IASLC Lung Cancer News - V2, N6

LUNG CANCER

V2/ N6 / DECEMBER 2017

NEWS

FOR THORACIC SPECIALISTS LungCancerNews.org new!

IASLC.org

INSIDE 2

Controversies Surrounding Use of New Techniques in Radiotherapy

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Patients with EGFR Mutation Should Postpone Brain Radiation for CNS Metastases: Pro and Con

11

FDA Corner

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IASLC 2017 Multidisciplinary Symposium in Thoracic Oncology NCI Corner Cannabis, Lung Cancer, and Therapy

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Bronchoscopy Ultrasound and Navigational Bronchoscopy Finally Arrive in Peru Studies Indicate Expanding Benefit of Checkpoint Inhibitors IASLC Consensus Statement on Liquid Biopsy

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21 22 23

IASLC 18th WCLC Special Session Provides Overview of Updated Guidelines for Molecular Testing Advocating for Inclusion of the Patient’s Voice Lung Cancer Awareness Month Gathers Support in Its Second Year Names and News Breaking News Writing for Publication: Voices of Nursing in Thoracic Oncology Lung Cancer Research Foundation and Free to Breathe Merge

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 GLOBAL RESEARCH

National Cancer Institute Adds Latest Clinical Trial to the ALCHEMIST Platform

By Cynthia L. Kryder, MS

Despite genomic advances in the treatment of advanced lung cancer over the past decade, few breakthroughs have emerged in the adjuvant treatment of patients with resected non-small cell lung cancer (NSCLC) in whom there is a 50% chance that the cancer will recur after standard treatment. Consequently, the US National Cancer Institute initiated the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) platform to investigate the role of genomic testing and personalized therapies in the treatment of operable, early-stage NSCLC. The ALCHEMIST trials are investigating the survival benefit of adding erlotinib (Tarceva), crizotinib (Xalkori), and nivolumab (Opdivo) as adjuvant therapy for patients with completely resected NSCLC. EA5142, which focuses on epidermal growth factor receptor (EGFR)and anaplastic lymphoma kinase (ALK)-

MEETING NEWS HIGHLIGHTS

IASLC WCLC 2017 Presidential Symposium Presents Leading Lung Cancer Research

By Cynthia L. Kryder, MS

The IASLC WCLC 2017 Presidential Symposium in Yokohama, Japan, recognized the authors of 3 exceptional lung cancer research abstracts.

Patient-reported Outcomes from the PACIFIC Trial According to previously reported efficacy and safety results of the PACIFIC trial, patients with locally advanced stage III NSCLC receiving durvalumab post completion of definitive concurrent chemoradiation had a significant improvement in progression-free survival (16.8 months vs. 5.6 months) Rina Hui (Figure 1), and a lower incidence of new lesions, including new brain metastases, compared with patients receiving placebo. Additionally, durvalumab was well tolerated with a manageable safety profile. Rina Hui, MBBS, FRACP, PhD, Crown Princess Mary Cancer Centre, Westmead, Australia, presented additional data on patient-reported outcomes, a secondary endpoint of the PACIFIC trial, a randomized, placebo-controlled, double-blind, phase III study in locally advanced, unresectable NSCLC. Dr. Hui and colleagues randomly assigned 713 patients who had previously received 2 or more cycles of platinum-based concurrent chemotherapy with definitive dose continued on page 16

negative patients, is the newest study in the ALCHEMIST initiative.1 ALCHEMIST aims to identify actionable alterations in patients with early-stage NSCLC and intends to accrue enough patients to power definitive analyses. Up to 8,000 participants at numerous sites across the United States will be screened.

ALCHEMIST is a 4-part trial, with targeted populations broken down as such: screening, approximately 8,000 patients; EGFR, approximately 450 patients; ALK, approximately 378 patients; and immunotherapy, 714 patients.

The ALCHEMIST Platform The ALCHEMIST platform is a series of integrated clinical trials comprising a screening trial and 3 prospective, randomized, phase III adjuvant clinical trials:2 • ALCHEMIST-Screening • ALCHEMIST-EGFR • ALCHEMIST-ALK • ALCHEMIST-Immunotherapy (EA5142) ALCHEMIST-Screening The primary goal of the ALCHEMIST screening trial is to genotype resected nonsquamous NSCLC for molecular abnormalities in EGFR and ALK genes.

Patients with pathologically confirmed stage IB (≥ 4 cm)-IIIA NSCLC are enrolled either before or after surgical resection. Patients with EGFR-positive or ALK-positive tumors are offered enrollment in ALCHEMIST-EGFR or ALCHEMIST-ALK, respectively. Patients who are negative for EGFR and ALK mutations or those with squamous histology are eligible for enrollment in EA5142.

All patients screened in this trial will be monitored for 5 years.

ALCHEMIST-EGFR Erlotinib is approved in several countries for use in patients with advanced NSCLC whose tumors harbor an EGFR mutation. ALCHEMIST-EGFR is investigat-

ing whether the addition of erlotinib will improve overall survival compared with placebo in patients with early-stage, fully resected, EGFR-positive NSCLC who have completed standard postoperative chemotherapy with or without radiation therapy. Eligible patients are randomly assigned to erlotinib or placebo for up to 2 years or until they experience unacceptable toxicity or a recurrence of their cancer. Patients will be monitored for up to 10 years after treatment.

ALCHEMIST-ALK Crizotinib is approved in several countries for patients with advanced lung cancer whose tumors test positive for the ALK rearrangement. ALCHEMISTALK seeks to determine whether adjuvant crizotinib improves overall survival versus placebo in patients with earlystage, ALK-positive NSCLC who have completed standard postoperative chemotherapy with or without radiation therapy. Eligible patients are randomly assigned to receive crizotinib or placebo for 2 years. As with ALCHEMIST-EGFR, patients enrolled in ALCHEMIST-ALK will be monitored for up to 10 years after treatment. As of May 2017, both the erlotinib and the crizotinib studies are observation-controlled.

ALCHEMIST-Immunotherapy (ANVIL; EA5142) Nivolumab is approved for patients with metastatic or recurrent NSCLC whose disease has progressed after platinum chemotherapy. The randomized, phase 3 ALCHEMIST immunotherapy trial, also known as EA5142 or Adjuvant Nivolumab in Resected Lung Cancers (ANVIL), seeks to determine whether immunotherapy with nivolumab improves overall survival continued on page 6

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IASLC LUNG CANCER NEWS / DECEMBER 2017

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

Utility and Controversies Surrounding Use of New Techniques in Radiotherapy

By Suresh Senan, MRCP, FRCR, PhD

Improved delivery of radiotherapy has contributed to the recent changes in guidelines for patients with lung cancer. The clinical impact of some Suresh Senan technical advances has been modest, but the cumulative effect of many developments has led to more precise treatment delivery, and has increased the confidence of clinicians to adopt new techniques. The impact of new technology is best illustrated by referring to selected clinical stages.

Early-stage Peripheral NSCLC The poster child of new technology is image-guided stereotactic ablative radiotherapy (SABR or SBRT), which is a technique for delivering high-dose, high-precision radiation. In early-stage peripheral non-small cell lung cancer (NSCLC), 5-year in-field tumor control

due to its ability to decrease radiation doses to surrounding organs. However, the options for managing tumor motion at current proton centers is generally

inferior to that available on a standard linear accelerator. At present, there are limited prospective data supporting a role for protons in early-stage NSCLC.

Locally Advanced Lung Cancer Since the introduction of CT-based treatment planning and improved set-up protocols, concurrent chemo-radiation

For patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, at progression on or after TKI therapy

TAGRISSO

®

(osimertinib)

PROVIDED BREAKTHROUGH PROGRESSION-FREE SURVIVAL VS DOUBLET CHEMOTHERAPY

An impressive 10.1 months of median PFS compared to 4.4 months with doublet chemotherapy1 • In a Phase III, randomized, open-label, head-to-head clinical trial of 419 patients, TAGRISSO outperformed doublet chemotherapy (pemetrexed plus carboplatin or cisplatin)1 PRO G RESSI O N - FR EE SU RVIVAL*

rates of 90% have been reported, and the introduction of SABR has been associated with improved cure rates at the population level. The superiority of SABR over conventional radiotherapy has been established in two randomized trials, results from one of which was presented at the IASLC 18th World Conference on Lung Cancer [Ball D, WCLC 2017].

SABR resulted in superior freedom from local failure (HR = 0.29, 95% CI 0.130, 0.662, P=0.002) and also longer overall survival (HR = 0.51, 95% CI 0.51, 0.911, P=0.020).

Minimal requirements for SABR planning and delivery were recently published by the European Society for Radiotherapy and Oncology, and include use of 4-D planning computed tomography (CT) scan and a standard linear accelerator with a cone-beam CT scan.

Newer developments include the clinical introduction of magnetic resonance imaging-guided SABR, which is undergoing evaluation in high-risk tumors such as centrally located NSCLC. The use of protons (charged particles) was considered previously to be a promising development for treating lung tumors,

PROBABILITY OF PROGRESSION-FREE SURVIVAL

HR=0.30

REDUCTION

1.0

in the relative risk of progression or death vs platinum-based doublet chemotherapy

0.8

10.1

0.6

MONTHS

4.4

0.4

TAGRISSO

MONTHS 0.2

Platinum-based doublet chemotherapy

0.0 0

3

6

9

12

15

18

MONTHS

No. at Risk TAGRISSO

70%

(95% CI: 0.23, 0.41) p<0.001

279

Doublet 140 chemotherapy

240

162

88

50

13

0

93

44

17

7

1

0

• TAGRISSO also demonstrated double the confirmed objective response rate compared to doublet chemotherapy (65% vs 29%)1 • A BICR assessment of CNS efficacy by RECIST v1.1 was conducted in the subgroup of 46/419 (11%) patients identified to have measurable CNS lesions on a baseline brain scan1 – An ORR of 57% was seen in the TAGRISSO group and 25% in the doublet chemotherapy group1 *As determined by investigator assessment (IA).

See more results from the AURA3 head-to-head study at TAGRISSOhcp.COM

LUNGCANCERNEWS.ORG / DECEMBER 2017

(CT-RT) has become established as the standard of care for most fit patients who present with locally-advanced NSCLC. Patients undergoing standard concurrent CT-RT to 60 Gy in the RTOG 0617, study achieved 5-year overall and progressionfree rates of 32% and 18%, respectively.1 The median overall survival of 28.7 months in this trial has also established

a new benchmark. The role of intensitymodulated radiotherapy (IMRT) remains a topic of debate, particularly as population studies suggest that benefits of IMRT are limited to larger central (T3-4) tumors. Results of RTOG 0617 support use of IMRT in locally-advanced NSCLC as this reduces rates of radiation pneumonitis, and was associated with a better

quality of life in the first 12 months post CT-RT. Some, but not all studies, suggested that delivery of higher radiation doses to the heart are associated with a poorer overall survival. However, other studies suggest that delivered heart doses may be a surrogate for other prognostic factors in stage III NSCLC, such as the extent and

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 TAGRISSO-treated 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 • 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%)

INDICATION 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 therapy.

Please see Brief Summary of complete Prescribing Information on adjacent pages.

Reference: 1. TAGRISSO [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017.

3

location of mediastinal nodal involvement, especially subcarinal nodes, rather than an independent predictor of outcome. The increased cardiac toxicity has also been correlated with the use of doses higher than the standard 60 Gy for CT-RT, and with schemes using non-standard fractionation schemes (>2 Gy, once daily). continued on next page

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IASLC LUNG CANCER NEWS / DECEMBER 2017

Proponents of proton radiation have therefore advocated its use as a means to decrease both lung and cardiac toxicity. The number of proton centers worldwide is increasing in a roughly exponential fashion, with approximately 20 operating centers, and 53 in development. However, little consensus has

been reached for using proton therapy for common types of cancer in adults.

A prospective randomized trial led by the MD Anderson Cancer Center compared the use of IMRT versus proton therapy in locally advanced NSCLC, and reported no differences in treatment failures, which were defi ned as either

grade ≥3 pneumonitis or local failure at 1 year.2 Proponents of protons have argued that the use of a newer delivery technique (intensity-modulated proton therapy) will improve outcomes, and the results of ongoing comparative trials are awaited. Treatment of mobile tumors in the lung and liver using protons remains

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

a

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].

a challenge, and only a minority (27%) of European proton and carbon ion therapy centers currently treat such tumors.3

Changing Paradigms in Locally Advanced Lung Cancer The published results of the PACIFIC trial have called into question the pre-

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 / DECEMBER 2017

vious focus on delivery of ever higher radiation doses. PACIFIC evaluated consolidation durvalumab or placebo every 2 weeks for a year, following CT-RT in patients with unselected stage III NSCLC after concurrent CT-RT to a dose of 54-66 Gy.4 Consolidation durvalumab resulted in an increase in

median PFS to 16.8 versus 5.6 months (HR 0.52) with the differences in PFS sustained at 12- and 18-month landmarks.

Durvalumab also resulted in a superior median time to death or distant metastases (23.2 vs 14.6 months; P < .001), and little increase in grade 3/4 treatmentrelated toxicity.

The above findings indicate that the addition of durvalumab consolidation to standard radiation doses combined with two cycles of platinum-containing chemotherapy, is sufficient to improve both local and distant tumor control. This, in turn, raises the question whether the focus of radiation research should simply

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

36

2.9

14

0

9

0.7

40

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.

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

5

be to limit radiation doses to 60 Gy, while further optimizing the integration of immune-oncology and other systemic approaches into CT-RT of stage III NSCLC. ✦ References 1. Bradley JD, Hu C, Komak RU, et al. Long-term results of RTOG 0617: A randomized phase 3 comparison of standard dose versus high dose conformal chemoradiation therapy +/- cetuximab for stage III NSCLC. J Am Coll Radiol.

2017:99, S105 (suppl) 2. Liao Z, Lee J, Komaki R, Gomez D, O'Reilly M, Allen P, et al. Bayesian randomized trial comparing intensity modulated radiation therapy versus passively scattered proton therapy for locally advanced non-small cell lung cancer. J Clin Oncol. 2016;34 suppl 15:8500.

3. Weber DC, Abrunhosa-Branquinho A, Bolsi A, et al. Profile of European proton and carbon ion therapy centers assessed by the EORTC facility questionnaire. Radiother Oncol.

2017;124:185-189.

4. Scott J. Antonia SJ, Villegas A, Davey Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer.

N Engl J Med. 2017 Sep 8. doi: 10.1056/ NEJMoa1709937. [Epub ahead of print]

2018

LUNG CANCER

MEE TINGS CALENDAR JANUARY Fifth AACR-IASLC International Joint Conference on Lung Cancer Translational Science: From the Bench to the Clinic January 8 - 11 San Diego, CA, US

FEBRUARY IASLC 18th Lung Cancer Targeted Therapies Meeting February 21 - 24 Santa Monica, CA

MARCH IASLC Lung Cancer Immunotherapy Meeting 2018 March 22 - 24 Madrid, Spain

APRIL ELCC 2018: European Lung Cancer Congress April 11 - 14 Geneva, Switzerland IASLC Africa Conference on Lung Cancer 2018 April 29 - May 1 Tangier, Morocco

JUNE ASCO Annual Meeting June 1 – 5 Chicago, IL

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

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

6

IASLC LUNG CANCER NEWS / DECEMBER 2017

ALCHEMIST Platform continued from page 1

and disease-free survival in patients with early-stage NSCLC who have completed standard postsurgical chemotherapy, with or without radiation therapy.

ANVIL will enroll patients with early-stage NSCLC with ALK and EGFR wild-type tumors. Patients with earlystage squamous-type NSCLC also may be enrolled. Central testing for the programmed death ligand (PD-L1) is performed using immunohistochemistry in all patients.

Eligible patients are randomly assigned to nivolumab for up to 1 year or standard of care–observation. Patients are stratified by stage, histology, prior adjuvant treatment, and PD-L1 status (≥1% or <1%). Co-primary endpoints are a 30% improvement in overall survival and/or a 33% improvement in disease-free survival favoring nivolumab. To date, ANVIL has enrolled more than 200 of 714 planned patients; the trial is currently open at more than 500 sites in the United States.

Implications for Practice The results of the ALCHEMIST trials, as well as other adjuvant therapy trials (see Table 1), have the potential to change the standard of care and improve survival for patients with resected, early-stage NSCLC. Positive results may prompt further investigation into the use of molecular agents in earlier-stage disease.

Perhaps most importantly, ALCHEMIST will provide information that will enable researchers to better characterize the

Table. Additional Adjuvant Therapy Trials

actionable mutations found in patients with early-stage NSCLC. Nevertheless, to meet proposed accrual targets, at least 8,000 patients must be screened. Because the clinical trial participation rate in the United States is only 3% to 6% of eligible patients,3 the US National Cancer Institute is making a coordinated effort to encourage screening and enrollment in ALCHEMIST trials. Regional, multidisciplinary ALCHEMIST teams that include surgeons, medical oncologists, clinical research associates, and patient advocates are working to promote the study and encourage participation.

The ALCHEMIST trials aim to provide a detailed view of the genomic landscape of early-stage NSCLC that could transform the approach to care for a molecularly defined subset of patients.

In addition, this trial will define standard practice in the larger cohort of patients whose tumors do not harbor readily identified “actionable” molecular abnormalities. ✦

Study China NCT02448797: Icotinib Versus Vinorelbine/Platinum as Adjuvant Therapy in Stage II-IIIA NSCLC With EGFR Mutation: A Randomized, Positive-controlled, Phase 3 Study (EVIDENCE, CCTC-1501)

Disease-free survival To evaluate the efficacy of icotinib as adjuvant therapy in treating patients with stage II-IIIA NSCLC that harbors an EGFR mutation

NCT02125240: Icotinib as an Adjuvant Therapy for Stage II-IIIA Adenocarcinoma With EGFR Mutation: A Placebo-controlled, Randomized, Double-blind, Phase III Study (ICWIP)

Disease-free survival To evaluate the efficacy of icotinib versus placebo as adjuvant therapy in patients with EGFR-mutation-positive stage II-IIIA lung adenocarcinoma

United States Percentage of patients with a major pathologic response based on surgical resection

NCT02927301: A Phase II, Open-Label, Multicenter, Single-Arm Study to Investigate the Efficacy and Safety of Atezolizumab as Neoadjuvant and Adjuvant Therapy in Patients With Stage IB, II, or IIIA Resectable and Untreated NSCLC

To evaluate the safety and efficacy of neoadjuvant and adjuvant atezolizumab in patients with stage IB, II, or IIIA NSCLC who are eligible for surgical resection with curative intent

NCT03130764: Identification of Tumor Neoantigens During Immune Checkpoint Blockade in Resectable NSCLC

To determine whether immu- Percentage rate of induced T-cell notherapy with durvalumab and tremelimumab is feasible response and potentially increases the chance of cure in patients with resected stage IB-IIIA NSCLC who have completed standard adjuvant therapy

References 1. Chaft JE, Dahlberg SE, Gerber DE, et al. EA5142 adjuvant nivolumab in resected lung cancers (ANVIL): the newest study in the ALCHEMIST platform. J Clin Oncol. 2017;35(suppl; abstr TPS8575).

2. The ALCHEMIST Lung Cancer Trials [website].

National Cancer Institute. Updated July 24, 2017. https://www.cancer.gov/types/lung/research/alchemist. Accessed July 27, 2017.

3. Cancer Research Institute [website]. Clinical trials.

2017. http://www.cancerresearch.org/cancerimmunotherapy/about-clinical-trials#sthash.

4MOWPCWY.dpuf. Accessed July 17, 2017.

Endpoint/Outcome Measures

Purpose

Multinational (European Union, Israel, Japan, Switzerland) NCT02504372: A Randomized, Phase 3 Trial With Anti-PD-1 Monoclonal Antibody Pembrolizumab (MK-3475) Versus Placebo for Patients With Early Stage NSCLC After Resection and Completion of Standard Adjuvant Therapy (PEARLS)

To evaluate the efficacy of adjuvant pembrolizumab versus placebo in patients with resected stage IB-IIIA NSCLC (with or without adjuvant chemotherapy)

Disease-free survival

THOUGHT LEADER PERSPECTIVE

with Jamie E. Chaft, MD, Regarding the ALCHEMIST Platform How do you envision immunotherapy interdigitating in the adjuvant and neoadjuvant setting in resectable nonsmall cell lung cancer (NSCLC)?

PACIFIC, which demonstrated a marked progression-free survival (PFS) advantage of 1 year of durvalumab after definitive concurrent chemoradiation in patients with unresectable NSCLC, gives us hope that this class of agents may likewise translate to benefit in those with resectable disease. Including EA5142, there are 4 active studies globally that will define the benefit of adjuvant anti-PD-1 or PD-L1 therapies after surgical resection and standard adjuvant chemotherapy. Some studies are planning to evaluate subsets of patients selected by tumor PD-L1. While I cannot predict how these studies will read out, I am confident we will ultimately be able to

define a subset of patients that are cured by this approach, and I remain hopeful that these large research efforts are molded as we learn more about predictive biomarkers of response to these agents.

Based on the tolerability of these drugs and intriguing responses seen in a very small study of neoadjuvant nivolumab, there are increasing efforts to study single agent immunotherapy agents and combinations with chemotherapy and other checkpoint inhibitors in the preoperative setting. This is particularly important, as it lends the opportunity to learn about the immunobiology of response and resistance and to offer standard adjuvant therapies in nonresponding patients.

There is also the theoretical advantage of having the larger tumor in situ when activating an immune response. I envi-

sion this approach becoming increasingly common on study and perhaps as part of standard care.

What is the optimal duration of IO Tx in this setting? How can we test this?

Each of the ongoing adjuvant studies is evaluating 1 year of therapy, as did the PACIFIC study. This duration of therapy is somewhat arbitrarily defined by necessity. as we have no data here. In advanced disease, these drugs can induce durable responses. We had little data on this same question in advanced until Checkmate 153 demonstrated a strong trend towards improved outcomes in those treated continuously versus stopping at 1 year. Given the different settings and the mechanisms of these drugs that can elicit antitumor immunity, I remain

Jamie E. Chaft

hopeful that a shorter course of therapy may be able to eliminate minimal residual disease in the adjuvant setting. If the ongoing adjuvant studies demonstrate a benefit of 1 year of therapy, I imagine it will be up to the NCI and the cooperative groups to pose the question of duration of therapy.

If successful, do you think IO Tx will ever substitute for chemotherapy? Or will we routinely graft it onto chemo, or give it subsequently after completion of adjuvant therapy?

The short answer is yes. I do think immunotherapy will eventually substitute for continued on next page

LUNGCANCERNEWS.ORG / DECEMBER 2017

7

I do think immunotherapy will eventually substitute for chemotherapy in some patients and may be combined with chemotherapy in some patients, although we do not yet know who to prescribe which therapy, which combination of therapies, or in which sequence. chemotherapy in some patients and may be combined with chemotherapy in some patients, although we do not yet know who to prescribe which therapy, which combination of therapies, or in which sequence. Given the time and resources needed to answer these questions, we would be prudent to await the mature survival data of the ongoing phase III studies looking at combinations and sequencing, as well as biomarkers. These data will enable rationally designed studies, ideally in the neoadjuvant setting where pathological tumor evaluation may give us early signals of benefit or lack thereof.

Do the negative results for EGFR mt (+) patient subset in the RADIANT trial discourage you from further testing EGFR TKIs in the adjuvant setting? In this regard, is ALCHEMIST still a reasonable trial?

Absolutely not. RADIANT wasn’t de-signed nor powered to answer the question of benefit of adjuvant EGFR TKI in patients with resected EGFR+ tumors. We would be remiss to dismiss this potentially curative approach based on too small a study. Not only is ALCHEMIST reasonable, it should

remain a priority. The more timely question is if and how we will extrapolate from the data the ALCHEMIST will provide when considering other TKIs, in particular osimertinib, which is not only superior to erlotinib/gefitinib in the firstline treatment of metastatic disease, but is also better tolerated. This is a consideration of utmost importance when treating patients in the adjuvant setting, some of whom are cured by surgery alone.

What is the optimal duration of adjuvant therapy in EGFR mt (+) or ALK (+) NSCLC? Should we take our cue from the breast cancer literature with regard to hormonal therapy and give these agents for more extended periods(i.e., 5 to 10 years or more)?

Instead of looking to the breast cancer literature to guide our study designs, perhaps we should look to GIST where, similar to EGFR and ALK+ tumors, GIST is driven by an oncogene mutation and treated with an adjuvant TKI. While adjuvant imatinib provides a DFS advantage when given for 1 year, it was not until 3 years of therapy when an overall survival advantage was seen. We may get some clues as to the optimal duration of therapy when ultimately evaluating

the data from the ALCHEMIST studies, looking at 2 years of adjuvant TKI and the industry-sponsored osimertinib trial evaluating 3 years, although crosstrial comparisons are not appropriate when different drugs are used. Dr. Lecia Sequist is completing a study evaluating 3 months versus 2 years of adjuvant afatinib, which should give some insight into even shorter durations of therapy, although I do think we have sufficient data from GIST and perhaps from breast cancer to suggest that the study of more than 2 years of therapy is of interest.

How, if at all, does the risk-benefit ratio transform in the perioperative setting compared to the metastatic/recurrent NSCLC venue?

The treatment of metastatic disease remains palliative and we must be cognizant of the side effects, quality of life impact, and cost of our therapies relative to the survival benefit gained. The earlystage setting is strikingly different, in that our therapies are intended to cure; therefore, the risk-benefit ratio may be shifted towards years or decades of quality life gained, not just months. However, many of these good-intentioned perioperative trials have not succeeded.

Pushing a patient through adjuvant therapy that is not biomarkerdriven remains a challenge. Our gains with cisplatin-based chemotherapy are small and toxicities are high; yet it remains our standard of care. As our drugs become more tolerable and are better matched to an individual’s tumor, we have more stable ground to stand on when pushing patients to consider adjuvant therapy. This is very relevant when we discuss durations of targeted therapy that may ultimately be 5 or more years.

The neoadjuvant setting is very different. As surgery remains the largest component of curative therapy, we must be cautious not to give therapies that interfere with the patient’s ability to proceed with surgery due to toxicity. However, we have the ability to monitor treatment efficacy by scans and therefore adapt or stop ineffective therapies, something we cannot do in the adjuvant setting. Further, patients are more fit to tolerate therapies preoperatively; therefore, added risk (if it does not interfere with surgery) is justified with the goal of increasing cure rates.✦

THOUGHT LEADER PERSPECTIVE

Commentary Regarding Immune Checkpoint Inhibitors

By Fabrice Barlesi, MD, PhD

Since the advent of adjuvant platinumbased chemotherapy as the standard of care, little progress has been achieved in significantly improving the cure rate of patients with resected early-stage lung cancer. However, attempts to biologically drive the postoperative management of these patients to provide more precise, more effective treatment has led to several trials. Some of these protocols have been based on actionable molecular alterations (e.g., EGFR),1-3 some based on targeting DNA repair pathway alterations (e.g., ERCC1, BRCA1),4,5 and some based on both.1 Unfortunately, while this type of strategy has proven technically feasible, none of these trials have provided patients with a substantial survival benefit.

Many explanations have been proposed to explain this lack of success, but there are 2 that come to the forefront.

First, the available data regarding the biology of early-stage non-small cell lung cancer (NSCLC) is lacking because these patients, until very recently, have been less frequently molecularly profiled6 compared to patients with advancedstage NSCLC, who are routinely molecularly tested and who benefit from targeted therapies. Second, the assumption that

amended design is featured in this issue of IASLC Lung Cancer News, are important; they offer our patients, both current and future, a better opportunity for cure.

The sequencing of more than 8,000 earlystage lung cancer cases will undoubtedly provide the scientific community with innovative pathways to be explored and new targets to be addressed.

The sequencing of more than 8,000 early-stage lung cancer cases will undoubtedly provide the scientific community with innovative pathways to be explored and new targets to be addressed. therapies that work in advanced NSCLC can be exported to the early-stage setting with similar outcome benefits is suspect since early-stage NSCLC is very likely a biologically different cancer.

Therefore, initiatives like the ALCHEMIST master protocol, whose

The linked therapeutic protocols will also provide us with key information.

Does an EGFR- or ALK-targeted therapy offer more chance of cure, or are these agents merely delaying time of recurrence? How do we biologically explain the detrimental effect seen in wild-type

Fabrice Barlesi

patients,7 and what are the risks for patients with an actionable molecular alteration who are already cured by surgery with or without adjuvant chemotherapy?

Besides actionable molecular alterations, and particularly in their absence, can immune checkpoint inhibitors change the outcome? On one hand, the immune system probably has a role in explaining why, at the same pathological postoperative stage, some patients are cured and others are not.

On the other hand, the likelihood of activating the immune system may be lower in those with occult, micrometastatic disease and earlier stage, compared continued on next page

8

IASLC LUNG CANCER NEWS / DECEMBER 2017

THOUGHT LEADER PERSPECTIVE

Erlotinib, Crizotinib, Nivolumab: Big Three in ALCHEMIST Platform

By Caicun Zhou, MD, and Fei Zhou, MD

Adjuvant chemotherapy is the standard of care for patients with resected, early-stage non–small cell lung cancer (NSCLC), including stage II, IIIA, and larger (≥4cm) IB tumors. The survival improvement observed with adjuvant chemotherapy is moderate, with a 5-year 5% absolute benefit. In an effort to break through this dilemma, the ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials) has been initiated to investigate the role of adjuvant erlotinib, crizotinib, and nivolumab based on molecular alterations. Specifically, patients with EGFR and ALK wild-type tumors are randomly assigned to nivolumab 240 mg every 2 weeks for up to 1 year of observation following standard of care.

Actually, the use of targeted tyrosine kinase inhibitor (TKI) therapy in adjuvant therapy of NSCLC is not a new idea.

For instance, trastuzumab for 1 year has

the gold standard in adjuvant setting, where a cure is the goal.

Another undetermined issue regarding adjuvant TKIs is the optimal duration. The planned duration of targeted therapy in all of the adjuvant studies to date and going forward has been 2 years, but no robust evidence supports this hypothesis. Updated survival data have shown that it is safe to prolong exposure to targeted TKIs, continuing treatment for 3 years or more with EGFR or ALKTKIs in advanced NSCLC. We have observed a survival benefit from prolonged delivery of adjuvant imatinib in gastrointestinal stromal tumors (GISTs) and adjuvant tamoxifen in estrogen receptor (ER)-positive breast cancer. It is possible that prolonged exposure to TKIs will result in greater benefits; however, the optimal duration of adjuvant TKIs needs to be further investigated, preferably after showing it is indeed a superior

One concern regarding adjuvant immunotherapy is that micrometastatic lesions may not be immunogenic enough to induce antitumor immunity, in which case anti-PD-1/PD-L1 inhibitors may prove of little use in the adjuvant setting. been established as a standard of care for patients with resected, early-stage HER2positive breast cancer. However, the role of targeted TKI in the adjuvant setting remains insufficiently investigated in NSCLC. Two early randomized clinical trials (RCTs; RADIANT and BR.19) evaluating adjuvant EGFR-TKI in completely resected NSCLC demonstrated no survival benefits in disease-free survival (DFS) or overall survival (OS) when compared with placebo. Notably, participants in these 2 trials were not selected based on EGFR mutations. Intriguingly, a subset analysis of RADIANT showed a trend towards better DFS in favor of erlotinib in patients with EGFR-activating mutations (Hazards ratio [HR], 0.61; 95% confidence interval [CI], 0.384– 0.981; P=0.0391). Subsequent trials have been designed to investigate adjuvant EGFR-TKIs in patients with EGFR mutations, including ALCHEMIST in the US, WJOG6401L in Japan, and ADJUVANT and EVIDENCE in China. We are optimistic that these trials will yield a positive result, at least showing a significant improvement in DFS. However, we have to admit that an OS benefit still remains

choice. But it’s important to note that median treatment duration of EGFR TKI (gefitinib in CTONG trail and erlotinib in Radiant) was only 22 months, suggesting that the toxicities of the TKIs may prevent their prolonged use.

The investigation of immune checkpoint agents inhibiting PD-1/PD-L1 pathways constitutes another strategy in adjuvant therapy. A number of trials are ongoing to evaluate the role of anti-PD-1/PD-L1 antibodies as adjuvant agents in early-stage NSCLC. The planned duration of these agents in most of these trials is 1 year. Recently, the PACIFIC trial demonstrated that a year of treatment with durvalumab, an anti-PD-L1 antibody, could significantly prolong progression-free survival (PFS) compared with placebo (PFS, 16.5 vs. 5.6 months; HR, 0.52; 95% CI, 0.42-0.65; P<0.001) after chemoradiotherapy in unselected stage III NSCLC. The most common grade 3 or 4 adverse event in durvalumab arm was pneumonia, which was similar in incidence to the placebo arm (4.4% vs. 3.8%), suggesting that 1 year of durvalumab was safe even after chemoradiotherapy. Data on anti-PD-1/

Caicun Zhou

PD-L1 antibodies in advanced NSCLC also indicate a manageable safety profiles after 2 years of drug exposure. It is possible that the prolonged delivery of these agents may provide greater benefits. Heterogeneity is one of hallmarks of cancer and it is more pronounced with advanced stages of disease; it is associated with primary or acquired resistance to therapy, including immunotherapy.

Early-stage lung cancer may be a more homogeneous disease, and immunotherapy may prove more effective. One concern regarding adjuvant immunotherapy is that micrometastatic lesions

Fei Zhou

may not be immunogenic enough to induce antitumor immunity, in which case anti-PD-1/PD-L1 inhibitors may prove of little use in the adjuvant setting.

Although debate will continue for a long time, we believe that the ALCHEMIST trial, if successful, will change the standard of care for patients with resected, early-stage NSCLC. More importantly, the ALCHEMIST will provide a broad overview of the genomic landscape of NSCLC in early stage and help us understand the dynamic change of genomic profiles during different stages of this disease. ✦

Barlesi continued from page 7

to those with macroscopic disease and advanced metastatic stage. If so, how can we increase the chance of activating the immune system in those with early-stage NSCLC? Are monotherapies with PD-1/PD-L1 inhibitors sufficient? Are combinations needed?

While chemotherapy is globally equally effective, how will immunotherapy perform in the neoadjuvant setting where tumor is still in place, and analyzable,8 compared to the adjuvant setting where the tumor has been removed and only micrometastatic disease is potentially present? How long should we keep patients on treatment? How long can we keep patients on treatment with acceptable toxicity and adequate compliance? As preclinical data are missing, all these questions have to be empirically answered, and 1 year of adjuvant immunotherapy has been chosen “arbitrarily” in currently recruiting trials.

Hopefully, future research results and IASLC World Conferences on Lung Cancer will provide us with the answers to these pressing questions! ✦

References 1. Wislez M, Barlesi F, Besse B, et al. Customized adjuvant phase II trial in patients with non-smallcell lung cancer: IFCT-0801 TASTE. J Clin Oncol.

2014;32:1256-1261.

2. Wu Y-L, Zhong W, Wang Q, et al. Gefitinib (G) versus vinorelbine+cisplatin (VP) as adjuvant treatment in stage II-IIIA (N1-N2) non-smallcell lung cancer (NSCLC) with EGFR-activating mutation (ADJUVANT): A randomized, phase III trial (CTONG 1104). J Clin. Oncol. 2017; 35:15_suppl (8500-8500).

3. Kelly K, Altorki NK, Eberhardt WEE, et al.

Adjuvant erlotinib versus placebo in patients with stage IB-IIIA non-small-cell lung cancer (RADIANT): A randomized, double-blind, phase III trial. J Clin Oncol. 2015;33(34):4007-4014.

4. Novello S, Grohé C, Michael Geissler M, et al.

Preliminary results of the International Tailored Chemotherapy Adjuvant Trial: The ITACA trial.

J Thorac Oncol. 2015; 10 (suppl 2): ORAL04.03 5. Massuti B, Cobo M, Rodriguez-Paniagua M, et al. SCAT phase III trial: Adjuvant CT based on BRCA-1 levels in NSCLC N+ resected patients.

Final survival results. A Spanish Lung Cancer Group trial. J Thorac Oncol. 2017; 12:11 (supple 2; abstract PL.0204) 6. Jamal-Hanjani M, Wilson GA, McGranahan N, et al. Tracking the evolution of non-small-cell lung cancer. N Engl J Med. 2017; 376(22):2109-2121.

7. Goss GD, O'Callaghan C, Lorimer I,et al. Gefitinib versus placebo in completely resected non-smallcell lung cancer: results of the NCIC CTG BR19 study. J Clin Oncol. 2013; 31:3320-3326.

8. Chaft JE, Forde PM, Smith KN, et al. Neoadjuvant nivolumab in early-stage, resectable non-small cell lung cancers. J Clin Oncol. 2017;35(15 suppl, abstr 8508)

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10

IASLC LUNG CANCER NEWS / DECEMBER 2017

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

Patients with EGFR Mutation Should Postpone Brain Radiation for CNS Metastases: Pro and Con

By Pranshu Mohindra, MD, MBBS, DABR®, Lecia Sequist, MD, and Laurie E. Gaspar, MD, MBA

Pranshu Mohindra

Since the initial approval of erlotinib, an oral tyrosine kinase inhibitor (TKI), for treatment of patients with previously treated locally advanced or metastatic non-small cell lung cancer (NSCLC), multiple additional treatment agents targeting EGFR mutation are now recommended for use in clinical practice.1 Estimated median survival for patients with previously untreated EGFR-mutant EGFRmt (+) NSCLC can extend well beyond 2 years; however, this increase in longevity has been linked with an increased incidence of brain metastases (BM).2,3 While whole-brain radiotherapy (WBRT) was previously considered the standard of practice, the concern for neurocognitive side effects has led

to the decreased use of WBRT in favor of stereotactic radiosurgery (SRS), as supported by phase-III trials that do not demonstrate a detriment in survival.4-6 EGFRmt (+) NSCLC provides a unique therapeutic setting where even with a diagnosis of BM, extended survival may be seen.7 A debate was conducted at the recently concluded 2017 IASLC meeting in Chicago, reviewing the pros and cons of withholding radiation therapy in patients with EGFRmt (+)-NSCLC diagnosed with BM. Key highlights from the debate presented by Dr. Lecia Sequist (Pro) and Dr. Laurie Gaspar (Con) are excerpted below.

Pro: Dr. Lecia Sequist

Con: Dr. Laurie E. Gaspar

1. A multi-institutional retrospective study evaluated upfront radiation (WBRT or SRS) approaches versus upfront EGFR-directed therapy approaches for these patients and showed a significant detriment in overall survival (OS) by delayed use of either of the radiation options.8 However, there are limitations in this experience, with other literature review showing mixed results: • The presence of central nervous system (CNS)-only disease in 76% of the patients likely biased the outcomes in favor of upfront radiation.

• Also, SRS was planned only at intracranial progression, not as planned consolidation of residual disease.

• In a literature review of other institutional experiences, mixed results were observed, with 2 other studies showing survival advantage with use of radiation, 1 study showing survival advantage with TKI alone, and 3 other studies showing no significant differences, although a trend of a 4- to 7-month survival improvement with radiation was noted.

2. All published studies to date used erlotinib- or gefitinib-based therapy, which have demonstrated less CNS penetration compared to newer EGFR TKIs. Outcomes are superior in the osimertinib era.

• AURA 2 study, a phase II study evaluating use of AZD9291 (osimertinib) in EGFR and T790M mutation positive tumors after previous EGFR TKI therapy, demonstrated a 54% overall response rates (ORR) within the brain (2016 World Conference on Lung Cancer, Vienna, Austria).

• The phase I BLOOM study evaluated the use of osimertinib in patients with EGFRmt (+) leptomeningeal disease. Among 21 patients, efficacy assessments confirmed radiological response in 7 and cytological CSF clearance in 2 patients (2016 ASCO Annual Meeting, Chicago, US).

• AURA 3 study demonstrated that the ORR in brain with osimertinib in comparison with chemotherapy in patients with progression after first-line TKI therapy were 70% vs. 31%, p = 0.015 (2017 ASCO Annual Meeting, Chicago, USA). In a follow-up detailed report of this phase 3 study, analysis of 144 patients with T790M-positive advanced NSCLC who develop BM demonstrated a significant improvement in progression-free survival (PFS) favoring osimertinib as against platinum-pemetrexed chemotherapy doublet: 8.5 months vs 4.2 months (HR, 0.32; 95% CI, 0.21 to 0.49).9 • In the FLAURA study comparing osimertinib to standard therapy (erlotinib or gefitinib) in EGFRmt (+) -NSCLC, in patients with BM (n = 116), the median PFS with osimertinib versus standard therapy was 15.2 months vs. 9.6 months (HR, 0.47; 95% CI, 0.30-0.74; P = 0.0009). The rates of CNS progression were 6% versus 15%, respectively (2017 ESMO Congress, Madrid, Spain).

Bottom line: Given the risk of radionecrosis or steroid dependence from SRS or cognitive decline from WBRT, and in light of particularly encouraging outcomes from recent studies evaluating osimertinib in BM, I support use of upfront systemic therapy to offer patients an opportunity for response and thereby delay the risk of side effects from the use of radiation therapy. I also favor consideration of SRS to any significant residual CNS lesions after initial response to TKIs, a sequence and therapeutic strategy employed increasingly at most academic centers, an approach that has not been permitted in most published studies.

1. The prognosis of EGFR+ BM and the time to salvage SRS/ WBRT is not as good as perceived, especially if BM occur while on TKI. • In the Massachusetts General Hospital experience, patients with EGFRmt (+) or ALK translocation who developed BM in the setting of prior TKI therapy had worse OS than those not on TKI prior to the BM diagnosis (median OS 9m vs. 19.6 m, p < 0.001).10 Further, after cranial radiotherapy, EGFR mutation status did not impact OS.10 • In a multi-institutional retrospective database, median OS after diagnosis of BM for EGFRmt patients was 23 months (17 months for TKI treated versus 30 months for TKI-naive patients, p < 0.01). When time-dependent analysis was performed, extended survival associated with EGFRmt (+) NSCLC was only noted in TKI-naive patients relative to those who developed BM while on TKI therapy.11 • Even on the AURA 3 study, despite the 70% ORR, median PFS for patients whose disease had progressed on first-line TKI and develop CNS disease was only 8.5 months.9 • In a phase-II Japanese study using gefitinib in EGFRm-NSCLC with brain metastases, despite a 87.8% ORR, the median time on gefitinib was only 10.6 months with intracranial progression being the most common cause of withdrawal.12 2. While neurocognitive effects following WBRT are well known, there are no comparable data on the neurocognitive effects of TKI. 3. In afatinib-treated patients in the LUX-Lung 3 and LUX-Lung 6 trials, the benefit of afatinib appeared higher in patients with prior WBRT with median PFS in entire cohort ranging from 8.2 to 11 months.13 4. Results reported in the study by Magnuson et al are compelling across all prognostic subpopulations.8 This multi-institutional retrospective study evaluated upfront radiation (WBRT or SRS) approaches versus upfront EGFR-directed therapy approaches for these patients and showed a significant detriment in OS by delaying implementation of either of the radiation options. Key findings are: • Median OS for upfront-SRS, upfront-WBRT and upfront EGFR-TKI, with SRS or WBRT at intracranial progression, were 46, 30, and 25 months, respectively, p < 0.001.

• In both radiation cohorts, 50% of patients were symptomatic at the time WBRT was initiated, compared to only 12% of patients in the EGFR-TKI cohorts.

• Even after controlling for variables that constitute the Disease Specific Graded Prognostic Assessment (DS-GPA) score7 and the EGFRm status, upfront SRS was independently associated with improved OS relative to EGFR-TKI and delayed radiation (adjusted HR, 0.39; 95% CI, 0.26 t 0.58, p < 0.001).

• Prior EGFR-TKI use and EGFR-TKI resistance mutations were exclusions, thereby suggesting the benefit of radiation was even more pronounced in the better prognostic group.

5. The biggest concern is the overall quality of life for patients with BM and the symptoms and sequelae from the metastatic intracranial burden. continued on next page

LUNGCANCERNEWS.ORG / DECEMBER 2017

Audience response: There was a lively discussion followed by an informal vote that (predictably) declared no clear winner. ✦

INFORMED: An Interview with Sean Khozin, MD, MPH The Information Exchange and Data Transformation (INFORMED) initiative was launched by the U.S. Food and Drug Administration (FDA) and the Innovation, Design, Entrepreneurship and Action (IDEA) Lab of the U.S. Department of Health and Human Services. INFORMED is intended to promote the use of big data analytics to analyze the large and disparate clinical evidence now available to researchers and regulators. Sean Khozin, MD, MPH, Acting Associate Director, Oncology Regulatory Science and Informatics at the FDA’s Oncology Center of Excellence and a founder of INFORMED, discussed the details of the initiative for IASLC Lung Cancer News readers.

References 1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Non-Smal Cell Lung Cancer version 9.2017, Natl. Compr. Cancer Network.

(2017). https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf (accessed October 21, 2017).

2. Jackman DM, Miller VA, Cioffredi LA, et al.

Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials.

Clin Cancer Res. 2009; 15:5267-5273.

3. Shin DY, Na II, Kim CH, Park S, Baek H, Yang SH. EGFR mutation and brain metastasis in pulmonary adenocarcinomas. J Thorac Oncol. 2014; 9:195-199.

4. Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: A randomised controlled trial. Lancet Oncol.

2009; 10:1037–1044.

5. Brown PD, Jaeckle K, Ballman KV, et al. Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: A randomized clinical trial. JAMA. 2016; 316:401–409.

6. Brown PD, Ballman KV, Cerhan JH, et al.

Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC•3): A multicentre, randomised, controlled, phase 3 trial.

Lancet Oncol. 2017; 18:1049–1060.

7. Sperduto PW, Yang TJ, Beal K, et al. Estimating survival in patients with lung cancer and brain metastases: An update of the graded prognostic assessment for lung cancer using molecular markers (Lung-molGPA). JAMA Oncol. 2017; 3:827–831.

8. Magnuson WJ, Lester-Coll NH, Wu AJ,et al.

Management of brain metastases in tyrosine kinase inhibitor-naïve epidermal growth factor receptormutant non-small-cell lung cancer: A retrospective multi-institutional analysis. J Clin Oncol. 2017; 35:1070–1077.

9. Mok TS, Wu YL, Ahn MJ, AURA3 Investigators, et al., Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med. 2017; 376:629–640.

10. Mak KS, Gainor JF, NiemierkoA, et al. Significance of targeted therapy and genetic alterations in EGFR, ALK, or KRAS on survival in patients with nonsmall cell lung cancer treated with radiotherapy for brain metastases. Neuro Oncol. 2015; 17:296–302.

11. Sperduto PW, Yang TJ, Beal K, et al. The effect of gene alterations and tyrosine kinase inhibition on survival and cause of death in patients with adenocarcinoma of the lung and brain metastases. Int J Radiat Oncol Biol Phys. 2016; 96:406–413.

12. Iuchi T, Shingyoji M, Sakaida T, et al. Phase II trial of gefitinib alone without radiation therapy for Japanese patients with brain metastases from EGFR-mutant lung adenocarcinoma. Lung Cancer.

2013; 82:282–287.

13. Schuler M, Wu YL, Hirsh V, et al. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases.

J Thorac Oncol. 2016; 11:380–390.

What are the goals of INFORMED? The primary goal of INFORMED is to expand and maintain organizational and technical infrastructure for big data analytics. This is done by functioning as an incubator for conducting collaborative regulatory science research focused on supporting innovations that enhance FDA’s mission of promotion and protection of public health.

Organizationally, INFORMED is serving as a sandbox, where we’ve paired new talent such as entrepreneurs-inresidence, engineers, and data scientists with subject matter experts such as oncologists at the FDA. The synergy we’ve created among groups with complementary skill sets is quite unique and has been very productive. We’re also continuously building and expanding robust technical infrastructure through internal agile software development and pilots with the technology groups, such as Palantir, at the leading edge of big data aggregation and analytics.

How has the development of precision medicine changed the process of drug development in the field of oncology?

As we all know, precision medicine is defined as the right therapy delivered to the right patient at the right time and in the right dose. The idea of precision medicine is driving the healthcare and drug development industry from a population health outlook to a patient-centered approach: holistic and individualized, as opposed to reductionist and generalized. A holistic approach considers a variety of intrinsic (e.g., genomic and proteomic) and extrinsic (e.g., environmental) variables in making drug development and treatment decisions that are tailored to the individual, not an entire population of patients as defined by traditional diagnostic terms and traditional clinical trial designs. For example, in the past decade, we’ve recognized that not all non-small cell lung cancer (NSCLC) patients have the same kind of disease, as we discovered mutations and translocations such as EGFR and ALK that greatly influence response to therapy and outcomes. Some molecular aberrations in NSCLC, such as BRAF and ROS1, occur in less than 2% of patients and when combined with other intrinsic and extrinsic variables, we end up with very small cohorts and in some cases N of 1s.

Developing drugs and delivering care that is precisely tailored to small groups and individual patients requires fundamental changes in how we approach drug discovery, clinical evidence generation, and healthcare delivery. It requires us to capture and analyze big data sets from traditional (e.g., conventional clinical trials) and novel pipelines (e.g., realworld data and biometric sensors), using new study designs to better understand the patient’s experience in the context

of a sustainable framework for precision delivery of therapies and healthcare services.

What types of organizations and researchers participate in INFORMED? As an incubator, INFORMED conducts collaborative research with innovators Sean Khozin in professional organizations, academia, nonprofits, and industry. For example, in the domain of real-world evidence generation, we have research collaborations with the American Society of Clinical Oncology’s CancerLinQ and a start-up called Flatiron Health. In the area of data sharing, we’re collaborating with a nonprofit called Project Data Sphere on open access data. We are also developing a framework for decentralized sharing of data at scale with IBM Watson Health based on blockchain, which allows users to access and add to a secure, shared ledger or spreadsheet of data. We’re also working with data science experts at MIT and Stanford on innovations based on artificial intelligence and algorithmic analytics that can help the drug development and the life sciences communities.

What is “systems thinking” and why is it emphasized in the INFORMED initiative?

Systems thinking is a prerequisite for enabling precision medicine and, as a theoretical foundation, can be an optimal framework for making regulatory decisions. Traditional sciences are largely siloed into specific disciplines and not organically designed as multidisciplinary units. Progress in traditional sciences is characterized by intense specialization into specific disciplinary boundaries. In contrast, regulatory science, which is what INFORMED is all about, takes a systems science view of the world, where the focus is on networks and relationships, and where progress is best characterized by becoming more inclusive and holistic, as opposed to being specialized into narrowly defined fields.

By quantifying networks and interconnected relationships, from the molecular level (e.g., systems biology) to the macro scale (e.g., market dynamics), systems thinking can allow for objective and data-driven regulatory decision-making in order to have the greatest positive impact on public health.

What should clinicians know about the INFORMED project?

INFORMED is a translational incubator at the intersection of data science, health tech, and the life sciences. The aim, however, is not technology for the sake of technology: we use advanced tools and methods to help diffuse innovations into the point of care by catalyzing the development and adoption of precision tools and therapeutics. Our systems view of the ecosystem is not about the system itself, but about enabling appropriate treatment decisions locally, where care is delivered. Therefore, empowering physicians and other healthcare providers is one of the focal points of our efforts, and we welcome and depend on their continued input and participation as the pillars of the healthcare delivery system. ✦

CORNER

Bottom line: The argument for upfront radiation is especially strong for SRS, as opposed to WBRT, so why wait and let a BM get larger or more symptomatic, and not be amenable to SRS? At the University of Colorado, these patients are given upfront SRS if possible, and then proceed to TKI. If SRS is not thought to be reasonable, then the TKI is started and SRS or WBRT is deferred until progression.

11

For prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of chemotherapy

The first and only 5-HT3 and NK1 combination agent approved for both acute and delayed CINV 1,2

CINV=chemotherapy-induced nausea and vomiting.

Indication AKYNZEO is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. AKYNZEO is an oral fixed combination of palonosetron and netupitant: palonosetron prevents nausea and vomiting during the acute phase and netupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy.

Important Safety Information Warnings and Precautions • Hypersensitivity reactions, including anaphylaxis, have been reported with or without known hypersensitivity to other 5-HT3 receptor antagonists • Serotonin syndrome has been reported with 5-HT3 receptor antagonists alone but particularly with concomitant use of serotonergic drugs. Serotonin syndrome can be life threatening. Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes, autonomic instability, neuromuscular symptoms, seizures, and gastrointestinal symptoms. Patients should be monitored for the emergence of serotonin syndrome, and if symptoms occur, discontinue AKYNZEO and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if AKYNZEO is used concomitantly with other serotonergic drugs Adverse Reactions • Most common adverse reactions: headache, asthenia, dyspepsia, fatigue, constipation and erythema Drug Interactions • Use with caution in patients receiving concomitant medications primarily metabolized by CYP3A4. The plasma concentrations of CYP3A4 substrates can increase when co-administered with AKYNZEO. The inhibitory effect on CYP3A4 can last for multiple days — Dexamethasone doses should be reduced when given with AKYNZEO. A two-fold increase in the systemic exposure of dexamethasone was observed 4 days after single dose of netupitant — Consider the potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) when administering with AKYNZEO. When administered with netupitant, the systemic exposure to midazolam was significantly increased • Avoid concomitant use of AKYNZEO in patients on chronic use of a strong CYP3A4 inducer such as rifampin as this may decrease the efficacy of AKYNZEO

Exceptional power

Exceptional results

Complete response (no emesis and no use of rescue medication) for 5 days across both acute and delayed CINV1

Complete response (no emesis and no use of rescue medication) in acute and delayed CINV1 100

90

%

50

P=.003

AKYNZEO® arm (n=135)

77%

Percentage of Patients

Percentage of Patients

100

99%

90%

90% P=.032

80%

Palonosetron arm (n=136)

AKYNZEO arm (n=135)

Palonosetron arm (n=136)

P=.002

50

Palonosetron arm (n=136)

AKYNZEO arm (n=135)

0

0

Overall Phase

Acute*

Delayed*

(0-120 hours)

(0-24 hours)

(25-120 hours)

*Secondary endpoint. Adjusted P-values for multiple comparisons using Cochran-MantelHaenszel test, stratified by gender.

Study designed with patients receiving cisplatin-based chemotherapy1,3

99% of patients receiving cisplatin experienced complete response during the acute phase with AKYNZEO1

Multicenter, randomized, double-blind, double-dummy, parallel-group study.1,3 • Primary endpoint: complete response in overall phase (0-120 hours)1 • Patients received cisplatin (≥50 mg/m2 either alone or in combination with other chemotherpy agents)3 — Median cisplatin dose: 75 mg/m2 for each group1 • Patients treated with AKYNZEO primarily had a diagnosis of lung/respiratory cancer (25.9%), head and neck cancer (24.4)%, or ovarian cancer (17.8%)3 • Dosing Schedule1,3: — AKYNZEO arm: Day 1: AKYNZEO and oral dexamethasone 12 mg. Days 2-4: Oral dexamethasone 8 mg once a day — Palonosetron arm: Day 1: Oral palonosetron 0.5 mg and oral dexamethasone 20 mg. Days 2-4: Oral dexamethasone 8 mg twice a day

For more information about optimizing CINV management of your patients, please visit us at AKYNZEO.com

Important Safety Information Use in Specific Populations • Avoid use of AKYNZEO in patients with severe hepatic impairment, severe renal impairment, or end-stage renal disease

Please see brief summary of Full Prescribing Information on the following page.

To report SUSPECTED ADVERSE REACTIONS, contact Helsinn at 1-855-541-3498 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

References: 1. AKYNZEO (netupitant/palonosetron) capsules. Full Prescribing Information. 2. Cada DJ, Leonard J, Baker DE. Formulary drug reviews: netupitant/palonosetron. Hosp Pharm. 2015;50(4):310-325. 3. Hesketh P, Rossi G, Rizzi G, et al.

Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic: a randomized dose-ranging pivotal study. Ann Oncol. 2014;25(7):1340-1346.

AKYNZEO® is a registered trademark of Helsinn Healthcare SA, Switzerland, distributed and marketed by Helsinn Therapeutics (U.S.), Inc. under license. © 2017 Helsinn Therapeutics (U.S.), Inc. All rights reserved. V-AKYN-US-0021 05/2017

AKYNZEO® (netupitant and palonosetron) capsules, for oral use BRIEF SUMMARY OF PRESCRIBING INFORMATION DOSAGE AND ADMINISTRATION Highly Emetogenic Chemotherapy, including Cisplatin Based Chemotherapy The recommended dosage in adults is one capsule of AKYNZEO administered approximately 1 hour prior to the start of chemotherapy with dexamethasone 12 mg administered orally 30 minutes prior to chemotherapy on day 1 and 8 mg orally once daily on days 2 to 4.

Anthracyclines and Cyclophosphamide Based Chemotherapy and Chemotherapy Not Considered Highly Emetogenic The recommended dosage in adults is one capsule of AKYNZEO approximately 1 hour prior to the start of chemotherapy with dexamethasone 12 mg administered orally 30 minutes prior to chemotherapy on day 1. Administration of dexamethasone on days 2 to 4 is not necessary.

AKYNZEO can be taken with or without food.

WARNINGS AND PRECAUTIONS Hypersensitivity: Hypersensitivity reactions, including anaphylaxis, have been reported with or without known hypersensitivity to other 5-HT3 receptor antagonists.

Serotonin Syndrome: The development of serotonin syndrome has been reported with 5-HT3 receptor antagonists.

Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue). Some of the reported cases were fatal. Serotonin syndrome occurring with overdose of another 5-HT3 receptor antagonist alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT3 receptor antagonist use occurred in a post-anesthesia care unit or an infusion center.

Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of AKYNZEO and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue AKYNZEO and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if AKYNZEO is used concomitantly with other serotonergic drugs.

ADVERSE REACTIONS 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 overall safety of AKYNZEO was evaluated in 1538 cancer patients and healthy volunteers in clinical trials. The data described below reflect exposure to AKYNZEO in 1169 cancer patients, receiving at least one cycle of cancer chemotherapy in 3 active-controlled trials, including 782 exposed to AKYNZEO for at least 4 cycles and 321 exposed for at least 6 cycles, up to a maximum of 12 cycles of chemotherapy. The median age was 55, 79% were female, 83% were White, 13% were Asian, and 4% were Hispanic. All patients received a single oral dose of AKYNZEO 1 hour prior to the start of each chemotherapy cycle. In all studies, dexamethasone was co-administered with AKYNZEO. Cisplatin Based Highly Emetogenic Chemotherapy: In a single-cycle study of patients receiving cisplatin-based highly emetogenic chemotherapy, 136 patients were treated with AKYNZEO. Table 1 shows adverse reactions defined as adverse events reported at an incidence of at least 3% and for which the AKYNZEO rate exceeded palonosetron alone.

Table 1: Adverse Reactions Occurring in ≥3% of Cancer Patients Receiving AKYNZEO and Cisplatin Based Highly Emetogenic Chemotherapy (Cycle 1) Adverse Reactions Dyspepsia Fatigue Constipation Erythema

AKYNZEO Palonosetron 0.5 mg netupitant 300 mg/ palonosetron 0.5 mg (N=136) (N=136) 4% 2% 4% 2% 3% 1% 3% 2%

Anthracyclines and Cyclophosphamide Based Chemotherapy: In a study of patients receiving anthracycline and cyclophosphamide based chemotherapy, 725 patients were treated with AKYNZEO during Cycle 1, and 635 of these patients continued for up to 8 cycles in a multiple-cycle extension. Table 2 shows adverse reactions defined as adverse events reported at an incidence of at least 3% and for which the AKYNZEO rate exceeded palonosetron alone during Cycle 1. The adverse reaction profile in subsequent cycles was similar to that observed in Cycle 1.

Table 2: Adverse Reactions Occurring in ≥3% of Cancer Patients Receiving AKYNZEO and Anthracyclines and Cyclophosphamide Based Chemotherapy (Cycle 1) Adverse Reactions Headache Asthenia Fatigue

AKYNZEO netupitant 300 mg/ palonosetron 0.5 mg (N=725)

Palonosetron 0.5 mg (N=725)

9% 8% 7%

7% 7% 5%

In addition to the adverse reactions shown above, there were reports of concomitant elevations of transaminases > 3 x ULN and total bilirubin in both arms of the two trials that compared AKYNZEO to oral palonosetron, and the frequency of these elevations was comparable between treatment groups. See Table 3.

Table 3: Liver Function Laboratory Abnormalities Laboratory Changes AST > 3 x ULN and/or ALT > 3 x ULN with Total Bilirubin > ULN AST > 10 x ULN and/or ALT > 10 x ULN with Total Bilirubin > ULN AST > 3 x ULN and/or ALT > 3 x ULN with Total Bilirubin ≥ 2 x ULN

AKYNZEO Palonosetron 0.5 mg netupitant 300 mg/palonosetron 0.5 mg (N=861) (N=861) 3 (0.3%)

5 (0.6%)

−

2 (0.2%)

1 (0.1%)

1 (0.1%)

In a multi-cycle safety study of 412 patients, the safety profile of AKYNZEO (n = 308) was comparable to aprepitant and palonosetron (n = 104) in patients undergoing initial and repeat cycles (median 5 cycles, range of 1-14 cycles) of chemotherapy, including carboplatin, cisplatin, oxaliplatin, and doxorubicin regimens. There were no reports of concomitant elevations of transaminases > 3 x ULN and total bilirubin in this study in either arm.

In a randomized, clinical non-inferiority study, that compared oral palonosetron 0.5 mg to intravenous palonosetron 0.25 mg in cancer patients scheduled to receive highly emetogenic cisplatin (≥70 mg/m2) based chemotherapy, there were two patients (0.5%; 2/369) in the intravenous palonosetron arm who had concomitant elevations of transaminases and total bilirubin. Neither experienced transaminase elevations of > 10 x ULN. DRUG INTERACTIONS Effects of AKYNZEO on other drugs Interaction with CYP3A4 substrates: Netupitant, a component of AKYNZEO is a moderate inhibitor of CYP3A4.

AKYNZEO should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. The plasma concentrations of CYP3A4 substrates can increase when co-administered with AKYNZEO. The inhibitory effect on CYP3A4 can last for multiple days.

Dexamethasone: A two-fold increase in the systemic exposure of dexamethasone was observed 4 days after single dose of netupitant. The duration of the effect was not studied beyond 4 days. Administer a reduced dose of dexamethasone with AKYNZEO.

Midazolam: When administered with netupitant, the systemic exposure to midazolam was significantly increased.

Consider the potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) when administering these drugs with AKYNZEO. Interaction with chemotherapeutic agents: The systemic exposure of chemotherapy agents metabolized by CYP3A4 can increase when administered with AKYNZEO. Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, cyclophosphamide, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. Caution and monitoring for chemotherapeutic related adverse reactions are advised in patients receiving chemotherapy agents metabolized primarily by CYP3A4.

Interaction with oral contraceptives: Clinically significant effect of AKYNZEO on the efficacy of the oral contraceptive containing levonorgestrel and ethinyl estradiol is unlikely.

Effects of other drugs on AKYNZEO Netupitant, a component of AKYNZEO is mainly metabolized by CYP3A4.

In vitro metabolism studies have suggested that CYP2D6 and to a lesser extent, CYP3A4 and CYP1A2 are involved in the metabolism of palonosetron.

CYP3A4 Inducers: Avoid concomitant use of AKYNZEO in patients who are chronically using a strong CYP3A4 inducer such as rifampin. A strong CYP3A inducer can decrease the efficacy of AKYNZEO by substantially reducing plasma concentrations of the netupitant component.

CYP3A4 Inhibitors: Concomitant use of AKYNZEO with a strong CYP3A4 inhibitor (e.g., ketoconazole) can significantly increase the systemic exposure to the netupitant component of AKYNZEO. However, no dosage adjustment is necessary for single dose administration of AKYNZEO. Serotonergic Drugs: Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary: Adequate and well-controlled studies with AKYNZEO have not been conducted in pregnant women. In animal reproduction studies, no effects on embryo-fetal development were observed following daily administration of netupitant in pregnant rats during the period of organogenesis at doses up to 3.7 times the human AUC (area under the plasma concentration-time curve) at the recommended single human dose to be given with each cycle of chemotherapy.

However, a dose-dependent increase in adverse effects on embryo-fetal development was observed following daily administration of netupitant in pregnant rabbits during the period of organogenesis with doses at least 0.2 times the human AUC at the recommended single human dose to be given with each cycle of chemotherapy. Daily administration of netupitant in rats up to 3.7 times the human AUC at the recommended human dose during organogenesis through lactation produced no adverse effects in the offspring. In animal reproduction studies with palonosetron, no effects on embryo-fetal development were observed following oral administration during the period of organogenesis at doses up to 921 and 1841 times the recommended human oral dose in rats and rabbits, respectively. AKYNZEO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data: Daily administration of up to 30 mg/kg netupitant in rats (3.7 times the human AUC at the recommended single human dose to be given with each cycle of chemotherapy) during the period of organogenesis produced no effects on embryo-fetal development. However, an increased incidence of external and skeletal abnormalities in rabbit fetuses was observed following daily administration of netupitant in rabbits at 10 mg/kg/day and higher (0.2 times the human AUC at the recommended single human dose to be given with each cycle of chemotherapy) during the period of organogenesis. These abnormalities included positional abnormalities in the limbs and paws, and fused sternebrae.

Reduction in fetal rabbit weight occurred at 30 mg/kg/day. Maternal toxicity in rabbits (i.e. loss of bodyweight during the treatment period) was also observed at 30 mg/kg/day. Daily administration of up to 30 mg/kg netupitant (3.7 times the human AUC at the recommended human dose) in rats during organogenesis through lactation produced no adverse effects in the offspring.

In animal reproduction studies with palonosetron, no effects on embryo-fetal development were observed in pregnant rats given oral doses up to 60 mg/kg/day (921 times the recommended human oral dose based on body surface area) or pregnant rabbits given oral doses up to 60 mg/kg/day (1841 times the recommended human oral dose based on body surface area) during the period of organogenesis.

Nursing Mothers: It is not known whether AKYNZEO is present in human milk. Because many drugs are present in human milk and because of the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness in patients below the age of 18 years have not been established.

Geriatric Use: Of the 1169 adult cancer patients treated with AKYNZEO in clinical studies, 18% were aged 65 and over, while 2% were aged 75 years and over. The nature and frequency of adverse reactions were similar in elderly and younger patients. Exploratory analyses of the impact of age on efficacy were performed in the two trials that compared AKYNZEO to palonosetron. In Study 1 in patients treated with cisplatin chemotherapy, among the patients less than age 65 years, 115 were treated with AKYNZEO and 116 were treated with palonosetron alone. Among the patients 65 years or older, 20 were treated with AKYNZEO and 20 were treated with palonosetron alone. The difference in Complete Response (CR) rates between AKYNZEO and palonosetron alone was similar between the two age groups in both the acute and delayed phases. In Study 2 in patients treated with anthracyclines plus cyclophosphamide chemotherapy, among the patients less than age 65 years, 608 were treated with AKYNZEO and 602 were treated with palonosetron alone. Among the patients 65 years or older, 116 were treated with AKYNZEO and 123 were treated with palonosetron alone. The difference in CR rates between AKYNZEO and palonosetron alone (4% in <65 years and 2% in ≥65 years) was similar between the two age groups in the acute phase. In the delayed phase, the difference in CR rates between AKYNZEO and palonosetron alone (9% in <65 years and 1% in ≥ 65 years) was numerically higher in patients <65 years. This difference between age groups in the delayed phase of Study 2 may be explained, in part, by higher CR in the delayed phase associated with palonosetron alone in the older age group (81%) relative to the younger patients treated with palonosetron alone (67%).

In general, use caution when dosing elderly patients as they have a greater frequency of decreased hepatic, renal or cardiac function and concomitant disease or other drug therapy.

Hepatic Impairment: No dosage adjustment for AKYNZEO is necessary for patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 8). Limited data are available with AKYNZEO in patients with severe hepatic impairment (Child-Pugh score >9)/ Avoid use of AKYNZEO in patients with severe hepatic impairment.

Renal Impairment: No dosage adjustment for AKYNZEO is necessary in patients with mild to moderate renal impairment. The pharmacokinetics and safety of netupitant has not been studied in patients with severe renal impairment, although severe renal impairment did not substantially affect pharmacokinetics of palonosetron. The pharmacokinetics for netupitant and palonosetron was not studied in patients with end-stage renal disease requiring hemodialysis.

OVERDOSAGE: No specific information is available on the treatment of overdosage with AKYNZEO. In the event of overdose, AKYNZEO should be discontinued and general supportive treatment and monitoring should be provided.

Because of the antiemetic activity of AKYNZEO, drug-induced emesis may not be effective. Dialysis studies have not been performed; due to the large volume of distribution, dialysis is unlikely to be an effective treatment for AKYNZEO overdose.

A total of 33 adult cancer patients were administered oral palonosetron at a dose of 90 μg/kg (equivalent to 6 mg fixed dose), as part of a dose ranging study. This is approximately 12 times the recommended oral dose of 0.5 mg palonosetron. This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed. The highest dose of netupitant administered to 1169 cancer patients was 300 mg. The highest dose of netupitant administered to 49 healthy subjects was 600 mg. A similar incidence of adverse events was observed when compared to lower doses of netupitant in the respective populations of cancer patients and healthy subjects.

Jointly manufactured by Catalent Pharma Solutions, Somerset, NJ and Helsinn Birex Pharmaceuticals, Dublin, Ireland for Helsinn Healthcare SA, Switzerland

AKYNZEO® is a registered trademark of Helsinn Healthcare, SA, Lugano, Switzerland, used under license.

AKYNZEO® is a registered trademark of Helsinn Healthcare, SA, Lugano, Switzerland, used under license.

Distributedand andmarketed marketed Helsinn Therapeutics (U.S.), Healthcare Inc. Distributed by by Eisai Inc., under license of Helsinn SA, Switzerland. © 2016 rightsreserved. reserved.NEPA0004 AKYN-US0363 © 2014 All All rights 10/14 9/16

LUNGCANCERNEWS.ORG / DECEMBER 2017

15

MEETING NEWS HIGHLIGHTS

IASLC 2017 Chicago Multidisciplinary Symposium in Thoracic Oncology

By Jyoti Patel, MD, and Heather A. Wakelee, MD

Specific presentations of note and impact included: Treatment disparities: Dr. Paul Walker presented results of an intervention to reduce black-white treatment disparities in early-stage NSCLC, which demonstrated significant impact of cancer care navigation.

Screening: Dr. Alexander Carlson discussed the attrition rate in community-based lung cancer screening in a “real-world” view of screening practices.

Basic science/mesothelioma: Dr. Michele Carbone provided an overview of the role of BAPI in modulating the gene-environment interaction in development of mesothelioma.

Pulmonary medicine: Dr. Lyssa Friedman presented study results that analyzed blood-based markers as an aid in the identification of malignant versus benign pulmonary nodules.

Radiation oncology: Dr. Matthew Farrell discussed novel radiation dose and fractionation data that highlight practice patterns in the US for management of limited stage small cell lung cancer.

Non-small cell lung cancer: Dr. Leora Horn presented data on ensartinib given after second-generation ALK therapy, which showed significant activity in a pretreated population. Dr. Shahid Ahmed provided an overview of pneumonitis predictors associated with pembrolizumab.

The IASLC Chicago Multidisciplinary Symposium in Thoracic Oncology is a dynamic meeting with a long tradition and will continue to be held annually, except in years like 2018 when the IASLC World Conference on Lung Cancer (WCLC) is held in North America. The conference is a fabulous opportunity to network across disciplines with other people with careers focused on thoracic malignancies and learn about the latest developments in prevention, detection and care with novel data presentations.✦

Discussing ALCHEMIST with Shakun Malik, MD Patients with completely resected early-stage non-small cell lung cancer (NSCLC) have approximately a 50% chance of experiencing disease recurrence following standard treatment. In 2014, the NCI initiated a group of randomized clinical trials, called the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials (ALCHEMIST), to test adjuvant treatments to prevent cancer recurrence in patients with early-stage NSCLC. At the time of its launch, Shakun Malik, MD, Head of Thoracic Cancer Therapeutics, Cancer Therapy Evaluation Program, Division of Cancer Treatment & Diagnosis at the NCI, described the Institute’s aspirations in a statement saying, “We believe that the findings from ALCHEMIST will not only help answer an important question about the addition of targeted therapies in earlier stage disease but will also help us in understanding the prevalence and natural history of these genomic changes in earlier stage lung cancer.”1 In terms of overall screening, ALCHEMIST has been a major undertaking. The ultimate goal is to test the tumor tissue of between 6,000 and 8,000 resected patients.

“Although we are slower than anticipated in accruing patients, we are steadily screening about 100 patients per month,” said Dr. Malik in a recent discussion with IASLC Lung Cancer News.

Tumor tissue from patients with nonsquamous NSCLC who participate in ALCHEMIST are first screened for genomic EGFR mutations and ALK translocations. Individuals with EGFR-driven NSCLC are offered enrollment in a trial testing the EGFR inhibitor erlotinib (A081105), and those whose tumors have ALK rearrangements are offered enrollment in a trial of crizotinib (E4512). Patients whose tumors have neither EGFR or ALK abnormalities or whose tumors have squamous histology—a group comprising about 80% of all enrolled patients—are eligible for enrollment in the ALCHEMISTImmunotherapy trial (EA5142; ANVIL).

Patients enrolled in the immunotherapy study are randomized to receive 240 mg of nivolumab intravenously every 2 weeks or to observation. Nivolumab is an immune checkpoint pathway inhibitor that binds the programmed cell death-1 receptor (PD-1) and prevents its activation via the ligand PD-L1, and it is currently approved by the FDA for use in individuals with metastatic NSCLC whose disease has progressed on or after chemotherapy. This drug has demonstrated benefits in those patients with metastatic NSCLC tumors without EGFR or ALK abnormalities,

and therefore is offered in ALCHEMIST as an adjuvant treatment for patients whose tumors do not have EGFR or ALK abnormalities.

The participants in the immunotherapy trial will receive treatment for up to 1 year, as opposed to patients in the EGFR and ALK trials who currently receive treatment for up to 2 years. Dr. Shakun Malik Malik explained this discrepancy in protocols, saying that, “There are no data at this time of the optimal duration of these therapies. Since immunotherapies work even after patient has stopped receiving them and are given intravenously, most of the trials are designed for them to be stopped after 1 year, and ALCHEMIST is following the same rationale.”

The ALCHEMIST immunotherapy trial also employs central immunohistochemical testing for the presence of the immune checkpoint protein PD-L1 in tumor samples.

Unlike the presence or absence of EGFR and ALK abnormalities, the presence or absence of PD-L1 expression is used for data stratification only, not to determine eligibility. Dr. Malik noted that this is because “the data thus far does not support the conclusion that patients with low levels of immune checkpoint proteins do not clinically benefit from immunotherapies.”

In addition to specific mutations present in tissue, the designers of ALCHEMIST also intend to provide more complete and detailed genomic data in the context of NSCLC. Dr. Malik noted that, “In addition to tumor tissue, we have also collected patients’ blood samples in order to conduct studies of the clinical significance of circulating tumor-free DNA (cfDNA) at a later time,” with respect to overall survival and disease-free survival as well as evaluating the concordance of cfDNA with tumor tissue-based biomarkers. ✦

References 1. NIH announces the launch of 3 integrated precision medicine trials [news release]. Bethesda, MD: National Cancer Institute Press Office; August 18, 2014. https://www.cancer.gov/news-events/press-releases/2014/ ALCHEMISTlaunch. Accessed October 25, 2017.

CORNER

The IASLC 2017 Chicago Multidisciplinary Symposium in Thoracic Oncology was held September 14-16, 2017 and brought together nearly 400 participants to discuss important topics in lung cancer prevention, detection, and care.

The multidisciplinary nature of the meeting was most apparent in the initial session, which included talks on tobacco control, barriers to screening, updates in pulmonary medicine, pathology perspective on sample utilization, “liquid biopsies,” access to care and health disparities and a trimodality discussion on oligmetastatic disease. Key controversies in immunotherapy were highlighted in the keynote addresses. The patient perspective was highlighted in a dynamic talk by Janet Freeman-Daly.

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IASLC LUNG CANCER NEWS / DECEMBER 2017

WCLC Presidential Symposium continued from page 1

#! $

#! $

Figure 1. Changes from Baseline Between Groups: Function and Global Health Status

radiation without disease progression to durvalumab (476 patients) or placebo (237 patients) for up to 12 months. Key symptoms, physical function, and global health status/quality of life were assessed using the EORTC QLQ-C30 v3 questionnaire and its lung cancer module, QLQLC13. Changes from baseline were analyzed using a mixed model for repeated measures.

Dr. Hui reported that compliance for questionnaire completion was above 80% in both groups and there were no between-group differences at baseline for key symptoms, physical function, or global health status/quality of life. She stated that treatment with durvalumab after concurrent chemoradiation therapy did not worsen symptoms, function, or global health status/quality of life for patients with locally advanced, unresectable NSCLC. Similarly, she noted that the change from baseline for key symptoms was minimal with both durvalumab and placebo (change in score from baseline <Âą10). â&#x20AC;&#x153;Combined with the efficacy and safety findings from PACIFIC, these data further support the use of durvalumab in this disease setting,â&#x20AC;? concluded Dr. Hui. Discussant Michael Boyer, MBBS, PhD, Sydney Cancer Centre, Sydney, Australia, commented that measuring patient-reported outcomes is a vital component of clinical trials such as PACIFIC to ensure that a survival improvement is not outweighed by a Michael Boyer negative impact on quality of life.

Mature Survival Results in a Spanish Lung Cancer Group Trial Bartomeu Massuti, MD, Alicante University Hospital, Alicante, Spain, presented the mature survival results

nation of fewer than 3 N1 or N2 nodes; less than lobe-specific systematic lymph node dissection; extracapsular invasion of N2 nodes; positive highest lymph node station; carcinoma in situ at bronchial resection margin; and positive pleural lavage cytology. Revised categories of R0, R(un), R1, and R2 were designated and tested for survival impact.

Dr. Edwards reported that 56% of cases became R(un) after recoding. The majority of cases were R(un) due to

intraoperative staging that proved less

rigorous than systematic lymph node ! "& %' ! dissection. He noted that in pN2 cases with the highest station positive, median survival was 14 months less compared with highest station-negative cases. In Dallas, US, remarked that relatively few node-positive cases, median survival DNA repair-driven clinical trials have was 20 months less for those with R(un) examined the role of BRCA1 in lung status compared with R0. cancer, as Dr. Massuti and colleagues Dr. Edwards stated that these have done. She noted that, although results show that the IASLC Proposed SCAT was negative for its primary end- Definition for Complete Resection has point of survival in the experimental relevance, according to the 8th Edition arm compared with the control arm, Database. High-quality surgical staging, it does provide evidence that patients he indicated, gives the most accurate with high BRCA1 expression levels have assignment of stage group and the most a worse prognosis and that BRCA1 status favorable survival data, stage by stage. may serve well as a stratification factor in Likewise, optimal staging data enable future trials. In addition, BRCA1 expres- the most appropriate decision-making sion might be even more important in for routine adjuvant therapy. determining the role of taxanes rather â&#x20AC;&#x153;In designing and analyzing clinical than platinating agents. trials of adjuvant therapies, undertaking a thorough evaluation and characterizaIASLC Lung Cancer Staging Project: tion of R status is critical,â&#x20AC;? concluded Dr. Analysis of Resection Margin Edwards. â&#x20AC;&#x153;Further detailed data collecStatus and Proposals for R Status tion will be necessary to see the full Descriptors impact of R status subcategories in a The residual tumor (R) classification, clinical setting, and we urge institutions which describes tumor status after sur- to participate in the IASLC Lung Cancer gery, reflects the effectiveness of treat- Staging Project. Our confirmation of the ment, has prognostic impact, and may IASLCâ&#x20AC;&#x2122;s proposed criteria is an imporaffect further treatment. John Edwards, tant step in promoting high-quality MD, University of Sheffield, Sheffield, intraoperative staging and detailed pathologic assessment.â&#x20AC;?

Discussa nt Kemp In designing and analyzing clinical trials Kemstine, MD, PhD, of adjuvant therapies, undertaking a University of Texasthorough evaluation and characterization Southwestern Medical of R status is critical. â&#x20AC;&#x201D;John Edwards, MD Center, Dallas, US, noted that these data United Kingdom, reported on the efforts confi rm that R(un) is problematic, as of the IASLC R Domain Subcommittee half of the cases had an uncertain comto analyze existing and potential R status plete resection and in this group survival criteria, including the 2005 proposed was poor, although better than R1 and IASLC definition for â&#x20AC;&#x153;uncertainâ&#x20AC;? resec- R2. He remarked that in the database of tion margin status using data collected 94,708 patients, only 15.5% of patients for the IASLC Lung Cancer Staging had sufficient information for analysis.

Project. Dr. Edwards reported the results In the future, it would be important to based on 14,712 patients undergoing sur- determine what components or comgery for NCSLC for whom full R status binations of components in the IASLC and survival data were available. database are problematic. â&#x153;Ś Dr. Edwards and colleagues reviewed data and reassigned cases to the uncer- Editorâ&#x20AC;&#x2122;s Note: This article is modified tain category [R(un)] if any of the fol- and reprinted from IASLC WCLC 2017 lowing parameters were present: exami- Daily News.

of SCAT, a randomized phase III multicenter trial that examined whether it might be possible to customize adjuvant chemotherapy based on BRCA1 expression in patients with resected node-positive NSCLC. Dr. Massuti explained that BRCA1 and BRCA2 are important DNA repair factors primarily involved in the repair of double-strand DNA breaks.

BRCA1 efficiency has been found to enhance resistance to cisplatin, whereas loss of BRCA1 function is associated with sensitivity to DNA-damaging chemotherapy. SCAT investigators hypothesized that a significant proportion of patients with high BRCA1 expression would be cisplatin-resistant and would benefit from single-agent docetaxel.

A total of 500 patients were randomly assigned to the control (108 patients) or experimental arm (392 patients). Patients in the control arm received docetaxel plus cisplatin. In the experimental arm, 110 patients with low BRCA1 expression levels received cisplatin and gemcitabine, 127 patients with intermediate levels received cisplatin and docetaxel, and 110 patients with high levels received docetaxel alone. Overall survival was the primary endpoint.

Dr. Massuti reported that customization of adjuvant chemotherapy according to BRCA1 levels did not yield significant differences in overall survival for the overall population in node-positive resected NSCLC. In the subgroup with low BRCA1 levels, experimental treatment with cisplatin/gemcitabine proved superior to the control group (74 months vs. 40.1 months). In addition, survival for the subgroup with high BRCA1 expression levels receiving treatment without platinum was similar to that for the control group. Dr. Massuti noted that higher BRCA1 expression levels were associated with male sex, squamous histology, and current or former smoking status.

Discussant Joan Schiller, University of Texas-Southwestern Medical Center,

â&#x20AC;&#x153;

â&#x20AC;?

LUNGCANCERNEWS.ORG / DECEMBER 2017

17

SUPPORTIVE CARE

Cannabis, Lung Cancer, and Therapy

By Emily Stone, MBBS, MMed, FRACP, and James Jett, MD

Cannabis, a generic term for various products derived from the plant cannabis sativa, has a long history of both medicinal and recreational use. Current pressure for the regulation of cannabis use1 highlights the need for clinicians working in the areas of lung cancer and pulmonary medicine to better understand its origins, forms, modes of consumption, benefits, and risks.

Background The term marijuana may be used interchangeably with the term cannabis, but marijuana generally refers to parts of the cannabis plant that have high levels of tetrahydrocannabinol (THC), whereas the term cannabis encompasses organic products, including cannabidiol (CBD) and other cannabinoids, marijuana, and hemp (cannabis plants that contain very low levels of THC).2 There are a number of cannabinoid derivatives, but the most familiar effects (euphoria and relaxation) are associated predominantly with THC. When consumed, cannabis is associated with several effects, some potentially appealing and some unsafe.

Various Forms, Origins, and Potency of Cannabis Products derived from cannabis include buds (dried cannabis flowers), resin, and oil. Cannabis products can be smoked or inhaled, ingested, or absorbed topically. The onset of action of cannabis differs depending on the mode of intake: rapid effects can be seen with smoked or vaporized cannabis (within 30 sec-

onds). The onset of psychotropic effects may be slower with ingestion (between 30 minutes and 2 hours after consumption).2 The potency of cannabis refers to the level of THC it contains. The level of THC has increased over recent years.3 The average THC level in cannabis in the United States increased from 4% in the mid-1990s to 12% by 2012. There has also been a rise in the production of sinsemilla, a high-potency strain of cannabis that is grown from clones, rather than from seeds.2

Cannabis and Lung Cancer The evidence assessing the link between the smoking of cannabis and lung cancer is limited. The best evidence comes from the pooling of studies. Zhang et al. pooled data from 6 studies in 4 countries and found no convincing association between cannabis smoking and the incidence of lung cancer.4 Limitations of this analysis include potential bias from self-reporting for both cannabis and tobacco use, imputed values for missing data on education level and tobacco smoking, the unknown variations in cannabis dose related to differences between cannabis plants, differences in processing and inhalation techniques, and the small numbers of heavy cannabis smokers.

Huang et al. reviewed pooled data from 6 studies (including the study by Zhang et al. and 2 of the studies in that review) and did not find an association between marijuana use and lung cancer. 5 Limitations were similar to those in the other study.

Emerging Therapeutic Products Medicinal use of cannabis (known as medical marijuana) has attracted headlines over the past few years. The use of medical marijuana has been approved in Canada, in Australia, in a number of other countries, and in more than half of the states in the US.1 The authors of antiemetic guidelines published by the American Society of Clinical Oncology in 2017 noted that FDA-approved oral cannabis derivatives may be useful for chemotherapy-related nausea and vomiting, but that the evidence is subject to methodologic limitations of the various relevant trials.6 Cannabis-derived products that have been approved for medical use include dronabinol capsules for chemotherapy-induced nausea and appetite stimulation in HIV-associated anorexia.7 Nabilone has also been approved by the FDA for chemotherapy-induced nausea.

Nabiximol (under FDA review but approved elsewhere) is used in multiple sclerosis for analgesia and spasticity.

There is moderate evidence that cannabis is beneficial for chronic pain and neuropathic pain.8 Medicinal cannabis, mainly CBD, has attracted attention for its possible anticonvulsant effect but, again, the evidence is not entirely clear.9

Summary The legal status of cannabis products is changing rapidly, but in a piecemeal fashion. This fragmentary evolution is reflected in the evidence surrounding both its adverse and beneficial effects.

Clinicians working in the field of lung

Emily Stone

James Jett, MD

cancer will benefit from a better understanding of both the science behind the effects of cannabis and the policy-related approaches. ✦ References 1. Hall W, Weier M. Assessing the public health impacts of legalizing recreational cannabis use in the USA. Clin Pharmacol Ther. 2015;97(6):607–615.

2. National Academies of Sciences, Engineering, and Medicine, Health and Medicine Division, Board on Population Health and Public Health Practice, Committee on the Health Effects of Marijuana: An Evidence Review and Research Agenda. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington (DC): National Academies Press (US); 2017. http://www.ncbi.nlm.nih.gov/ books/NBK423845/ 3. ElSohly MA, Mehmedic Z, Foster S, Gon C, Chandra S, Church JC. Changes in cannabis potency over the last 2 decades (1995-2014): analysis of current data in the United States. Biol Psychiatry. 2016;79(7):613–619 4. Zhang LR, Morgenstern H, Greenland S, et al.

Cannabis smoking and lung cancer risk: pooled analysis in the International Lung Cancer Consortium. Int J Cancer. 2015;136(4):894–903.

5. Huang YH, Zhang ZF, Tashkin DP, Feng B, Straif K, Hashibe M. An epidemiologic review of marijuana and cancer: an update. Cancer Epidemiol Biomarkers Prev. 2015;24(1):15–31.

6. Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2017; 35(28):3240-3261.

7. Jatoi A, Windschitl HE, Loprinzi CL, et al.

Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study.

J Clin Oncol. 2002;20(2):567–573.

8. Hill KP. Marijuana treatment for Chronic Pain and other Medical and Psychiatric Problems: A Clinical Review. JAMA. 2015;313(24):2474-2483.

9. Friedman D, Devinsky O. Cannabinoids in the treatment of epilepsy. N Engl J Med. 2015;373(11): 1048–1058.

MEETING NEWS HIGHLIGHTS

Bronchoscopy Ultrasound and Navigational Bronchoscopy Finally Arrive in Peru

By Luis E. Raez, MD

Under the sponsorship of the IASLC, the Peruvian Association for Bronchology and Interventional Pulmonology (APBNI) organized a seminar on bronchoscopy ultrasound (EBUS) and navigational bronchoscopy in Lima, Peru, on July 21, 2017. IASLC members Dr. Pedro Garcia-Mantilla, a pulmonologist at the Guillermo Almenara Hospital in Lima, and Dr. Francisco Tarrazzi, from the Memorial Cancer Institute in Miami, US, were among the faculty; Dr. Garcia-Mantilla was the Chair. They taught EBUS using real-life cases, working on several Peruvian patients who needed staging during the seminar and who had not had the opportunity before because these technologies were not previously available. They were joined by Dr. Adnan Majid from Harvard Medical School, Boston, US, and Dr. Rex Yung from Johns Hopkins University, Baltimore, US. This is a great development for patients at hospitals in Peru and in other countries in the region that not only do not have the equipment for EBUS but also lack trained physicians to use it with the highest quality standards. Dr. Garcia-Mantilla has been working very hard in the last few years to bring these technologies to South America to benefit patients in the Latin-American region. IASLC sponsorship has supported several educational events in the region over the last 2 years. ✦

Dr. Francisco Tarrazzi (second from left) and Dr. Pedro Garcia-Mantilla (third from the left) with operating room personnel, teaching and bringing bronchoscopy ultrasound to Peru and to the region.

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IASLC LUNG CANCER NEWS / DECEMBER 2017

MEETING NEWS HIGHLIGHTS

Studies Indicate Expanding Benefit of Checkpoint Inhibitors

By Cynthia L. Kryder, MS and Lori L. Alexander, MTPW, ELS, MWC

An oral abstract session at the IASLC World Conference on Lung Cancer (WCLC) 2017 drew a standing-roomonly crowd to hear updates on studies of 3 immunotherapy drugs: pembrolizumab, nivolumab, and atezolizumab, and their role in advanced non-small cell lung cancer (NSCLC). The results of these studies indicate that the benefits of PD-L1/PD-1 checkpoint inhibitors has been maintained over longer follow-up and are now extending into new settings.

Pembrolizumab KEYNOTE-024 Julie Brahmer, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, US, presented updated data from KEYNOTE-024, an international randomized phase III trial in which pembrolizumab was compared with platinum-based chemotherapy as first-line therapy for advanced NSCLC positive for PD-L1 (tumor proportion score of 50% or more) in 305 patients.

The initial findings of KEYNOTE-024, after 11.2 months of follow-up, demonstrated that pembrolizumab yielded significantly longer progression-free and overall survival; the estimated 6-month overall survival was 80.2% for pembrolizumab compared with 72.4% for chemotherapy alone (P = 0.005).

Dr. Brahmer reported that, after a median follow-up of 25.2 months, pembrolizumab continues to be associated with an overall survival benefit.

The median overall survival was 30.0 months for patients who received pembrolizumab compared with 14.2 months for chemotherapy (P = 0.002). She added that the improvement in overall survival with pembrolizumab was maintained despite significant crossover to pembrolizumab in the chemotherapy arm.

Pembrolizumab also continued to demonstrate a favorable safety profile despite twice the duration of exposure compared to chemotherapy.

Penelope Bradbury, MB, BCh, FRACP, MD (UK), Princess Margaret Cancer Centre, University of Toronto, Canada, who discussed the abstract, noted that the findings firmly establish pembrolizumab as first-line therapy for

patients with advanced NSCLC with PD-L1 expression of 50% or more. She added that further evaluation of treatment beyond progression is needed.

KEYNOTE-021, Cohort G The significant benefit of pembrolizumab was also sustained in cohort G of the multicenter open-label, phase I/ II KEYNOTE-021 study, in which the efficacy and safety of pembrolizumab plus pemetrexed and carboplatin was compared with that of pemetrexed and carboplatin alone as first-line therapy for patients with stage IIIB/IV nonsquamous NSCLC, independent of PD-L1 status. Primary analysis of cohort G data (123 patients) at a minimum follow-up of 6 months (median, 10.6 months) demonstrated that pembrolizumab significantly improved the objective response rate (estimated treatment difference, 26%; P = 0.0016) and PFS. The hazard ratio for overall survival improved at a median follow-up of 14.5 months.

Corey J. Langer, MD, Perelman School of Medicine, Philadelphia, US, reported results at a median of 18.7 months of follow-up. The median PFS was significantly longer for pembrolizumab plus chemotherapy (19.0 vs. 8.9 months), and overall survival improved further (median, NR vs. 20.9 months) (Table 1).

“The incremental overall survival benefit, though not statistically significant, continues despite a high—approximately 75%—crossover rate to anti-PD-1/PD-L1 therapy in the chemotherapy-alone arm,” said Dr. Langer. He added the pembrolizumab continued to be associated with a manageable safety profile. The combination was granted accelerated approval by the US Food and Drug Administration (FDA) in May 2017.

Pembrolizumab after Local Ablative Therapy A third study of pembrolizumab was a phase II trial to evaluate the efficacy of pembrolizumab after local ablative therapy for oligometastatic NSCLC. Joshua Bauml, MD, Assistant Professor of Medicine at the Perelman Center for Advanced Medicine, Philadelphia, US, who reported on the study, said that it

Table 1. Updated Results of KEYNOTE 021, Cohort G Outcome

Median Follow-up: 10.6 Mos.

Median Follow-up: 14.5 Mos.

Median Follow-up: 18.7 Mos.

Progression-free survival (HR; 95% CI)

0.53; P = 0.010

0.50; P = 0.0038

0.54 (0.33-0.88); P = 0.0067

Overall survival (HR, 95% CI)

0.90 (0.42-1.91); P = 0.39

0.69 (0.36-1.31); P= 0.13

0.59 (0.34-1.05); P = 0.03

has been unclear historically whether systemic therapy can provide additional benefit to local ablative therapy in the setting of metastatic disease.

Dr. Bauml reported data for 44 patients with oligometastatic NSCLC, defined as 4 sites or less. Most patients (77%) had adenocarcinoma, and most (64%) had 1 metastatic site. The most common metastatic sites were the brain (17 patients), lung (15 patients), and bone (8 patients). Metastases were metachronous in 61%.

Pembrolizumab, 200 mg every 21 days, was started within 4 to 12 weeks after local ablative therapy and was continued for 6 months, with a provision to continue for a full year in the absence of disease progression or toxicity. The median follow-up was 15 months.

Dr. Bauml reported that the estimated 18-month PFS rate was 64% +/- 9% and the estimated 18-month overall survival rate was 79% +/- 8%. The most common attributable adverse events were grade 1 or 2 fatigue (34%) and arthralgia (29%).

Attributable grade 3 events included 1 episode each of colitis, pneumonitis, and adrenal insufficiency.

In discussing the abstract, Dr. Bradbury said that these preliminary data indicate that incorporating a PD-1 inhibitor with local ablative therapy appears feasible. Given the nature of the grade 3 adverse events, she posed the question of whether toxicity was associated with the location of ablative therapy.

Atezolizumab BIRCH Enric Carcereny Costa, MD, Catalan Institute of Oncology Badalona, Germans Trias i Pujol Hospital Badalona, Barcelona, Spain, presented updated survival data from BIRCH, a phase II trial of atezolizumab monotherapy in PD-L1selected patients with locally advanced or metastatic NSCLC. Dr. Costa highlighted data for 138 patients who received first-line treatment with atezolizumab.

All patients had tumors that expressed PD-L1 at a level of at least 5%; a subgroup of patients had expression levels of 50% or more.

In the primary analyses, atezolizumab monotherapy showed meaningful and durable clinical benefit across multiple lines of therapy (first-line, second-line, and beyond). Dr. Costa reported that after nearly 3 years of follow-up (median 34.3 months), the apparent survival benefit remained durable. In addition, efficacy was demonstrated in patients

with either wild-type or mutated tumors (EGFR or KRAS). Median overall survival was 26.9 months for 65 patients who had PD-L1 expression of 50% or more and 24.0 months for all patients; the corresponding investigator-assessed objective response rates were 35% and 26%.

Among evaluable patients, the overall response rate was 31% for patients with EGFR-mutant tumors (4 of 13 patients) vs. 23% for patients with wild-type EGFR (24 of 103 patients), and 31% for KRASmutant tumors (10 of 32 patients) vs 24% for wild-type KRAS (16 of 66 patients).

No new safety signals were observed.

Dr. Costa noted that data from ongoing phase III trials such as the IMpower110 study will further define the role of atezolizumab monotherapy as first-line therapy for this group of patients. Discussant Martin Schuler, MD, University Hospital Essen, Essen, Germany, remarked that pembrolizumab remains the standard of care for people with NSCLC with high PD-L1 expression (tumor proportion score of at least 50%), excluding EGFR-mutant and ALKrearranged lung cancers.

OAK In the randomized phase III OAK trial, atezolizumab demonstrated superior survival compared with docetaxel in patients with NSCLC who had received 1 or 2 previous lines of chemotherapy, independent of PD-L1 status. Miyako Satouchi, MD, PhD, Hyogo Cancer Center, Akashi, Japan, reported on the characteristics of the long-term survivors from the OAK primary population (850 patients), defined as patients who lived 2 years or longer after randomization.

The survival rate was higher for the atezolizumab arm compared to the docetaxel arm (Table 2). After a minimum follow-up of 26 months, the atezolizumab arm included more longterm survivors than the docetaxel arm.

The group of long-term survivors who received atezolizumab were enriched for nonsquamous histology and high PD-L1expressing tumors, but 40% of patients had tumors with low or no PD-L1 expression. The objective response rate for atezolizumab long-term survivors was higher than those who did not live 2 years, but 25 long-term survivors (21%) had progressive disease as their initial disease assessment.

Dr. Satouchi noted that long-term survival with atezolizumab was associated with extended treatment duration and was not limited to patients who had a

LUNGCANCERNEWS.ORG / DECEMBER 2017

Table 2. Long-Term Results of OAK

Table 3. Updated Results of CheckMate-012

Atezolizumab

Docetaxel

2-year overall survival rate, ITT population (%)

31

21

Long-term survivors (%)*

28

18

40

5

Objective response rate (%) Patients who received subsequent therapy after disease progression (%)

19

14

52

Outcome

Result (95% CI)

Objective response rate (%)

46

Duration of response (median, mos.)

10 (5.1-26.3)

Progression-free survival (median, mos.)

6 (4.8-8.3)

Overall survival (median, mos.)

19 (14.1-23.8)

3-year overall survival (%)

25

*Long-term defined as more than 2 years; calculated after a minimum follow-up of 26 months.

ITT, intent-to-treat

radiographic response. Median treatment exposure for atezolizumab long-term survivors was 18 months. Dr. Bradbury indicated that treatment with atezolizumab could continue beyond progression if the investigator believed the patient was deriving a clinical benefit. She noted that progressive disease, according to RECIST v1.1 criteria, encompasses several different scenarios and the question of whether to treat after progression remains unanswered.

Nivolumab CheckMate-012 Rosalyn Juergens, MD, PhD, Juravinski Cancer Centre at McMaster University, Hamilton, Canada, presented a 3-year update of the safety and efficacy of firstline nivolumab combined with platinumbased doublet chemotherapy in the randomized phase I CheckMate-012 study.

Fifty-six chemotherapy-naive patients with stage IIIB/IV NSCLC were randomly assigned, based on histology, to 3 cohorts combining nivolumab with platinum-based doublet chemotherapy regimens: nivolumab + pemetrexedâ&#x20AC;&#x201C;cisplatin; nivolumab + paclitaxelâ&#x20AC;&#x201C;carboplatin; and nivolumab + gemcitabineâ&#x20AC;&#x201C;cisplatin.

Nivolumab plus chemotherapy had a tolerable and manageable safety profile, and no new safety signals were observed after a minimum follow-up of 46 months.

For all patients, objective response rate and overall survival were similar, irrespective of tumor PD-L1 expression (Table 3). Three-year survivors included patients with PD-L1 expression of less than 1% and never-smokers; 69% of 3-year survivors received subsequent systemic therapy.

In discussing the abstract, Dr. Schuler noted that although CheckMate-012 provides interesting clinical signals with regard to immunotherapy-chemotherapy combinations in unselected patients, single-arm studies or small randomized phase II trials should not be the basis for changes in the standard of care in unselected NSCLC populations. Multiple sufficiently powered, pivotal phase III studies are underway; he eagerly awaits the results.

IFCT-1502 CLINIVO Real-life experience with nivolumab in 902 patients with advanced NSCLC was the topic of the presentation by Nicolas Girard, MD, Hospices Civils de Lyon, Lyon, France. Dr. Girard reported the results of a retrospective medical-record analysis of patients with squamous (317 patients) and nonsquamous (585 patients) stage IIIB/IV NSCLC who received at least 1 dose of nivolumab.

Endpoints included overall survival, best response, maximum toxicity of nivolumab, and predictors of response.

Median age was 64 years; 782 patients (86%) were smokers and 197 (22%) had brain metastases. Nivolumab was administered as second-, third-, or fourth-line treatment and beyond to 27%, 32%, and

41% of patients, respectively. The objective response rate for nivolumab was 19%, with stable disease in 36%, and progressive disease in 45% of patients; 1% were not evaluable. Toxicities occurred in 313 (35%) patients treated with nivolumab, including grade 3 or higher events in 11% of patients. Median overall survival and progression-free survival were also calculated (Figure 1). Prognostic factors of overall survival included performance status and the presence of at least 2 brain metastases, whereas sex, age at initiation of nivolumab, smoking history, TNM stage, and histology were not associated with overall survival.

Postâ&#x20AC;?nivolumab treatment was given to 426 (47%) patients;319 of these patients (75%) receiving systemic ther-

apy. Patients with a performance status of 0 or 1, those who received 1 or 2 prior lines of therapy, and those without brain metastases at the time of nivolumab initiation were more likely to receive treatment after nivolumab. Best response to the first post-nivolumab treatment was objective response in 16%, stable disease in 42%, and progressive disease in 42% of patients.

Dr. Girard concluded that these efficacy and safety results for nivolumab are commensurate with available data on nivolumab and other immunotherapy agents. He noted that post-nivolumab treatment may be delivered to many patients, including those with a performance status of 2 or worse, or brain metastases, with highly variable efficacy and impact on overall survival. â&#x153;Ś

#216.; %( ! , - 2B2;@?

02;?<>21 ;

6-month survival rate: 64.2% (95% CI: 61.0-67.4) 12-month survival rate: 44.7% (95% CI: 41.4-48.0) 18-month survival rate: 32.7% (95% CI: 29.4-35.9)

:<;@5 ?A>B6B.9 >.@2 !

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Figure 1. IFCT-1502 Clinivo Overall Survival and Progression-Free Survival: Nivolumab-treated Patients

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IASLC LUNG CANCER NEWS / DECEMBER 2017

E V O LV I N G S TA N D A R D S O F C A R E

E V O LV I N G S TA N D A R D S O F C A R E

IASLC Consensus Statement on Liquid Biopsy

IASLC 18th WCLC Special Session Provides Overview of Updated Guidelines for Molecular Testing

By Christian Rolfo, MD, PhD, MBAh, and Philip C. Mack, PhD

In just the past decade, tremendous advancements in the treatment of metastatic non-small cell lung cancer (NSCLC) have been made due to the identification of targetable oncogenic molecular drivers on which the tumors are dependent for their growth and survival. Precision oncology—treating the patient with therapies predicted to be effective based on the specific molecular characteristics of their tumor—can add years of quality life for those patients.

Historically, tissue biopsy specimens have been used as the sole source of tumor molecular information, but unfortunately, adequate tissue is not always easy to obtain from all patients with advanced NSCLC. In addition, the necessity to monitor responses to treatment and to identify emergent molecular mechanisms of resistance has become increasingly important but is limited by the challenges of traditional tissue rebiopsies. In this context, the isolation of tumor-derived DNA, RNA and cells from the peripheral circulation (a concept termed liquid biopsy) is emerging as a versatile and powerful tool for the optimization of NSCLC clinical management via the identification of predictive biomarkers, either prior to treatment or at progression. However, despite several potential advantages, liquid biopsy is still far from completely replacing tissue biopsy, and its role in clinical practice needs to be precisely defined and validated.

For this reason, a multidisciplinary panel of International Association for the Study of Lung Cancer (IASLC) members, experts in the field of thoracic oncology and liquid biopsy, evaluated the current available evidence with the aim of producing a set of recommendations for the use of liquid biopsy for molecular analysis in order to guide the routine clinical management of advanced NSCLC patients.

The consensus statement will address: • Blood sample acquisition and handling, plus subsequent extraction

Christian Rolfo

• • • • • •

• • •

Philip C. Mack

of circulating cell-free tumor DNA (cftDNA) Platforms for molecular analysis and requirements for their use Role in treatment-naive patients Monitoring treatment response Clinical value in patients with progressive disease Results reporting and molecular tumor boards Ethical considerations with regards to germline mutations and informed consent Role of liquid biopsy in immune oncology Molecular characterization of cftRNA and circulating tumor cells Liquid specimens beyond peripheral blood

The possibility of using a non-invasive method to understand and identify molecular targets and mechanisms of resistance for current drugs, both targeted agents and immunotherapies, will be extremely beneficial for patients, as will harnessing these strategies to identify new biomarkers. The future of liquid biopsies is undeniably exciting, but there is a need to more clearly understand the latest developments; therefore, this timely consensus statement will be published in an upcoming issue of the Journal of Thoracic Oncology, the official journal of the IASLC. ✦

Experts in molecular testing discussed various issues on this topic in October at the IASLC 18th WCLC. Neil Lindeman, MD, led off the session with an overview of the update to the College of American Pathologists (CAP), International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) 2013 molecular testing guideline in lung cancer. Dr. Lindeman explained that updating guidelines at least every 5 years is standard practice. He discussed several factors that influenced the current update, including the emergence of new biomarkers and targeted therapies; advances in testing technology, such as next-generation sequencing (NGS) and blood-based liquid biopsy; and reconsideration of squamous cancers and small cell lung cancers (SCLCs) Dr. Lindeman reviewed the draft recommendations (Table 1), noting that the 2013 recommendations remain largely unchanged. He explained that ROS1 testing is recommended and should be performed on all patients with advancedstage adenocarcinoma, irrespective of clinical characteristics. Molecular testing for BRAF, RET ERBB2 (HER2), MET, and KRAS is not currently indicated as a rouNeil Lindeman tine stand-alone test outside the context of a clinical trial; however, it is appropriate to include these as part of larger testing panels performed either initially or when routine EGFR, ALK, and ROS1 testing is negative.

Revisions of the guideline are based on evidence from an unbiased review of published experimental literature since 2013 and include recommendations from an expert panel of renowned, worldwide leaders in the field. A draft of the guidelines was available for open comment during the development process, and the update is on schedule to be published in the Journal of Thoracic Oncology, the Journal of Molecular Diagnosis, and Archives of Pathology & Laboratory Medicine. ✦ Table 1. Overview of New Draft Recommendations for Molecular Testing Since 2013

New Biomarker Testing Added ROS1 for all patients Add BRAF, ERBB2, MET, RET if doing a large panel PD1/PDL1 are important, but in a different guideline No mandate to test squamous cancers or SCLCs

Testing Technologies IHC is acceptable for ALK and screening for ROS1 Methods of testing for EGFR T790M resistance need high sensitivity Other resistance mutations require further study Smears are acceptable, sensitivity reduced to 20% tumor content Cell-free DNA is appropriate when a tissue sample is difficult to obtain If testing of cell-free DNA is negative, tissue biopsy is needed NGS panels are preferred over multiple single assays

Editor’s note. Murry W. Wynes, PhD, IASLC Director of Scientific Affairs, is acknowledged and thanked for his contributions to this article.

IASLC Lung Cancer News can now be read online!

LungCancerNews.org

IHC = immunohistochemistry

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21

ADVOCACY AND SURVIVORSHIP ADVOCACY AND SURVIVORSHIP

Advocating for Inclusion of the Patient’s Voice

Lung Cancer Awareness Month Gathers Support and Momentum in Its Second Year

By Lori L. Alexander, MTPW, ELS, MWC

By Keightley Amen, BA, ELS

Since 2006, the Bonnie J. Addario Lung Cancer Foundation (ALCF) has brought together a diverse group of physicians, organizations, industry partners, and individuals, along with patients, survivors, and their families, to identify solutions and to make timely and meaningful changes in the research and management of lung cancer. Arising from the experience of its founder, Bonnie Addario, a stage IIIB lung cancer survivor, ALCF has become one of the largest philanthropies focused on lung cancer, raising more than $40 million to fund lung cancer research and deliver programs to patients since its inception. Among ALCF’s most important goals are to empower individuals with lung cancer through education and to ensure that the patient’s voice and perspective are integrated into all aspects of research and patient care.

Among Ms. Addario’s latest initiatives is an article to address the need to integrate the patient’s voice into value frameworks developed by healthcare systems to assist in decision-making regarding access to treatment.

Collaborating with other patient advocates and advocacy groups, Ms. Addario recently published the article, Patient Value: Perspectives from the Advocacy Community.1 “All frameworks around the world working on healthcare must include the patient voice,” says Ms. Addario. “The patient voice is mandatory to address the delivery of great patient healthcare.

Patients around the globe want to live as long as possible and want to be part of the solution regarding access to all the possibilities.”

Ms. Addario and her coauthors note that many value frameworks reflect traditional clinical and economic values held by healthcare professionals without inclusion of outcomes that are relevant to patients. She notes that patient advocates should also be involved in the process because of their knowledge and perspective on how specific treatments will affect the patient population under consideration.

“Anyone who designs a program to sell products must involve the customer in the design. The customer in healthcare is the patient, and patients can be the change agents from development to delivery and simultaneously help to save millions of dollars in healthcare costs,” says Ms. Addario.

While many people remain unaware of the advancements in the field of lung cancer and research spending still lags behind the funds spent to combat other types of cancer,2 lung cancer is the leading cause of cancer death worldwide.1 To bolster research spending, raise public awareness, and reduce the widespread stigma associated with the disease, the International Association for the Study of Lung Cancer (IASLC) coordinated the second annual Lung Cancer Awareness Month Coalition (LCAM) in November 2017. LCAM is a cooperative effort among nonprofit lung cancer advocacy organizations, industry, healthcare professionals, and patients – and the campaign gained tremendous support and momentum in its second year.

LCAM kicked off the month of November with a media program at The National Press Club in Washington, DC. A prestigious panel of physicians, LCAM partners, and survivors discussed lung cancer’s vast threat; the stigma associated with the disease; current advocacy efforts; and the research, diagnosis, and treatment breakthroughs bringing new hope to patients and their families.

Dusty Donaldson, survivor and a cochair of the Lung Cancer Action Network, served as moderator. Experts included the IASLC CEO Fred Hirsch, MD, PhD; Melissa Culligan, RN, MS, director of clinical research in thoracic surgery at the University of Maryland and chair of the International Thoracic Oncology Nursing Forum; Jennifer King, PhD, director of science and research at the Lung Cancer Alliance; and John F.P. Bridges, PhD, associate professor in the Johns Hopkins Bloomberg School of Public Health.

Other partner organizations on hand to engage the press included the Addario Lung Cancer Foundation, American Lung Association, Life & Breath Rally, Lung Cancer Alliance, Lungevity, and Cancer Survivors Against Radon.

Following the kickoff and throughout the month, LCAM ran online banner and video ads, as well as a halfpage advertisement in the New York Times. In addition, LCAM continued to leverage social media: The campaign has more than 40,000 Facebook followers and 220 Twitter followers.

The IASLC encourages its members to use #LCAM, #LCSM, #HOPELIVES, #MoreResearchMoreSurvivors, when talking about lung cancer on social media so that all parties working to combat the disease can consolidate their efforts.

Bonnie J. Addario

In the article, Ms. Addario and her coauthors explore the varying definitions of patient value and make positive recommendations for working together to strengthen the patient’s voice in the development of frameworks. The authors call on framework developers, the patient advocacy and research communities, the healthcare industry, and decision-makers to undertake specific actions to ensure patient value is included in current and future value frameworks. “This is justified on compassionate and economic grounds: better health outcomes result when patients receive treatment tailored to individual needs,” they write.

The call to action for the research community is to advance methodologies for recording, quantifying, and assessing patient values, including in randomized controlled trials, and sharing these methodologies through publication to build an evidence base.

The ALCF has strong ties to the global research community and generously supports innovative research through fellowships across multiple cancer types, including the ALCFIASLC Fellowship Award for the Early Detection of Lung Cancer. ALCF also works in tandem with the Addario Lung Cancer Medical Institute (ALCMI), established in 2008, a patient-centric international research consortium composed of more than 23 member institutions in the United States and Europe. ✦ Reference 1. Addario BJ, Fadich A, Fox J, et al. Patient value: perspectives from the advocacy community.

Health Expect. 2017 Sep 20 [Epub ahead of print].

LCAM aims to include as many partners as possible, including international groups and allied health. For 2017, the following organizations joined the collaborative effort as official partners, bringing the number to more than 30: • National Lung Cancer Forum for Nurses • Clifton F. Mountain Foundation for Research and Education in Lung Cancer • Pembe Hanim (Turkey) • Citizens for Radioactive Radon Reduction • International Thoracic Oncology Nurses Forum • Israeli Lung Cancer Foundation • Polish Lung Cancer Group For a full list of LCAM partners, visit www.lcam.org/partners/.

A critical part of the LCAM campaign is to share and promote the stories of lung cancer survivors and their caregivers and families. On the LCAM website, many have posted their “Stories of Hope. More Time. More Life.” Some remind readers how lung cancer can happen to anyone, others describe the research that saved their lives, and many share a message of hope and advocacy. LCAM encourages more people to share their stories at www. lcam.org/share-your-story and receive an LCAM kit, including a hat, T-shirt, pin, and car magnet. Additionally, LCAM is offering complimentary resources to providers that will include IASLC lung cancer information as well as items to share with their patients/survivors and caregivers.

To receive your provider resources, visit, www.lcam.org/provider-resources/ ✦

LCAM gratefully acknowledges its industry sponsors: Lilly Oncology, Bristol-Myers Squibb, Merck, Novartis, Helsinn, AstraZeneca, and Incyte.

References 1. World Health Organization. Cancer fact sheet.

Accessed October 27, 2017, from http://www.who. int/mediacentre/factsheets/fs297/en/.

2. National Institutes of Health. Estimates of funding for various research, condition, and disease categories. Accessed October 27, 2017, from https:// report.nih.gov/categorical_spending.aspx.

22

IASLC LUNG CANCER NEWS / DECEMBER 2017

Names and News Carolyn M. Dresler, MD, MPA, is the recipient of the 2017 IASLC Joseph W. Cullen Prevention/Early Detection Award. Dr. Dresler is currently the Associate Director for Medical & Health Sciences, Center for Tobacco Products, US Food & Drug Administration (FDA), a position she has held since 2012. As an IASLC Board member (2011-2015), Dr. Dresler helped the IASLC to establish the Tobacco Control and Smoking Cessation Committee and served as a member of the Committee.

Tony Mok, BMSc, MD, FRCP(C), FRCP (Glasgow), FASCO, is the recipient of the 2017 IASLC Paul A. Bunn, Jr. Scientific Award. Prof. Mok is currently the Li Shu Fan Medical Foundation-Endowed Professor, Department of Clinical Oncology, Chinese University of Hong Kong, Prince of Wales Hospital. He also holds an honorary professorship at the Guangdong Provincial People’s Hospital in China, as well as a guest professorship at Peking University School of Oncology. A past president of the IASLC (2013– 2015), Prof. Mok was recently elected IASLC Treasurer and will fulfill that role from 2017–2021.

Ramón Rami-Porta, MD, PhD, is the recipient of the 2017 IASLC Merit Award. Dr. Rami-Porta was appointed this year as the Clinical Chief of the Department of Thoracic Surgery at Hospital Universitari Mútua Terrassa, in Terrassa (Barcelona), Spain. He is also a Collaborating Professor of Thoracic Surgery at Escola Universitária Gimbernat, Autonomous University of Barcelona. Dr. Rami-Porta served as Chair of the IASLC Staging and Prognostic Factors Committee from 2009 to 2016 and is the Executive Editor of the second editions of the IASLC Staging Manual in Thoracic Oncology and the IASLC Staging Handbook in Thoracic Oncology, published in 2016.

Yasushi Yatabe, MD, PhD, is the recipient of the 2017 IASLC Mary J. Matthews Pathology/Translational Research Award. Dr. Yatabe has served as Chief of the Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan, since 2000.

Dr. Yatabe is Co-Editor of the IASLC Atlas of ALK and ROS1 Testing in Lung Cancer and IASLC Atlas of PD-L1 Immunohistochemistry Testing in Lung Cancer.

• Alectinib (Alecensa) received full FDA approval for the first-line treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) as determined by an FDA-approved test. The approval was based on results from the phase III ALEX study that compared alectinib to crizotinib. In addition, the FDA also converted alectinib’s initial accelerated approval in December 2015 to a full approval for the treatment ALK-positive, metastatic NSCLC following disease progression on or intolerance to crizotinib (second-line). (11/06/17) • Seribantumab (MM-121), an investigational drug candidate, received FDA orphan drug designation for the treatment of heregulin-positive NSCLC. Seribantumab is a fully human monoclonal antibody designed to block tumor survival signals and enhance the anti-tumor effect of combination therapies by targeting the cell surface receptor HER3 (ErbB3) in patients with high heregulin. (10/30/17) • Afatinib (Gilotrif) received FDA priority review to a supplemental new drug application for the frontline treatment of patients with metastatic NSCLC whose tumors harbor EGFR exon 21 (L861Q), G719X, or S768I substitution mutations.

Supplemental new drug application approval was based on data from the LUXLung 2, 3, and 6 trials in which “…afatinib showed activity in patients with NSCLC tumors that contained the more frequently reported types of uncommon EGFR mutations.” (10/10/17) • Osimertinib (Tagrisso) received FDA breakthrough therapy designation for the first-line treatment of patients with metastatic EGFR-mutations positive NSCLC. Breakthrough therapy designation was based on data from the phase III FLAURA trial of osimertinib versus standard-of-care EGFR tyrosine kinase inhibitors in previously untreated patients with locally advanced or metastatic EGFR mutationpositive NSCLC. (10/09/17) • Durvalumab (Imfinzi) received FDA acceptance for priority review status of supplemental biologics license application for the treatment of patients with locally advanced (stage III) unresectable NSCLC whose disease has not progressed following platinum-based chemoradiation therapy. The supplemental biologics license application was based on positive progression-free survival data from the phase III PACIFIC trial, which continues to evaluate overall survival, the other primary endpoint. (9/28/17) • Bevacizumab-awwb (Mvasi) received FDA approval as a biosimilar to bevacizumab (Avastin) for the treatment of multiple types of cancer. Bevacizumab-awwb is the first biosimilar approved in the US for the treatment of cancer and is approved for the treatment of adult patients with certain colorectal, lung, brain, kidney and cervical cancers. For non-squamous NSCLC, the approved indication is in combination with carboplatin and paclitaxel for first-line treatment of unresectable, locally advanced, recurrent or metastatic disease. (9/14/17)

ADVOCACY AND SURVIVORSHIP

The Lung Cancer Research Foundation and Free to Breathe Merge to Fight Lung Cancer Effective September 30, 2017, the Lung Cancer Research Foundation and Free to Breathe have merged organizations, with the goal of closing the funding gap for lung cancer research. The mission to improve lung cancer outcomes by funding research for the prevention, diagnosis, treatment, and cure of lung cancer continues in the newly formulated organization, and the Lung Cancer Research Foundation name will be retained.

“As a lung cancer researcher, I know firsthand the significant impact both organizations have had on the lung cancer community,” said Brendon M. Stiles, MD, Chair of the Lung Cancer Research Foundation’s Board of Directors. “Over the last decade we have seen steady progress in the field of lung cancer research, which has led to improved patient outcomes.”

Both the Lung Cancer Research Foundation and Free to Breathe have a long history of funding innovative, high-reward research across the spectrum of basic, clinical, and translational research with the potential to extend survival and improve quality

of life for people with lung cancer. The newly expanded organization has funded a cumulative 342 grants, totaling nearly $34 million, the highest amount of funding provided by a lung cancer research organization to date.

“By coming together, we can build upon the momentum we have established separately to expand our Scientific Grant Program and increase funding for lung cancer research,” said Nancy M. Sanford, Executive Director, the Lung Cancer Research Foundation.

“We are proud of the research our organizations have funded thus far and are thrilled that we are uniting to increase our grant funding moving forward.” ✦ For more information, visit www.lungcancerresearchfoundation.org or www.freetobreathe.org.

LUNGCANCERNEWS.ORG / DECEMBER 2017

23

NURSING

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 Deb Whippen, Editorial Rx, Inc. PRODUCTION DIRECTOR Doug Byrnes GRAPHIC DESIGNER Amy Boches, biographics 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.

Writing for Publication: Expanding the Voices of Nursing in Thoracic Oncology

By Kathleen A. Gamblin, RN, BSN, OCN

The nursing perspective and the views of other ancillary specialties are frequently missing in the thoracic oncology literature. This deficiency needs to be addressed; the current model of healthcare delivery in the US and around the world includes an ever-expanding role for nurses, nurse practitioners, and physician assistants, and their voices need to be heard.

Writing for publication is an excellent way for nurses to share their unique knowledge and expertise on particular subjects or to share their perspective or personal story as it relates to other subjects within nursing. Writing for publication can also be used for career advancement; in some positions within nursing, there are now requirements for publishing annually. In modern society with its increasing emphasis on technology, nurses have the ability to write not only for written publications such as journals or books, but they also have the opportunity to write online content: this can include content for websites and online journals as well as professional blogs. If a nurse is interested in writing and would like to gain experience writing, many healthcare institutions offer opportunities for their nurses to publish and may supply the appropriate subject matter on which to write. These institutional opportunities include newsletters, website content, and articles requested by community publications.

For those interested in writing their own selections, the nurse must determine their subject, motivation, and audience.

Do they wish to educate the reader on a new process or initiative, contribute to the body of knowledge within a certain nursing area, or take a critical look at or suggest a change in clinical practice? Once the topic is clear, the author can choose the best venue in which their publication can be shared, including in the area of thoracic oncology. For instance, in the area of thoracic oncology patient navigation, while much has been written about the navigation of breast cancer, thoracic patient navigation remains a relatively newer area. The book Oncology Nurse Navigation: Delivering Patient-Centered Care Across the Continuum, published by the Oncology Nursing Society, highlighted thoracic oncology as a distinct disease-specific site to be navigated. The portion of the chapter on thoracic navigation outlined the work and processes of the thoracic oncology nurse navigator,

with special attention paid to the topics of compassion fatigue, burnout, and moral distress that can be common for the thoracic oncology nurse. This publication set the stage for further writing on the topic of thoracic oncology nurse navigation.

Another example of writing by nurses in the area of thoracic oncology is the recent book published by the Oncology Nursing Society—Oncology Nurse Navigation: Case Studies. This book features a chapter specific to a case study of thoracic oncology nurse navigation. The case study was written to show the progression of a patient through the disease process, and it establishes the role of and the importance of the thoracic oncology nurse navigator. Mindful of efforts to establish a certification process for oncology nurse navigation, the chapter concludes with evidence-based questions that can be used for future certification efforts in oncology nurse navigation.

If nurses are new to writing or have colleagues who are interested in writing, but have little experience, there are many helpful articles on the process of writing for publication. Some professional organizations offer mentorship to new writers. For instance, the Clinical Journal of Oncology Nursing has a Writing Mentorship Program, which offers a novice writer the opportunity to be paired with an experienced, published author to produce an article over a 6-month time frame. (https://cjon.ons.org/content/ writing-mentorship-program).

As a published author of both journal articles and 2 edited textbooks, I can say that while the process can feel overwhelming at times, the editors and reviewers I have had the privilege to work with have been nothing but helpful and encouraging along the way. There is a deep satisfaction in seeing your name in print as an author. ✦

Official Journal of the International Association for the Study of Lung Cancer Editor-in-Chief: Alex A. Adjei, MD, PhD, FACP, Mayo Clinic, Rochester, MN, USA

ISSN: 1556-0864 A subscription to JTO LV D EHQHȇW RI membership in the IASLC. To join, visit www.IASLC.org.

The Journal of Thoracic Oncology ( JTO), the official journal of the International Association for the Study of Lung Cancer, is the primary educational and informational publication for topics relevant to detection, prevention, diagnosis, and treatment of thoracic malignancies. JTO emphasizes a multidisciplinary approach, and includes original research (clinical trials and translational or basic research), reviews, and opinion pieces. The audience consists of epidemiologists, medical oncologists, radiation oncologists, thoracic surgeons, pulmonary specialists, radiologists, pathologists, and research scientists with a special interest in thoracic oncology.

To subscribe visit jto.org

WCLC 2018 HONORARY CHAIR

Dr. Frances Shepherd, MD, FRCP(C), OOnt, OC

SAVE

THE DATE!

WCLC 2018 CO-PRESIDENTS

Dr. Natasha Leighl, MD, MMSc, FRCPC Dr. Andrea Bezjak, MDCM, MSc, FRCPC Dr. Gail Darling, MD, FRCSC, FACS Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

SEPTEMBER 23â&#x20AC;&#x201C;26, 2018

TAKE ACTION

Against Lung Cancer!