IASLC Lung Cancer News - V3, N2 by IASLC

LUNG CANCER

V3/ N2 / APRIL 2018

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

INSIDE 6

PD-L1 IHC Blueprint Project: Ongoing Progress Toward Consistency Among Assays

Q&A with TMB Expert Dr. Solange Peters

CheckMate-227: IO Combination Success in First Line NSCLC

Using Deep Learning Systems to Radiologically Predict Pathologic Invasiveness in Lung Adenocarcinoma

CMS-Proposed Coverage Restrictions for NGS

PACIFIC Trial Leads to Durvalumab Approval in United States

Barriers to Access to New Lung Cancer Drugs in Latin America

Management of Pulmonary Nodules Detected by CT Screening

C.A.I.R.O Journal Club’s Fourth Anniversary

European Perspective on ALCHEMIST

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 PREVENTION AND TOBACCO CONTROL

FDA’s New Nicotine-Focused Regulatory Framework Supported by Evidence Reviews on Electronic Cigarettes cigarettes (ECs) and other noncombustible nicotine delivery products to help smokers transition away from cigarettes.

By K. Michael Cummings, PhD, MPH, and Graham Warren, MD, PhD

On July 28, 2017, the U.S. Food and Drug Administration (FDA) announced a new emphasis in the federal government’s regulatory framework toward tobacco product regulation. This new emphasis would focus on nicotine and would support innovations to promote tobacco harm reduction based on the continuum of risk for nicotine-containing products.1 The reason for this shift was the recognition that, although people smoke for the nicotine, the toxic smoke in combustible tobacco products is the main culprit in causing tobacco-related diseases and death. Given the FDA’s mandate to protect public health and the recognition that the evolving marketplace of nicotine products now allows smokers to get nicotine

Recent Reports: Slightly Different Areas of Emphasis

from a greater variety of less-dangerous products, the FDA announced a threepronged regulatory strategy involving: 1. Reducing the nicotine in traditional cigarettes to nonaddictive levels, 2. Increasing the number of approved nicotine replacement therapies available to smokers, and 3. Recognizing the potential of electronic

Two recent comprehensive reviews of the scientific evidence on ECs provide new evidence supporting the FDA’s new regulatory approach. The National Academy of Sciences, Engineering, and Medicine (NASEM) report on the public health consequences of ECs and a new evidence review on ECs and heated tobacco products commissioned by Public Health England (PHE) both come to similar conclusions, although there are differences in what is emphasized in each report.2,3 Both reports acknowledge that using an EC is far less risky than using combuscontinued on page 2

THOUGHT-LEADER PERSPECTIVE

with Dr. D. Ross Camidge In January 2018, the response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group—an international collaboration of cancer treatment, scientific, and imaging experts— published a new guideline on addressing central nervous system (CNS) metastases in clinical trial designs for systemic agents.1 IASLC Lung Cancer News caught up with the guidelines’ lead author D. Ross Camidge, MD, PhD, Joyce Zeff Chair in Lung Cancer Research and Director of Thoracic Oncology at the University of Colorado Cancer Center, for a question and answer interview.

Q: How did these guidelines come about? A: The first RANO-BM guidelines focused on defining the extent of the problem— how poor we have been at designing trials to appropriately include or exclude those with CNS disease, and the best way to generate data on CNS efficacy within

such trials. They also described the “twocompartment model,” which means that CNS and extra-CNS efficacy data should be captured and presented separately, which is going to be key moving forward. These new guidelines now represent a very “how-to-do-it” description for improving clinical trial designs regarding drug development in cancers at risk of CNS spread. Obviously, lung cancer is one of the most significant cancers in this regard.

Q: Please summarize the three clinical scenarios for clinical trial design that you describe in the guideline. A: At the start of the drug-development process you either suspect, based on previous clinical or preclinical data, that your drug is very unlikely to have activity in the brain (Scenario A), is very likely to have activity in the brain (Scenario B), or you just don’t know (Scenario C). In Scenario A, it’s all about protecting the patient and the drug-development pro-

cess, but without inappropriately restricting access to a drug with activity in the rest of the body. So in Scenario A, the guidelines push to allow patients with CNS disease into a trial if the CNS disease is treated, asymptomatic, and stable, with each of these key words being very clearly defined. In Scenario B, it’s about capturing CNS data accurately. So, for example, pursuing CNS imaging at the same frequency as body imaging, clearly defining what can and cannot be considered a CNS target lesion, and pushing for the two-compartment model in terms of data presentation. If a CNS signal is present, then we also propose “step-up inclusion criteria,” expanding eligibility to include symptomatic parenchymal disease and even leptomeningeal disease as the trial proceeds. In Scenario C, it’s about having a trial generate the data on CNS efficacy to then inform later Scenario A– or B– type designs as early as possible. So, for example, we propose adding dedicated

CNS substudies at the recommended phase II dose in phase I trials, or rapid parallel CNS cohorts in later-phase trials.

Q: What about how CNS data should be presented? A: Looking back over the past few years, especially in thoracic cancers, it is astonishing how uncritical we have been about the supposed CNS efficacy data we have been presented with. The guidelines discuss in detail how we could do better. For example, why is it assumed that comparable progression-free survival in those continued on page 8

IASLC LUNG CANCER NEWS / APRIL 2018

Electronic Cigarettes from page 1 tible tobacco cigarettes, that ECs may be helpful to smokers who are trying to stop smoking cigarettes, and that ECs should not be used by nonsmokers, especially youth.1,2 Both reports also acknowledge that ECs contain chemical constituents that are not inert and are likely to have some negative health effects on their own. In other words, ECs are not completely safe to use. Whereas both reports acknowledge that nonsmokers, especially children, should not use ECs, the NASEM report concludes that EC use by youth can lead to increased risk of using cigarettes, whereas the PHE report focuses on populationlevel effects and found no evidence that the growing popularity of ECs has reversed the declining trend in youth smok- Dr. K. Michael Cummings ing. Both reports recommend that trends in EC use and smoking behaviors by youth should be closely monitored. Additionally, both reports Dr. Graham Warren note injuries from exploding EC devices and poisonings from ingestion of e-liquids as concerns that warrant immediate remedial actions by government regulators to improve product safety. Overall, both reports acknowledge that data evaluating long-term health risks are lacking and that more research is needed to assess health outcomes. The NASEM report is more comprehensive

Pfizer Inc. (NYSE:PFE) announced in early February that the U.S. Food and Drug Administration (FDA) accepted and granted Priority Review to the New Drug Application for lorlatinib, an investigational ALK-targeted TKI for the treatment of patients with ALK-positive metastatic NSCLC, previously treated with one or more ALK-targeted TKIs. The European Medicines Agency and the Japan Pharmaceutical and Medical Devices Agency have also accepted marketing applications for the use of lorlatinib. ✦

than the PHE report in defining areas where scientific evidence is insufficient to allow reliable conclusions to be made about the risks and benefits of ECs. However, both reports suggest that the risks of cancer, cardiovascular disease, and respiratory diseases due to ECs are expected to be reduced compared with smoking combustible tobacco because

toxicants and carcinogens present in cigarette smoke are either absent or are present at much lower concentrations in EC aerosols. Both reports also highlight recent studies showing a marked decline in levels of biomarkers of exposure to toxicants and carcinogens in EC users who do not smoke when compared with smokers, which is strongly sug-

gestive of a health benefit as compared with combustible tobacco. Although the PHE report claims that the overall risk of harm from ECs is estimated at less than 5% compared with smoking tobacco, the NASEM report did not attempt to quantify the relative risks of ECs compared to smoking cigarettes, given the absence of long-term data.

The first and only third-generation EGFR TKI1

TAGRISSO®—ELEGANT DESIGN MEETS SELECTIVE TARGETING exon 19

exon 21 L858R EGFR

TAGRISSO

TAGRISSO binds irreversibly to EGFR with exon 19 deletions, a mutation seen in approximately 46% of EGFRm metastatic NSCLC2,3

T790M

EGFR

TAGRISSO

TAGRISSO binds irreversibly to EGFR with exon 21 L858R substitution, a mutation seen in approximately 39% of EGFRm metastatic NSCLC2,3

TAGRISSO inhibits mutated EGFR with the T790M mutation, which is responsible for resistance in more than half of EGFRm metastatic NSCLC cases at progression2,4

EGFRm=epidermal growth factor receptor mutation, NSCLC=non-small cell lung cancer, TKI=tyrosine kinase inhibitor.

INDICATION

TAGRISSO (osimertinib) is indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor therapy.

IMPORTANT SAFETY INFORMATION

• There are no contraindications for TAGRISSO • Interstitial Lung Disease (ILD)/Pneumonitis occurred in 3.5% and was fatal in 0.6% of 833 TAGRISSOtreated patients. Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms 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 833 TAGRISSO-treated patients, 0.7% of patients were found to have a QTc > 500 msec, and 2.9% of patients had an increase from baseline QTc > 60 msec. No QTc-related arrhythmias were reported. 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

LUNGCANCERNEWS.ORG / APRIL 2018

Real-world Applications Although the conclusions from these reports are useful to provide general consensus on the potential health effects of ECs, there remain many unanswered questions for real-world applications. For example, dual use of cigarettes and ECs is a controversial real-world pattern of use that remains a public health concern for two

primary reasons: dual use is a prevalent but understudied phenomenon observed in the general population, and potential health benefits gained from using ECs may be reduced or negated by continued smoking. Research is needed to better understand and define dual use of ECs and smoking as different patterns of use that are likely to affect estimates of the risks

and benefits of ECs on population health. Both reports suggest that ECs may help smokers transition away from cigarette use, but conclusive evidence of a benefit for smoking cessation remains unclear, particularly as it relates to sustained longterm abstinence from smoking. Much of the difficulty in establishing a benefit for ECs has do with the scarcity of random-

TAGRISSO is designed to target EGFR sensitizing mutations and EGFR T790M mutations.1 TAGRISSO binds irreversibly to these key drivers of disease and resistance while demonstrating a lower affinity for wild-type EGFR2

With a lower affinity for wild-type EGFR, TAGRISSO binds at approximately 9-fold lower concentrations2 wild-type EGFR

TAGRISSO

• Cardiomyopathy occurred in 1.9% and was fatal in 0.1% of 833 TAGRISSO-treated patients. Left Ventricular Ejection Fraction (LVEF) decline ≥ 10% and a drop to < 50% occurred in 4% of 655 TAGRISSO-treated patients. Conduct cardiac monitoring, including an 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 or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue TAGRISSO • Keratitis was reported in 0.7% of 833 TAGRISSO-treated patients 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 • Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during TAGRISSO treatment 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 • The most common adverse reactions (≥ 20%) in patients treated with TAGRISSO were diarrhea (41%), rash (34%), dry skin (23%), nail toxicity (22%), and fatigue (22%)

Please see accompanying complete Brief Summary of Prescribing Information on adjacent pages. References: 1. Cross DAE, Ashton SE, Ghiorghiu S, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4: 1046-1061. 2. TAGRISSO [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017. 3. Shigematsu H, Lin L, Takahashi T, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 2005;97(5): 339-346. 4. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240-2247.

ized controlled trials demonstrating a benefit for ECs as a cessation aid. Data from observational studies appear to be increasingly supportive of a benefit of ECs for smoking cessation but are also much harder to interpret due to selection biases, variations in the types of ECs used by smokers, and variability in the patterns continued on page 4

IASLC LUNG CANCER NEWS / APRIL 2018

Electronic Cigarettes from page 3 of use of ECs. Converging evidence suggests that cigarette smokers who switch completely to ECs and use them on a regular, daily basis are more likely to remain off cigarettes compared to those who quit unassisted or use cigarettes and ECs simultaneously (i.e., dual use). Carefully designed studies are needed to conclusively support the efficacy of ECs

for long-term smoking cessation and to identify individuals who will benefit most from ECs as a cessation aid.

The Bottom Line Although the evidence of ECs’ risks and benefits remains incomplete, the overarching message from both of these evidence reviews is that across a range of studies and outcomes, ECs pose less risk to an individual than combustible

tobacco cigarettes.2-4 For clinicians who are confronted with the task of advising their patients about the risks and benefits of ECs, they can now tell smokers that that although many of the effects of ECs are still unknown, data increasingly suggest that ECs pose a fraction of the risk of smoking cigarettes.5 In contrast to the evolving potential risks associated with ECs, there is unequivocal evidence of the adverse effects of smoking across a broad

TAGRISSO® (osimertinib) tablets, for oral use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. INDICATIONS AND USAGE TAGRISSO is indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy. DOSAGE AND ADMINISTRATION Patient Selection Confirm the presence of a T790M EGFR mutation in tumor or plasma specimens prior to initiation of treatment with TAGRISSO [see Indications and Usage (1) and Clinical Studies (14) in full Prescribing Information]. Testing for the presence of the mutation in plasma specimens is recommended only in patients for whom a tumor biopsy cannot be obtained. If this mutation is not detected in a plasma specimen, re-evaluate the feasibility of biopsy for tumor tissue testing. Information on FDA-approved tests for the detection of T790M mutations is available at http://www.fda.gov/ companiondiagnostics. Recommended Dosage Regimen The recommended dose 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 Modification Adverse Reactions Table 1. Recommended Dose Modifications for TAGRISSO Target Organ Pulmonary

Cardiac

Other

b †

Adverse Reactiona Interstitial lung disease (ILD)/Pneumonitis QTc† interval greater than 500 msec on at least 2 separate ECGsb

QTc interval prolongation with signs/symptoms of life-threatening arrhythmia Symptomatic congestive heart failure or asymptomatic left ventricular dysfunction that persists ≥ 4 weeks Adverse reaction of Grade 3 or greater severity If improvement to Grade 0-2 within 3 weeks If no improvement within 3 weeks

Dose Modiﬁcation Permanently discontinue TAGRISSO. 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.

Permanently discontinue TAGRISSO.

Withhold TAGRISSO for up to 3 weeks. Resume at 80 mg or 40 mg daily. 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

Drug Interactions Strong CYP3A4 Inducers If concurrent use is unavoidable, increase TAGRISSO dosage to 160 mg daily when coadministering 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 full Prescribing Information]. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS The following information for ILD/ Pneumonitis, QTc Interval Prolongation, Cardiomyopathy and Keratitis reflects exposure to TAGRISSO in 833 patients with EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) who received TAGRISSO at the recommended dose of 80 mg once daily in AURA3 (n=279), AURA Extension (n=201), AURA2 (n=210), and an expansion cohort in the first-in-human trial of osimertinib (AURA1, n=143). Interstitial Lung Disease/Pneumonitis Interstitial lung disease (ILD)/pneumonitis occurred in 3.5% (n=29) of TAGRISSO-treated patients (n=833); 0.6% (n=5) 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 full Prescribing Information].

spectrum of health conditions.1-3 Despite this evidence, many smokers falsely believe that vaping is as harmful as smoking, but data simply do not support these beliefs.3 Smokers should be clearly counseled that smoking is a proven risk factor for poor health and should be encouraged to abandon their cigarettes either with FDA-approved smoking-cessation medications or by switching to ECs, if used to keep them from smoking.5,6 ✦

QTc Interval Prolongation Heart rate-corrected QT (QTc) interval prolongation occurs in patients treated with TAGRISSO. Of the 833 patients treated with TAGRISSO in clinical trials, 0.7% (n=6) were found to have a QTc greater than 500 msec, and 2.9% of patients (n=24) had an increase from baseline QTc greater than 60 msec [see Clinical Pharmacology (12.2) in full Prescribing Information]. No QTc-related arrhythmias were reported. Clinical trials of TAGRISSO did not enroll patients with baseline QTc of greater than 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 full Prescribing Information]. Cardiomyopathy Across clinical trials, cardiomyopathy (defined as cardiac failure, congestive heart failure, pulmonary edema or decreased ejection fraction) occurred in 1.9% (n=16) of 833 TAGRISSOtreated patients: 0.1% (n=1) of cases were fatal. Left Ventricular Ejection Fraction (LVEF) decline greater than or equal to 10% and a drop to less than 50% occurred in 4.0% (26/655) of patients who had baseline and at least one follow-up LVEF assessment. Conduct cardiac monitoring, including an 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 or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue TAGRISSO [see Dosage and Administration (2.4) in full Prescribing Information]. Keratitis Keratitis was reported in 0.7% (n=6) of 833 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. 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 postimplantation fetal loss when administered during early development at a dose exposure 1.5 times the exposure at the recommended human 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 in patients at the 80 mg dose level. 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) and Clinical Pharmacology (12.3) in 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 full Prescribing Information] QTc Interval Prolongation [see Warnings and Precautions (5.2) in full Prescribing Information] Cardiomyopathy [see Warnings and Precautions (5.3) in full Prescribing Information] Keratitis [see Warnings and Precautions (5.4) in 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 described below reflect exposure to TAGRISSO (80 mg daily) in patients with EGFR T790M mutation-positive metastatic NSCLC in an open-label, randomized, active-controlled trial (AURA3, n=279) and in two single arm trials, AURA Extension (n=201) and AURA2 (n=210). 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 trial enrollment. AURA3 Trial The safety of TAGRISSO was evaluated in AURA3, a multicenter international open label randomized (2:1) controlled trial conducted in 419 patients with unresectable or metastatic EGFR T790M mutation-positive NSCLC who had progressive disease following first line EGFR TKI treatment. A total of 279 patients received TAGRISSO 80 mg orally once daily until intolerance to therapy, disease progression, or investigator determination that the patient was no longer benefiting from treatment. A total of 136 patients received pemetrexed plus either carboplatin or cisplatin every three weeks for up to 6 cycles; patients without disease progression after 4 cycles of chemotherapy could continue maintenance pemetrexed until disease progression, unacceptable toxicity, or investigator determination that the patient was no longer benefiting from treatment. Left Ventricular Ejection Fraction (LVEF) was evaluated at screening and every 12 weeks. The median duration of treatment was 8.1 months for patients treated with TAGRISSO and 4.2 months for chemotherapytreated patients. The trial population characteristics were: median age 62 years, age less than 65 (58%), female (64%), Asian (65%), never smokers (68%), and ECOG PS 0 or 1 (100%). The most common adverse reactions (≥20%) in patients treated with TAGRISSO were diarrhea (41%), rash (34%), dry skin (23%), nail toxicity (22%), and fatigue (22%). Serious adverse reactions were reported in 18% of patients treated with TAGRISSO and 26% in the chemotherapy group. No single serious adverse reaction was reported in 2% or more patients treated with TAGRISSO. One patient (0.4%) treated with TAGRISSO experienced a fatal adverse reaction (ILD/pneumonitis). 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 (1.8%), neutropenia (1.1%), and diarrhea (1.1%). Adverse reactions resulting in permanent discontinuation of TAGRISSO occurred in 7% of patients treated with TAGRISSO. The most frequent adverse reaction leading to discontinuation of TAGRISSO was ILD/pneumonitis (3%). Tables 2 and 3 summarize common adverse reactions and laboratory abnormalities which occurred in TAGRISSO-treated patients in AURA3. AURA3 was not designed to demonstrate a

LUNGCANCERNEWS.ORG / APRIL 2018

About the Authors: Dr. Cummings is a Professor and Co-leader of the Tobacco Research Program in the Department of Psychiatry and Behavioral Sciences and Member of the Cancer Prevention and Control Program, Hollings Cancer Center, Medical University of South Carolina. Dr. Warren is a Professor Joint Appointment (Primary Appointment in Radiation Oncology), Vice Chairman for Research in Radiation Oncology, and Member of the Cancer Prevention and Control Program,

Hollings Cancer Center, Medical University of South Carolina. References: 1. Gottlieb S, Zeller M. A Nicotine-Focused Framework for Public Health. N Engl J Med. 2017;377(12):1111-1114. 2. National Academies of Sciences, Engineering, and Medicine. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press; 2018. 3. McNeill A, Brose LS, Calder R, et al. Evidence Review of E-Cigarettes and Heated Tobacco Products: A Report Commissioned by Public

Health England. London: Stationery Office; 2018. https://www.gov.uk/government/publications/ e-cigarettes-and-heated-tobacco-productsevidence-review. Accessed February 7, 2018. 4. Newton JN, Dockrell M, Marczylo T. Making sense of the latest evidence on electronic cigarettes. Lancet. 2018 Feb 5. [Epub ahead of print]. 5. Wise JW. Doctors should state clearly that vaping is much lower risk than smoking, says report. BMJ. 2018;360:k575. 6. American Cancer Society. ACS Position Statement on Electronic Cigarettes. https:// www.cancer.org/ecigaretteposition. Accessed February 19, 2018.

TAGRISSO® (osimertinib) tablets, for oral use 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 AURA3 Adverse Reaction

TAGRISSO (N=279)

All Gradesa (%)

Grade 3/4a (%)

Gastrointestinal disorders Diarrhea 41 1.1 Nausea 16 0.7 Stomatitis 15 0 Constipation 14 0 Vomiting 11 0.4 Skin disorders Rashb 34 0.7 Dry skinc 23 0 Nail toxicityd 22 0 Prurituse 13 0 Metabolism and Nutrition Disorders Decreased appetite 18 1.1 Respiratory, Thoracic and Mediastinal Disorders Cough 17 0 Musculoskeletal and Connective Tissue Disorders Back pain 10 0.4 General Disorders and Administration Site Conditions 22 1.8 Fatiguef

Chemotherapy (Pemetrexed/Cisplatin or Pemetrexed/Carboplatin) (N=136) All Gradesa Grade 3/4a (%) (%) 11 49 15 35 20

1.5 3.7 1.5 0 2.2

5.9 4.4 1.5 5.1

0 0 0 0

2.9

0.7

5.1

* NCI CTCAE v4.0. a No grade 4 events were reported. b Includes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, erythema, folliculitis, acne, dermatitis and acneform dermatitis. c Includes dry skin, eczema, skin ﬁssures, xerosis. d Includes nail disorders, nail bed disorders, nail bed inﬂammation, nail bed tenderness, nail discoloration, nail disorder, nail dystrophy, nail infection, nail ridging, nail toxicity, onychoclasis, onycholysis, onychomadesis, paronychia. e Includes pruritus, pruritus generalized, eyelid pruritus. f Includes fatigue, asthenia.

Table 3.

Common Laboratory Abnormalities (>20% for all NCI CTCAE Grades) in AURA3 TAGRISSO (N=279)

Laboratory Abnormality

Leukopenia Lymphopenia Thrombocytopenia Neutropenia a

Chemotherapy (Pemetrexed/Cisplatin or Pemetrexed/Carboplatin) (N=131a) Change from Change from Change from Change from Baseline to Baseline Baseline to Baseline Grade 3 or All Grades Grade 3 or Grade All Grades Grade 4 (%) 4 (%) (%) (%) 61 1.1 75 5.3 63 8.2 61 9.9 46 0.7 48 7.4 27 2.2 49 12

Based on the number of patients with available follow-up laboratory data

AURA Extension and AURA2 Trials The safety of TAGRISSO was evaluated in two single arm trials, AURA Extension (n=201) and AURA2 (n=210). A total of 411 patients with EGFR 790M mutation-positive NSLC who received one or more prior EGFR therapies including an EGFR TKI were treated with TAGRISSO (80 mg daily). The majority of patients were heavily pretreated. Prior to enrollment, 68% of patients had received at least 2 prior treatment regimens, 46% had received 3 or more prior lines of therapy, and 63% had received prior platinum-based chemotherapy. Median duration of exposure to TAGRISSO was 7.7 months (range: <0.1 to 11.6 months). The toxicity profile of TAGRISSO observed in the AURA Extension and AURA2 trials was generally consistent with the toxicity profile observed in the AURA3 trial. Four patients (1%) treated with TAGRISSO developed fatal adverse reactions of ILD/pneumonitis. Discontinuation of therapy due to adverse reactions occurred in 5.6% of patients treated with TAGRISSO. The most frequent adverse reactions that led to discontinuation were ILD/pneumonitis. DRUG INTERACTIONS Effect of Other Drugs on Osimertinib Strong CYP3A Inducers Coadministering TAGRISSO with a strong CYP3A4 inducer decreased the exposure of osimertinib compared to administering TAGRISSO alone [see Clinical Pharmacology (12.3) in full Prescribing Information]. Decreased osimertinib exposure may lead to reduced efficacy. Avoid coadministering TAGRISSO with strong CYP3A inducers (e.g., phenytoin, rifampin, carbamazepine, St. John’s Wort) [note: effect of St. John’s Wort varies widely and is preparationdependent]. Increase the TAGRISSO dosage when coadministering with a strong CYP3A4 inducer if concurrent use is unavoidable [see Dosage and Administration (2.4) in full Prescribing Information]. No dose adjustments are required when TAGRISSO is used with moderate and/or weak CYP3A inducers.

LUNG CANCER

NEWS

EDITOR Corey J. Langer, MD, FACP ASSOCIATE EDITORS Fabrice Barlesi, MD, and Caicun Zhou, MD IASLC CEO Fred R. Hirsch, MD, PhD MANAGING EDITOR AND PUBLISHER Joy Curzio, Curzio Communications 2

Effect of Osimertinib on Other Drugs Coadministering TAGRISSO with a BCRP substrate increased the exposure of the BCRP substrate compared to administering the BCRP substrate alone [see Clinical Pharmacology (12.3) in full Prescribing Information]. Increased BCRP substrate exposure may increase the risk of exposurerelated toxicity. Monitor for adverse reactions of the BCRP substrate (e.g., rosuvastatin, sulfasalazine, topotecan), unless otherwise instructed in its approved labeling, when coadministered with TAGRISSO. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on data from animal studies and its mechanism of action, 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 human 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 in patients at the recommended dose of 80 mg), 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 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 full Prescribing Information]. Because of the potential for serious adverse reactions in breastfed infants from osimertinib, advise a lactating woman not to breastfeed during treatment with TAGRISSO and for 2 weeks after the final dose. Females and Males of Reproductive Potential Contraception 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 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 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 full Prescribing Information]. Pediatric Use The safety and effectiveness of TAGRISSO in pediatric patients have not been established. Geriatric Use Three hundred and forty-six (42%) of the 833 patients in AURA3 (n=279), AURA Extension (n=201), AURA2 (n=210), and an expansion cohort in the first-in-human trial of osimertinib (AURA1, n=143) 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 (9.8% versus 6.8%) and more frequent dose modifications for adverse reactions (10.1% versus 6.0%) in patients 65 years or older as compared to those younger than 65 years. Renal Impairment No dose adjustment is recommended in patients with mild, [creatinine clearance (CLcr) 60-89 mL/min, as estimated by the Cockcroft Gault method (C-G)] moderate, (CLcr 30-59 mL/min, as estimated by C-G) or severe (CLcr 15-29 mL/min) renal impairment. There is no recommended dose of TAGRISSO for patients with end-stage renal disease [see Clinical Pharmacology (12.3) in full Prescribing Information]. Hepatic Impairment No dose adjustment is recommended in patients with mild hepatic impairment [total bilirubin less than or equal to upper limit of normal (ULN) and AST greater than ULN or total bilirubin between 1.0 to 1.5 times ULN and any AST] or moderate hepatic impairment (total bilirubin between 1.5 to 3 times ULN and any AST). There is no recommended dose for TAGRISSO for patients with severe hepatic impairment [see Clinical Pharmacology (12.3) in full Prescribing Information]. Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 TAGRISSO is a registered trademark of the AstraZeneca group of companies. ©AstraZeneca 2017 Iss. 03/17 3338004 4/17

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 editor@iaslclungcancer.net. 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 / APRIL 2018

IMMUNOTHERAPY

PD-L1 IHC Blueprint Project: Ongoing Progress Toward Consistency Among Assays and the study was performed by members of the IASLC Pathology Committee and coordinated by IASLC.

Fred R. Hirsch, MD, PhD

Immunotherapy is a very encouraging development in the treatment of patients with lung cancer. At this phase of its refinement, we struggle with the challenge of how to select the right patients for the right treatment. Patient selection is paramount because only 20% to 30% of patients with advanced NSCLC will benefit from immunotherapy. PD-L1 protein expression has been the biomarker of choice for clinical trials. Based on trial results, PD-L1 immunohistochemistry (IHC) assays have been approved either as a companion diagnostic (e.g., pembrolizumab) or as a complemen- Dr. Fred R. Hirsch tary diagnostic (e.g., nivolumab and atezolizumab). In some cases, biomarkers for PD-L1 are still under clinical exploration with other agents in clinical trials (e.g., durvalumab and avelumab). A clinical challenge is that each pharmaceutical company testing these agents in clinical trials is pursuing their own unique PD-L1 assay, each of which differs regarding antibody clones, staining platforms, and definitions of cutoff levels for positive versus negative status or for high PD-L1 expression levels versus low PD-L1 expression levels. In an effort to provide consistency in this area, members of the IASLC pathology panel and other IASLC members proposed a comparative study of the performance of the various PD-L1 IHC assays. The study was encouraged by the U.S. Food and Drug Administration as well as by the American Association for Cancer Research and the American Society of Clinical Oncology. A steering committee consisting of representatives from multiple pharmaceutical companies (AstraZeneca, Genentech/ Roche, Bristol-Myers Squibb, Merck Pharmaceuticals, and, later, Pfizer and Merck MSD), and the two diagnostic companies (Ventana and Dako) was established,

Study Findings to Date Phase I of the Blueprint Project was a feasibility study evaluating 39 tumors stained with four distinct antibodies: Dako 28.8 (for use with nivolumab), Dako 22C3 (for use with pembrolizumab), Ventana SP263 (for use with durvalumab), and Ventana SP142 (for use with atezolizumab). All staining was performed according to the standard procedure delineated in the clinical trials. The results from phase I were published in the Journal of Thoracic Oncology.1 The results showed that three assays (Dako 22.8/22C3 and Ventana SP263) yielded very similar PD-L1 expression levels on tumor cells, whereas Ventana SP142 stained fewer tumor cells (Fig. 1). Regarding PD-L1 expression on immune cells, the variation among the different assays was much greater. Phase II of the Blueprint Project also included Dako 73-10 (for use with avelumab). The goal of this phase was validation of the phase I observations, specifically regarding interobserver variability. Phase II included a larger panel of pathologists (25 from 15 countries) and examined a larger number of “real life” tumors (81 NSCLC tumors). The results from phase II were presented by Ming-Sound Tsao, MD, at the 2017 World Conference on Lung Cancer in Yokohama, Japan.2 Results verified that the three assays (Dako 28.8/22C3 and Ventana SP263) showed very similar levels of PD-L1 expression on tumor cells, whereas Ventana SP142—similar to what was seen in the phase I analysis—stained fewer tumor cells. The newer assay Dako 73-10 stained a slightly higher percentage of tumor cells. Furthermore, phase II demonstrated, in general, reasonably good interobserver concordance among the 25 pathologists. Comparison of PD-L1 expression based on tumor versus cytology specimens also showed good correlation and there was good correlation between PD-L1 assessment using glass slides (e.g., microscope) or digital scans.

THOUGHT-LEADER PERSPECTIVE

with TMB Expert Dr. Solange Peters Solange Peters, MD-PhD, PD-MER, runs the Thoracic Malignancies Program in the Department of Oncology at the University of Lausanne, Switzerland. Her main field of interest is new biomarker discovery and validation in preclinical/clinical settings, and she is also involved in developing multimodality trials for locally advanced NSCLC. She has been elected President of the European Society for Medical Oncology (ESMO) for the 2020-2021 term. Here, Dr. Peters discusses the global importance of the Blueprint Project’s efforts regarding standardization of PD-L1 assays and terminology. She also defines tumor mutation burden (TMB) and shows how it might complement PD-L1 and speculates on the evolving complexity of biomarker identification and use in predicting immune response.

Q: How has the Blueprint Project affected thoracic oncology practice in Europe? Are there similar or duplicative projects in Europe? A: The Blueprint Project has changed the practice in Europe. There are

similar initiatives at national, or even regional, levels in Europe. The initiatives—a German ring trial,1 a French initiative,2 and a few others in Europe and beyond3,4—started more less at the same time as the Blueprint Project, with results being reported around the same time. It is very reassuring that they are all reporting similar results and describing, with accuracy, the same conclusions. The Blueprint Project is important because we don’t usually speak about potential and probable regional/interinstitutional differences and variations in the way immunohistochemistry might be performed and interpreted. I think that the convergence of the regional data in combination with the international reliability of the IASLC Project is extremely strong. All of the initiatives aim to harmonize the determination of PD-L1 positivity. This picture has been confused and confounded by the various pharmaceutical companies that were each using a different way to assess PD-L1, at every step of this assessment methodology. With the publication of the

Blueprint results, there is now a stronger effort to try to standardize the way PD-L1 is defined. For example, every university hospital in Switzerland, which is a small country, is using the same platform, the same antibody, and the same quality-assessment processes including round robins to ensure that PD-L1 is being defined exactly the same way across the country.

Q: To what extent will TMB supplement or supplant PD-L1 testing? A: We don’t have a prospective evaluation of the predictive ability of TMB yet; the only data we have come from convergent retrospective analyses. However, what we have learned from these retrospective data is that TMB will be a very good biomarker in the future and that it is independent from PD-L1. The two biomarkers don’t correlate but might complement each other; they basically describe two different phenomena. When you speak about TMB, you speak about the potential presence of neoantigens, which might elicit an immune response—it’s about how immunogenic a tumor is

supposed to be. On the other hand, when you look at PD-L1, it’s related to the end process. It describes how much the immune response has really been taking place in the tumor after the many steps of activation, presentation, cross-priming, and trafficking of T cells. Therefore, you describe two different processes: one focuses on tumor immunogenicity, and the other on effector-phase microenvironment. Both are interesting in trying to predict the immune sensitivity of tumors, and testing for both might be recommended practice in the future. We know from the press release that Checkmate-227 will probably prospectively prove that TMB is predictive.5 I still haven’t seen real data trying to combine the use of both biomarkers (TMB and PD-L1). At the end of the next few years, we might not have just one biomarker, but a kind of signature for predicting the immunogenicity and the potential immune sensitivity of tumors.

LUNGCANCERNEWS.ORG / APRIL 2018

Thus far, the PD-L1 Blueprint Project has underscored that interchangeability of the three assays (Dako 28.8/22C3 and Ventana SP263) is a possibility. However, the clinical cutoffs chosen for positive status/high expression levels versus negative status/ low expression levels might be the determining factor in clinical associations, rather than the actual choice of assays. Phase IIB of the PD-L1 Blueprint Project is ongoing and will compare PD-L1 expression based on large tumor specimens versus smaller biopsies and cytologies from the same tumors.

Finding Scientific Value through Partnership We hope the PD-L1 Blueprint Project will provide scientific evidence that interchangeability among at least some of the PD-L1 assays can be accomplished safely; it appears that only cutoff values for the definitions of low versus high PD-L1 expression (or positive versus negative status) may vary among the different PD-L1/PD-1 antibodies. Fig. 1. PD-L1 Expression on Tumor Cells

If that is the case, PD-L1 assessment will be more easily and consistently determined, and we will gain a better understanding of its clinical importance. Furthermore, the Blueprint Project will determine the suitability of smaller biopsies and cytology specimens for PD-L1 expression evaluation, compared with larger specimens. This determination is critically important because the majority of patients with advanced lung cancer will have small biopsies or cytology samples as the primary diagnostic material. It is the IASLC Blueprint team’s goal to apply all five of the PD-L1 assays to a welldefined clinical cohort that is treated with an immunotherapy agent so that response rates and outcomes can be compared across assays in the same population. As a capstone, The IASLC PD-L1 Blueprint Project has demonstrated the feasibility and value of having several industry partners (who, in the clinical world, would be considered competitors) working together toward common scientific goals. Although certain challenges had to be overcome, the Blueprint Project has gathered these industry partners around the same table, each agreeing to solve important clinical issues. It has been my pleasure as CEO of the IASLC to be the mediator of this initiative and to coordinate these studies. ✦ About the Author: Dr. Hirsch is CEO of the International Association for the Study of Lung Cancer and Professor of Medicine and Pathology at University of Colorado Cancer Center. References: 1. Hirsch FR, McElhinny A, Stanforth D, et al. J Thorac Oncol. 2017 Feb;12(2):208-222. 2. Tsao MT, Kerr K, Yatabe Y, et al. PL 03.03 Blueprint 2: PD-L1 Immunohistochemistry Comparability Study in Real-Life, Clinical Samples. J Thor Oncol. 2017;12(Suppl 2):S1606.

Journal of Thoracic Oncology Vol. 12 No.2:208-222

Q: What is your take on gene signature analyses as well as other putative predictors of response to immunotherapy agents? A: Use of immune signatures is closer to use of PD-L1 expression in that you try to look in the tumor cells and microenvironment and see how much the immune interaction with the tumor has given rise to immunogenic reaction. When you look at immune–gene signature—at least the ones that have been prospectively assessed until now—you describe a kind of surrogate of PD-L1 in that the same end process is described. Interestingly, the IMpower150 trial, presented at ESMO 2017, showed that the immune–gene signature was no more predictive than PD-L1 regarding patient selection and therapeutic outcome.6 I’m still not convinced that the immunerelated genes we’ve been using add anything to PD-L1. On the contrary, TMB, immunogenic signatures, and PD-L1 will probably correlate very strongly. For the time being, I think we should look for better and stronger immune– gene signatures or expression profiles. I think we have to determine how we can better characterize and qualify the interaction of the cancer cells with the microenvironment, which will teach us

what we want to examine and how we want to go about this.

Q: Are there any other predictors on the horizon? A: TMB testing is fundamentally just about calculating the probability of the presence of some strong epitopes in the tumor, suitable for immune system recognition—it’s just a probabilistic approach. There is a huge effort ongoing to identify the actual neoantigens in tumors, and there are a lot of algorithms being developed to try to predict the best epitopes for immunoreactivity. You can also test the tumor and immune system of a patient to see if it recognizes this epitope, but this is complex, and data are disappointing to date. Future research might be focused on identification of new antigens, potentially building on that by expanding the pool of T cells to attack them. We are quite far from there, however, and researching this is going to be tricky, expensive, and time consuming. I think, for the time being, we have already done quite a lot of work to try to harmonize TMB and to learn how to measure it and how to make it a practically approachable option for immuneresponse prediction; I think this is going continued on page 10

CheckMate-227: Immunotherapy Combination Success in First Line NSCLC Tumors with high TMB responded well to combination in large patient population. By now the results of the phase III limumab vs. nivolumab alone vs. chemoCheckMate-227 study are known therapy in patients whose tumors express by most. The primary endpoint of PD-L1. Part 1B evaluated the IO combiprogression-free survival was met, and nation vs. nivolumab plus chemotherapy the immunotherapy (IO) combination of vs. chemotherapy alone in patients whose nivolumab and ipilimumab was proven tumors do not express PD-L1. Part 2 superior to chemotherapy in the first line evaluates nivolumab combined with for patients with NSCLC and high tumor chemotherapy vs. chemotherapy alone mutation burden (TMB; ≥ 10 mutations/ in a broad population; the primary endmegabase, mut/mb), regardless of PD-L1 point is overall survival. ✦ expression status. Approximately 45% of evaluable patients had tumors with high (For more on TMB, see the interview with TMB, which was evaluated using the Dr. Solange Peters on page 6.) FoundationOne CDx assay. The safety profile was consistent with previously reported studies of 3 mg/ E D I T O R ’ S N O T E kg of nivolumab administered every 2 weeks and 1 mg/kg of The results of this study, as ipilimumab given every 6 weeks. reported in the recent press CheckMate-227 enrolled release, are tantalizing. It propels the role of TMB more than 2,500 patients with into the forefront. Assuming an overall survival squamous and nonsquamous advantage emerges, it is possible that immunotherapy combinations may start to replace empiric histologies. There are three parts combinations of chemotherapy and checkpoint to the study, with PFS reported inhibitors in treatment-naive, advanced NSCLC, for all of Part 1. Part 1a evaluated regardless of PD-L1 status, although this remains combination nivolumab and ipi- speculative. –Corey Langer, MD, Editor

IASLC LUNG CANCER NEWS / APRIL 2018

MEETING NEWS

Using Deep Learning Systems to Radiologically Predict Pathologic Invasiveness in Lung Adenocarcinoma By Masahiro Yanagawa, MD, PhD, and Noriyuki Tomiyama, MD, PhD

Fig. 1. Learning Process

of image recognition) was constructed with two successive pairs of convolution (used in mathematical calculations for model processing) and max-pooling (used to correct image displacement) layers and two fully connected perceptron layers. The output layer was composed of two nodes for the two conditions: adenocarcinoma in situ (AIS) and non-AIS. Although only a small set of CT images was used as training data, the DL system produced an accuracy rate that was almost identical to that of the radiologists. In addition, the area under the curve (AUC) for the DL system was almost the same as the AUC for the most experienced radiologist, who had a significantly higher AUC than the radiologist with the least amount of experience. Although the process that the DL system used to reach its conclusions is unknown, DL systems in the future may be able to predict pathologic invasiveness in lung adenocarcinoma from CT images, resulting in differentiating AIS, minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IVA). Radiologists often diagnose pulmonary

Improvement in computer capacity, the expansion of computer networks, and the emergence of big data have resulted in a boom in artificial intelligence (AI). AI is structured by building a model that can imitate the human brain. Deep Learning (DL) is one of the AI systems based on the neural network that is used in thoracic imaging to detect pulmonary nodules and to reduce false positives through improved diagnostic accuracy. The neural network begins by simulating neural cells and trying to simulate the human brain. This simulation model is called perceptron. By making layers with perceptron and then arranging these layers, multilayer perceptron is constructed and, thereby, all nodes are fully connected in the model. This system, therefore, can solve more complicated problems than conventional computer systems, which is generally used in standard imaging (Fig. 1). In addition to detection of pulmonary nodules, AI technology has been applied to and developed in other areas of thoracic imaging. Malignant disease can

be distinguished from benign disease, and segmentation and measurement of disease, through 3D analysis, is also possible. Diffuse lung diseases can be diagnosed using a case-retrieval system that uses a database of images, as well as literature searches to help radiologically differentiate disease. Image quality is also improved due to use of noise-reduction algorithms, such as PixelShine, to create iterative reconstructions of images. We, the authors, were fortunate to have the opportunity to present research on lung adenocarcinoma using a DL system during the 2017 the Radiological Society

Dr. D. Ross Camidge from page 1

Fig. 1. Potential Effects of Choosing CNS Sites of Disease as Target Lesions on Overall Response Rate by Line of Therapy

of North America Scientific Assembly and Annual Meeting. Our research compared the results of radiologic prediction of pathologic invasiveness in lung adenocarcinoma among three radiologists and a DL system. The 3D Convolutional Neural Network (3D-CNN) was developed in conjunction with the department of technology in our institution (Hirohiko Niioka, Institute for Datability Science) and was used as the DL system (Tensorflow version 0.12.1) in the study. The 3D model of the convolutional neural network (CNN) structure (CNN being the mainstream of DL in the field

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with and without brain metastases tells us about a drug’s CNS efficacy if prior local treatment, which local treatment (wholebrain versus stereotactic radiosurgery), and the number of CNS lesions are not described?

Q: What excites you about these new approaches? A: Recently, in later-line trials of some targeted agents, CNS lesions exposed to a highly CNS-penetrant drug are appearing hyper-responsive, with the CNS response rate seeming to exceed the extra-CNS rate, perhaps because the CNS lesions are behaving like disease in an earlier line of therapy. Whereas, for a less CNSpenetrant drug, CNS lesions may appear hypo-responsive compared to the rest of the body (Fig. 1). Consequently, the overall response rate could be manipulated depending on the proportion of CNS versus extra-CNS disease included among the assessed target lesions. I think watching the field’s evolution regarding the demand for better-quality data that include the proportion of CNS disease contained within the overall target lesion dataset and

Modified from Morgan RL, Camidge DR. J Thorac Oncol. 2017.2

present CNS and extra-CNS efficacy data separately will be amazing to see.

Q: Are we heading toward separate CNS drug doses and schedules being described? A: For some drugs, yes. One of the other novel things in these guidelines is a description of how to formally explore dedicated CNS doses and schedules during drug development. So, in the absence of toxicity, dose and schedule exploration needn’t stop because a systemic target

exposure or response rate was not seen. Instead, this exploration could continue among those with measurable CNS disease using the CNS response rate to see if higher continuous or intermittent doses are more beneficial for the CNS.

Q: Any final thoughts? A: Just this: Over the next few years, our shared desire to improve outcomes should make us adopt clinical trial designs that more robustly address our clinical and research needs and engage in better presen-

tations of relevant and accurately interpretable CNS data. If we do that, then everyone—patients, researchers, practitioners, and the pharmaceutical industry alike— will benefit. ✦ References: 1. Camidge DR, Lee EQ, Lin NU, et al. Clinical trial design for systemic agents in patients with brain metastases from solid tumours: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group. Lancet Oncol. 2018 Jan;19(1):e20-e32. 2. Morgan RL, Camidge DR. Reviewing RECIST in the Era of Prolonged and Targeted Therapy. J Thorac Oncol. 2017 Nov 4. [Epub ahead of print].

LUNGCANCERNEWS.ORG / APRIL 2018

C AT E G O R Y H E A D I N G

Keeping It Personal: CMS-Proposed Coverage Restrictions for NGS Challenge Innovation in Personalized Care By Jason N. Rosenbaum, MD, and Dara L. Aisner, MD, PhD

Within the span of a few weeks, the U.S. Food and Drug Administration (FDA), the Center for Medicare and Medicaid Services (CMS), and the IASLC all issued guidelines, recommendations, or regulatory policy statements aimed at optimizing molecular testing for cancer.1-3 All three proposals are fundamentally driven by the desire to ensure positive outcomes for patients. Despite the best intentions, however, restrictive regulations and reimbursement decisions threaten to undermine the delivery of personalized medicine in lung cancer care. The recent FDA approval of nextgeneration sequencing (NGS) assays2 as companion diagnostics is a welcome recognition of the value these types of assays routinely provide to patients. Unfortunately, a concurrent National Coverage Analysis proposal by CMS curtails the flexibility and adaptability that make the technique so powerful.3 The proposal restricts reimbursement for any NGS-based oncology study to (among other things): FDA-approved assays, patients with advanced cancer, and patients who have not been previously tested on the same platform. These restrictions severely undermine the ability of clinical laboratories to provide personalized care. Importantly, linking reimbursement to FDA approval constrains the ability of any laboratory—even institutions providing FDAapproved assays—to adapt existing assays to include new biomarkers, test on different sample types, or make use of new technology because, by definition, FDAapproved assays cannot be modified and still maintain their FDA-approved status. The updated joint guidelines for molecular testing of patients with lung cancer by the IASLC, College of American Pathologists, and Association for Molecular Pathology1 represent an important step in personalizing care for the estimated 1.8 million patients diagnosed with lung cancer worldwide.4 Support of these guidelines is driven by the belief that “patients with…advanced lung cancer in which…targetable molecular alterations typically occur should receive the molecular testing required to identify them.” Moreover, “testing should extend beyond those molecular alterations for which targeted therapies are approved by regulatory agencies.” Implicit

in this philosophy is a deep appreciation for a dynamism in the field of genomic medicine that challenges the ability of dedicated experts—let alone governmen- Dr. Jason N. Rosenbaum tal agencies—to keep abreast. New therapies, biomarkers, and technologies develop so rapidly that an expert panel published the original version of the guidelines in 2013,5-7 with the first formal revision initiated by mid-2015—a very rapid pace for guideline development. During the past decade, NGS has afforded critical flexibility to the field of molecular diagnostics. All of the genes included in the IASLC recommendations (ALK, ROS1, RET, MET, BRAF, ERBB2 [HER2], and KRAS) can be interrogated for relevant mutations simultaneously from the same specimen. Additional genes with contextual or promising relevance may be included as well (e.g., TP53, 8 FGFR1/2/3, 9 NTRK1/2/3 10). Alterations including single-nucleotide changes, copy number alterations, and genomic rearrangements can be identified in concert. Promising metrics such as tumor mutational burden11 can be evaluated in ways that are impossible for

single-gene assays. The flexibility of NGS platforms extends beyond which and how many genes are included; assays may be designed to favor lowinput specimens, Dr. Dara L. Aisner such as the fineneedle aspirates (FNAs) and small biopsies common to lung cancer diagnosis, or to support rapid results for the most clinically actionable results, such as EGFR and ALK variants. Assays also may be designed to achieve very high sensitivities, for applications such as detection of resistance variants via circulating tumor DNA (or “liquid biopsy”).

precision oncology by severely hampering the ability of laboratories to adapt to changes in the field. For example, adding new gene targets or analysis methods to an existing assay would not be possible through current proposed regulatory mechanisms. Although any CMS decision applies only to the United States, continued development of the field will be severely impaired if laboratories in the United States are forced to curtail their current efforts, to say nothing of the potential ramifications if other countries directly follow the CMS example.

Constraining Innovation, Curtailing Patient Care

In healthy tissue, appropriate regulatory mechanisms are essential. Absence of regulation—but also overactive regulatory pathways—can both lead to cancer. The time, hierarchy, and degree of regulation must be appropriate, so they do not impede the processes they are intended to promote and protect. Regulatory mechanisms operate most effectively with input from multiple sources, at multiple levels, with appropriate responses to change. There can be no doubt that the maintenance of standards and guidelines in

The rigidity of the CMS proposal potentially constrains clinical care for patients with cancer. For example, the recent guidelines include the option for testing cytopathology specimens not processed through formalin (such as direct smears). This approach, although not FDA approved, is clearly beneficial to patients in expediting results and reducing the requirements for repeat testing.12 The proposal also imposes real challenges to the growth and development of

The rigidity of the CMS proposal potentially constrains clinical care for patients with cancer.

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PACIFIC Trial Leads to Durvalumab Approval in United States The U.S. Food and Drug Administration approved durvalumab on February 16, 2018, for the treatment of patients with stage III NSCLC whose tumors are unresectable and whose cancer has not progressed after treatment with chemoradiation— the first drug for this indication. The approval was based on the phase III PACIFIC trial, a randomized trial of 713 patients in which sequential treatment with the PD-L1 inhibitor durvalumab was compared to placebo in patients with locally advanced, unresectable stage III NSCLC whose disease had not progressed following platinum-based chemotherapy concurrent with radiation therapy. The median progression-free survival (PFS) for durvalumab was 16.8 months compared to 5.6 months for placebo. Overall survival data have not yet been reported. ✦

EDITOR’S NOTE Ostensibly, the PACIFIC trial is highly positive, with durvalumab yielding a striking, unprecedented PFS benefit compared to the control arm. However, some questions and concerns remain regarding this trial. Most concerning, a significant percentage of patients did not undergo pretreatment PET scanning, which has become standard in North America. Based on prior studies, approximately 15% to 20% of patients with apparent stage III NSCLC will be upstaged to stage IV by PET imaging; meaning, these patients were actually receiving durvalumab in the metastatic setting. Under these circumstances, durvalumab, we assume, would fare better than placebo. In

addition, there was some imbalance in the percentage of patients with > 25% PD-L1 expression favoring the study drug. Also, there were no data on the percentage of patients who received < 60 Gy of radiation. Finally, the control arm appears to have underperformed historic controls—median PFS is usually 10 to 13 months. Obviously, overall survival data are needed to determine whether durvalumab truly is practice changing. We must see an increase in cure rates, not just in PFS, for routine use of durvalumab to be accepted, at least in the United States. However, cost may influence whether durvalumab is adopted worldwide. –Corey Langer, MD, Editor

IASLC LUNG CANCER NEWS / APRIL 2018

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

Barriers to Access to New Lung Cancer Drugs in Latin America By Pedro N. Aguiar Jr., MD, MSc, and Gilberto L. Lopes Jr., MD, MBA

After often-painful but effective and still incomplete economic reforms, more rational government spending, and the increased trade brought about by globalization, Latin America has lifted itself out of the misery of its recent past and has started to tackle its large but still appalling economic disparities. With development has come an epidemiologic transition, making chronic non-communicable diseases the most important cause of mortality in the region.1 Lung cancer incidence in Latin America is increasing, and approximately 70% of patients present with advanced disease2; estimates suggest there will be 541,000 new cases and 445,000 deaths due to lung cancer in Latin America by 2030.3 Latin American countries invest only $7 or $8 per patient with cancer, whereas the corresponding figures for the United Kingdom, Japan, and the United States are $183, $244, and $460, respectively.4

LUNG CANCER IN DEVELOPING As a result, North America, Europe, and Japan consumed 88% of the new pharmaceutical products launched from 2005 to 2009, whereas the rest of the world was responsible for only 12% of expenditures in medications.5 The high cost of innovative therapies, such as targeted therapies and immune checkpoint inhibitors, is likely to make these numbers even more disparate in the future. In the United States, the average yearly cost of new drugs for patients with cancer often exceeds $100,000,6 which is obviously unaffordable in lower-income countries. In recent years, pharmaceutical companies have started to offer medications

Fig. 1. Lung Cancer Drug Prices

at lower prices outside of North America, Western Europe, and Japan. Economists call this “price discrimination”: when the cost of development of a service or product is significantly higher than the cost of producing extra units of the product, companies make more money and consumers have greater access to theraCOUNTRIES pies if the company sells the product or service with different prices in different markets, based on the specific market’s ability to pay. Although the United States has the highest prices worldwide, when drug costs are evaluated in relation to each country’s gross domestic product per capita,7 it becomes apparent that new cancer medications are even farther out of reach in other locations.8 Figure 1 illustrates prices for innovative lung cancer drugs in Latin America and in the United States. When adjusted by income, the cost of immune checkpoint inhibitors is higher in Latin America than in the United States. Patient selection by PD-L1 expression, and hopefully by even better biomarkers in

the future, should improve cost effectiveness and decrease the budgetary effects of new drugs by limiting or curtailing use in patients who are unlikely to benefit.9 However, in the meantime, we must develop policies that can help increase access.

Barriers: Access to Care There are also disparities within each Latin American country. In the region, healthcare provision often comes in two varieties: public health systems (funded by governments) and private services (funded mostly by employer and employee contributions). The public health system is responsible for the treatment of approximately 75% to 90% of residents, depending on the country.10 In public health systems, EGFR and ALK TKIs and immune checkpoint inhibitors are not yet widely available. In Brazil, the monthly cost of anti-EGFR TKIs is more than three times the amount hospitals and clinics receive from the government for the

CMS-Proposed Coverage Restrictions Dr. Solange Peters from page 7 to be the main area of progress for the next 2 to 3 years.

Q: Do you have any other comments? A: Complexity continues to increase regarding immunotherapy agents now that combinations are being used. When we start to use new immunotherapy drugs like IDO inhibitors or other immune

modifiers (LAG3, OX40, TIM3), for example, we may end up delineating patient populations by their markers. A patient’s signature for PD-1/PD-L1 will be rendered even more complex by the fact that, when combination therapy is used, there is involvement of a second signaling pathway or protein that is targeted by the second drug. ✦ (Note: References are available in the online version of this article.)

from page 9

genomic medicine is essential for the delivery of safe and effective personalized care; identifying the best routes to ensure safety and efficacy is paramount. It is also critical that medical professionals be permitted to take maximal advantage of the technology at their disposal in the delivery of that care. FDA and CMS certainly have a role to play in ensuring the safety and reliability of assays; however, regulations should be developed and implemented with the input and consideration of professional organizations such as the

treatment of patients with advanced lung cancer. 11 Only services with additional forms of funding (such as philanthropy or supplementation by state governments, the ministry of education, or others) are able to purchase first-generation anti-EGFR TKIs. In Panama, gefitinib is available through the National Institute of Oncology healthcare system, which treats some patients from the public health system, but patients in other healthcare systems and those without insurance have no access to EGFR TKIs.2 As a result, the proportion of patients with access to targeted therapy in Latin America is very low. Indeed, even molecular testing is done less often than it should be. A database including 11,684 patients with lung cancer treated in Brazil showed that only 13% of patients were tested in 2011, a number that improved to 58% in 2016 (mostly reflecting increased testing in the private sector, however12). Little has been published on access to new cancer medications in low- and middleincome countries. A survey of Southeast Asia (which includes, among others, Thailand, Malaysia, Indonesia, Singapore, and Philippines), a region demographically similar to Latin America, showed that only 10% to 20% of eligible patients had access to the EGFR TKIs erlotinib and gefitinib. This contrasted to 80% in Singapore, a high-income country located in Southeast Asia.2 continued on page 14

IASLC, CAP, and AMP, among others to achieve all the advantages and promise of precision diagnostics in lung cancer. That is the only way to ensure that the precision oncology continues to evolve, while preserving the safety of patients. ✦ About the Authors: Dr. Rosenbaum is with the Department of Pathology and Laboratory Medicine at the Perelman School of Medicine, University of Pennsylvania. Dr. Aisner is with the Department of Pathology at the University of Colorado School of Medicine.

(Note: References are available in the online version of this article.)

LUNGCANCERNEWS.ORG / APRIL 2018

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

Management of Pulmonary Nodules Detected by CT Screening By Annemie Snoeckx, MD, and Paul E. Van Schil, MD, PhD

No universally accepted guidelines or management protocols exist for diagnosis and treatment of screen-detected nodules. Radiologic management of pulmonary nodules has made a substantial shift in the past decade. Research has shown that not all nodules are equal, and a tailored approach is required because of differences in lung cancer probability. Clinical setting, time of detection, and nodule Dr. Annemie Snoeckx characteristics determine which specific algorithm should be used. To allow standardization and quality assurance in the management of screendetected nodules, the American College of Radiology developed Lung-RADS, which is now the standard of practice for lung cancer screening in the United States. However, no European guidelines exist for screen-detected nodules. Although time of detection is not taken into account for incidental nodules, this differs for screen-detected nodules. Solid nodules detected during the baseline screening round are not equal to incident solid nodules (detected after baseline screening), and, in particular, those nodules that are new. The latter may be fast growing and have a higher probability of malignancy—with a cancer risk of 2% to 8%—thus requiring a different, more aggressive approach.1,2 Manual measurements are still the current practice in the daily evaluation of incidental nodules. It is, however, recommended that screen-detected solid nodules be assessed by semiautomatic volume measurements with calculation of volume-doubling time, as discussed in the IASLC Lung Cancer News February article about the recently published European position statement on lung cancer screen-

ing.1 Volumetric measurements are far more sensitive than two-dimensional measurements to detect growth.3 Size and growth are crucial criteria in the management of pulmonary nodules; nevertheless, careful morphologic evaluation (Fig. 1) and use of lung cancer–prediction models may help in assessing malignancy risk. Currently, nodule characterization with differentiation between solid and subsolid types determines management. However, this visual characterization suffers from a high degree of intraDr. Paul E. Van Schil and interobserver variability.4,5 Artificial intelligence and deep learning are reshaping the imaging world and may help solve this problem in the not-too-distant future. (See the article by Drs. Yanagawa and Tomiyama on page 8 for more on Deep Learning.)

Surgical Considerations With the start of national and international screening studies, a new clinical problem has arisen for European thoracic surgeons—namely, how to deal with small pulmonary nodules and how to reduce the false-positive rate. A recent paper by a task force of the European Society of Thoracic Surgeons (ESTS) addressed thoracic surgical issues6 and made 10 general recommendations concerning CT screening in Europe. Specific topics covered included implementation of CT screening in Europe, participation of thoracic surgeons in CT screening programs, training and clinical profile for surgeons, the use of minimally invasive thoracic surgery and related surgical issues such as quality control, and, finally, associated elements of CT screening (such as smoking cessation programs, radiologic interpretation, and pathology reports). This paper is highly recommended for European centers starting a screening program.

In general, it has been clearly demonstrated that the main goal of surgery for an invasive lung cancer is to obtain a complete resection, which, in and of itself, is a major prognostic factor. This mostly implies a lobectomy for tumors larger than 2 cm and at least a lobespecific systematic nodal dissection as defined in 2005 by a working group of the IASLC.7 The new adenocarcinoma classification published in 2011 by a common task force of the IASLC, American Thoracic Society, and European Respiratory Society and accumulating phase II data, mainly from Japan, has had important surgical implications.8 New entities, including adenocarcinoma in situ and minimally invasive adenocarcinoma, were introduced. This new classification clearly resulted in a paradigm shift. The concept of sublobar resection, including wide wedge resection and anatomical segmentectomy, was reconsidered for smaller (< 2 cm), early-stage lung cancers. Anatomical segmentectomy is generally preferred to wide wedge resection because of concerns of local recurrence.9 Subcentimeter lung cancers—T1a disease—represent a specific subgroup, as they comprise the smallest lesions.10 Regarding the specific surgical approach, the ESTS task force recommends the use of minimally invasive procedures as much as possible.6 These are defined by using a camera and video monitor and access incision of less than 8 cm in length without any rib retraction, spreading, or resection. Video-assisted and robotic-assisted procedures are also acceptable. For screen-detected cancers smaller than 3 cm, mortality should be less than 1%, morbidity less than 5%, and length of hospital stay approximately 3 days. ✦ (Note: References are available in the online version of this article.) About the Authors: Dr. Snoeckx is with the Department of Radiology, Antwerp University Hospital and Antwerp University, Belgium. Dr.

ESMO-IASLC European Lung Cancer Congress The Heine Hansen Award recipient is IASLC Lung Cancer News Associate Editor Fabrice Barlesi, MD. His lecture will be “The Power of Multiple H.” “I’m unbelievably grateful to the ESMO and to the IASLC for this prestigious award, which honors not only me but all of the

French teams that are diligently working in the field of lung cancer care and research,” Dr. Barlesi said. To access the online program, visit esmo.org/Conferences/ELCC-2018Lung-Cancer/Programme. The official hashtag for the conference is #ELCC18. ✦

A panel discussion from last year’s meeting featuring (left to right) Drs. Fred Hirsch, Andrew Nicholson and David Carbone.

Fig. 1. Chest CT in a 71-year-old Woman with a 50-Pack-Year Smoking History

Chest CT in a 71-year-old woman with a 50-pack-year smoking history. Axial images in lung window setting show three nodules in the right lower lobe. Histopathologic examination after lobectomy showed that all three lesions had a different growth pattern, consistent with three primary tumors. The largest spiculated nodule with ground glass component (A) is an adenocarcinoma with predominant acinar growth pattern. The smallest lobulated nodule (B) is a moderately differentiated squamous cell carcinoma and the small spiculated nodule (C) is an adenocarcinoma with predominant lepidic growth pattern.

Van Schil is with the Department of Thoracic and Vascular Surgery, Antwerp University Hospital and Antwerp University, Belgium.

For information on placing advertisements, please contact Kevin Dunn at kdunn@cunnasso.com

Images are for illustrative purposes only. References: 1. Saunders LR, Bankovich AJ, Anderson WC, et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med. 2015;7(302):302ra136. 2. Schneider BJ, Kalemkerian GP. Personalized therapy of small cell lung cancer. In: Ahmad A, Gadgeel SM, eds. Lung Cancer and Personalized Medicine: Novel Therapies and Clinical Management. Vol 890. Cham, Switzerland: Springer International Publishing; 2016:149-174. 3. Johnson DH, Schiller JH, Bunn PA Jr. Recent clinical advances in lung cancer management. J Clin Oncol. 2014;32(10):973-982.

DLL3 UNCOVERED: ABBVIE IS INVESTIGATING AN EMERGING BIOMARKER IN SCLC1

Is DLL3 the clue we’ve been waiting for? Small cell lung cancer (SCLC) is one of the most aggressive tumor types in all of cancer.2-3 For decades, there have been limited changes in the management of SCLC, and an unmet need still remains.2 Now preclinical research on Delta-like ligand 3 (DLL3) has identified a biomarker to further explore in SCLC.1 DLL3 is a highly specific tumor antigen detectable on the surface of the majority (~85%) of SCLC tumor cells, with minimal-to-no expression in normal adult tissue.1 AbbVie is conducting research into the DLL3 protein to assess its role in tumorigenesis and uncover its full potential as an emerging biomarker in SCLC.

Visit DiscoverDLL3.com to explore the science behind AbbVie’s research in SCLC.

IASLC LUNG CANCER NEWS / APRIL 2018

MEETING NEWS HIGHLIGHT

Lung Cancer 360 Forum Overview: C.A.I.R.O Journal Club’s Fourth Anniversary By C.A.I.R.O Journal Club Executive Board

In early February, the Critical Appraisal Initiative for Research in Oncology (C.A.I.R.O) Journal Club celebrated its fourth anniversary by hosting a Lung Cancer 360 Forum in the Bibliotheca Alexandrina. The Forum was a 2-day interactive educational event that gathered 205 senior and early-career oncology physicians and pharmacists involved in the management and care of patients with lung cancer. The attendees came from different Egyptian cities including Cairo, Alexandria, Mansoura, Zagazig, Tanta, and Assiut and represented major university hospitals, specialized governmental, and private cancer care centers. C.A.I.R.O Journal Club was born as a successor to the “Oncology Marathon” that originally started in 2013. Early meetings were in the form of roundtable workshops focused on critical appraisal of recently published studies, with an

Barriers from page 10

Barriers: Regulatory Approval Delays Another barrier to access are delays in regulatory approval compared to the United States. An analysis of a basket of 23 cancer drugs approved after 2002 in Brazil showed that it took ANVISA, the local agency, more than 2 years13 longer than the U.S. Food and Drug Administration to approve new medications. Osimertinib obtained approval in Mexico and Brazil in September 2016 and December 2016, respectively, approximately 1 year after the United States. Osimertinib was approved in Argentina in June 2017. A particularly egregious example, however, was the 5 extra years that it took to bring crizotinib to Brazil. It was only after calculations of life-years lost and mobilization of patient advocacy groups and the public that the drug was finally approved (and ANVISA started to accept outcomes other than overall survival in its review process). Brazil is still waiting for the approval of a second-generation ALK TKI. In Argentina and Mexico, ceritinib has been approved since 2015. (Read this article online to see a visual timeline of drug approvals in Latin America.)

Hope on the Horizon Although it is an uphill struggle, progress is being made. Latin America has started to reform its healthcare systems to face noncommunicable diseases and cancer.

C.A.I.R.O Journal Club Executive Board Members:

The C.A.I.R.O Journal Club meeting serves as a collaborative forum for attendees.

emphasis on methodology, assessment of internal and external validity, and application of evidence. The meetings soon evolved into large-scale monthly educational events with a multi-institutional and multidisciplinary orientation. During the Forum—which included internationally and national renowned scholars in the field of thoracic oncology—radiologists, pathologists, surgeons, and medical, radiation, and

clinical oncologists comprehensively discussed the experiences of patients with early and advanced NSCLC. The sessions covered the basic knowledge needed for diagnosis and proper management and provided an opportunity to apply this knowledge through interactive case discussions and a hands-on radiotherapy training workshop. There is a tremendous revolution in the landscape of oncology diagnosis and

Such reforms include increased training of professionals, expanded cancer registries and national cancer control plans, and the implementation of policies to improve primary prevention (especially curtailing tobacco consumption), early diagnosis, and treatment of cancer in general and of lung cancer, in particular. We hope that access to new cancer medications will also become a priority,14 and that all stakeholders—including governments, pharmaceutical companies, patients, physician organizations, and the general public— will join forces to face this challenge. ✦

income countries. Nat Rev Clin Oncol. 2013 Jun;10(6):314-322. 5. Wilking N, Jönsson B. A pan-European comparison regarding patient access to cancer drugs. www.med.mcgill.ca/epidemiology/courses/ EPIB654/Summer2010/Policy/Cancer_Report Karolinska.pdf. Accessed July 30, 2017. 6. Mailankody S, Prasad V. Five Years of Cancer Drug Approvals. JAMA Oncol. 2015;1(4):539. 7. The World Bank. Purchasing Power Parities and the Real Size of World Economies – A Comprehensive Report of the 2011 International Comparison Program. 1st ed. Washington, DC: World Bank Group; 2015. 8. Goldstein DA, Clark J, Tu Y, et al. A global comparison of the cost of patented cancer drugs in relation to global differences in wealth. Oncotarget. 2017;8(42):71548-71555. 9. Aguiar PN, Perry LA, Penny-Dimri J, et al. The effect of PD-L1 testing on the cost-effectiveness and economic impact of immune checkpoint inhibitors for the second-line treatment of NSCLC. Ann Oncol. 2017;28(9):2256-2263. 10. Health Coverage Reaches 46 Million More in Latin America and the Caribbean, says new PAHO/WHO–World Bank report. The World Bank website. worldbank.org/en/news/pressrelease/2015/06/22/health-coverage-reaches46-million-more-in-latin-america-and-thecaribbean-says-new-paho-who-world-bankreport. Published 2015. Accessed July 30, 2017. 11. Aguiar P, Roitberg F, Tadokoro H, De Mello RA, Del Giglio A, Lopes G. P2.03-006 How Many Years of Life Have We Lost in Brazil Due to the Lack of Access to Anti-EGFR TKIs in the National Public Health System? J Thorac Oncol. 2017;12(11):S2129. 12. S Palacio, G Lopes, R Mudad, E Prado. P1. 06-018 EGFR Mutations and ALK Gene Rearrangements: Changing Patterns of Molecular Testing in Brazil. J Thorac Oncol. 2017;12(11):S1992. 13. Martin de Bustamante M, Martin de Bustamante M, Duttagupta S, et al. Regulatory Approval for Oncology Products In Brazil: A Comparison Between The Fda And Anvisa Approval Timelines. Value Health. 2015 Nov;18(7):A826. 14. Strasser-Weippl K, Chavarri-Guerra Y, VillarrealGarza C, et al. Progress and remaining challenges for cancer control in Latin America and the Caribbean. Lancet Oncol. 2015 Oct;16(14):1405-1438.

About the Authors: Dr. Aguiar is a BoardCertified Clinical Oncology Physician in Brazil. He has a Masters Degree in Clinical Oncology by Universidade Federal de São Paulo, São Paulo, Brazil and is a PhD Fellow in the Faculdade de Medicina do ABC, Santo André, Brazil. Dr. Lopes is Medical Director for International Programs, Associate Director for Global Health, and Associate Professor of Medicine at the Sylvester Comprehensive Cancer Center at the University of Miami. References: 1. Marrero SL, Bloom DE, Adashi EY. Noncommunicable diseases: a global health crisis in a new world order. JAMA. 2012;307(19):2037-2038. 2. Raez LE, Santos ES, Rolfo C, et al. Challenges in Facing the Lung Cancer Epidemic and Treating Advanced Disease in Latin America. Clin Lung Cancer. 2017;18(1):e71-e79. 3. Lung cancer in the Americas. Pan American Health Organization website. paho.org/hq/index. php?option=com_docman&task=doc_download &gid=22070&itemid=&lang=en. Published 2014. Accessed January 1, 2017. 4. Lopes Gde L Jr, de Souza JA, Barrios C. Access to cancer medications in low-and middle-

• 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)

management, which requires continuous medical education. Thus, comprehensive educational events such as this constitute an excellent forum for in-depth knowledge updates, interaction, and collaboration between different specialties involved in cancer care. ✦

Deep Learning Systems from page 8 nodules by morphologically evaluating the margins and internal characteristics according to previous data. Naturally, there are limitations to the diagnostic performance. For example, localized ground-glass nodules (GGN) include all pathologic subtypes of adenocarcinoma (i.e., AIS, MIA, and IVA). However, most radiologists cannot differentiate IVA from GGN on CT images. Therefore, unlike nodule detection, in differentiating between benign and malignant disease, there might be some cases in which a DL system identifies malignant lesions that the radiologist cannot believe or verify. Therefore, much higher accuracy and sensitivity will be needed for DL to contribute to malignancy diagnosis. Although DL can provide useful and informative results, it does not replace the radiologist. Nor does DL have the ability to manage and decide treatment strategies, so it is, therefore, important for radiologists to intelligently use the information derived from DL. We expect that future research will focus on the use of AI technology in different areas of radiology. ✦ About the Authors: Dr. Yanagawa is with the Department of Radiology, Osaka University Graduate School of Medicine, Osaka, Japan. Dr. Tomiyama is with the Department of Radiology, Osaka University Graduate School of Medicine, Osaka, Japan.

LUNGCANCERNEWS.ORG / APRIL 2018

GLOBAL RESEARCH

By Tiziana Vavalà, MD, and Silvia Novello, MD, PhD

Approximately 1.8 million new lung cancer cases worldwide are diagnosed annually, and 85% of these cases are NSCLC. Only 25% to 30% of patients with NSCLC are suitable for potentially curative resection. Despite optimal surgical management and postoperative treatments, nearly one-third of patients with stage I NSCLC and at least 30% to 50% of those with stages II and III disease will still die from recurrent disease.1,2 Lung adenocarcinoma is the most commonly diagnosed histologic subtype of NSCLC.3 Introduction of targeted therapies, specifically those directed toward EGFR active mutations and ALK rearrangement, have improved outcomes in a subset of patients with advanced NSCLC harboring those alterations; however, the role of molecular testing and targeted therapies for earlier-stage NSCLC remains unclear, and practice varies worldwide.4,5

The ALCHEMIST Platform The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) applies the umbrella design to identify and screen patients with EGFR active mutations and ALK rearrangement in early-stage resected non-squamous NSCLC through three integrated protocols, with further trials anticipated or planned in the future. Patients with squamous NSCLC have been subsequently planned to be included for those sites who had Institutional Review Board/Ethics Committee approval for ALCHEMIST-Immunotherapy (EA5142) trial at the time of patient pre-registration (Fig. 1). In the ALCHEMIST SCREENING (A151216) trial, patients with nonsquamous (and squamous for approved sites) stage Ib (> 4 cm)-IIIA NSCLC are evaluated and considered for one of the ALCHEMIST therapeutic protocols. As part of this trial, non-squamous tumor samples and blood specimens are genotyped for EGFR mutations and ALK rearrangement and are collected for whole-exome or -genome analysis. If either of these molecular drivers are present, patients are subsequently referred to one of two treatment trials

In Case You Missed It: Read Online for more detailed information about the ALCHEMIST trial at http://bit.ly/2n7V3GW.

(ALCHEMIST-EGFR [A081105] or ALCHEMIST-ALK [E4512]), which are testing erlotinib (for EGFR mutations) or crizotinib (for ALK rearrangement) versus observation in patients with completely resected non-squamous NSCLC after standard therapy. Patients with squamous histology and those who are negative for EGFR or ALK alterations undergo PD-L1 testing and are eventually referred to the Nivolumab After Surgery and Chemotherapy in Treating Patients With Stage IB-IIIA Non-small Cell Lung Cancer (ANVIL) trial (ALCHEMISTImmunotherapy [EA5142]). All patients who are not enrolled in previous subtrials will be monitored on A151216 for relapse and survival for 5 years.

Improved Clinical Trial Efficiency The usual drug-development paradigm of phase I followed by phase II and phase III to define a clinical benefit is challenged by the presence of target therapies and the incorporation of biomarker assessment for medical treatment. 7 Enrichment, umbrella, and basket trial designs are gaining popularity; they offer novel strategies to accelerate the drug- Dr. Tiziana Vavalà development process, with the goal of delivering personalized therapies to eligible patients more quickly. Among innovative trial designs, the umbrella infrastructure usually Dr. Silvia Novello has the flexibility to add (or drop/modify) subtrials of molecularly targeted drugs and companion diagnostics based on accumulating evidence from the ongoing trial or newly emerging data elsewhere.8 The ALCHEMIST platform, with its current design, significantly enhances the prospect of cure, particularly if positive results emerge from these biomarker-driven trials. ALCHEMIST has prompted a new vision of lung cancer though a genomic landscape, and it is defining a systematic approach of cure in a molecularly defined subset of patients.8 This approach to clinical research is even more relevant in Europe, where delays in access to anticancer drugs and to molecu-

Fig. 1. ALCHEMIST Schema and Update

Courtesy of Dr. Ramaswamy Govindan

European Perspective on ALCHEMIST

lar testing have postponed the choice of a target approach for patients with oncogene addiction. For example, crizotinib, the ALK first-generation TKI for first-line treatment of patients with ALK-rearranged NSCLC, was approved for reimbursement in Italy only recently (in February 2017) whereas the U.S. Food and Drug Administration (FDA) granted an accelerated approval in August 2011.9,10 This delay has limited therapeutic options for eligible patients over the past 4 years and has also compromised the proper implementation of detection testing in clinical practice. This consideration is supported by recent data from the Italian Observational Prospective Trial. In this trial, 1,787 patients with advanced or recurrent NSCLC were evaluated between November 2014 and November 2015. Of the participants, 1,351 (75.6%) presented with adenocarcinoma, 280 (15.7%) presented with squamous carcinoma, and the rest presented with mixed or poorly differentiated histologies; 1,353 patients (76%) were tested for EGFR, but only 942 (53%) were evaluated for ALK. As stated by the authors, this was probably due to the costs of analysis (fluorescence in situ hybridization was often the main, or only, tool applied for ALK translocation); without a fully reimbursed first-line ALK inhibitor, clinicians opted to postpone the analysis, giving priority to the EGFR test in a daily clinical practice.11 Moreover, in the same study, it was clearly shown that only 707 (40%) patients received a second-line treatment. It is well known that after first-line therapy, the general conditions of patients with lung cancer may dramatically worsen, inducing clinicians to start a classical second-line treatment rather than asking and waiting for a molecular report or repeating a tissue biopsy.11 As a consequence, a high percentage of patients lose the opportunity to receive appropriate second-line targeted therapy. ALCHEMIST is, in any

case, a proactive attempt to avoid the same mistakes in early-stage NSCLC. All cited issues highlight the profound and challenging effects of ALCHEMIST, not only in Europe, but also from a global perspective. ALCHEMIST is a strong academic effort to improve clinical trial efficiency and the first opportunity to systematically characterize the presence of molecular changes in the early-stage setting, using innovative technologies to translate research data early in the drug-development process and improve adjuvant treatment. The ALCHEMIST approach could be a valuable way to answer the need for a better, sciencebased, consensual position on methodology, inspiring greater commitments from politicians and healthcare decision makers to ensure broad, quick, and equal access to innovative antitumor drugs. ✦ About the Authors: Dr. Vavalà is Oncologist and Referent for Thoracic Malignacies at SC of Oncology at ASL CN1, Saluzzo Hospital, Italy. Prof. Novello is Professor of Medical Oncology at Department of Oncology at San Luigi Hospital, University of Turin, Italy.

(Note: References are available in the online version of this article.)

IASLC Lung Cancer News: Additional Content Online The National Cancer Institute’s (NCI’s) Lung Cancer Specialized Programs of Research Excellence (SPORE) and their affiliates met in June 2017 to discuss current trends in translational lung cancer research, plan collaborations, and design new projects. Read an overview of the meeting by Roy S. Herbst, MD, PhD, on lungcancernews.org. ✦

IASLC 2018 Meetings

www.iaslc.org/events

Schedule

IASLC Africa Conference on Lung Cancer 2018 April 29-May 1 Tangier, Morocco

IASLC Latin America Conference on Lung Cancer 2018 August 15-18 Cordoba, Argentina

IASLC 19th World Conference on Lung Cancer September 23-26 Toronto, Canada

IASLC Asia Conference on Lung Cancer 2018 November 7-10 Guangzhou, China