Background

This study is an open-labeled, randomized, multicenter phase III study to investigate the efficacy and safety of bevacizumab (B) with or without erlotinib (E) in Chinese EGFR-mutated non-small cell lung cancer (NSCLC) patients (NCT02759614).

Methods

Patients with advanced non-squamous NSCLC harbouring EGFR-mutation were randomly (1:1) assigned to receive either combination with erlotinib (150 mg daily) plus bevacizumab (15 mg/kg iv q3w) or erlotinib (150 mg daily). Random assignment was stratified by sex (female/male), disease stage (stage IIIb vs. stage IV vs. recurrence), and EGFR gene mutation (exon 19 deletion vs. exon 21 L858R). The primary endpoint was Progression-free survival (PFS), as determined by an independent review committee (IRC). Secondary endpoints were PFS by investigator, tumor response (by IRC and investigator), overall survival (OS), time to failure (TTF), safety, patient-reported outcome (PRO) and exploratory biomarker analysis. Next-generation sequencing (NGS) of a 448-gene panel and transcriptome sequencing (RNA-Seq) was used for resistance biomarker analysis of paired frozen tissue samples.

Results

From Mar 31, 2016 to Jul 26, 2017, 311 patients from 14 centers across China were randomized to receive BE (N = 157) or E (N = 154). Median follow-up time was 22 months for BE and 21.5 months for E. Baseline characteristics were well balanced in each arm. The median PFS by IRC was 18.0 months (95% CI 15.2-20.7) in BE and 11.3 months (95%CI 9.8-13.8) in E (p < 0.001) (HR = 0.55,95%CI 0.41-0.75). The median PFS per investigator was 18.0 months (95% CI 15.2-20.7) in BE and 11.2 months (95%CI 9.7-12.5) in E (p < 0.001) (HR = 0.57,95% CI 0.44-0.75). The objective response rate by IRC in the BE and E groups was 86.3% and 84.7%, respectively (p = 0.741). The most common grade 3 or worse adverse events in BE group were hypertension, proteinuria and rash; and in the E alone group were rash, elevated alanine aminotransferase and elevated aspartate aminotransferase. Results for resistance biomarker analysis will be presented onsite.

Conclusions

As compared with E alone, B plus E showed superior efficacy with acceptable tolerability. This regimen could be a new standard first-line regimen in EGFR mutated NSCLC.

Clinical trial identification

NCT02759614.

Editorial acknowledgement

Li Zhang, from Shanghai Roche Pharmaceuticals Ltd.

Legal entity responsible for the study

Guangdong Association of Clinical Trials (GACT).

Funding

Shanghai Roche Pharmaceuticals Ltd.

Disclosure

Q. Zhou: Honoraria (self): AstraZeneca; Honoraria (self): Roche. Y. Wu: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self): Pierre Fabre; Honoraria (self): Pfizer; Honoraria (self): Sanofi; Advisory / Consultancy: Merck; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim. All other authors have declared no conflicts of interest.

Background

A nationwide genome screening project in Japan (LC-SCRUM-Japan) has been established for the development of molecular-targeted therapies for lung cancers.

Methods

Since 2013, ALK/ROS1/RET fusions have been analyzed by RT-PCR and FISH, and since 2015, multi-gene alterations have been also analyzed by a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay. A large-scale clinico-genomic database has been developed based on the molecular screening and the monitoring of therapeutic efficacy and patient survival.

Results

As of December, 2018, 263 institutions were participating and 5360 non-squamous non-small cell lung cancer patients had been enrolled. The success rates of RT-PCR and NGS were 94% and 91%, respectively. Of 4874 available samples, a total of 2135 targetable gene alterations (521 KRAS mut, 157 ROS1 fus, 136 MET ex14skip/amp, 131 BRAF mut, 128 ERBB2 ex20ins, 126 RET fus, 118 ALK fus, 73 EGFR ex20ins, 10 AKT1 mut, 9 NRG1 fus, 6 FGFR2/3 fus, 2 NTRK3 fus and others) were detected. Through this screening, 963 genotype-matched patients to molecular-targeted clinical trials were identified, and 172 of them (18%) were enrolled into the trials, resulting in the approval of ROS1- and BRAF-targeted therapies in Japan. Based on our database, in patients with EGFR/ERBB2 ex20ins, MET ex14skip and RET fusions, the median overall survivals were 18.5 (95%CI, 15.4-28.1), 38.0 (8.8-NR) and 51.3 (33.4-73.4) months, respectively. In these 3 subtypes, the objective response rate of 1^st-line platinum-containing chemotherapies were 33%, 23% and 30%, respectively, and the progression-free survivals were 6.0 (95%CI, 5.0-7.0), 6.8 (4.4-8.4) and 10.5 (8.1-15.2) months, respectively. These historical data are valuable for evaluating efficacy of novel targeted drugs.

Conclusions

Our large-scale screening and clinico-genomic database contribute to the development of novel targeted therapies, especially for ROS1-, BRAF-, EGFR/ERBB2 ex20ins-, MET- and RET-positive lung cancers. In addition to the tissue-based NGS assay, NGS with liquid biopsy and multi-target qPCR assay will be started for further development of targeted drugs and companion diagnostics from 2019 in LC-SCRUM-Japan.

Clinical trial identification

UMIN000010234.

Legal entity responsible for the study

National Cancer Center Japan.

Funding

Astellas Pharma, AstraZeneca, Amgen, Eisai, Ono Pharmaceutical, Kyowa Hakko Kirin, MSD, Merck Serono, Daiichi Sankyo, Taiho Pharmaceutical, Takeda Pharmaceutical, Pfizer, Novartis Pharma, Eily Lilly.

Disclosure

S. Matsumoto: Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Chugai Pharma; Honoraria (self): Pfizer; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): MSD. K. Yoh: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Lilly Japan; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharma; Honoraria (self): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self), Research grant / Funding (institution): Daiichi Sankyo; Honoraria (self): Kirin Pharmaceuticals ; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Ono Pharmaceutical. T. Kato: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharma; Advisory / Consultancy: Nitto Denko; Advisory / Consultancy, Research grant / Funding (institution): AbbVie; Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self): Roche; Honoraria (self): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical ; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self): Bristol-Myers Squibb Japan; Honoraria (self), Research grant / Funding (institution): Merck Sharp & Dohme; Honoraria (self): Novartis; Honoraria (self): Sumitomo Dainippon Pharma; Honoraria (self): Quintiles; Honoraria (self): Takeda; Research grant / Funding (institution): Kyowa Hakko Kirin; Research grant / Funding (institution): Astellas Pharma . K. Nishino: Honoraria (self): Chugai Pharma. S. Sugawara: Honoraria (self): AstraZeneca; Honoraria (self): Chugai Pharma ; Honoraria (self): Nippon Boehringer Ingelheim; Honoraria (self): Taiho Pharmaceutical ; Honoraria (self): Pfizer ; Honoraria (self): Lilly; Honoraria (self): Novartis; Honoraria (self): Kyowa Hakko Kirin; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Ono Pharmaceutical; Honoraria (self): MSD K.K . Y. Ohe: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Lilly Japan; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Kyorin ; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Takeda; Honoraria (self), Advisory / Consultancy: Celltrion; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb Japan; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Bayer; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self): MSD ; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self): Kyowa Hakko Kirin; Research grant / Funding (institution): Sumitomo Dainippon Pharma; Research grant / Funding (institution): Ignyta. T. Seto: Honoraria (self): Astellas Pharma; Honoraria (self), Research grant / Funding (institution): AstraZeneca ; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): Chugai Pharma; Honoraria (self), Research grant / Funding (institution): Lilly; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self), Research grant / Funding (institution): Nippon Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Takeda; Honoraria (self): Thermo Fisher Scientific; Research grant / Funding (institution): Bayer Yakuhin; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Kissei Pharmaceutical; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Merck Serono. N. Furuya: Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self): Bristol-Myers Squibb Japan; Honoraria (self): Lilly; Honoraria (self): Chugai Pharma; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Ono Pharmaceutical . K. Goto: Advisory / Consultancy: Otsuka; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Chugai Pharma; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical ; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Lilly; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self): Quintiles; Honoraria (self), Research grant / Funding (institution): Merck Serono; Honoraria (self), Research grant / Funding (institution): Life Technologies; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self): AbbVie; Honoraria (self), Research grant / Funding (institution): Riken Genesis; Honoraria (self): Nippon Kayaku; Honoraria (self), Research grant / Funding (institution): Takeda; Honoraria (self): Otsuka; Honoraria (self): SRL Diagnostics. All other authors have declared no conflicts of interest.

Background

Tissue-based assessment of actionable mutations in pts with NSCLC is limited by invasive biopsies and adequacy of biopsied tumour material. Blood-based testing may overcome such limitations, allowing multiplex profiling in a single test. BFAST (NCT03178552) is an ongoing multicentre, open-label, multi-cohort study evaluating the relationship between blood-based next-generation sequencing (NGS) detection of actionable genetic alterations in cell-free DNA, and the activity of targeted therapies and immunotherapy in pts with treatment-naïve advanced NSCLC. We present first results from the ALK+ cohort.

Methods

Pts ≥18 years with stage IIIB/IV ALK+ NSCLC (detected by blood-based NGS) received oral alectinib 600mg twice daily. Asymptomatic/treated central nervous system (CNS) metastases were permitted. All pts (with/without CNS disease) had 8-weekly restaging and brain scans. Primary endpoint: confirmed investigator (INV)-assessed objective response rate (ORR; RECIST v1.1). Key secondary endpoints: independent review facility (IRF)-assessed ORR; INV- and IRF-assessed duration of response (DoR), progression-free survival (PFS), overall survival; and safety.

Results

Of 2,219 pts screened, blood-based NGS yielded results in 2,188 pts. Overall, 119 pts (5.4%) had ALK+ disease; 87 pts were enrolled and received alectinib. EML4 was the fusion partner in 73 (84%) pts, with TP53 mutations detected in 38 (44%) pts. Median blood-based tumour mutational burden was 2 (range, 0–21). Median follow-up: 12.6 months (range, 2.6–18.7). Confirmed ORR: 87.4% (95% CI 78.5–93.5) by INV and 92.0% (95% CI 84.1–96.7) by IRF. The 12-month INV-confirmed DoR was 75.9% (95% CI 63.6–88.2). In 35 (40%) pts with asymptomatic baseline CNS disease, ORR by INV was 91.4% (95% CI 76.9–98.2). Median PFS: not reached; 12-month PFS by INV was 78.4% (95% CI 69.1–87.7). Safety data were consistent with the known safety profile of alectinib.

Conclusions

Blood-based detection of ALK fusions results in high ORR and clinical benefit in pts receiving alectinib. These data validate the clinical utility of blood-based NGS as an additional method to inform clinical decision-making in ALK+ NSCLC.

Clinical trial identification

NCT03178552.

Editorial acknowledgement

Medical Writing support was provided by Nicola Griffin of Gardiner-Caldwell Communications and funded by F. Hoffmann-La Roche.

Legal entity responsible for the study

F. Hoffmann-La Roche Ltd.

Funding

F. Hoffman-La Roche Ltd.

Disclosure

S.M. Gadgeel: Honoraria (self), Advisory / Consultancy: Ariad, AstraZeneca, Bristol-Myers Squibb, Pfizer and F. Hoffmann-La Roche Ltd/Genentech. T.S.K. Mok: Leadership role: Sanonics Ltd; Honoraria (self), Advisory / Consultancy: ACEA Biosciences, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chimed, Cirina, Fishawack Facilitate, Ignyta, Janssen, Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, OncoGenex, Pfizer, F. Hoffmann-La Roche Ltd/Genentech, SFJ Pharm; Research grant / Funding (self): AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Merck Sharp & Dohme, Novartis, Pfizer, F. Hoffmann-La Roche Ltd, SFJ Pharmaceutical and XCovery. S. Peters: Honoraria (self), Advisory / Consultancy: AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Eli Lilly, F. Hoffmann-La Roche Ltd, Janssen, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Regeneron and Takeda; Speaker Bureau / Expert testimony: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, F. Hoffmann-La Roche Ltd, Merck Sharp & Dohme, Novartis and Pfizer. J.A.A. Alexander: Honoraria (self), Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim Bristol-Myers Squibb, Pfizer and F. Hoffmann-La Roche Ltd/Genentech, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Takeda. N.B. Leighl: Research grant / Funding (self): F. Hoffmann-La Roche, Array, Guardant and AstraZeneca; Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, F. Hoffmann-Lar Roche, Pfizer ; Advisory / Consultancy: Excovery. V. Sriuranpong: Honoraria (self), Advisory / Consultancy: AstraZeneca, Novartis, F. Hoffmann-La Roche Ltd, Pfizer, Sanofi, Eisai, Boehringer, Taiho, Merck Sharp & Dohme, Bristol-Myers Squibb ; Research grant / Funding (institution): AstraZeneca, Novartis, F. Hoffmann-La Roche Ltd, Pfizer, Boehringer, Eisai, Taiho, Lilly and Merck Sharp & Dohme. M. Perol: Honoraria (self): F. Hoffmann-La Roche Ltd, AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Takeda, Chugai, Boehringer Ingelheim, Eli Lilly, Amgen and AbbVie. G. De Castro Jr.: Advisory / Consultancy: AstraZeneca, Merck Sharp & Dohme, Bristol-Myers Squibb, F. Hoffmann-La Roche Ltd, Novartis, Boehringer Ingelheim, Pfizer, Bayer; Speaker Bureau / Expert testimony: Merck Sharp & Dohme, Bristol-Myers Squibb, Novartis, AstraZeneca, Pfizer, F. Hoffmann-La Roche Ltd, Bayer, TEVA ; Travel / Accommodation / Expenses: Merck Sharp & Dohme, Bristol-Myers Squibb, F. Hoffmann-La Roche Ltd, Bayer, Novartis, Boehringer Ingelheim, AstraZeneca, Pfizer and Bayer.. E. Nadal: Honoraria (self), Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, F. Hoffmann-La Roche Ltd, Janssen, Merck Sharp & Dohme, Pfizer and Takeda. F. De Marinis: Honoraria (self): F. Hoffmann La Roche Ltd, Bristol-Myers Squibb, AstraZeneca and Merck. J. Han: Honoraria (self): Roche, AstraZeneca, BMS, MSD, Takeda; Advisory / Consultancy: AstraZeneca, BMS, MSD, Lilly, Novartis, Pfizer, Takeda; Research grant / Funding (self): Roche, Pfizer, ONO . M. Yan: Full / Part-time employment: F. Hoffmann-La Roche Ltd.. T. Riehl: Full / Part-time employment: Genentech, Inc. E. Schleifman: Full / Part-time employment: Genentech, Inc. S.M. Paul: Full / Part-time employment: Genentech, Inc. S. Mocci: Full / Part-time employment: Genentech, Inc. D. Shames: Full / Part-time employment: Genentech, Inc. M.S. Mathisen: Full / Part-time employment: Genentech, Inc. R. Dziadziuszko: Honoraria (self), Advisory / Consultancy: F. Hoffmann-La Roche Ltd, Pfizer, Boehringer Ingelheim, Clovis Oncology, Novartis, AstraZeneca and Tesaro..

Background

Prognosis is historically poor for pts with NSCLC with brain metastases. We present a pooled analysis from 4 clinical trials that evaluated outcomes in pts with PD-L1–positive NSCLC with stable brain metastases at baseline treated with pembro vs chemotherapy (chemo).

Methods

This post hoc analysis pooled data for pts with previously treated or untreated PD-L1–positive (PD-L1 TPS ≥1%) advanced NSCLC in KEYNOTE-001 (NCT01295827), KEYNOTE-010 (NCT01905657), KEYNOTE-024 (NCT02142738), and KEYNOTE-042 (NCT02220894) assigned to pembro (2 mg/kg, 10 mg/kg, or 200 mg Q3W, or 10 mg/kg Q2W) vs docetaxel (for previously treated NSCLC) or platinum-based chemo (for previously untreated NSCLC) Q3W. All studies included pts with stable brain metastases (ie, no symptoms or intracranial progression). Response (systemic, including in brain) was assessed per RECIST v1.1 by blinded, independent central review.

Results

3170 pts were included, 293 with and 2877 without baseline brain metastases; median (range) follow-up at data cutoff was 18.4 (0.5–43.7) mo and 12.6 (0.1–42.5) mo, respectively. HRs for OS and PFS were less than 1 with pembro vs chemo irrespective of baseline brain metastasis status (Table). Objective response rates were similar with pembro vs chemo but duration of response was longer with pembro. Fewer treatment-related AEs occurred with pembro vs chemo both in pts with brain metastases (66% vs 84%) and without (67% vs 88%); immune-mediated AEs and infusion reactions occurred in 21% vs 9%, respectively, with brain metastases and 25% vs 8% without.Table:

1482O

Conclusions

Pembro improved clinical outcomes and was well-tolerated vs chemo in pts with stable brain metastases, and provided similar outcomes in pts with and without brain metastases. Pembro is standard treatment in pts with advanced PD-L1–positive NSCLC, irrespective of brain metastases at baseline.

Clinical trial identification

NCT01295827; NCT01905657; NCT02142738; NCT02220894.

Editorial acknowledgement

Sheri Arndt, PharmD, of C4 MedSolutions, LLC (Yardley, PA, USA), a CHC Group company, funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

A.S. Mansfield: Honoraria (institution): AbbVie; Honoraria (institution): BMS; Honoraria (institution): Genentech; Research grant / Funding (institution): NIH; Honoraria (institution): Novartis; Honoraria (institution): Verily; Officer / Board of Directors, Non-remunerated activity/ies, unremunerated medical society/research group/foundation leadership as board member: Mesothelioma Applied Research Foundation. R.S. Herbst: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Merck; Advisory / Consultancy, consultant/advisory board member: AbbVie; Advisory / Consultancy, consultant/advisory board member: AstraZeneca; Advisory / Consultancy, consultant/advisory board member: Biodesix; Advisory / Consultancy, consultant/advisory board member: BMS; Advisory / Consultancy, consultant/advisory board member: Eli Lilly; Advisory / Consultancy, consultant/advisory board member: EMD Serono; Advisory / Consultancy, consultant/advisory board member: Genentech/Roche; Advisory / Consultancy, consultant/advisory board member: Heat Biologics; Advisory / Consultancy, consultant/advisory board member: Infinity Pharmaceuticals ; Advisory / Consultancy, consultant/advisory board member: Loxo Oncology; Advisory / Consultancy, consultant/advisory board member: Merck; Advisory / Consultancy, consultant/advisory board member: Nektar Therapeutics; Advisory / Consultancy, consultant/advisory board member: Neon Therapeutics; Advisory / Consultancy, consultant/advisory board member: NextCure; Advisory / Consultancy, consultant/advisory board member: Novartis; Advisory / Consultancy, consultant/advisory board member: Pfizer; Advisory / Consultancy, consultant/advisory board member: Sanofi; Advisory / Consultancy, consultant/advisory board member: Seattle Genetics; Advisory / Consultancy, consultant/advisory board member: Spectrum Pharmaceuticals; Advisory / Consultancy, consultant/advisory board member: Symphogen; Advisory / Consultancy, consultant/advisory board member: Tesaro; Advisory / Consultancy, consultant/advisory board member: ARMO BioSciences; Advisory / Consultancy, consultant/advisory board member: Genmab; Advisory / Consultancy, consultant/advisory board member: Tocagen; Advisory / Consultancy, board member (nonexecutive/independent): Junshi Biosciences. Commercial research grants from AstraZeneca, Eli Lilly, and Merck; consultant/advisory board member for AbbVie, AstraZeneca, Biodesix, BMS, Eli Lilly, EMD Serono, Genentech/Roche, Heat Biologics, Infinity Pharmaceuticals, Loxo Oncology, Merck, Nektar Therapeutics, Neon Therapeutics, NextCure, Novartis, Pfizer, Sanofi, Seattle Genetics, Shire, Spectrum Pharmaceuticals, Symphogen, Tesaro, ARMO BioSciences, Genmab, and Tocagen; board member (nonexecutive/independent) for Junshi Biosciences. G. Castro Jr: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Boehringer Ingelheim; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy: Yuhan; Speaker Bureau / Expert testimony: TEVA; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono. R. Hui: Honoraria (institution), Advisory / Consultancy: MSD; Advisory / Consultancy: AstraZeneca; Honoraria (institution), Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Honoraria (institution), Advisory / Consultancy: BMS. N. Peled: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), grants, personal fees, and honoraria for serving as an advisor: AstraZeneca; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), grants, personal fees, and honoraria for serving as an advisor: Boehringer Ingelheim; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), grants, personal fees, and honoraria for serving as an advisor: BMS; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), grants, personal fees, and honoraria for serving as an advisor: Eli Lilly; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), grants, personal fees, and honoraria for serving as an advisor: MSD; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), grants, personal fees, and honoraria for serving as an advisor: Novartis; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), grants, personal fees, and honoraria for serving as an advisor: Pfizer; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), grants, personal fees, and honoraria for serving as an advisor: Roche; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), grants, personal fees, and honoraria for serving as an advisor: NovellusDx; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), grants, personal fees, and honoraria for serving as an advisor: FMI; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), grants, personal fees, and honoraria for serving as an advisor: Gaurdant360. D. Kim: Research grant / Funding (institution): Alpha Biopharma; Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Hanmi; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): ONO Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): TP Therapeutics; Research grant / Funding (institution): Xcovery; Research grant / Funding (institution): Yuhan. S. Novello: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony: AbbVie; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD. M. Satouchi: Honoraria (institution), Research grant / Funding (institution): AstraZeneca; Honoraria (institution), Research grant / Funding (institution): MSD; Honoraria (institution), Research grant / Funding (institution): Chugai; Honoraria (institution): Taiho; Honoraria (institution), Research grant / Funding (institution): Pfizer; Honoraria (institution), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (institution), Research grant / Funding (institution): BMS; Honoraria (institution), Research grant / Funding (institution): Ono; Honoraria (institution), Research grant / Funding (institution): Novartis; Honoraria (institution), Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Ignyta. Y. Wu: Honoraria (institution), Advisory / Consultancy: AstraZeneca; Honoraria (institution): Eli Lilly; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (institution): Pierre Fabre; Honoraria (institution): Pfizer; Honoraria (institution): Sanofi; Advisory / Consultancy: Merck ; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim. E.B. Garon: Advisory / Consultancy: Dracen; Advisory / Consultancy: EMD Serono; Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Neon Therapeutics; Research grant / Funding (institution): Iovance Biotherapeutics; Research grant / Funding (institution): Dynavax; Research grant / Funding (institution): Mirati Therapeutics. M. Reck: Honoraria (institution), honoraria for consulting and lectures: Amgen; Honoraria (institution), honoraria for consulting and lectures: AstraZeneca; Honoraria (institution), honoraria for consulting and lectures: BMS; Honoraria (institution), honoraria for consulting and lectures: Boehringer Ingelheim; Honoraria (institution), honoraria for consulting and lectures: Celgene; Honoraria (institution), honoraria for consulting and lectures: Merck; Honoraria (institution), honoraria for consulting and lectures: MSD; Honoraria (institution), honoraria for consulting and lectures: Eli Lilly; Honoraria (institution), honoraria for consulting and lectures: Pfizer; Honoraria (institution), honoraria for consulting and lectures: AbbVie; Honoraria (institution), honoraria for consulting and lectures: Roche; Honoraria (institution), honoraria for consulting and lectures: Novartis. A.G. Robinson: Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Roche; Research grant / Funding (institution): AstraZeneca. A. Samkari: Full / Part-time employment, employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.: Merck Sharp & Dohme Corp. B. Piperdi: Full / Part-time employment, employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and owns stock in Merck & Co., Inc., Kenilworth, NJ, USA.: Merck Sharp & Dohme Corp. V. Ebiana: Full / Part-time employment, employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.: Merck Sharp & Dohme Corp. J. Lin: Full / Part-time employment, employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. : Merck Sharp & Dohme Corp. T.S.K. Mok: grants or research support from AstraZeneca, BMS, Clovis Oncology, Merck Sharp & Dohme, Novartis, Pfizer, Roche, SFJ Pharmaceuticals, and XCovery; speakers\' fees from AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, BMS, Taiho, and Takeda Oncology; honoraria from AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Boehringer Ingelheim, Merck Serono, Merck Sharp & Dohme, Novartis, SFJ Pharmaceuticals, ACEA Biosciences, Inc., Vertex Pharmaceuticals, BMS, OncoGenex Pharmaceuticals, Inc., Celgene, Ignyta, Inc., Fishawack Facilitate Ltd, Takeda Oncology, and Janssen; major stockholder in Sanomics Ltd.; advisory board member for AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Boehringer Ingelheim, Clovis Oncology, Merck Serono, Merck Sharp & Dohme, Novartis, SFJ Pharmaceuticals, ACEA Biosciences, Inc., Vertex Pharmaceuticals, BMS, geneDecode Co., Ltd., OncoGenex Technologies Inc., Celgene, Ignyta, Inc., Cirina, Fishawack Facilitate Ltd., Janssen, Takeda, and ChiMed; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Merck Sharp & Dohme; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): SFJ Pharmaceuticals; Research grant / Funding (institution): XCovery; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Roche/Genentech; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: Boehringer Ingelheim; Speaker Bureau / Expert testimony: Merck Sharp & Dohme; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: Taiho; Speaker Bureau / Expert testimony: Takeda Oncology; Honoraria (self): AstraZeneca; Honoraria (self): Roche/Genentech; Honoraria (self): Pfizer; Honoraria (self): Eli Lilly; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Merck Serono; Honoraria (self): Merck Sharp & Dohme; Honoraria (self): Novartis; Honoraria (self): SFJ Pharmaceuticals; Honoraria (self): ACEA Biosciences, Inc.; Honoraria (self): Vertex Pharmaceuticals; Honoraria (self): BMS; Honoraria (self): OncoGenex Pharmaceuticals, Inc.; Honoraria (self): Celgene; Honoraria (self): Ignyta, Inc.; Honoraria (self): Fishawack Facilitate Ltd; Honoraria (self): Takeda Oncology; Honoraria (self): Janssen; Shareholder / Stockholder / Stock options: Sanomics Ltd.; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Novartis; Advisory / Consultancy: SFJ Pharmaceuticals; Advisory / Consultancy: ACEA Biosciences, Inc.; Advisory / Consultancy: Vertex Pharmaceuticals; Advisory / Consultancy: BMS; Advisory / Consultancy: geneDecode Co.; Advisory / Consultancy: OncoGenex Technologies Inc.; Advisory / Consultancy: Celgene; Advisory / Consultancy: Ignyta, Inc., Advisory / Consultancy: Cirina; Advisory / Consultancy: Fishawack Facilitate Ltd.; Advisory / Consultancy: Janssen; Advisory / Consultancy: Takeda;Advisory / Consultancy: ChiMed.