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 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):19393-1944.
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, V3.217. https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf. 2. Öberg K, et al. Ann Oncol. 212;23(Suppl 7):vii12-vii123. 3. Öberg K, et al. Ann Oncol. 212;23(Suppl 7):vii124-vii13. 4. Kunz, PL. J Clin Oncol. 215;33(16):1855-1863. 5. Robert C, et al. Lancet. 214;384(9948):119-1117. 6. Garon EB, et al. N Engl J Med. 215;372(21):218-228. 7. Herbst RS, et al. Lancet. 216;387(127):154-155. 8. Bellmunt J, et al. N Engl J Med. 217;376:115-126.
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)
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
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
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 = 16 2.6% PD-L1 + PD-L1 positive tumors Carcinoid, n = 35 pnet, n = 26 24.5% 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
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 = 25 63. (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)
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, 2.-34.7) 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
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, 4.5-31.7) Data cutoff date: February 2, 217
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
Change From Baseline in Tumor Size (RECIST v1.1, investigator review) Change From Baseline, % 1 8 6 4 2-2 -4-6 -8-1 Carcinoid Change From Baseline, % 1 8 6 4 2-2 -4-6 -8 pnet -1 Partial response Stable disease Progressive disease Data cutoff date: February 2, 217
Longitudinal Change From Baseline in Tumor Size (RECIST v1.1, investigator review) Change From Baseline, % 12 1 8 6 4 2-2 -4-6 -8-1 Carcinoid 3 6 9 12 15 18 21 24 Time, Months Change From Baseline, % 12 1 8 6 4 2-2 -4-6 -8-1 pnet 3 6 9 12 15 18 21 24 Time, Months Responder Nonresponder Data cutoff date: February 2, 217
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 (1.5-1.9) Time to response 1.8 months Duration of response Partial response Progressive disease 9.2 months (6.9-11.1) Duration of response Partial response Progressive disease Ongoing response 2.3 months (ongoing) 5 1 1 5 2 2 5 5 1 1 5 2 2 5 Time, Months Time, Months Bar length is equivalent to the time to the last imaging assessment Data cutoff date: February 2, 217
Progression-Free Survival (RECIST v1.1, investigator review) Carcinoid pnet 1 44% 27% 1 4% 27% Progression-Free Survival, % 9 8 7 6 5 4 3 2 1 2 Median (95% CI) 5.6 (3.5-1.7) 1 Median (95% CI) 4.5 (3.6-8.3) 5 1 15 2 25 No. at risk Time, months Progression-Free Survival, % 9 8 7 6 5 4 3 5 1 15 2 25 No. at risk Time, months 25 16 8 4 2 16 7 4 2 2 Data cutoff date: February 2, 217
Carcinoid Overall Survival pnet Overall Survival, % 1 9 8 7 6 5 4 3 2 1 83% 65% 93% 87% Median (95% CI) 21.1 (9.1-22.4) 5 1 15 2 25 3 Time, months Overall Survival, % 1 9 8 7 6 5 4 3 2 1 Median (95% CI) 21. (2.2-NR) 5 1 15 2 25 3 Time, months No. at risk No. at risk 25 2 15 11 7 1 16 14 14 12 7 Data cutoff date: February 2, 217
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: https://clinicaltrials.gov/ct2/show/nct262867.