Chemotherapy and Immunotherapy in Combination Non-Small Cell Lung Cancer (NSCLC)

Chemotherapy and Immunotherapy in Combination Non-Small Cell Lung Cancer (NSCLC) Jeffrey Crawford, MD George Barth Geller Professor for Research in Cancer Co-Program Leader, Solid Tumor Therapeutics Program Duke Cancer Institute

Disclosures Jeffrey Crawford, MD Scientific Advisor: AstraZeneca, Merck, Pfizer DSMB Member: Beyond Spring, Celgene, G1 Therapeutics, Janssen, Merrimack, Mylan, Roche Principal Investigator/Institutional Research Funding: Amgen, AstraZeneca, Bayer

Introduction Limited randomized data of chemotherapy and immunotherapy Keynote 21G, randomized phase II trial of carboplatin and pemetrexed +/- pembrolizumab in Stage IV NSCLC 1,2 Pacific trial, randomized placebo controlled phase III trial of durvalumab after chemoradiotherapy in Stage III NSCLC 3,4 1 Langer CJ, et al. Lancet Oncol. 2016;17(11):1497-1508 2 Borghaei H. ESMO, 2017 3 Paz-Ares L. ESMO 2017 4 Antonia S. NEJM, 2017, 377:1919-29. 3

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Cohort G of the KEYNOTE-021 study (ClinicalTrials.gov, NCT02039674) was an open-label, randomized phase 2 trial of pembrolizumab plus pemetrexed-carboplatin (PC) vs PC alone in patients with previously untreated advanced nonsquamous NSCLC Primary analysis (minimum 6-month follow-up; median, 10.6 months) 1 Significant improvements in ORR (55% vs 29%; P = 0.0016) and PFS (HR, 0.53; P = 0.010) HR for OS, 0.90 (P = 0.39) ASCO updated analysis (median follow up, 14.5 months) 2 Improvements in ORR and PFS maintained HR for OS, 0.69 (P = 0.13) KEYNOTE-021 Cohort G Manageable safety profile in both analyses Pembrolizumab plus pemetrexed-carboplatin has received accelerated approval from the U.S. Food and Drug Administration for treatment of first-line nonsquamous NSCLC This presentation reports updated efficacy/safety with 5 additional months of follow-up (median, 18.7 months) 1. Langer CJ, et al. Lancet Oncol. 2016;17(11):1497-1508. 2. Papadimitrakopoulou VA, et al. 2017. J Clin Oncol. 35(suppl): abstract 9094.

Study Population 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 0 or 1 No untreated brain metastases No ILD or pneumonitis requiring systemic steroids KEYNOTE-021 Cohort G R (1:1) a N = 123 Pembrolizumab 200 mg Q3W for 2 years + Pemetrexed 500 mg/m 2 + Carboplatin AUC 5 mg/ml/min Q3W for 4 cycles Pemetrexed 500 mg/m 2 + Carboplatin AUC 5 mg/ml/min Q3W for 4 cycles 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 No alpha allocated for updated analysis; all P values are nominal (one-sided P < 0.025) a Randomization was stratified by PD-L1 TPS <1% vs 1%.

Study Population 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 0 or 1 No untreated brain metastases No ILD or pneumonitis requiring systemic steroids KEYNOTE-021 Cohort G R (1:1) a N = 123 Pembrolizumab 200 mg Q3W for 2 years + Pemetrexed 500 mg/m 2 + Carboplatin AUC 5 mg/ml/min Q3W for 4 cycles Pemetrexed 500 mg/m 2 + Carboplatin AUC 5 mg/ml/min Q3W for 4 cycles 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 No alpha allocated for updated analysis; all P values are nominal (one-sided P < 0.025) Pemetrexed 500 mg/m 2 Q3W permitted as maintenance therapy a Randomization was stratified by PD-L1 TPS <1% vs 1%.

Study Population 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 0 or 1 No untreated brain metastases No ILD or pneumonitis requiring systemic steroids KEYNOTE-021 Cohort G R (1:1) a N = 123 Pembrolizumab 200 mg Q3W for 2 years + Pemetrexed 500 mg/m 2 + Carboplatin AUC 5 mg/ml/min Q3W for 4 cycles b Pemetrexed 500 mg/m 2 + Carboplatin AUC 5 mg/ml/min Q3W for 4 cycles b 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 No alpha allocated for updated analysis; all P values are nominal (one-sided P < 0.025) PD Pembrolizumab 200 mg Q3W for 2 years PD, progressive disease. a Randomization was stratified by PD-L1 TPS <1% vs 1%. b Indefinite maintenance therapy with pemetrexed 500 mg/m 2 Q3W permitted.

Pembro + PC N = 60 PC Alone N = 63 Median (range) age, y 62.5 (40 77) 66.0 (37 80) Women 38 (63) 37 (59) ECOG PS 1 35 (58) 34 (54) Adenocarcinoma histology 58 (97) 55 (87) Stage IV disease 59 (98) 60 (95) Smoking status Current or former Never 45 (75) 15 (25) 54 (86) 9 (14) Stable brain metastases 9 (15) 6 (10) PD-L1 TPS <1% 1% 49% 50% Pembro, pembrolizumab. All data are n (%) unless otherwise stated. Data cut-off: May 31, 2017. Baseline Characteristics 21 (35) 19 (32) 20 (33) 23 (37) 23 (37) 17 (27)

ORR, % (95% CI) Confirmed ORR (RECIST v1.1 by Blinded, Independent Central Review) 100 90 80 70 60 50 40 30 20 10 0 56.7 Pembrolizumab + PC Δ24.8% (95% CI, 7.2% 40.9%) P = 0.0029 a 31.7 PC Alone Compared with prespecified analysis 1 : 3 additional responses observed: 1 in pembro + PC arm 2 in PC alone arm 1 complete response developed in each arm Similar between-arm difference in ORR Similar pattern of response across PD- L1 distribution 1. Langer CJ, et al. Lancet Oncol. 2016;17(11):1497-1508. a P value is descriptive (one-sided P < 0.025). Data cut-off: May 31, 2017.

P r o g r e s s io n -F r e e S u r v iv a l, % Progression-Free Survival (RECIST v1.1 by Blinded, Independent Central Review) 1 0 0 9 0 57% 37% 52% 29% Events, n/n HR (95% CI) 8 0 7 0 6 0 Pembro + PC 26/60 PC alone 40/63 0.54 (0.33 0.88) P = 0.0067 a 5 0 4 0 3 0 2 0 1 0 Median (95% CI) 19.0 (8.5 NR) 8.9 (6.2 11.8) 0 0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 N o. a t r is k T im e, m o n th s 60 51 43 32 24 22 17 9 1 0 63 42 35 25 18 13 8 5 1 0 a P value is descriptive (one-sided P < 0.025). Data cut-off: May 31, 2017.

O v e r a ll S u r v iv a l, % Overall Survival Events, n/n HR (95% CI) 1 0 0 9 0 8 0 7 0 6 0 5 0 4 0 3 0 2 0 1 0 N o. a t r is k Median (95% CI) NR (22.8 NR) 20.9 (14.9 NR) 77% 69% 0 0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 T im e, m o n th s 70% 56% 60 57 55 51 46 44 36 22 7 1 63 58 57 51 43 39 29 18 9 0 a 24 additional deaths since primary analysis (pembro + PC, n = 7; PC alone, n = 17). b P value is descriptive (one-sided P < 0.025). Data cut-off: May 31, 2017. Pembro + PC 20/60 a 0.59 (0.34 1.05) PC alone 31/63 a P = 0.03 b

Exposure and AE Summary Pembro + PC n = 59 Limited change in toxicity since last presentation of results 1 No additional fatal AEs 1 additional AE leading to discontinuation in each group PC Alone n = 62 Median (range) exposure, mo 10.1 (0 25.0) 4.9 (0 25.0) Treatment-related AEs, n (%) Any grade 55 (93) 57 (92) Grades 3 5 24 (41) 18 (29) Leading to discontinuation 9 (15) 9 (15) Leading to death 1 (2) 2 (3) a Fatal AEs were sepsis in the pembro + PC group and one case each of pancytopenia and sepsis in the PC alone group. Data cut-off: May 31, 2017. 1. Papadimitrakopoulou VA, et al. 2017. J Clin Oncol. 35(suppl): abstract 9094.

Incidence, % 100 90 80 70 60 50 40 30 20 10 0 Treatment-Related AEs With Incidence 15% 68 59 55 44 45 34 31 27 24 22 19 18 19 15 19 15 13 10 Grade 1 2 3 4 Pembro + PC PC alone 19 17 17 17 15 13 13 11 11 6 AST, aspartate aminotransferase; ALT, alanine aminotransferase. Data cut-off: May 31, 2017.

Incidence, % 16 14 12 10 8 6 AEs With Possible Immune Etiology Grade 14 1 2 3 4 Pembro + PC PC alone 8 7 5 4 2 0 3 2 Hypothyroidism Hyperthyroidism Pneumonitis Infusion reactions No grade 5 AEs with possible immune etiology 0 2 2 2 2 Severe skin toxicity 0 Colitis Data cut-off: May 31, 2017.

Data cut-off: May 31, 2017. Treatment-Related AEs With Incidence 15% Pembro + PC n = 59 PC Alone n = 62 Adverse Event, n (%) Any Grade Grades 3 5 Any Grade Grades 3 5 Fatigue 40 (68) 2 (3) 27 (44) 0 (0) Nausea 35 (59) 1 (2) 28 (45) 0 (0) Anemia 20 (34) 7 (12) 34 (55) 9 (15) Vomiting 18 (31) 1 (2) 11 (18) 0 (0) Rash 16 (27) 1 (2) 9 (15) 0 (0) Diarrhea 14 (24) 0 (0) 9 (15) 1 (2) Decreased appetite 13 (22) 0 (0) 12 (19) 0 (0) Aspartate aminotransferase increased 11 (19) 1 (2) 8 (13) 1 (2) Constipation 11 (19) 0 (0) 6 (10) 0 (0) Dysgeusia 11 (19) 0 (0) 7 (11) 0 (0) Alanine aminotransferase increased 10 (17) 1 (2) 8 (13) 1 (2) Blood creatinine increased 10 (17) 0 (0) 4 (6) 0 (0) Neutrophil count decreased 10 (17) 4 (7) 8 (13) 2 (3) Lacrimation increased 9 (15) 0 (0) 7 (11) 0 (0)

AEs With Possible Immune Etiology Pembro + PC n = 59 PC Alone n = 62 Adverse Event, n (%) Any Grade Grades 3 4 Any Grade Grades 3 4 Hypothyroidism 8 (14) 0 (0) 2 (3) 0 (0) Hyperthyroidism 5 (8) 0 (0) 1 (2) 0 (0) Pneumonitis 4 (7) 1 (2) 0 (0) 0 (0) Infusion reactions 1 (2) 1 (2) 3 (5) 0 (0) Severe skin toxicity 1 (2) 1 (2) 1 (2) 1 (2) Colitis 1 (2) 0 (0) 0 (0) 0 (0) No grade 5 AEs with possible immune etiology Data cut-off: May 31, 2017.

PACIFIC: Study Design Phase III, Randomized, Double-blind, Placebo-controlled, Multicenter, International Study Patients with stage III, locally advanced, unresectable NSCLC who have not progressed following definitive platinum-based ccrt ( 2 cycles) Durvalumab 10 mg/kg q2w for up to 12 months N=476 Co-primary endpoints PFS by BICR using RECIST v1.1* OS 18 years or older WHO PS score 0 or 1 Estimated life expectancy of 12 weeks Archived tissue was collected All-comers population 1 42 days post-ccrt R 2:1 randomization, stratified by age, sex, and smoking history N=713 Placebo 10 mg/kg q2w for up to 12 months N=237 Key secondary endpoints ORR (per BICR) DoR (per BICR) Safety and tolerability PROs *Defined as the time from randomization (which occurred up to 6 weeks post-ccrt) to the first documented event of tumor progression or death in the absence of progression. ClinicalTrials.gov number: NCT02125461 BICR, blinded independent central review; ccrt, concurrent chemoradiation therapy; DoR, duration of response; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PROs, patient-reported outcomes; PS, performance status; q2w, every 2 weeks; RECIST, Response Evaluation Criteria in Solid Tumors; WHO, World Health Organization

Baseline Characteristics, Stratification Factors, and Prior Therapy in the Intention-to-Treat Population

Baseline Characteristics, Stratification Factors, and Prior Therapy in the Intention-to-Treat Population

Probability of death or distant metastasis Time to Distant Metastasis or Death by BICR (ITT) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Durvalumab Placebo 1 3 6 9 12 15 18 21 24 27 30 Time from randomization (months) No. at risk Durvalumab 476 407 336 288 173 91 46 22 4 1 0 Placebo 237 184 129 106 63 32 16 5 4 0 0 Stratified hazard ratio, 0.52 (95% CI, 0.39 0.69) Two-sided P<0.0001 Durvalumab Placebo Median time (95% CI), 23.2 (23.2 NR) 14.6 (10.6 18.6) months BICR, blinded independent central review; ITT, intention-to-treat

Antitumor Activity in the Intention-to-Treat Population

Safety Summary* Durvalumab (N=475) Placebo (N=234) Any-grade all-causality AEs, n (%) 460 (96.8) 222 (94.9) Grade 3/4 142 (29.9) 61 (26.1) Grade 5 21 (4.4) 13 (5.6) Leading to discontinuation 73 (15.4) 23 (9.8) Any-grade treatment-related AEs, n (%) 322 (67.8) 125 (53.4) SAEs, n (%) 136 (28.6) 53 (22.6) Any-grade immune-mediated AEs, n (%) 115 (24.2) 19 (8.1) Grade 3/4 16 (3.4) 6 (2.6) *Two patients randomized to placebo received at least one dose of durvalumab and were considered part of the durvalumab arm for safety reporting. Safety analysis set. AE, adverse event; SAE, serious adverse event

Pneumonitis or Radiation Pneumonitis Pneumonitis (grouped terms) or radiation pneumonitis, n (%)* Durvalumab (N=475) Placebo (N=234) Any grade 161 (33.9) 58 (24.8) Grade 3/4 16 (3.4) 6 (2.6) Grade 5 5 (1.1) 4 (1.7) Leading to discontinuation 30 (6.3) 10 (4.3) Safety analysis set (all-causality). *Pneumonitis/radiation pneumonitis was assessed by investigators with subsequent review and adjudication by the study sponsor. In addition, pneumonitis, as reported in the table, is a grouped term, which includes acute interstitial pneumonitis, interstitial lung disease, pneumonitis, and pulmonary fibrosis. Two patients randomized to placebo received at least one dose of durvalumab and were considered part of the durvalumab arm for sa fety reporting.

Conclusions 1) In a randomized phase II trial in patients with advanced NSCLC, the addition of pembrolizumab was associated with improved PFS and OS, a) Associated increases in toxicity were largely Grade I/II b) Results of phase III trial are awaited 2) In a placebo, controlled phase III trial, durvalumab treatment was associated with improved PFS in patients with Stage III NSCLC after prior chemoradiotherapy a) Expected immune related toxicities were seen, along with an increase in radiation pneumonitis, predominantly Grade I/II b) Overall survival results are pending

Implications for Clinical Practice 1) The addition of immune checkpoint therapy in combination with chemotherapy in stage IV NSCLC or sequentially after chemoradiotherapy will be practice changing. 2) Extrapolation to other cancers should await well conducted controlled clinical trials. 3) To better understand the adverse event profile of combined strategies large phase IV trials and registries are needed.