Pembrolizumab/Chemo Not Effective in Extrapulmonary Poorly Differentiated Neuroendocrine Carcinomas

The combination of pembrolizumab (Keytruda) and irinotecan- or paclitaxel-based chemotherapy was not found to be effective in pretreated, biomarker-unselected patients with extrapulmonary poorly differentiated neuroendocrine carcinomas.

The combination of pembrolizumab (Keytruda) and irinotecan- or paclitaxel-based chemotherapy was not found to be effective in pretreated, biomarker-unselected patients with extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PDNECs) arising in different organs, according to data from part B of a phase 2 trial (NCT03136055) presented during the 2021 NANETS Annual Symposium.1

Results showed that among 22 evaluable patients, the combination of pembrolizumab and chemotherapy yielded an objective response rate (ORR) of 5%, which was comprised of 1 partial response (PR; 5%). Four patients had stable disease (18%), and 11 patients experienced disease progression (50%). Six patients were determined to be unevaluable (27%).

“Biomarker studies and correlative tests to evaluate potential markers of response/resistance are planned, and there is an urgent unmet need to [find] effective therapies for [patients with] previously treated EP-PDNEC,” Jennifer A. Chan, MD, MPH, lead study author, clinical director of the Gastrointestinal Cancer Center, director of the Program in Carcinoid and Neuroendocrine Tumors, and senior physician at the Dana-Farber Cancer Institute, said during a presentation of the data. “Combinations strategies with immunotherapy plus platinum-based chemotherapy in the frontline setting, [as well as] dual checkpoint inhibitor therapy, remain of interest.”

The efficacy of immune checkpoint inhibitor therapy has not been established in patients with EP-PDNEC, aside from Merkel cell carcinoma. However, in extensive-stage small cell lung cancer, checkpoint inhibitor therapy has regulatory approval for use in the frontline setting with platinum and etoposide, as well as in the salvage setting. Notably, salvage chemotherapy has shown limited activity in patients with EP-PDNEC, irrespective of the regimen utilized.

In the study, investigators sought to examine the safety and efficacy of pembrolizumab-based therapy in biomarker-unselected patients with EP-PDNEC. The study was split into 2 parts. Part A examined pembrolizumab monotherapy, and part B evaluated pembrolizumab plus chemotherapy.

Results from part A, which read out previously, found single-agent pembrolizumab to be inactive in this population.2 The immunotherapy elicited an ORR of 7% and resulted in a median progression-free survival (PFS) of 1.9 months. In the most recent update, investigators reported results from part B of the study.

The trial enrolled those with locally advanced or metastatic EP-PNEC who had progressive disease after at least 1 previous chemotherapy regimen, and an ECOG performance status of 0 or 1. Those with mixed histology were permitted if they have more than 50% NEC, and those with well-differentiated grade 3 neuroendocrine tumors and Merkel cell carcinoma were excluded.

Patients could not have previously received an anti–PD-1, anti–PD-L1, or anti–PD-12 agent. Moreover, they could not have central nervous system metastases or active autoimmune disease or immunodeficiency.

The primary end point of the study was ORR by RECIST v1.1 criteria, and secondary end points included safety, PFS, overall survival (OS), and duration of response (DOR). Exploratory end points comprised irRECIST vs RECISTv1.1; baseline peripheral blood, mononuclear cell, and tumor immune cell profiles; T-cell receptor repertoire change from baseline to post-treatment time points; tumor mutation profile; and Ki67 index and PD-L1 expression.

In part B of the study, participants were administered intravenous pembrolizumab at a dose of 200 mg every 21 days for up to 35 treatments plus physician’s choice of irinotecan at 125 mg/m2 on days 1 and 8 of every 21-day cycle or paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 21-day cycle. There was an initial safety lead-in of 6 to 12 patients who were treated with pembrolizumab plus irinotecan.

Overall, 22 patients were enrolled to the study. The median age of participants was 57 years (range, 34-75), and the majority were male (68%) and had an ECOG performance status of 1 (55%). Fifty percent of patients had primary disease in the gastrointestinal system, 23% in the pancreas, 5% in the gynecologic system, and 23% had an unknown primary site.

Additionally, 36% of patients had small cell histology, 27% had large cell, 14% had mixed tumors, and 23% had a histology that was not otherwise specified. The median Ki67 expression was 68% (range, 30%-95%), and the median number of prior lines of systemic therapy received was 1 (range, 1-3). Ninety-five percent of patients received prior platinum-based treatment.

In terms of treatment administration, 77% of patients received irinotecan (n = 17), and 23% received paclitaxel (n = 5). The median number of treatment cycles administered was 3 (range, 0-16), and the most common reasons for treatment discontinuation were disease progression (76%), adverse effects (AEs; 10%), and withdrawal of consent/other therapy (14%).

Additional data from part B of the trial showed that the median PFS was 2.0 months, and the median OS was 4.9 months.

The combination of pembrolizumab plus irinotecan was found to be safe, based on results from the safety lead-in. Grade 3/4 treatment-related AEs were reported in 36% of patients (n = 8/22), the most common of which was fatigue.

Investigators took a closer look at the 1 patient who achieved a PR with the chemoimmunotherapy regimen and noted that the primary disease site was in the colon and the histology was mixed large cell/adenocarcinoma. Mutations found in the tumor included PIK3CA, TP53, ATR, CTNNB1, PRKDC, and AURKA.

Other biomarker studies and correlative tests to examine potential markers or response or resistance to this kind of approach are planned.

References

  1. Chan JA, Raj NP, Aggarwal RR, et al. Pembrolizumab-based therapy in previously treated extrapulmonary poorly-differentiated neuroendocrine carcinomas: results of part B (pembrolizumab plus chemotherapy). Presented at: 2021 NANETS Annual Symposium; November 3-6, 2021; virtual. Abstract 172.
  2. Mulvey C, Raj NP, Chan JA, et al. Phase II study of pembrolizumab-based therapy in previously treated extrapulmonary poorly differentiated neuroendocrine carcinomas: results of part A (pembrolizumab alone). J Clin Oncol. 2019;37(suppl 4):363. doi:10.1200/JCO.2019.37.4_suppl.363