Lancet Oncol 2016;17(11):1497-508. Updated Results from KEYNOTE-021 Cohort G: A Randomized, Phase 2 Study of Pemetrexed and Carboplatin (PC) with or without Pembrolizumab (pembro) as First-Line Therapy for Advanced Nonsquamous NSCLC Borghaei H et al. Proc ESMO 2017;Abstract LBA49.

KEYNOTE-021 Cohort G: Response Rates and Updated Survival Analyses HR = 0.59 p = 0.03 Endpoint Pembro + PC (n = 60) PC alone (n = 63) HR p-value ORR 56.7% 31.7% — 0.0029 mPFS 19.0 mo 8.9 mo 0.54 0.0067 mOS Not reached 20.9 mo 0.59 0.03 Borghaei H et al. Proc ESMO 2017;Abstract LBA49.

KEYNOTE-189 Phase III Trial Design Pembrolizumab 200 mg + pemetrexed 500 mg/m2 + (cisplatin 75 mg/m2 or carboplatin AUC 5) q3wk x 4 cycles* Estimated accrual (n = 646) Stage IV nonsquamous NSCLC No sensitizing EGFR mutation or ALK translocation Treatment naïve R Placebo + pemetrexed 500 mg/m2 + (cisplatin 75 mg/m2 or carboplatin AUC 5) q3wk x 4 cycles† 2:1 * Followed by pembrolizumab 200 mg with pemetrexed 500 mg/m2 q3wk until disease progression † Followed by placebo with pemetrexed 500 mg/m2 q3wk until disease progression Press release: Significant improvement in overall and progression-free survival in the first-line setting with pembrolizumab plus chemotherapy versus chemotherapy alone www.clinicaltrials.gov; NCT02578680. http://investors.merck.com/news/press-release-details/2018

Love N et al. Proc IASLC 2017;Abstract 75. A Biomarker-Driven Algorithm for Sequencing of Systemic Therapy for Metastatic Non-Small Cell Lung Cancer: A Survey of 25 Investigators Love N et al. Proc IASLC 2017;Abstract 75.

Love N et al. Proc IASLC 2017;Abstract 75. TPS = PD-L1 tumor proportion score Low TPS = 10%; high TPS = 60% Low TPS High TPS No targetable mutation EGFR mutation ALK rearrangement ROS1 rearrangement BRAF V600E mutation MET exon 14 mutation RET rearrangement HER2 mutation The New Taxonomy of Metastatic Non-Small Cell Lung Cancer T790M mutation-positive T790M mutation-negative Nonsquamous Squamous (no targetable mutation)  Targeted treatment Chemotherapy ± biologic Chemotherapy + checkpoint inhibitor Checkpoint inhibitor Love N et al. Proc IASLC 2017;Abstract 75. 

First-Line Treatment for Metastatic Squamous NSCLC Survey of clinical investigators (n = 25) TPS 10% Carboplatin/nab paclitaxel TPS 60% Love N et al. Proc IASLC 2017;Abstract 75. 

First-Line Treatment for Metastatic Nonsquamous NSCLC and No Identified Targetable Mutation Survey of clinical investigators (n = 25) TPS 10% TPS 60% Love N et al. Proc IASLC 2017;Abstract 75. 

Re-treated pts with irAE Re-treated pts without irAE Safety of Re-treatment with Immunotherapy After Immune-Related Toxicity in Patients with Lung Cancer Treated with Anti-PD-1/PD-L1 Therapy MSKCC cohort: Recurrent or new irAEs in re-treated patients Number of patients re-treated after a serious irAE (n = 38) Number of patients with new or recurrent irAE (n = 19) n (%) Re-treated pts with irAE 24% recurrent/26% new Re-treated pts without irAE p-value Grade of initial irAE 1/2 vs 3/4 12 (50) vs 7 (50) 1.0 Hospitalization for initial irAE 7 (87) 1 (13) 0.02 Steroid taper >4 weeks 7 (70) 3 (30) 0.15 Time to initial irAE <3 months >3 months 15 (63) 4 (29) 9 (37) 10 (71) 0.04 Deaths (due to irAE)   in re-treated pts 2/38 (5%) Objective response 3/38 (8%) irAE after re-treatment by initial irAE, n/N (%) Re-treated pts Arthralgia or myalgia 4/5 (80) Colitis 4/7 (57) Rash 2/5 (40) Pneumonitis 2/6 (33) Santini FC, ASCO 2017;Abstract 9012.

Immunotherapy Re-treatment OS/PFS PFS, OS similar in re-treated vs discontinued cohorts among pts who achieved CR/PR before initial irAE OS PFS P = 0.9 P = 0.31 Months Probability of PFS Probability of OS 0.25 0.50 0.75 1.00 10 20 30 Retreated Discontinued 40 Santini FC, ASCO 2017;Abstract 9012.

PACIFIC: Phase III Trial of Durvalumab After Chemoradiation Therapy in Stage III, Locally Advanced, Unresectable NSCLC Durvalumab 10 mg/kg q2wk for up to 12 months N = 476 Coprimary endpoints PFS by BICR using RECIST v1.1 Overall survival Stage III, locally advanced, unresectable NSCLC with no disease progression after definitive platinum-based cCRT (≥2 cycles) 18 years or older WHO PS 0 or 1 Estimated life expectancy of ≥12 weeks Archived tissue All-comers population 1-42 days post-cCRT 2:1 randomization, stratified by age, sex and smoking history N = 713 Key secondary endpoints ORR (per BICR) DoR (per BICR) Safety and tolerability Patient-reported outcomes Placebo 10 mg/kg q2wk for up to 12 months N = 237 cCRT = concurrent chemoradiation therapy; BICR = blinded independent central review Paz-Ares L et al. Proc ESMO 2017;Abstract LBA1.

PACIFIC: Progression-Free Survival (by BICR) Stratified hazard ratio, 0.52 Two-sided p < 0.001 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Durvalumab (N = 476) Placebo (N = 237) Median PFS, months 16.8 5.6 12-month PFS rate 55.9% 35.3% 18-month PFS rate 44.2% 27.0% PFS probability Durvalumab Placebo 3 6 9 12 15 18 21 24 27 Time from randomization (months) Paz-Ares L et al. Proc ESMO 2017;Abstract LBA1; Antonia SJ et al. N Engl J Med 2017;377(20):1919-29.

SQUIRE Trial: Phase III Study Design Gem-Cis + Neci q3w (N = 545) Necitumumab (800 mg D1, D8) Gemcitabine (1,250 mg/m², D1, D8) Cisplatin (75 mg/m², D1) Neci q3w (800 mg D1, D8) PD PRCRSD Maximum of 6 cycles Screening Entry criteria: Stage IV squamous NSCLC1,2 ECOG PS 0-2 1 R Gem-Cis q3w (N = 548) Gemcitabine (1,250 mg/m², D1, D8) Cisplatin (75 mg/m², D1) 1 Randomization (R) stratified by ECOG PS (0-1 vs 2) and geographic region (North America, Europe and Australia vs South America, South Africa and India vs Eastern Asia) Primary Endpoint: Overall survival (OS) Secondary Endpoints: Response rate, PFS, safety and other Exploratory Endpoints: Correlation with EGFR expression (H-score) and other 1 AJCC TNM Classification, 7th edition, 2009; 2 UICC TNM Classification of Malignant Tumors, 7th edition, 2009 Thatcher N et al, Lancet Oncology 2015;16(7):763-74.

SQUIRE Trial: Overall Survival OS Nec + Gem + Cis (n = 545) Gem + Cis (n = 548) HR, p-value Median OS 1-y OS 2-y OS 11.5 mo 48% 20% 9.9 mo 43% 17% 0.84, 0.01 Deaths 418 (77%) 442 (81%) Thatcher N et al. Lancet Oncology 2015;16(7):763-74.

SQUIRE Trial: Secondary Endpoints and Safety Gem/Cis + Neci  (n = 545) Gem/Cis  (n = 548) ORR (CR + PR) 31% 29% p = 0.40 DCR 82% 77% p = 0.043 Median PFS 5.7 mo 5.5 mo HR: 0.85 (0.74-0.98) p = 0.020 Safety Higher rate of serious adverse events in Gem/Cis + Neci arm: 38% vs 48% Slightly higher rate of AEs leading to discontinuation in Gem/Cis + Neci arm: 25% vs 31% Low rate of treatment-related fatal adverse events: 2% vs 3% Main differential adverse events in Gem/Cis + Neci arm: rash, hypomagnesemia, venous thromboembolic events Thatcher N et al. Lancet Oncology 2015;16(7):763-74.

REVEL Trial: Phase III Study Design Ramucirumab 10 mg/kg + Docetaxel 75 mg/m2 q3wk N = 628 Stage IV NSCLC after 1 platinum-based chemo +/- maintenance Prior Bev allowed All histologies ECOG PS 0 or 1 Treatment until disease progression or unacceptable toxicity R Placebo + Docetaxel 75 mg/m2 q3wk N = 625 1:1 Stratification factors: ECOG PS 0 vs 1 Gender Prior maintenance East Asia vs ROW Primary endpoint: Overall survival Secondary endpoints: PFS, ORR, safety, patient-reported outcomes using the Lung Cancer Symptoms Scale (LCSS) Bev = bevacizumab; ORR = objective response rate; PFS = progression-free survival; ROW = rest of the world Garon EB et al; Lancet 2014;384(9944):665-73

OS by Histology Median overall survival Ramucirumab + docetaxel Placebo + docetaxel Hazard ratio p-value All patients (n = 628, 625) 10.5 mo 9.1 mo 0.86 0.023 Nonsquamous (n = 465, 447) 11.1 mo 9.7 mo 0.83 0.020 Squamous (n = 157, 171) 9.5 mo 8.2 mo 0.88 0.319 Most subgroups had numerically longer survival on the ramucirumab arm. Garon EB et al; Lancet 2014;384(9944):665-73.

REVEL: PFS and RR in ITT and SCC Ramucirumab + docetaxel Placebo + docetaxel Hazard ratio (95% CI) p-value Median PFS ITT (n = 628, 625) SCC (n = 157, 171) 4.5 mo 4.2 mo 3.0 mo 2.7 mo 0.76 (0.68-0.86) 0.761 (0.606-0.957) <0.001 0.019 ORR ITT (n = 628, 625) SCC (n = 157, 171) 22.9% 26.8% 13.6% 10.5% — — <0.001 <0.001 DCR ITT (n = 628, 625) SCC (n = 157, 171) 64.0% 59.9% 52.6% 45.0% <0.001 0.015 Garon EB et al; Lancet 2014;384(9944):665-73.

Oxnard G et al. Plasma genotyping for predicting benefit from osimertinib in patients (pts) with advanced NSCLC. Proc ESMO 2016;Abstract 135O_PR.

Association between Plasma Genotyping and Outcomes with Osimertinib Sensitivity of plasma genotyping for detection of EGFR mutations: T790M: 70% Exon 19 del: 82% Exon 21 L858R: 86% Plasma positive for T790M in 31% of cases negative for T790M in tumor Outcome Tumor T790M + T790M - Plasma ORR (n = 173, 58, 164, 102) 62% 26% 63% 46% Median PFS (n = 179, 58, 169, 104) 9.7 mo 3.4 mo 8.2 mo Oxnard GT et al. J Clin Oncol 2016;34(28):3375-82. Oxnard GT et al. Proc ESMO 2016;Abstract 135O_PR.

Wakelee HA et al. Proc ASCO 2016;Abstract 9001. Epidermal Growth Factor Receptor (EGFR) Genotyping of Matched Urine, Plasma and Tumor Tissue from Non-Small Cell Lung Cancer (NSCLC) Patients (Pts) Treated with Rociletinib Wakelee HA et al. Proc ASCO 2016;Abstract 9001.

Plasma and Urine Detection Is Sensitive and Complements Tissue T790M Testing Tissue as reference, plasma sensitivity = 80.9% (313/387) Plasma vs tissue T790M Tissue Total Positive Negative Inadequate Plasma (BEAMing) 313 23 38 374 74 17 108 387 40 55 482 Urine sensitivity = 81.1% (142/175), with tissue as a reference Tissue as reference, urine sensitivity = 81.1% (142/175) Urine vs tissue T790M Tissue Total Positive Negative Inadequate Urine 142 11 16 169 31 5 6 42 2 175 22 213 Wakelee HA et al. Proc ASCO 2016;Abstract 9001.

Plasma, Tissue and Urine Identify Unique and Overlapping Subsets of Patients with T790M Mutation-Positive Disease 181 samples had matched pretreatment T790M results in plasma, tissue and urine 57% were positive by all 3 sample types Wakelee HA et al. Proc ASCO 2016;Abstract 9001.

Drilon A et al. Lancet Oncol 2016;17(12):1653-60. Cabozantinib in Patients with Advanced RET-Rearranged Non-Small-Cell Lung Cancer: An Open-Label, Single-Centre, Phase 2, Single-Arm Trial Drilon A et al. Lancet Oncol 2016;17(12):1653-60.

Cabozantinib in Patients with RET-Rearranged NSCLC Best confirmed response Partial response Stable disease Maximum reduction from baseline measurement (%) Best response % (n) PR 28% (7/25) ORR 28% Median PFS: 5.5 months Median DoR: 7.0 months Median OS: 9.9 months Of the 7 patients with confirmed PR, disease shrinkage of ≥30% was noted at the first response assessment in 5 (71%). Drilon A et al. Lancet Oncol 2016;17(12):1653-60.