Pembrolizumab for Patients With PD-L1 Positive Advanced Carcinoid or Pancreatic Neuroendocrine Tumors: Results From the KEYNOTE-028 Study

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1 Pembrolizumab for Patients With PD-L1 Positive Advanced Carcinoid or Pancreatic Neuroendocrine Tumors: Results From the KEYNOTE-28 Study Abstract 427O Mehnert JM, Bergsland E, O Neil BH, Santoro A, Schellens JHM, Cohen RB, Doi T, Ott PA, Pishvaian MJ, Puzanov I, Aung KL, Hsu C, Le Tourneau C, Soria J-C, Élez E, Tamura K, Gould M, Zhao G, Stein K, Piha-Paul SA

Programmed Death 1 (PD-1) and Pembrolizumab Tumors can exploit the PD-1 pathway to escape T-cell induced antitumor activity 1 Binding of PD-1 to PD-L1 and PD-L2 inhibits T-cell antitumor immune

2 Programmed Death 1 (PD-1) and Pembrolizumab Tumors can exploit the PD-1 pathway to escape T-cell induced antitumor activity 1 Binding of PD-1 to PD-L1 and PD-L2 inhibits T-cell antitumor immune response Tumors express varying levels of PD-L1 Pembrolizumab is a high-affinity antibody against PD-1 that blocks its interaction with PD-L1 and PD-L2 Robust antitumor activity and favorable safety profile in multiple tumor types Sui X, et al. Oncotarget. 215;6(23):

3 Rationale for Pembrolizumab in Carcinoids and Pancreatic Neuroendocrine Tumors (pnets) Systemic therapies are available for patients with advanced or metastatic carcinoids/pnets 1-3 Dependent on tumor type, systemic therapy may include Somatostatin analogues, cytotoxic chemotherapy, everolimus, interferon-2α, cisplatin/carboplatin plus etoposide, sunitinib, peptide receptor radionuclide therapy Many patients experience treatment failure or are unable to receive standard therapy 4 Prolonged survival with pembrolizumab in melanoma 5, non-small cell lung cancer 6,7, and urothelial cancer 8 suggested potential antitumor activity in other solid tumors 1. National Comprehensive Cancer Network (NCCN). Neuroendocrine tumors, V Öberg K, et al. Ann Oncol. 212;23(Suppl 7):vii12-vii Öberg K, et al. Ann Oncol. 212;23(Suppl 7):vii124-vii Kunz, PL. J Clin Oncol. 215;33(16): Robert C, et al. Lancet. 214;384(9948): Garon EB, et al. N Engl J Med. 215;372(21): Herbst RS, et al. Lancet. 216;387(127): Bellmunt J, et al. N Engl J Med. 217;376:

4 KEYNOTE-28 (ClinicalTrials.gov, NCT25486) Multicohort phase 1b study evaluating safety and antitumor activity of pembrolizumab in a variety of PD-L1 positive advanced solid tumors This is the first report from the carcinoid and pnet cohorts of KEYNOTE-28 Results from a biomarker evaluation across all cohorts are being presented separately in abstract 84PD Ott P, et al. Relationship of PD-L1 and a T-cell inflamed gene expression profile (GEP) to clinical response in a multicohort trial of solid tumors (KEYNOTE [KN]28)

5 KEYNOTE-28 (NCT25486): Phase Ib Multicohort Study of Pembrolizumab for PD-L1+ Advanced Solid Tumors Patients Carcinoid tumors or well or moderately differentiated pnets Failure of or inability to receive standard therapy ECOG PS or 1 1 measurable lesion PD-L1 positivity a No autoimmune disease or interstitial lung disease Pembrolizumab 1 mg/kg IV q2w Response assessment* CR, PR, or SD Confirmed PD b or unacceptable toxicity Treat for 24 months or until progression b or intolerable toxicity Discontinue pembrolizumab *Response assessment: Every 8 weeks for first 6 months; every 12 weeks thereafter Primary endpoints: ORR per RECIST v1.1 (investigator review) Secondary endpoints: PFS, OS, duration of response, and safety a At least 1% modified proportion score or interface pattern (QualTek IHC using 22C3 antibody clone); b If SD or better when pembrolizumab discontinued and subsequently have PD, patients may be eligible to resume pembrolizumab for 1 year; c If clinically stable, patients are to remain on pembrolizumab until progressive disease is confirmed on a second scan performed 4 weeks later

antibody clone Positivity: membranous PD-L1 expression in 1% of cells in tumor nests or positive bands in

6 Analysis of PD-L1 Expression Tumor samples: archival or newly obtained core or excisional biopsy of a nonirradiated lesion Immunohistochemistry: assessed at central laboratory using QualTek assay and 22C3 antibody clone Positivity: membranous PD-L1 expression in 1% of cells in tumor nests or positive bands in stroma Examples of PD-L1 staining in neuroendocrine tumor specimens from KEYNOTE-28 PD-L1 negative PD-L1 positive

6% PD-L1 + PD-L1 positive tumors Carcinoid, n = 35 pnet, n = 26 24.

7 PD-L1 Screening: Carcinoid/pNET Cohorts Patients screened for PD-L1 Carcinoid, n = 179 pnet, n = 19 Not evaluable (N = 9) Not evaluable (N = 3) Samples evaluable for PD-L1 Carcinoid, n = 17 pnet, n = % PD-L1 + PD-L1 positive tumors Carcinoid, n = 35 pnet, n = % PD-L1 + Patients treated as of January 1, 217 Carcinoid, N = 25 pnet, N = 16 a Patients with CNS metastases that were stable for 4 weeks could enroll

8 Characteristic Median age, years (range) Carcinoid N = 25 a Patients could have received 1 type of prior therapy Data cutoff date: February 2, 217 Baseline Characteristics pnet N = 16 Characteristic, n (%) Carcinoid N = (43 81) 61. (35 8) Stable brain metastases, n (%) 1 (4) Male, n (%) 8 (32) 5 (31) Race, n (%) White Asian Black or African American Other/not specified ECOG PS, n (%) 1 Metastatic staging MX M M1 Unknown/missing 15 (6) 5 (2) 3 (12) 2 (8) 6 (24) 19 (76) 2 (8) 21 (84) 2 (8) 9 (56) 2 (13) 3 (19) 2 (13) 1 (63) 6 (38) 1 (6) 2 (13) 11 (69) 2 (13) Site of disease, n (%) Lung Gut Other Prior therapies for recurrent/metastatic disease, n (%) 1 2 Unknown Select prior therapies, a n (%) Chemotherapy Somatostatin analogues Everolimus Sunitinib Investigational therapy 9 (36) 7 (28) 9 (36) 3 (12) 5 (2) 11 (44) 6 (24) 18 (72) 6 (24) 3 (12) 3 (12) pnet N = 16 1 (6) 5 (31) 8 (5) 2 (13) 9 (56) 6 (38) 1 (63) 4 (25) 1 (6)

9 Treatment-Related AEs: Carcinoid Occurring in 1% patients n (%) Any 17 (68) Diarrhea 7 (28) Fatigue 6 (24) Hypothyroidism 4 (16) Pyrexia 3 (12) Weight decreased 3 (12) Decreased appetite 3 (12) AST increase 3 (12) ALT increase 3 (12) Median follow-up: 2.2 months (range, ) No grade 4 or 5 events occurred Grade 3 n (%) Any 8 (32) Diarrhea 3 (12) ALT increase 2 (8) AST increase 2 (8) Feces discolored 1 (4) Fatigue 1 (4) Decreased appetite 1 (4) Hyperglycemia 1 (4) Hypovolemia 1 (4) Arthralgia 1 (4) Dyspnea 1 (4) Pneumonitis 1 (4) Dermatitis 1 (4) ALT, alanine aminotransferase; AST, aspartate aminotransferase Data cutoff date: February 2, 217

10 Treatment-Related AEs: pnet Occurring in 1% Patients n (%) Any 11 (69) Fatigue 6 (38) Diarrhea 4 (25) Pruritus 3 (19) Hypothyroidism 2 (13) Myalgia 2 (13) Rash 2 (13) Grade 3 n (%) Any 1 (6) Fatigue 1 (6) No grade 4 or 5 events occurred Median follow-up duration: 2.7 months (range, ) Data cutoff date: February 2, 217

11 Antitumor Activity (RECIST v1.1, investigator review a ) Carcinoid (N = 25) pnet (N = 16) Objective response rate, % (95% CI) 12% (3-31) 6% (.2-3) Best overall response, n (%) Complete response Partial response 3 (12%) 1 (6%) Stable disease 15 (6%) 14 (88%) 6 months 8 (32%) 5 (31%) Progressive disease 7 (28%) 1 (6%) a Only confirmed responses are included Data cutoff date: February 2, 217

12 Change From Baseline in Tumor Size (RECIST v1.1, investigator review) Change From Baseline, % Carcinoid Change From Baseline, % pnet -1 Partial response Stable disease Progressive disease Data cutoff date: February 2, 217

13 Longitudinal Change From Baseline in Tumor Size (RECIST v1.1, investigator review) Change From Baseline, % Carcinoid Time, Months Change From Baseline, % pnet Time, Months Responder Nonresponder Data cutoff date: February 2, 217

14 Treatment Exposure and Response Duration (RECIST v1.1, investigator review) Carcinoid pnet Median (range) (n =3 ) Time, months (n = 1) Time to response 1.9 months ( ) Time to response 1.8 months Duration of response Partial response Progressive disease 9.2 months ( ) Duration of response Partial response Progressive disease Ongoing response 2.3 months (ongoing) Time, Months Time, Months Bar length is equivalent to the time to the last imaging assessment Data cutoff date: February 2, 217

15 Progression-Free Survival (RECIST v1.1, investigator review) Carcinoid pnet 1 44% 27% 1 4% 27% Progression-Free Survival, % Median (95% CI) 5.6 ( ) 1 Median (95% CI) 4.5 ( ) No. at risk Time, months Progression-Free Survival, % No. at risk Time, months Data cutoff date: February 2, 217

16 Carcinoid Overall Survival pnet Overall Survival, % % 65% 93% 87% Median (95% CI) 21.1 ( ) Time, months Overall Survival, % Median (95% CI) 21. (2.2-NR) Time, months No. at risk No. at risk Data cutoff date: February 2, 217

17 Conclusions Pembrolizumab was generally well-tolerated in both study cohorts Safety profile was consistent with previous experience for pembrolizumab monotherapy in other tumor types Pembrolizumab provided an ORR of 12% in patients with carcinoid tumors and 6% in patients with pnets Responses were durable, with all lasting 6 months Median time to response was <2 months in both cohorts Given the heavily pretreated patient populations, the 12-month PFS and OS rates were encouraging Further evaluation of pembrolizumab in carcinoids and pnets is warranted KEYNOTE-158 is evaluating pembrolizumab in larger cohorts of patients with advanced solid tumors, including neuroendocrine tumors, with additional biomarker evaluation 1 1. National Institutes of Health, Available at:

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