM, et al. Nivolumab Plus Erlotinib in Patients With EGFR-Mutant Advanced NSCLC. J Thorac Oncol. 2018;13(9):1363-1372. Rudin CM, Cervantes A, Dowlati A, et al. MA15.02 - Long-Term Safety and Clinical Activity Results from a Phase Ib Study of Erlotinib Plus Atezolizumab in Advanced NSCLC. Presented at: IASLC 19th World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada. Planchard D, Barlesi F, Gomez-Roca C, et al. Phase I, safety, tolerability and preliminary efficacy study of tremelimumab (Trem) in combination with gefitinib (Gef) in EGFR-mutant (EGFR-mut) NSCLC (GEFTREM). Ann Oncol. 2016;27(suppl_6):1245P-1245P. Felip E, De Braud FG, Maur M, et al. Ceritinib plus nivolumab (NIVO) in patients (pts) with anaplastic lymphoma kinase positive (ALK+) advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2017;35(15_suppl):2502. Kim D-W, Gadgeel SM, Gettinger SN, et al. Safety and clinical activity results from a phase Ib study of alectinib plus atezolizumab in ALK+ advanced NSCLC (aNSCLC). J Clin Oncol. 2018;36(15_suppl):9009. Shaw AT, Lee S-H, Ramalingam SS, et al. Avelumab (anti–PD-L1) in combination with crizotinib or lorlatinib in patients with previously treated advanced NSCLC: Phase 1b results from JAVELIN Lung 101. J Clin Oncol. 2018;36(15_suppl):9008.

LUNGCANCERNEWS.ORG / DECEMBER 2018

Nivolumab from page 8 due to early exposure to treatment; and downstaging, with improved resectability, becomes possible.

Table 1. Pathologic Response

Major response Complete response Less < 90% Total

24 18

80.0 60.0

20.0

100.0

NADIM Study Details The NADIM Study (CA209-547) was a phase II, single-arm, open-label multicenter study aimed to assess the feasibility, safety, and efficacy of combined neoadjuvant chemotherapy (paclitaxel and carboplatin) and immunotherapy (Fig. 1, page 8). The primary endpoint was progression-free survival (PFS) at 24 months from diagnosis, with the data cut-off of June 30, 2018. Efficacy results are available for the subset of 30 patients who underwent surgery; no intraoperative complications were documented. Seven of the 30 patients had postsurgical complications, but there was no postoperative mortality. Regarding clinical results, tumor responses after neoadjuvant therapy

(100% compliance rate), according to RECIST criteria v1.1 and assessed per CT-SCAN, were as follows: the overall response rate was 70% (21 of 30 patients) and included three complete responses (10%) and 18 partial responses (60%). Stable disease was reported for the remaining nine of 30 patients (30%). Pathologic complete response rates, as shown in Table 1, are unprecedented and highly promising in the context of neoadjuvant therapy of NSCLC. Downstaging occurred in 90% of patients. Toxicity was acceptable. Historically, complete surgical resection,3, 4 tumor downstaging,5 pathologic complete response, and major pathologic responses (mPR)6 have been associated with longterm survival in resectable NSCLC in a retrospective series. The rate of The rate of mPR in this study is quite mPR in this study is quite high, high, particularly in the setting of stage particularly in the setting of stage III NSCLC. This potentially bodes well III NSCLC. This potentially bodes for the future. To this end, a number of well for the future. To this end, a phase III trials are comparing combined number of phase III trials are comimmunotherapy and chemotherapy to paring combined immunotherapy chemotherapy alone in the neoadjuvant and chemotherapy to chemothersetting in resectable NSCLC. Results of apy alone in the neoadjuvant setthese studies should be available in the ting in resectable NSCLC. Results next 1 to 3 years. of these studies should be available

in the next 1 to 3 years. Whether mPR is an adequate surrogate for long-term survival in early-stage NSCLC remains to be seen, but these studies should address that issue, and these trials will ultimately determine whether the promise of immunotherapy can be extended to the curative setting. ✦ References: 1. Langer CJ, Leighton JC, Comis RL, et al. Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer (NSCLC): A phase II toxicity, response, and survival analysis (FCCC 93-024). J Clin Oncol. 1995;13(8):1860-1870. 2. Forde PM, Chaft JE, Smith V, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med. 2018;378(21):1976-1986. 3. Sugarbaker DJ, Herdon J, Kohman LJ, et al. Results of cancer and leukemia group B protocol 8935: A multi-institutional phase II trimodality trial for stage IIIA (N2) non-small-cell lung cancer-Cancer and Leukemia Group B Thoracic Surgery Group. J Thorc Cardiovasc Surg. 1995;109(3):473-485. 4. Kirn DH, Lynch TJ, Mentzer SJ, et al. Multimodality therapy of patients with stage IIIA, N2 non-small–cell lung cancer: Impact of preoperative chemotherapy on resectability and downstaging. J Thorac Cardiovasc Surg. 1993;106(4):696-702. 5. Choi Y S, shim Y M, Kim J, Kim K. Recurrencefree survival and prognostic factors in resected pN2 non-small cell lung cancer. Eur J Cardiothorac Surg. 2002;22(5):695-700. 6. Hellmann M, Chaft JE, William WN, et al. Pathologic response after neoadjuvant chemotherapy in resectable non-small lung cancers: proposal for the use of “major pathologic response” as a surrogate endpoint. Lancet Oncol. 2014;15(1):e42-e50. 7. Martini N, Kris MG, Flehinger BJ, et al. Preoperative chemotherapy for stage IIIa (N2) lung cancer: The Sloan-Kettering experience with 136 patients. Ann Thorc Surg. 8. Martín N. Mediatinal lymph node dissection for lung cancer: The Memorial experience. Chest Surg Clin N Am. 1995;5(2):189-203.

Names and News James P. Allison and Tasuku Honjo Jointly Awarded the Nobel Prize for Discovering Immunotherapy James P. Allison, PhD, and Tasuku Honjo, PhD, MD, were jointly awarded the 2018 Nobel Prize in Physiology or Medicine for their breakthrough accomplishments in cancer immunotherapy, leading to creation of a new highly effective and rapidly developing class of drugs, the immune checkpoint inhibitors, which have recently transformed the therapeutic landscape in thoracic malignancy. Dr. Honjo, of Kyoto University, discovered the programmed cell death protein-1 (PD-1) that is expressed on the surface of T cells and its connection with the immune response. He also realized that if the protein expression was blocked, or inhibited, the immune response against a cancer would be bolstered. PD-1 inhibitors were developed after blockade was shown to be an effective method of cancer control by Dr. Honjo. PD-1 expression levels

quickly became a biomarker to predict efficacy for this new class of agents, and results for some patients, including many with metastatic disease, have been dramatic. Dr. Allison, of the University of Texas MD Anderson Cancer Center, has also researched T-cell proteins. His work in CTLA-4 led to development of successful blockade of this protein, thereby “taking the brakes off ” of the immune system and increasing anti-tumor T-cell activ-

Dr. James P. Allison

Dr. Tasuku Honjo

ity. Almost a decade after his work began, ipilimumab yielded increased overall survival and disease-free survival for patients with advanced melanoma, compared with other traditional therapies. This agent, in combination with PD-1 inhibitors, is also being tested in patients with advanced NSCLC and SCLC, with some success, particularly in patients with high tumor mutation burden. Previously, researchers had been working on protein-related immunebased solutions to numerous autoimmune conditions and other diseases. Drs. Honjo and Allison, however, revolutionized cancer care—leading to an increased number of options and to better results for patients in later disease stages. Immunotherapy is not without its side effects, but ongoing research is working to determine how best to minimize toxicity and which combinations or dose schedules are most effective. ✦

LUNG CANCER

NEWS

EDITOR Corey J. Langer, MD, FACP ASSOCIATE EDITORS Fabrice Barlesi, MD, PhD, and Caicun Zhou, MD, PhD MANAGING EDITOR AND PUBLISHER Joy Curzio, Curzio Communications COPY EDITOR Alana Williams PRODUCTION DIRECTOR Doug Byrnes GRAPHIC DESIGNER Kelli Schmidt, KSchmidt Designs LLC

IASLC Lung Cancer News is published bimonthly by the International Association for the Study of Lung Cancer (IASLC). IASLC Headquarters is located at 13100 East Colfax Avenue, Unit 10, Aurora, CO, 80011, US. Purpose and Audience: IASLC Lung Cancer News features news about lung cancer research, patient care, tobacco control, and expert commentary from lung cancer leaders. The target audience for this publication is physicians and other specialists involved in the research and treatment of patients with lung cancer and other thoracic oncologic disorders. Correspondence: Address correspondence to Corey J. Langer, MD, FACP, Editor, c/o curziocommunications@gmail.com. Change of Address: Postmaster send address changes to IASLC Lung Cancer News, c/o IASLC Headquarters, 13100 East Colfax Avenue, Unit 10, Aurora, CO, 80011, US. Subscription: To initiate or cancel a subscription to IASLC Lung Cancer News or to update your mailing address, please email membership@iaslc.org or call +1-720-325-2956. Advertising: For information on advertising rates or reprints, contact Kevin Dunn, Cunningham Associates, 201-767-4170, kdunn@cunnasso.com. All advertising is subject to acceptance by IASLC. IASLC is not responsible for the content of advertising and does not endorse any advertiser or its products or services. Disclaimer: The ideas and opinions expressed in IASLC Lung Cancer News do not necessarily reflect those of the International Association for the Study of Lung Cancer. The mention of any product, service, or therapy in this publication should not be construed as an endorsement, and the Association accepts no responsibility for any injury or damage to person or persons arising out of or related to any use of material contained in this publication or to any errors or omissions. IASLC MISSION To embrace the study of the etiology, epidemiology, prevention, diagnosis, treatment, and all other aspects of lung cancer and other thoracic malignancies; to provide education and information about lung cancer and other thoracic malignancies to IASLC members, to the medical community at large, and to the public; to use all available means to eliminate lung cancer and other thoracic malignancies as a health threat for the individual patient and throughout the world.

IASLC LUNG CANCER NEWS / DECEMBER 2018

R A D I AT I O N O N C O L O G Y

Prophylactic Cranial Irradiation in Locally Advanced NSCLC Falls Flat By John Armstrong, MD, FRCPI, DABR, FFRRCSI

RTOG 0214, a phase III randomized trial, is the biggest trial to date testing prophylactic cranial irradiation (PCI) in locally advanced NSCLC. 1 The trial, presented at Dr. John Armstrong the IASLC World Conference on Lung Cancer this past September, evaluated patients with stage III NSCLC whose disease had not progressed after treatment with surgery and/or radiation therapy with or without chemotherapy. PCI failed to improve survival, which could have been due to a number of factors, despite a reduction in brain metastases for patients who received PCI.

Study Details Participants were stratified by stage (IIIA vs. IIIB), histology (nonsquamous vs. squamous), and therapy (surgery vs. none) and were randomly assigned to PCI or observation. The primary endpoint of the study was overall survival (OS). Of the 356 patients entered, 340 were eligible for analysis. The median follow-up time was 2.1 years for all patients, and 9.2 years for living patients. The trial failed to meet accrual targets and was underpowered to detect a significant survival difference. PCI had no effect on OS. PCI did, however, significantly reduce the risk of brain metastases; patients in the observation arm were 2.33 times more likely to develop brain metastases than those in the PCI arm (p = 0.004). Nevertheless, there was a relative lack of efficacy in reducing brain

metastases. The 10-year risk was 28.3% without PCI versus 16.7% with PCI. Thus, PCI yielded an absolute risk reduction of 11.6%. This means that PCI benefits just one in 8.6 patients. In contrast, in limited-stage small cell lung cancer (where PCI improves OS), PCI reduced the risk of brain metastases from 58% to 33%. For SCLC, PCI benefits one in four patients.2

Inadequate Effect Within the Brain Completion of imaging prior to random assignment is important. The trial mandated CT scans or brain MRIs with or without contrast. However, CT imaging can miss a significant number of brain metastases detectable by MRI. The trial MRIs were done with and without contrast but were not necessarily volumetric studies. Therefore, an unknown number of patients on both arms of the trial probably had small, undetected brain metastases at enrolment. In this group of patients with NSCLC, the risk of developing brain metastases was 28.3% without PCI versus 58% in the SCLC metanalysis.2 The biologic basis for PCI is that the brain represents a sanctuary site (perhaps because of the blood–brain barrier), where cancer cells survive the effects of chemotherapy. However, the relatively low baseline risk in this series suggests that the brain is not a sanctuary site and that failure in the brain is a manifestation of general failure of systemic control. The reduction of risk from 28.3% without PCI to 16.6% denotes a 40% control rate. Therefore, PCI failed to eliminate 60% of occult or microscopic brain metastases. The dose used was 30 Gy in 15 fractions, which is probably a very low biologic dose. When biologically effective dose (BED) is calculated using an estimated alpha/beta ratio of 3.9 for NSCLC, we can compare

INDUSTRY AND REGULATORY NEWS Pembrolizumab/Carboplatin Plus Paclitaxel or Nab-Paclitaxel Approved for First-Line Treatment of Metastatic Squamous NSCLC October 30, 2018—The U.S. Food and Drug Administration (FDA) approved pembrolizumab, an anti–PD-1 agent, in combination with carboplatin and either paclitaxel or nab-paclitaxel for the first-line treatment of patients with metastatic squamous NSCLC. The approval was based on the results of the KEYNOTE-407 trial, a pivotal phase III trial in which patients who received pembrolizumab in combination with carboplatin and either paclitaxel or nab-paclitaxel experienced significantly improved overall survival, regardless of PD-L1 expression status. Risk of death was reduced by 36% for patients receiving the pembrolizumab/ chemotherapy combination compared with chemotherapy alone (HR = 0.64; 95% CI: 0.49-0.85; p = 0.0017). This is the first approval for an anti–PD-1 regimen for this indication regardless of PD-L1 expression status. ✦

Fig. 1A. Neurotoxicity in the Patients Who Received Prophylactic Cranial Irradiation Fig. 1B. Neurotoxicity in the Control Group

De Ruysscher et al. J Clin Oncol. 2018;36(23):2366-2377. Reprinted with permission.

this schedule to other commonly used fractionation schedules.3 The 60 Gy/30 fractions RTOG standard dose for the locally advanced NSCLC gives a BED of 90.77 Gy. The 50 Gy in 25 fractions used by the Lung Cancer Study Group randomized trial of postoperative radiation had a BED of 75.64 Gy.4 That dose was very effective in controlling microscopic or occult disease remaining after surgery in the mediastinum. Consequently, a similar BED might well be required to control similar disease within the brain. Yet the 30 Gy in 15 fractions used in RTOG 0214 has a BED of only 45.38 Gy. Therefore, it is not surprising that it was not particularly effective in achieving this objective.

Neurotoxicity The main concern about PCI is the risk of neurotoxicity. These concerns prevented the investigators from using a higher dose. A recently published smaller randomized trial in the Netherlands presented comprehensive data regarding incidence and durability of several aspects of neurotoxicity (Fig. 1).5

Perspective on the Future of PCI RTOG 0214 is the largest trial to address this topic. The investigators should consider amalgamating their data with data from the other trials to perform a metanalysis. At present, there is no evidence that PCI improves survival, so it cannot be recommended. Future trials testing other therapies for locally advanced NSCLC could incorporate translational analyses, which might, in theory, identify a phenotype where the risk of brain metastases is so high that PCI (or alternatively routine

volumetric MRIs in follow up) might be reconsidered.6 Meanwhile, the recently reported trial of adjuvant immune therapy (PACIFIC ) suggests that immune therapy may be as effective in the brain as elsewhere in the body. In the PACIFIC trial, the incidence of brain metastases was 5.5% using consolidative durvalumab after definitive chemoradiation versus 11% without.7 ✦ About the Author: Prof. Armstrong is a professor at St. Luke’s Radiation Oncology Network, Dublin, Ireland. References: 1. Sun A, Hu C, Gore E, et al. 10-Year Updated Analysis of NRG Oncology/RTOG 0214: A Phase III Comparison of PCI vs. Observation in Patients with LA-NSCLC. Presented at: IASLC 19th World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada. 2. Aupérin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with smallcell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med. 1999;341(7):476-484. 3. Santiago A, Barczyk S, Jelen U, Engenhart-Cabillic R, Wittig A. Challenges in radiobiological modeling: can we decide between LQ and LQ-L models based on reviewed clinical NSCLC treatment outcome data? Radiat Oncol. 2016;11:67 4. Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. Lung Cancer Study Group. N Engl J Med. 1986 Nov 27;315(22):13771381 5. De Ruysscher D, Dingemans AC, Praag J, et al. Prophylactic Cranial Irradiation Versus Observation in Radically Treated Stage III NonSmall-Cell Lung Cancer: A Randomized Phase III NVALT-11/DLCRG-02 Study. J Clin Oncol. 2018;36(23):2366-2377. 6. Grinberg-Rashi H, Ofek E, Perelman M, et al. The Expression of Three Genes in Primary Non–Small Cell Lung Cancer Is Associated with Metastatic Spread to the Brain. Clin Canc Res. 2009;15(5):1755-1761. 7. Antonia S,Villegas A, Daniel D et al. Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer. N Engl J Med. 2017;377:1919-1929

LUNGCANCERNEWS.ORG / DECEMBER 2018

Investigators at the National Cancer Institute (NCI) compared the transcriptional profiles of lung cancers from African American patients to those from white patients and identified molecular differences that may result in population differences in tumor biology. Researchers led by Brid M. Ryan, PhD, MPH, an investigator from the Laboratory of Human Carcinogenesis at the Center for Cancer Research, published their results in the journal of Clinical Cancer Research.1 Molecular differences between lung tumors in African American and white patients could lead to differences between these populations in risk and response to treatment. As more precision medicine oncology treatments are approved, understanding the molecular profiles of patients and tumors is becoming ever more important, but African American patients are still under-represented in clinical trials in oncology. Dr. Ryan and her colleagues com-

pared the expression levels of both protein coding messenger RNA (mRNA) and noncoding micro-RNA (miRNA) transcripts in tumor and lung samples from African American and white patients with NSCLC. Genes and miRNAs that were differentially expressed only in tumors from African American patients were enriched for those involved in stem cell and invasion pathways, a finding that Dr. Ryan noted is consistent with observations in other types of cancer in African American patients, including breast, colorectal, and prostate cancer. Dr. Ryan told the IASLC Lung Cancer News, “Precision medicine is fundamentally about improving health outcomes by providing the most precise, molecular-based cancer diagnosis and matching it to the most effective, least toxic therapy.” To that end, she and her colleagues used a tool called the Connectivity Map to predict the effects that these transcriptional profiles would have on the response to various oncology drugs.2 Drug resistance

was predicted in Af rican American patients to 53 drugs that were expected to be effective in white patients, Dr. Brid M. Ryan including irinotecan. The authors noted that several of these drugs, including betulinic acid, rosiglitazone, and adiphenine, target stem cell and invasion pathways. In addition to drug responses, the authors analyzed the mRNA and miRNA profiles of the cancer samples to evaluate population differences in the immune infiltration of the tumor microenvironment. The data suggested that inflammatory marker profiles could vary between African American and white patients, but no difference was observed in the expression of the checkpoint inhibitor genes PD-L1 or PD-L2. Another checkpoint inhibitor gene, CTLA-4, was more highly

expressed in tumors from African American patients, but the investigators could not determine whether expression was increased in tumor cells, infiltrating T cells, or both. The authors are currently working on ways to test and validate potential differences in drug responses in preclinical models as a step toward exploring population differences in a clinical setting. They are also expanding their research into other aspects of tumor biology beyond mRNA and miRNA profiles. Their ultimate goal, Dr. Ryan said, “is to map [the molecular differences between tumor subtypes], understand [their effects], and then, as much as we can, leverage [that information] to improve lung cancer outcomes.” ✦

CORNER

NCI Corner: Racial Differences in the Transcriptomes of Lung Tumors

References: 1. Mitchell KA, Zingone A, Toulabi L, Boeckelman J, Ryan BM. Comparative Transcriptome Profiling Reveals Coding and Noncoding RNA Differences in NSCLC from African Americans and European Americans. Clin Cancer Res. 2017;23(23):7412-7425. 2. The Connectivity Map. Broad Institute website. clue.io/cmap. Accessed February 22, 2018

PAT H O L O G Y

The Future Is Now: Pathology Is Going Digital By Sanja Dacic, MD, PhD, and Douglas J. Hartman, MD

The pathology community initially showed resistance to digital pathology implementation in routine practice mostly because of pathologists’ lack of experience with the ever-changing technology, traditional thinking that review of digital images is more time consuming than light microscopy, and lack of approval from regulatory agencies. However, the U.S. Food and Drug Administration (FDA) approved the first whole-slide imaging system for primary diagnosis in April 2017. This decision should pave the way for standardization of digital pathology in practices and should encourage the pathology community to adopt digital diagnostic tools on a much larger scale.

Globalization of Pathology Digital pathology is a rapidly growing field that represents a significant part of pathology clinical practice in some medical centers, particularly in the areas of consultation, frozen section diagnosis, quality assurance quantification of immunohistochemical assays (i.e., PD-L1 and

immune cells), and identification of microorganisms in tissue sections. The major advantage of digital pathology is the ability to create networks among patholo- Dr. Sanja Dacic gists, which allow them to efficiently share a large number of challenging cases either at the time of intraoperative consultation or for a second opinion. Pathology practices can also deliver services to remote locations without physical access to subspecialty expertise, which is particularly important given the increasing emphasis in the field on improving diagnostic excellence and quality. At the same time, providers, particularly in large academic centers, have the ability to archive noteworthy cases for teaching and research purposes, while enhancing revenues for their expanding consultation practices. On the other hand, there is concern that the implementation of digital pathology may result in outsourcing of small pathology practices to centers with highly

sought expertise, subsequently eliminating onsite pathologists in small hospitals or even across the world and leading to the globalization of pathology practice. This Dr. Douglas J. Hartman is a valid concern that has been already experienced with the development of the large integrated healthcare networks, although one has to keep in mind that high operating cost for implementation and maintenance of equipment needed for digital pathology services, together with identification of a team of skilled people who will make this service happen, might be challenging. Although storage costs are decreasing, digital pathology still generates a large amount of data (200 MB to one-half GB per digital slide) and, therefore, cloud storage represents an attractive solution regarding equipment costs. Cloudbased services make images easily and, usually, more affordably accessible; however, these services can be vulnerable to external breaches (i.e., hacking).

Therefore, data safety is a critical issue that hospitals must address. One recent improvement has been the development of a single repository to hold all imaging data for a healthcare network (i.e., enterprise imaging).

Emerging Complementary Technologies Several nontraditional methods for examining tissue are being developed. These include super resolution, multiplex fluorescence, microscopy with ultraviolet sectioning excitation (MUSE), and optical coherence tomography/in vivo microscopy. In addition to these nontraditional methods, there have been technologic advancements with whole-slide imaging that cannot be achieved by light microscopy, such as 3D imaging. In the research arena, 3D reconstruction of whole-slide images has been used for classification of lung adenocarcinoma. This technology is not currently used in clinical surgical pathology, but it has made its way into forensic pathology as virtual autopsy (virtopsy). A current practice in pathology laboratories is to take static digital images of surgically resected specimens. continued on page 12

IASLC LUNG CANCER NEWS / DECEMBER 2018

Pathology Going Digital from page 11 Using 3D reconstruction technology, this could result in better radiologic– pathologic correlation as well as in improvements in radiologic interpretation. This approach may also improve the accuracy of the tumor-size measurement, which is a major determinant in the T staging of lung cancer. Finally, artificial intelligence (AI)— deep learning, in particular—has been proposed as another tool that can improve and transform clinical practice. There is great enthusiasm for AI applications in radiology and cardiology imaging (e.g., MRI and ultrasound) that can potentially be automated to the point of generating a diagnosis. For radiology applications, AI has been mostly applied in a “second-look” function, so it seems reasonable that this functionality will also transition to digital pathology. It is difficult to predict where AI will be applied in pathology, but it will not replace pathologists in the near future

INDUSTRY AND REGULATORY NEWS Dacomitinib Approved as EGFR TKI September 27, 2018—The U.S. Food and Drug Administration (FDA) approved dacomitinib for the firstline treatment of patients with metastatic NSCLC who have sensitizing EGFR mutations. Approval was based on the ARCHER 1050 trial, which compared the safety and efficacy of dacomitinib to gefitinib in 452 patients with unresectable, metastatic NSCLC. Patients were required to have no prior therapy for metastatic disease or recurrent disease with a minimum of 12 months disease-free after completion of systemic non-EGFR TKI-containing therapy; an ECOG PS of 0 or 1; and EGFR exon 19 deletion or exon 21 L858R substitution mutations. Patients were randomly assigned to receive either 45 mg of dacomitinib orally once daily or 250 mg of gefitinib orally once daily until disease progression or unacceptable toxicity. The trial showed that dacomitinib improved overall survival over gefitinib (34.1 vs. 26.8 months, p = 0.0438; HR 0.76, 95% CI [0.5820.993]). ✦

Department of Pathology, University of Pittsburgh Medical Center Image Analysis Center. There are multiple scanners and work stations where pathologists assist in the interpretation of frozen sections and difficult cases from hospitals across the United States and worldwide.

because humans plus AI have performed better than each individually.1 In summary, the digital pathology space is starting to expand, having been given FDA approval. Digital pathology represents a disruptive technology that will facilitate more advanced diagnostic skills for pathologists. It should be viewed as another sophisticated tool in a patholo-

An example of the whole-slide image of acid-fast staining. A computer algorithm detects acid-fast bacteria (inserts). This is an example of how image analysis can assist pathologists in making the correct diagnosis.

gist’s armamentarium that can improve diagnostic accuracy and, subsequently, enhance the management of complex diseases by a multidisciplinary team, with the end result hopefully being better patient outcomes. About the Authors: Dr. Dacic is a professor of pathology, University of Pittsburgh Medical

Center, and is a member of the IASLC’s Pathology Committee. Dr. Hartman is an associate professor of pathology and associate director, Division of Pathology Informatics, University of Pittsburgh Medical Center. ✦ References: 1. Dreyer KJ, Geis JR. When machines think: radiology’s next frontier. Radiology. 2017;285(3):713718.

PREVENTION & TOBACCO CONTROL

Fighting the Tobacco Scourge: Implementation of Tobacco-Control Measures Begets Public Health Success By Jeffrey Drope, PhD; Cary Adams, MBA; Clifford E. Douglas, JD; Jacqui Drope, MPH; and Sonali Johnson, PhD

There is clear evidence of success in recent global efforts to curb tobacco use, the largest preventable cause of disease and premature death in the world. Since 2012, global cigarette consumption has declined slightly each year from a high of approximately 6.3 trillion sticks; the proportion of people using tobacco has also decreased (less than 21% of adults report current smoking). However, this success is uneven and is largely dependent on governments’ commitment to and level of effectiveness in implementing tobacco-control policies. The many existing examples of successful government action to ameliorate the tobacco epidemic demonstrate that tobacco-control policies work; however, there is justified concern that too many governments have been slow to strengthen their countries’ tobacco-control policies. In recent years, the tobacco-control community has developed and refined a set of evidence-based provisions that have contributed significantly to reducing tobacco use. These measures are enshrined in the World Health Organization’s (WHO) Framework Convention on Tobacco Control, which came into force in 2005 and to which

most countries are now a party. Most of to the decline of more than one million these measures aim to reduce the demand smokers, and the tax revenue is helping to for tobacco including increasing tobacco provide universal healthcare for millions taxes, expanding smoke-free environ- of low-income Filipinos. Unfortunately, ments, requiring stronger warnings on the WHO reported in 2017 that only 760 tobacco packaging and in advertisements million people live in countries where tax (where permitted), and restricting the levels reach the recommended 75% of marketing of tobacco products. tobacco price. Among the proven policy intervenCreation of smoke-free environtions, the most effective tobacco-control ments makes the places where people measure is substantially increasIn the Philippines, a large excise tax increase on ing excise taxes on tobacco products in 2013 contributed greatly to the decline of more than one million smokers, and tobacco products. the tax revenue is helping to provide universal The relationship is healthcare for millions of low-income Filipinos. straightforward: governments raise taxes, tobacco companies typically raise prices to live, work, eat, and engage in recrepreserve their profits, and the higher prices ational activities markedly healthier for deter consumption. Notably, consumption everyone, particularly for nonsmokers. decreases more among young people and As of early 2018, less than 20% of the those with lower income, thereby protect- world’s population enjoyed some protecing several potentially more vulnerable tion from second-hand smoke through groups. Because the decline in consump- smoke-free public and work places. The tion is typically less than the tax increase, implementing countries have enjoyed countries not only benefit from lower immediate health rewards after going consumption—including lower healthcare smoke free. For example, research costs and higher productivity—but also demonstrates a significant decrease from increased tax revenues. Some gov- in community rates of heart attack in ernments are reinvesting a portion of these jurisdictions that have gone smoke free. revenues into healthcare, further benefit- Furthermore, smoke-free places serve to ting societal well-being. In the Philippines, “de-normalize” smoking, making smoka large excise tax increase on tobacco ing a less acceptable behavior. Moreover, products in 2013 contributed greatly continued on page 15

LUNGCANCERNEWS.ORG / DECEMBER 2018

Richard Pazdur, MD, is director of the U.S. Food and Drug Administration’s (FDA’s) Oncology Center of Excellence. Below, he discusses the current status of and future directions for the FDA’s approval of oncology drugs.

Q: Has the accelerated conditional approval process been a success in your view? Are there aspects you would like to tweak or improve? A: The accelerated approval process has been highly successful in bringing anti-cancer drugs to patients sooner based on earlier endpoints and smaller trials. We recently published a study that showed that, since its inception in 1992, we granted accelerated approval to 64 oncology drugs for 93 new indications, including 53 new molecular entities.1 Of the accelerated approvals that fulfilled their post-marketing requirement, benefit was verified a median of 3.4 years after the initial accelerated approval. Failure to confirm benefit is rare; in the few instances (5%) in which accelerated approval was withdrawn, several drugs were able to return to the market once the correct biomarker population was identified (e.g., EGFR tyrosine kinase domain mutations with gefitinib in advanced NSCLC) or the dose and schedule of the drug was optimized (e.g., gemtuzumab ozogamicin). Tweaks or improvements to accelerated approval would require changes in the law. One possible improvement would be to align better with the European concept of conditional approval (a preliminary benefit–risk assessment, followed by confirmation of benefit–risk).

pathway to using pathologic complete response rate for accelerated approval for high-risk neoadjuvant breast cancer. In 2013, pertuzumab was granted accelerated approval in neoadjuvant HER2-positive breast cancer and was granted regular approval in 2017. There are still many issues to sort out in lung cancer, including how to optimally design neoadjuvant studies, how to standardize pathologic assessment of response, and what endpoints to use. There is certainly a lot of interest within the industry in using neoadjuvant trials to expedite drug development, as evidenced by numerous recently launched randomized trials investigating immunotherapy in this setting.

Q: How much bio-correlative work is mandatory from the perspective of approvals based on phase II studies? A: Bio-correlative work is critical. As demonstrated by the development of oncogenedirected targeted therapies for EGFR and ALK, it is crucial to understand the biology of how the genomic changes drive the growth and progression of cancer and how inhibiting the pathway leads to regression of the tumor. In addition, bio-correlative work through serial biopsy at progression has led to a deeper understanding of underlying resistance mechanisms, which, in turn, has led to second and third generations of these oncogene-directed targeted therapies.

Q: Do you perceive pressure, either political or societal, to approve more Q: What is your perspective on the approval process in rare oncogenicdriven disease (e.g., RET- or ROS1-positive NSCLC) based on phase II, rather than phase III, studies? A: Recent approvals of crizotinib for ROS1 NSCLC or dabrafenib with trametinib in BRAF-mutant NSCLC show that for rare oncogene-driven subsets, durable response rates in a single-arm trial may be sufficient. A response, depending on its depth, location, and durability, may be meaningful to patients. Sometimes a randomized trial looking at survival improvements may not be feasible for several reasons: a rare patient population, which limits accrual; high response rates in early clinical development, which render a randomized trial of a new agent versus toxic chemotherapy lacking in equipoise; and crossover to the targeted therapy following progression, which diminishes the ability to detect an improvement in survival. Q: Assuming phase II studies lead to approval in oncology, what are the thresholds for response rates, progression-free survival rates, and overall survival rates? A: We don’t have any absolute thresholds for approval; it very much depends on the context of the cancer, the setting, the availability of other treatments, the toxicity profile, and the magnitude and durability of effect. We did perform a meta-analysis published in the Journal of Clinical Oncology in 2015 that showed that drugs with high response rates, such as targeted therapies, are likely to also have large progression-free survival gains over traditional chemotherapy.2

Q: Can activity in the neoadjuvant setting lead to approvals, or is this premature? A: We held a workshop with the IASLC in March 2018 to discuss issues with neoadjuvant lung cancer trials. One key area for discussion was how can we learn from the breast cancer community, which has a long history of conducting neoadjuvant trials. In fact, in 2014, we finalized a guidance describing the

agents more quickly?

A: There are ebbs and flows in the sociopolitical environment surrounding the FDA. A lot has changed in society since the 1962 Kefauver-Harris Amendment to the Federal Food, Drug, and Cosmetic Act that granted the FDA pre-market authority to review drugs based on safety Ultimately, we need to do what is and efficacy. In the past right for patients—both current few decades, there has patients, by ensuring timely access to been a call for the FDA safe and effective drugs, and future to be more responsive patients, by ensuring that highto society at large and to quality evidence is generated. incorporate the voice of the patient into its decision-making process. Some criticize the FDA either for being too cautious or for being too quick to approve drugs. Ultimately, we need to do what is right for patients—both current patients, by ensuring timely access to safe and effective drugs, and future patients, by ensuring that high-quality evidence is generated.

Q: Finally, what is your perspective on “right-to-try” laws? Are they ethical? Are they safe? Are there ways to monitor adverse events?

A: It is premature to comment on “right-to-try” laws, as the legislation is recent, and the agency is still adopting its position on these laws. ✦ References: 1. Beaver JA, Howie LJ, Pelosof L, et al. A 25-Year Experience of US Food and Drug Administration Accelerated Approval of Malignant Hematology and Oncology Drugs and Biologics: A Review. JAMA Oncol. 2018;4(6):849-856. 2. Blumenthal GM, Karuri SW, Zhang H, et al. Overall response rate, progression-free survival, and overall survival with targeted and standard therapies in advanced non-small-cell lung cancer: US Food and Drug Administration trial-level and patient-level analyses. J Clin Oncol. 2015;33(9):10081014.

CORNER

FDA Approval Processes in the Era of Targeted Therapies: A Conversation with Dr. Richard Pazdur

IASLC LUNG CANCER NEWS / DECEMBER 2018

G L O B A L I N I T I AT I V E S

The State of Lung Cancer in Egypt: Progress Is at Hand By C.A.I.R.O Journal Club Executive Board

Egypt faced major turmoil in 2011, with subsequent dramatic political changes and a rapidly developing economic crises that, within a few months, led to a significant increase in the proportion of the population living below the poverty line. As per the World Bank, Egypt is defined as a lower-middle–income country with a gross national income per capita of US$1,006 to US$3,955. Despite the fact that Egypt is grouped with countries such as India, Morocco, Indonesia, Sudan, Yemen, and Myanmar in this classification, it is clearly visible that the gross national income per capita is not a reliable index for healthcare quality.1 These countries each face several diverse obstacles challenging their goal to provide high-quality healthcare for their citizens. Egypt, for example, has one of the highest gross number of oncologists and cancer centers in the Middle East and Africa; however, it has one of the lowest health expenditures per capita compared to other lowermiddle–income countries. Such economic challenges mostly affect the disciplines with rapidly evolving diagnostic and therapeutic advances—the top of which is NSCLC. The number of specialized healthcare providers and facilities can barely deliver basic care for the population of more than 95 million. In addition, several university hospitals and dedicated cancer centers that had previously met the basic needs for lung cancer treatment according to the past decade’s standards are now falling short according to today’s standards. Lung cancer represents the most lethal malignancy in Egypt (similar to most countries); however, it is the fourth most common cancer in men,

C.A.I.R.O Journal Club Executive Board Members: • Dr. Ahmed Magdy Rabea (Cairo University) • Dr. Amr Shafik (Ain Shams University) • Dr. Basel Refky (Mansoura University) • Dr. Emad Shash (Cairo University) • Dr. Khaled Abdel Aziz (Ain Shams University) • Dr. Loay Kassem (Cairo University) • Dr. Noha Rashad (Maadi Armed Forces Compound) • Dr. Omar Abdel-Rahman (Ain Shams University)

allow more diverse treatment options. Fourth, renegotiating TKI prices to be covered by the Ministry of Health reimbursement system could provide costeffective patient care that could reduce the number of clinic visits and inpatient admissions in already-crowded cancer care facilities. Finally, by encouraging international multicenter clinical trials testing new agents, many patients could gain access to unavailable drugs free of charge. In addition, such trials could help define subgroups that benefit the most from newer agents and, hence, The C.A.I.R.O Journal Club meeting serves as a collaborative forum for attendees. could offer the opportunity for smart, cost-effective personalization of care. 2 and it is relatively rare in women. This those with national and international priFor example, immunotherapy costs the gender difference in incidence is mainly vate insurance coverage, where patients United States US$174 billion per year.5 due to differences in tobacco smoking have access to further biology-driven Recently, several voices have been presrates. According to Giovino et al.,3 Egypt therapies such as EGFR and ALK TKIs, suring low- and middle-income counremains one of the countries with the bevacizumab, and immune checkpoint tries’ health authorities to adopt recent lowest percentages of female smokers in inhibitors. The authors estimate that no advances such as immunotherapy and the world. Egypt does not have a national more than 10% of patients receive this newer-generation TKIs into the reimscreening program, and most patients type of care. bursement system. Such expansion present with either locally advanced or should be cautiously considered. metastatic disease. Can We Enhance Our In a country where tobacco and occuExisting Resources? pational exposures are the main cause of Barriers to Lung Cancer Care Despite the limitation in the governmen- lung cancer, directing resources toward Heterogeneity in the level of diagnos- tal health expenditure, many resources anti-tobacco campaigns and early tic and therapeutic options remains the can be optimized to provide state- detection among high-risk populations crux of the lung cancer problem in Egypt. of-the-art should also There are three large categories of oncol- cancer care be considered a priority. In ogy practice in Egypt. at no addiour opinion, The first and largest are the public tional cost. governmental hospitals, which offer First, across centralization of the full reimbursement for all basic diag- t h e t h r e e nostic and therapeutic interventions. major oncoltherapeuThese hospitals (which include dedi- ogy service tic policies Heterogeneity in the level of diagnostic and cated cancer centers, university hos- categories, via national therapeutic options remains the crux of the pitals, and Ministry of Health public fewer than guidelines lung cancer problem in Egypt. hospitals) serve more than half of all 10% of all and decenpatients with lung cancer in Egypt and patients with tralization offer standard chemotherapeutic agents lung cancer have access to a multidis- of the services provided through well(pemetrexed and targeted agents are not ciplinary team. This is mainly caused distributed, dedicated thoracic multireimbursed for NSCLC treatment; how- by nonuniform distribution of oncol- disciplinary teams could help decrease ever, pemetrexed is available for patients ogy specialists across different regions cancer-related suffering on an individual with mesothelioma), standard 3D radia- in Egypt. Redistribution of oncologists, and country-wide level. ✦ tion therapy, cardiothoracic surgery, and radiation oncologists, thoracic surgeons, palliative care. and other related healthcare providers References: 1. Data: World Bank Country and Lending Groups. Second is the public insurance sector, could significantly improve the quality The World Bank website. datahelpdesk.worldbank.org/knowledgebase/articles/906519-worldwhich allows for the same standard of lung cancer care. Second, dedicated bank-country-and-lending-groups. Accessed options provided by the public hospi- palliative care units are scarce in Egypt. March 28, 2018. tals in addition to limited additional Investing in this extremely impor- 2. Ibrahim AS, Khaled HM, Mikhail NN, Baraka H, Kamel H. Cancer incidence in Egypt: results diagnostics (including baseline PET- tant service, which has been proven to of the national population-based cancer registry CT) and therapeutic options (includ- improve quality of life, symptom severprogram. J Cancer Epidemiol. 2014;2014:437971. ing pemetrexed [for both malignant ity, depression, and possibly survival, 3. Giovino GA, Mirza SA, Samet JM, et al. Tobacco use in 3 billion individuals from 16 pleural mesothelioma and NSCLC] and is a must.4 Third, some molecular tests countries: an analysis of nationally representaEGFR tyrosine-kinase inhibitors [TKIs] (such as EGFR mutations and ALK reartive cross-sectional household surveys. Lancet. 2012;380(9842):668-679. in second-line treatment). The authors rangement) are already sponsored by the estimate that somewhere in the range pharmaceutical industry. Increasing 4. Haun MW, Estel S, Rucker G, et al. Early palliative care for adults with advanced cancer. Cochrane of 35% to 40% of patients receive this awareness among oncologists could Database Syst Rev. 2017 Jun 12;6:CD011129. type of care. increase the number of patients tested 5. Andrews A. Payers’ Perspectives in Oncology American health and drug benefits. American Finally, there are private hospitals/clin- (which stands currently at only approxiHealth & Drug Benefits. 2015;8(Special issue). ics that cater to out-of-pocket payers and mately 20% of all patients) and, hence,

LUNGCANCERNEWS.ORG / DECEMBER 2018

Tobacco-Control Measures from page 12 youth observe smoking less frequently and are less likely to initiate smoking as a result. By 2017, a little more than half of the world’s population lived in countries where tobacco packaging has large, graphic warning labels to alert people to the dangers of tobacco use. Taking the next step, an increasing number of countries have emulated Australia by legislating that tobacco products can only be in plain, standardized packs, eliminating logos and colors, and thereby diminishing the appeal to consumers, including children. The main reason that tobacco products remain popular globally is because the tobacco industry markets its products aggressively. In the United States, the tobacco industry’s annual marketing budget is consistently more than $8 billion. Tobacco firms seek to present products that convey glamour, coolness, and success. The health community and government authorities must vigorously present the starkly contrasting narrative of disease and death: smoking steals an average of nearly 11 years from a smoker’s life, and more than half of smokers die from a tobacco-attributable disease. The vector for tobacco use is distinctly human: the tobacco industry fights tobacco control by almost any means including litigation, aggressive lobbying, and even corruption. The best way to fight this scourge is to work together to champion proven tobaccocontrol measures. Countries where broad coalitions of participants from

Dr. Fred R. Hirsch from page 6 total membership to approximately 7,500 worldwide—and 18 new staff. According to Dr. Hirsch, the landscape of lung cancer care has significantly changed in every aspect during his tenure as CEO, which has contributed to this growth. “Educational need grows with development in the field, which of course adds additional demands for the organization and its staff,” he said. “We at the IASLC know that it is important to meet this need, worldwide, as demonstrated by our first educational meeting in Africa this past year.” While serving as the CEO, Dr. Hirsch continued to pursue his research interests as a professor of medicine and pathology at the University of Colorado School of Medicine. His research has helped identify and validate prognostic markers for lung cancer outcomes and predictive

different parts of the health, consumer, environmental, academic, and human rights sectors are speaking out loudly have realized greatest success in driving down tobacco use and saving lives. At the WHO Framework Convention on Tobacco Control Eighth Conference of the Parties in October, 2018, Parties worked together again toward more effective implementation. ✦ About the Authors: Dr. Drope is vice president of economic and health policy research for the American Cancer Society and professor in residence of Global Public Health at Marquette University. Mr. Adams is chief executive officer of the Union for International Cancer Control. Mr. Douglas is vice president for tobacco control for the American Cancer Society and adjunct professor at the University of Michigan School of Public Health. Ms. Drope is managing director of Global Cancer Prevention and Early Detection at the American Cancer Society. Dr. Johnson is head of advocacy at the Union for International Cancer Control. References: 1. Global Adult Tobacco Survey – Philippines Country Report 2015. World Health Organization website. who.int/tobacco/surveillance/survey/ gats/phl_country_report.pdf?ua=1. Accessed September 11, 2018. 2. Drope J, Schluger N, Cahn Z, et al. The Tobacco Atlas. The Tobacco Atlas website. tobaccoatlas.org/wp-content/uploads/2018/03/ TobaccoAtlas_6thEdition_LoRes_Rev0318.pdf. Accessed September 11, 2018. 3. Lightwood J, Glantz S. 2009. Declines in Acute Myocardial Infarction following Smokefree Laws and Individual Risk Attributable to Secondhand Smoke. Circulation 124, 14: 1373-1379. 4. World Health Organization. 2017. Global Report on the Tobacco Epidemic. Geneva: WHO 5. Federal Trade Commission. Federal Trade Commission Cigarette Report for 2015. Washington DC, 2017.

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Meetings Schedule IASLC 19th Lung Cancer Targeted Therapies Meeting February 20-23, 2019 Santa Monica, California | #LCTT19

IASLC Small Cell Lung Cancer Meeting 2019 April 3-5, 2019 | New York, New York | #SCLC19

2019 European Lung Cancer Congress April 10-13, 2019 | Geneva, Switzerland | #ELCC19

IASLC Mesothelioma Meeting 2019 July 10-12, 2019 | New York, New York | #MESO19

IASLC 20th World Conference on Lung Cancer markers for personalized lung cancer therapies, contributing to his co-authorship of several IASLC atlases and informing the IASLC Blueprint PD-L1 harmonization project. “Because of the rapid and robust progress in lung cancer research, it’s very important to continue to increase collaboration and synergy with other organizations in the field,” Dr. Hirsch noted. “Because of the IASLC’s ability to provide valuable worldwide education, I would like to see the IASLC become the main reference organization for more advocacy groups and patients.” The IASLC Lung Cancer News (ILCN) leadership and staff are especially grateful to Dr. Hirsch for his dedication to the publication, which he initiated. According to Corey Langer, the ILCN Editor, “Dr Hirsch has been an invaluable role model for his peers and colleagues. In many ways, he has left an indelible mark on this organization.” ✦

September 7-10, 2019 Barcelona, Spain | #WCLC2019

IASLC North America Conference on Lung Cancer 2019 October 9-12, 2019 Chicago, Illinois | #NACLC19

IASLC Latin America Conference on Lung Cancer 2019 October 18-19, 2019 | Mexico City, Mexico #LACLC19

*MSI status will be reported for samples determined to have high microsatellite instability. ÂŠ 2018 Foundation Medicine, Inc. | MKT-0255-01