Phase II study of pembrolizumab-based therapy in previously treated extrapulmonary poorly differentiated neuroendocrine carcinomas: Results of Part B (pembrolizumab + chemotherapy).
Authors: Chan Jennifer A. , Raj Nitya Prabhakar , Aggarwal Rahul Raj , Calabrese Susan , DeMore April , Dhawan Mallika Sachdev , Fattah Delaire , Fong Lawrence , Grabowsky Jennifer , Hope Thomas A , Kolli Kanti Pallav , Munster Pamela N. , Perez Kimberly , Reidy Diane Lauren , Von Fedak Sofia , Zhang Li , Bergsland Emily K. 
Published: June 2021

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Background: The efficacy of immune checkpoint inhibitor (CPI) therapy has not been established in extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PDNECs). In small cell lung cancer, CPI therapy is approved for use in the first-line and salvage settings. We investigated the efficacy and safety of pembrolizumab (PEM)-based therapy in biomarker-unselected patients (pts) with EP-PDNECs. PEM alone (Part A, N=14) was inactive (ASCO GI 2019; Abstr#363). We now report the results of Part B (PEM plus chemotherapy). Methods: We conducted an open label, multicenter, phase 2 study of PEM-based therapy in pts with EP-PDNECs, excluding Merkel cell carcinoma and well differentiated grade 3 neuroendocrine tumors (NET), with disease progression on first-line systemic therapy. In Part B of this trial, patients were treated with PEM 200 mg IV every 3 week cycle plus dealers’ choice chemotherapy (chemo): weekly irinotecan (IRI, 125 mg/m2 day 1,8 of every 21 day cycle) or weekly paclitaxel (PAC, 80 mg/m2). After PEM/IRI safety lead-in (N=6), 16 additional pts (total N=22) were enrolled. This was based on a primary endpoint of objective response rate (ORR) by RECIST 1.1 and a plan to test Ha ORR 31% vs H0 ORR 10% with 80% power at a type I error rate of 0.05. Secondary endpoints include safety, overall survival (OS), and progression-free survival (PFS). Serial blood samples and baseline tumor biopsies were required in all pts. Results: Preliminary data from Part B are available. Of 22 pts enrolled, male/female 15/7; median age 57 years (range 34-75); ECOG PS 0/1: 10/12; 6 large cell, 8 small cell, 8 NOS. Primary sites of disease: GI 73%, GYN 5%, unknown 23%. Ki67 index (available for 18 pts) median 68% (range 30 to >95%). Chemo choice: 17 IRI (77%) and 5 PAC (23%). PEM/IRI was safe based on lead-in. Median number of cycles of therapy administered was 3 (range 0-13). Treatment-related Gr 3 or 4 AE occurred in 7 (32%) of 22 pts overall: 4 (18%) had at least one Gr 3 AE attributed to PEM (1 pt each with pain, ALT increase, or nausea; 2 with fatigue); 7 (32%) had at least one Gr 3/4 AE attributed to chemo (2 with fatigue, 2 with neutropenia; 1 each with pain, ALT increase, hyponatremia, diarrhea, nausea, and/or acute kidney injury). No grade 5 AE. ORR was 9%: PR in 2 pts (9%), SD 3 pts (14%), PD 13 pts (60%); 4 pts (18%) unevaluable (off study before first scheduled scan). Median PFS 2 mo. At last follow-up, 5 pts (23%) were alive with 1 pt still on treatment. Median OS 4 mo. Of 21 pts off treatment, 76% off for PD, 10% off for AE, 14% off for withdrawal of consent/other therapy. Conclusions: PEM + chemotherapy was not effective in this pretreated, biomarker-unselected population of EP-PDNECs arising in different organs. Biomarker studies are planned (Parts A/B). Clinical trial information: NCT03136055.