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Clinical Studies

Pembrolizumab alone and pembrolizumab plus chemotherapy in previously treated, extrapulmonary poorly differentiated neuroendocrine carcinomas

British Journal of Cancer volume 129, pages 291–300 (2023)Cite this article

Subjects

Abstract

Background

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.

Methods

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.

Results

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.

Discussion

Treatment with pembrolizumab alone and pembrolizumab plus chemotherapy was ineffective in advanced, progressive EP-PDNECs.

Clinical trial registration

ClinicalTrials.gov NCT03136055.

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Fig. 1: Study schema.
Fig. 2: Tumour responses and clinical outcomes.
Fig. 3: Pre- and on-treatment tumour growth rate.

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Data availability

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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Acknowledgements

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.

Funding

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).

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  1. These authors contributed equally: Nitya Raj, Jennifer A. Chan.

Authors and Affiliations

  1. Memorial Sloan Kettering (MSK) Cancer Center, New York, NY, USA

    Nitya Raj, April DeMore, Sippy Punn & Diane Reidy-Lagunes

  2. Dana-Farber Cancer Institute, Boston, MA, USA

    Jennifer A. Chan, Kimberly Perez & Sofia Von Fedak

  3. University of California San Francisco (UCSF), San Francisco, CA, USA

    Stephanie J. Wang, Rahul R. Aggarwal, Susan Calabrese, Lawrence Fong, Jennifer Grabowsky, Thomas A. Hope, Kanti Pallav Kolli, Claire K. Mulvey, Pamela N. Munster, Li Zhang & Emily K. Bergsland

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Contributions

NR, JAC and EKB conceived/designed the work that led to this submission, acquired data, and interpreted the results. SJW acquired data and interpreted results. RRA, SC, LF, JG, TAH, KPK, CKM, PNM, KP, DR-L and LZ interpreted the results. AM, SP and SvF acquired the data. All authors of this manuscript participated in drafting and/or revising the manuscript and approved the final manuscript version. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding authors

Correspondence to Nitya Raj or Emily K. Bergsland.

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Competing interests

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.

Ethics approval and consent to participate

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 129, 291–300 (2023). https://doi.org/10.1038/s41416-023-02298-8

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