Metastatic NSCLC: Expanding Role of Immunotherapy. Evan W. Alley, MD, PhD Abramson Cancer Center at Penn Presbyterian

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1 Metastatic NSCLC: Expanding Role of Immunotherapy Evan W. Alley, MD, PhD Abramson Cancer Center at Penn Presbyterian

2 Disclosures: No relevant disclosures Please note that some of the studies reported in this presentation were published as abstracts only and/or presented at a conference. These data and conclusions are included because expert faculty found them to be important scientific contributions but should be considered to be preliminary until published in a peerreviewed journal.

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4 Keynote 1: OS by PD-L1 Expression PD-L1 > 5% HR:.53 PD-L1 > 1% HR:.76 R Herbst et al. Lancet 216

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6 Role of Immunotherapy in Advanced NSCLC in 216 Platinum-refractory NSCLC: Pembrolizumab (PD-L1>1%) Nivolumab (PD-L1 any) Atezolizumab (PD-L1 any) Treatment-Naive NSCLC: Pembrolizumab (PD-L1>5%)

7 KEYNOTE-21 Cohort G: Pem/Carbo +/- Pembrolizumab Key Eligibility Criteria Untreated stage IIIB or IV nonsquamous NSCLC No activating EGFR mutation or ALK translocation Provision of a sample for PD-L1 assessment a ECOG PS -1 No untreated brain metastases No ILD or pneumonitis requiring systemic steroids R (1:1) a N=123 Pembrolizumab 2 mg Q3W for 2 years + Carboplatin AUC 5 mg/ml/min + Pemetrexed 5 mg/m 2 Q3W for 4 cycles b Carboplatin AUC 5 mg/ml/min + Pemetrexed 5 mg/m 2 Q3W for 4 cycles b PD Pembrolizumab 2 mg Q3W for 2 years End Points Primary: ORR (RECIST v1.1 per blinded, independent central review) Key secondary: PFS Other secondary: OS, safety, relationship between antitumor activity and PD-L1 TPS Langer et al, Lancet Oncology, 216

8 Updated Results from Keynote-21 Cohort G: PFS and OS Progression-free survival Overall survival Treatment Events, n/n Median, mos. HR P-value Events, n/n Median, mos. HR P-value Pembro + PC 28/6 PC alone 43/ (8.5-NR) 9.3 ( ) b 22/6 35/63 NR (24.5-NR) 21.1 (14.9-NR) b Median follow-up: > 24 months a P value is descriptive (one-sided P <.25). Data cut-off: May 31, 217. Borghaei et al, ESMO 9-17; Langer WCLC 1-17 Gentzler et al, ASCO 6-18 b

9 PFS and OS 21G (ASCO 18) PFS OS Progression-Free Survival, % % 3% 5% 25% No. at risk Time, months No. at risk Time, months Overall Survival, % 7% 55% 67% 48%

10 Study Design Patients: Metastatic nonsquamous NSCLC First line metastatic treatment Measurable disease ECOG PS -1 Tissue for biomarker available EGFR wild type EML4/ALK fusion negative No active CNS metastases Stratify: PD-L1 prop score: 1%, <1% Smoking status cisplatin vs carboplatin R A N D O M I Z A T I O N 2:1 N=57 Carboplatin/Cisplatin Pemetrexed Pembrolizumab 2 mg Q3W X4 cycles Carboplatin/Cisplatin Pemetrexed +Saline X4 cycles Pemetrexed Pembrolizumab Pemetrexed +Saline PD PD Pembrolizumab Primary Endpoint: PFS target HR.7 Secondary Endpoints: OS, ORR, AE Exploratory Endpoints: QoL Follow 1

11 Keynote 189: Results Pem/Carbo +/- Pembro

12 Keynote 189: Results by PD-L1 status OS TPS <1% TPS 1-49% TPS 5% TPS <1% TPS 1-49% TPS 5% PFS HR.59 ( ) HR.55 (.34-.9) HR.42 ( ) HR.75 ( ) HR.55 ( ) HR.36 ( )

13 Role of Immunotherapy in Advanced NSCLC in 216 Platinum-refractory NSCLC: Pembrolizumab (PD-L1>1%) Nivolumab (PD-L1 any) Atezolizumab (PD-L1 any) Treatment-Naive NSCLC: Pembrolizumab (PD-L1>5%)

14 Role of Immunotherapy in Advanced NSCLC in 217 Platinum-refractory NSCLC: Pembrolizumab (PD-L1>1%) Nivolumab (PD-L1 any) Atezolizumab (PD-L1 any) Treatment-Naive NSCLC: Pembrolizumab (PD-L1>5%) Pem/Carbo+Pembrolizumab (non-squamous, PD-L1 any)

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24 KEYNOTE-47 Study Design (NCT ) Key Eligibility Criteria Untreated stage IV NSCLC with squamous histology ECOG PS or 1 Pembrolizumab 2 mg Q3W + Carboplatin AUC 6 Q3W + Paclitaxel 2 mg/m 2 Q3W OR nab-paclitaxel 1 mg/m 2 Q1W for 4 cycles (each 3 wk) Pembrolizumab 2 mg Q3W for up to 31 cycles Provision of a sample for PD-L1 assessment R (1:1) No symptomatic brain metastases No pneumonitis requiring systemic steroids Placebo (normal saline) Q3W + Carboplatin AUC 6 Q3W + Paclitaxel 2 mg/m 2 Q3W OR nab-paclitaxel 1 mg/m 2 Q1W for 4 cycles (each 3 wk) Placebo (normal saline) Q3W for up to 31 cycles Stratification Factors PD-L1 expression (TPS a <1% vs 1%) Choice of taxane (paclitaxel vs nab-paclitaxel) Geographic region (east Asia vs rest of world) End points Primary: PFS (RECIST v1.1, BICR) and OS Secondary: ORR and DOR (RECIST v1.1, BICR), safety Optional Crossover b Pembrolizumab 2 mg Q3W for up to 35 cycles PD b BICR, blinded independent central radiologic review. a Percentage of tumor cells with membranous PD-L1 staining assessed using the PD-L1 IHC 22C3 pharmdx assay. b Patients could crossover during combination therapy or monotherapy. To be eligible for crossover, PD must have been verified by BICR and all safety criteria had to be met.

25 Frequency of PD-L1 TPS Categories Frequency, % % 37.% 34.2% 35.2% 26.3% 26.% Pembro + Chemo Placebo + Chemo 2.5% 1.8% <1% 1-49% 5% Not evaluable Not evaluable refers to specimens with an inadequate number of tumor cells or no tumor cells seen; these patients were included in the PD-L1 TPS <1% group for randomization stratification but excluded from analyses of efficacy by TPS. Data cutoff date: Apr 3, 218.

26 Overall Survival at IA2, ITT Events HR (95% CI) P Pembro + Chemo 3.6%.64.8 Placebo + Chemo 42.7% ( ) O S, % Median (95% CI) 15.9 mo (13.2-NE) 11.3 mo ( ) Months N o. at R isk Data cutoff date: Apr 3,

27 Overall Survival at IA2 by PD-L1 TPS TPS <1% TPS 1-49% TPS 5% Events HR (95% CI) Pembro + Chemo 3.5%.61 ( ) Placebo + Chemo 44.4% Events HR (95% CI) 3.1%.57 (.36-.9) 43.3% Events HR (95% CI) 31.5%.64 ( ) 41.1% O S, % O S, % O S, % Median (95% CI) 15.9 mo (13.1-NE) 1.2 mo ( ) Median (95% CI) 14. mo (12.8-NE) 11.6 mo ( ) Median (95% CI) NR (11.3 mo-ne) NR (7.4 mo-ne) Months Months Months N o. at R isk N o. at R isk N o. at R isk Data cutoff date: Apr 3, 218.

28 1 9 8 Progression-Free Survival at IA2, ITT (RECIST v1.1, BICR) Events HR (95% CI) P Pembro + Chemo 54.7%.56 <.1 Placebo + Chemo 7.1% (.45-.7) PFS, % Median (95% CI) 6.4 mo ( ) 4.8 mo ( ) Months N o. at R isk BICR, blinded, independent central review. Data cutoff date: Apr 3, 218.

29 Summary and Conclusions Pembrolizumab plus chemotherapy significantly improved OS (HR.64) over chemotherapy alone Benefit was observed irrespective of PD-L1 TPS: HR.61 for TPS <1%,.57 for TPS 1-49%, and.64 for TPS 5% PFS (HR.56) and ORR (P =.4) were also improved with pembrolizumab plus chemotherapy and responses were more durable AE frequency and severity were mostly similar between arms Observed events consistent with known safety profiles of pembrolizumab and chemotherapy, with no new safety signals identified Rates of discontinuation due to AEs were higher in the pembrolizumab plus chemotherapy arm, but generally low overall Immune-mediated AEs were more frequent in the pembrolizumab arm, with frequency and severity consistent with those observed for pembrolizumab monotherapy Data suggest pembrolizumab plus carboplatin and paclitaxel or nab-paclitaxel should become a new standard-of-care for first-line treatment of metastatic squamous NSCLC, irrespective of PD-L1 expression

30 Role of Immunotherapy in Advanced NSCLC in 217 Platinum-refractory NSCLC: Pembrolizumab (PD-L1>1%) Nivolumab (PD-L1 any) Atezolizumab (PD-L1 any) Treatment-Naive NSCLC: Pembrolizumab (PD-L1>5%) Pem/Carbo+Pembrolizumab (non-squamous, PD-L1 any)

31 Role of Immunotherapy in Advanced NSCLC in 218 Platinum-refractory NSCLC: Pembrolizumab (PD-L1>1%) Nivolumab (PD-L1 any) Atezolizumab (PD-L1 any) Treatment-Naive NSCLC (nonsquamous): Pembrolizumab (PD-L1>5%) Pem/Carbo+Pembrolizumab (PD-L1 any) Treatment-Naive NSCLC (squamous): Pembrolizumab (PD-L1>5%) Pac/Carbo+Pembrolizumab (PD-L1 any) Nab-Pac/Carbo+Pembro (PD-L1 any)

32 Practical Strategy for PD-L1>5% Pembrolizumab alone Older, frail patients Lower metastatic burden Significant co-morbidity Combination Pembrolizumab and Chemo Younger, heartier patients Higher metastatic burden More aggressive tumors Limited co-morbidity

33 Practical Strategy for PD-L1 1-49% Pembrolizumab alone (but PFS and OS were not significant in this cohort) Older, even frailer patients Minimal metastatic burden Significant co-morbidity Chemo-averse Combination Pembrolizumab and Chemo Majority of pts, even those with modest tumor burden Limited to moderate co-morbidity

34 Practical Strategy for PD-L1 % Combination Pembrolizumab and Chemo Virtually all pts De facto standard of care

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