To date, single-agent immune checkpoint inhibitor (CPI) therapy has proven to be ineffective against biomarker-unselected extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PDNECs). The efficacy of CPI in combination with chemotherapy remains under investigation.
Patients with advanced, progressive EP-PDNECs were enrolled in a two-part study of pembrolizumab-based therapy. In Part A, patients received pembrolizumab alone. In Part B, patients received pembrolizumab plus chemotherapy. Primary endpoint: objective response rate (ORR). Secondary endpoints: safety, progression-free survival (PFS) and overall survival (OS). Tumours were profiled for programmed death-ligand 1 expression, microsatellite-high/mismatch repair deficient status, mutational burden (TMB), genomic correlates. Tumour growth rate was evaluated.
Part A (N = 14): ORR (pembrolizumab alone) 7% (95% CI, 0.2–33.9%), median PFS 1.8 months (95% CI, 1.7–21.4), median OS 7.8 months (95% CI, 3.1–not reached); 14% of patients (N = 2) had grade 3/4 treatment-related adverse events (TRAEs). Part B (N = 22): ORR (pembrolizumab plus chemotherapy) 5% (95% CI, 0–22.8%), median PFS 2.0 months (95% CI, 1.9–3.4), median OS 4.8 months (95% CI, 4.1–8.2); 45% of patients (N = 10) had grade 3/4 TRAEs. The two patients with objective response had high-TMB tumours.
Treatment with pembrolizumab alone and pembrolizumab plus chemotherapy was ineffective in advanced, progressive EP-PDNECs.
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The data generated and analysed for this study are available within this manuscript, and the accompanying tables and figures, with the exception of identifiable information. Any additional inquiries should be referred to the corresponding author.
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We wish to thank all of the patients participating in this study and their caregivers, along with the investigators and research study teams at UCSF, MSK and DFCI. In addition, we would like to thank Merck for supporting this multicenter study through the Merck Investigator Studies Programme.
This work was supported and funded by Merck & Co.; additional support provided by the National Cancer Institute of the National Institutes of Health under Award Numbers P30CA082103 (USCF), P30CA008748 (MSK), and P30CA006516 (DFCI).
Dr. Nitya Raj: research funding (ITM, Corcept Therapeutics), consulting/advisory boards (Ipsen Pharma, HRA Pharma, Progenics Pharmaceuticals, AAA). Dr. Jennifer Chan: consulting/advisory boards (TerSera, AAA, Curium), honorarium (Ipsen), stock ownership (Merck). Dr. Rahul Aggarwal: research funding (Merck). Dr. Lawrence Fong: research funding (Roche/Genentech, Abbvie, Bavarian Nordic, Bristol Myers Squibb, Dendreon, Janssen, Merck, Partner Therapeutics), advisory boards (Actym, Allector, Astra Zeneca, Atreca, Bioalta, Bolt, Bristol Myer Squibb, Daiichi Sankyo, Immunogenesis, Innovent, Merck, Merck KGA, Nutcracker, RAPT, Scribe, Senti, Soteria, Sutro, Roche/Genentech). Dr. Thomas Hope: research funding (Clovis Oncology, GE Healthcare, Philips, AAA), consulting (Bayer, Curium, ITM, RayzeBio), advisory boards (Blue Earth Diagnostics, Ipsen), stock ownership (RayzeBio). Dr. Claire Mulvey: research funding (Genentech). Dr. Pamela Munster: research funding (Merck). Dr. Kimberly Perez: consulting/scientific advisory boards (Lantheus, Helsinn/QED). Dr. Diane Reidy-Lagunes: research funding (Merck, Ipsen, Novartis). The remaining authors declare no competing interests.
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The study was reviewed by the University of California San Francisco (UCSF), Memorial Sloan Kettering Cancer Center (MSK), and Dana-Farber Cancer Institute (DFCI) Institutional Review Boards and was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. All patients provided written informed consent before study enrolment.
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Raj, N., Chan, J.A., Wang, S.J. et al. Pembrolizumab alone and pembrolizumab plus chemotherapy in previously treated, extrapulmonary poorly differentiated neuroendocrine carcinomas. Br J Cancer (2023). https://doi.org/10.1038/s41416-023-02298-8