Clinical Study

Pembrolizumab monotherapy in patients with previously treated metastatic high-grade neuroendocrine neoplasms: joint analysis of two prospective, non-randomised trials

Abstract

Background

Metastatic high-grade neuroendocrine neoplasms (G3NENs) have limited treatment options after progression on platinum-based therapy. We addressed the role of Pembrolizumab in patients with previously treated metastatic G3NENs.

Methods

Two open-label, phase 2 studies enrolled patients with G3NEN (Ki-67 > 20%) to receive Pembrolizumab at 200 mg I.V. every 3 weeks. Radiographic evaluation was conducted every 9 weeks with overall response rate as the primary endpoint.

Results

Between November 2016 and May 2018, 29 patients (13 males/16 females) with G3NENs were enrolled. One patient (3.4%) had an objective response and an additional six patients (20.7%) had stable disease, resulting in a disease control rate of 24.1%. Disease control rate (DCR) at 18 weeks was 10.3% (3/29). There was no difference in the DCR, PFS or OS between the PD-L1-negative and -positive groups (p 0.56, 0.88 and 0.55, respectively). Pembrolizumab was well tolerated with only 9 grade 3, and no grade 4 events considered drug-related.

Conclusions

Pembrolizumab can be safely administered to patients with G3NENs but has limited activity as a single agent. Successful completion of our trials suggest studies in G3NENs are feasible and present an unmet need. Further research to identify active combination therapies should be considered.

Clinical trial registration number

NCT02939651 (10/20/2016).

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Fig. 1: Waterfall plot depicting best overall response to therapy by patient.
Fig. 2: Kaplan-Meier curve showing progression free survival (PFS) among 29 patients who received Pembrolizumab.
Fig. 3: Kaplan Meier curve showing overall survival since treatment initiation among 29 patients who received Pembrolizumab.

References

  1. 1.

    Dasari, A., Mehta, K., Byers, L. A., Sorbye, H. & Yao, J. C. Comparative study of lung and extrapulmonary poorly differentiated neuroendocrine carcinomas: a SEER database analysis of 162,983 cases. Cancer 124, 807–815 (2018).

    Article  Google Scholar 

  2. 2.

    Fazio, N. & Milione, M. Heterogeneity of grade 3 gastroenteropancreatic neuroendocrine carcinomas: new insights and treatment implications. Cancer Treat. Rev. 50, 61–67 (2016).

    Article  Google Scholar 

  3. 3.

    Yachida, S., Vakiani, E., White, C. M., Zhong, Y., Saunders, T., Morgan, R. et al. Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. Am. J. Surg. Pathol. 36, 173–184 (2012).

    Article  Google Scholar 

  4. 4.

    Tang, L. H., Basturk, O., Sue, J. J. & Klimstra, D. S. A Practical approach to the classification of WHO Grade 3 (G3) well-differentiated neuroendocrine tumor (WD-NET) and poorly differentiated neuroendocrine carcinoma (PD-NEC) of the pancreas. Am. J. Surgical Pathol. 40, 1192–1202 (2016).

    Article  Google Scholar 

  5. 5.

    Inzani, F., Petrone, G. & Rindi, G. The New World Health Organization Classification for Pancreatic Neuroendocrine Neoplasia. Endocrinol. Metab. Clin. North Am. 47, 463–470 (2018).

    Article  Google Scholar 

  6. 6.

    Klimstra, D. S. K. G., La Rosa, S., Rindi G. in Classification of neuroendocrine neoplasms of the digestive system. WHO Classification of Tumours Digestive System Tumours (ed. Board The WHO Classification of Tumours Editorial) 5th edn., 16–21 (International Agency for Research on Cancer, Lyon, 2019).

  7. 7.

    Sorbye, H., Baudin, E. & Perren, A. The problem of high-grade gastroenteropancreatic neuroendocrine neoplasms: well-differentiated neuroendocrine tumors, neuroendocrine carcinomas, and beyond. Endocrinol. Metab. Clin. North Am. 47, 683–698 (2018).

    Article  Google Scholar 

  8. 8.

    Velayoudom-Cephise, F. L., Duvillard, P., Foucan, L., Hadoux, J., Chougnet, C. N., Leboulleux, S. et al. Are G3 ENETS neuroendocrine neoplasms heterogeneous? Endocr. Relat. Cancer 20, 649–657 (2013).

    Article  Google Scholar 

  9. 9.

    Sorbye, H., Strosberg, J., Baudin, E., Klimstra, D. S. & Yao, J. C. Gastroenteropancreatic high‐grade neuroendocrine carcinoma. Cancer 120, 2814–2823 (2014).

    CAS  Article  Google Scholar 

  10. 10.

    Sorbye, H., Welin, S., Langer, S. W., Vestermark, L. W., Holt, N., Osterlund, P. et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann. Oncol Off. J. Eur. Soc. Med. Oncol. 24, 152–160 (2013).

    CAS  Article  Google Scholar 

  11. 11.

    Lepage, C., Ciccolallo, L., De Angelis, R., Bouvier, A., Faivre, J. & Gatta, G. European disparities in malignant digestive endocrine tumours survival. Int. J. Cancer 126, 2928–2934 (2010).

    CAS  PubMed  Google Scholar 

  12. 12.

    Galanis, E., Frytak, S. & Lloyd, R. V. Extrapulmonary small cell carcinoma. Cancer 79, 1729–1736 (1997).

    CAS  Article  Google Scholar 

  13. 13.

    Klimstra, D. S., Modlin, I. R., Coppola, D., Lloyd, R. V. & Suster, S. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas 39, 707–712 (2010).

    Article  Google Scholar 

  14. 14.

    Yao, J. C., Hassan, M., Phan, A., Dagohoy, C., Leary, C., Mares, J. E. et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 26, 3063–3072 (2008).

    Article  Google Scholar 

  15. 15.

    Kunz P. L. Carcinoid and neuroendocrine tumors: building on success. J. Clin. Oncol. 33, 1855–1863 (2015).

  16. 16.

    Walenkamp, A. M., Sonke, G. S. & Sleijfer, D. T. Clinical and therapeutic aspects of extrapulmonary small cell carcinoma. Cancer Treat. Rev. 35, 228–236 (2009).

    CAS  Article  Google Scholar 

  17. 17.

    Moertel, C. G., Kvols, L. K., O’Connell, M. J. & Rubin, J. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Cancer 68, 227–232 (1991).

    CAS  Article  Google Scholar 

  18. 18.

    Rindi, G., Inzani, F. & Solcia, E. Pathology of gastrointestinal disorders. Endocrinol. Metab. Clin. North Am. 39, 713–727 (2010).

    CAS  Article  Google Scholar 

  19. 19.

    Mitry, E., Baudin, E., Ducreux, M., Sabourin, J., Rufie, P., Aparicio, T. et al. Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin. Br. J. Cancer 81, 1351 (1999).

    CAS  Article  Google Scholar 

  20. 20.

    Heetfeld, M., Chougnet, C. N., Olsen, I. H., Rinke, A., Borbath, I., Crespo, G. et al. Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. Endocr. Relat. cancer 22, 657–664 (2015).

    CAS  Article  Google Scholar 

  21. 21.

    Olsen, I. H., Sorensen, J. B., Federspiel, B., Kjaer, A., Hansen, C. P., Knigge, U. et al. Temozolomide as second or third line treatment of patients with neuroendocrine carcinomas. Sci. World J. 2012, 170496 (2012).

    Article  Google Scholar 

  22. 22.

    Hentic, O., Hammel, P., Couvelard, A., Rebours, V., Zappa, M., Palazzo, M. et al. FOLFIRI regimen: an effective second-line chemotherapy after failure of etoposide-platinum combination in patients with neuroendocrine carcinomas grade 3. Endocr. Relat. cancer 19, 751–757 (2012).

    CAS  Article  Google Scholar 

  23. 23.

    Wolchok, J. D., Kluger, H., Callahan, M. K., Postow, M. A., Rizvi, N. A., Lesokhin, A. M. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).

    CAS  Article  Google Scholar 

  24. 24.

    Motzer, R. J., Rini, B. I., McDermott, D. F., Redman, B. G., Kuzel, T. M., Harrison, M. R. et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J. Clin. Oncol. 33, 1430–1437 (2015).

    CAS  Article  Google Scholar 

  25. 25.

    Brahmer, J., Reckamp, K. L., Baas, P., Crinò, L., Eberhardt, W. E., Poddubskaya, E. et al. Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015).

    CAS  Article  Google Scholar 

  26. 26.

    Hellmann, M. D., Ott, P. A., Zugazagoitia, J., Ready, N. E., Hann, C. L., De Braud, F. G., et al. Nivolumab (nivo)±ipilimumab (ipi) in advanced small-cell lung cancer (SCLC): First report of a randomized expansion cohort from CheckMate 032. (American Society of Clinical Oncology, 2017).

  27. 27.

    Chung, H. C., Lopez-Martin, J. A., Kao, S. C.-H., Miller, W. H., Ros, W., Gao, B., et al. Phase 2 study of pembrolizumab in advanced small-cell lung cancer (SCLC): KEYNOTE-158. (American Society of Clinical Oncology, 2018).

  28. 28.

    Nghiem, P., Bhatia, S., Daud, A., Friedlander, P., Kluger, H., Kohrt, H. et al. 22LBA Activity of PD-1 blockade with pembrolizumab as first systemic therapy in patients with advanced Merkel cell carcinoma. Eur. J. Cancer 51, S720–S721 (2015).

    Article  Google Scholar 

  29. 29.

    Nghiem, P., Bhatia, S., Lipson, E. J., Sharfman, W. H., Kudchadkar, R. R., Brohl, A. S. et al. Durable tumor regression and overall survival in patients with advanced merkel cell carcinoma receiving pembrolizumab as first-line therapy. J. Clin. Oncol. 37, 693–702 (2019).

    CAS  Article  Google Scholar 

  30. 30.

    Horn, L., Mansfield, A. S., Szczesna, A., Havel, L., Krzakowski, M., Hochmair, M. J., et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N. Engl. J. Med. 379, 2220–2229 (2018).

  31. 31.

    Kim, S. T., Ha, S. Y., Lee, S., Ahn, S., Lee, J., Park, S. H. et al. The impact of PD-L1 expression in patients with metastatic GEP-NETs. J. Cancer 7, 484–489 (2016).

    CAS  Article  Google Scholar 

  32. 32.

    Kim, H. S., Lee, J. H., Nam, S. J., Ock, C.-Y., Moon, J.-W., Yoo, C. W. et al. Association of PD-L1 expression with tumor-infiltrating immune cells and mutation burden in high-grade neuroendocrine carcinoma of the lung. J. Thorac. Oncol. 13, 636–648 (2018).

    Article  Google Scholar 

  33. 33.

    Vijayvergia, N., Boland, P. M., Handorf, E., Gustafson, K. S., Gong, Y., Cooper, H. S. et al. Molecular profiling of neuroendocrine malignancies to identify prognostic and therapeutic markers: a Fox Chase Cancer Center Pilot Study. Br. J. Cancer 115, 564 (2016).

    CAS  Article  Google Scholar 

  34. 34.

    Snyder, A., Makarov, V., Merghoub, T., Yuan, J., Zaretsky, J. M., Desrichard, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).

    Article  Google Scholar 

  35. 35.

    Bergsland, E. K., Roy, R., Stephens, P., Ross, J. S., Bailey, M. & Olshen, A. Genomic profiling to distinguish poorly differentiated neuroendocrine carcinomas arising in different sites. J. Clin. Oncol. 34(15_suppl), 4020- (2016).

    Article  Google Scholar 

  36. 36.

    Reck, M., Rodríguez-Abreu, D., Robinson, A. G., Hui, R., Csőszi, T., Fülöp, A. et al. Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N. Engl. J. Med. 375, 1823–1833 (2016).

    CAS  Article  Google Scholar 

  37. 37.

    Hamid, O., Robert, C., Daud, A., Hodi, F. S., Hwu, W.-J., Kefford, R. et al. Safety and tumor responses with lambrolizumab (anti–PD-1) in melanoma. N. Engl. J. Med. 369, 134–144 (2013).

    CAS  Article  Google Scholar 

  38. 38.

    Yao, J. C., Campana, D., Hijioka, S., Raderer, M., Guimbaud, R., Gajate, P., et al. 1308OActivity & safety of spartalizumab (PDR001) in patients (pts) with advanced neuroendocrine tumors (NET) of pancreatic (Pan), gastrointestinal (GI), or thoracic (T) origin, & gastroenteropancreatic neuroendocrine carcinoma (GEP NEC) who have progressed on prior treatment (Tx). Ann. Oncol. 29(suppl_8), 467–478 (2018).

  39. 39.

    Strosberg, J. R., Mizuno, N., Doi, T., Grande, E., Delord, J.-P., Shapira-Frommer, R. et al. Pembrolizumab treatment of advanced neuroendocrine tumors: Results from the phase II KEYNOTE-158 study. J. Clin. Oncol. 37(4_suppl), 190- (2019).

    Article  Google Scholar 

  40. 40.

    Patel, S. P., Othus, M., Chae, Y. K., Giles, F. J., Hansel, D. E., Singh, P. P., et al. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART SWOG 1609) in patients with non-pancreatic neuroendocrine tumors. Clin. Cancer Res. pii: clincanres.3356.2019 (2020). https://doi.org/10.1158/1078-0432.CCR-19-3356. Epub ahead of print.

  41. 41.

    Paz-Ares, L., Dvorkin, M., Chen, Y., Reinmuth, N., Hotta, K., Trukhin, D. et al. Durvalumab plus platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet 394, 1929–1939 (2019).

    CAS  Article  Google Scholar 

  42. 42.

    Ferrata, M., Schad, A., Zimmer, S., Musholt, T. J., Bahr, K., Kuenzel, J., et al. PD-L1 expression and immune cell infiltration in gastroenteropancreatic (GEP) and non-GEP neuroendocrine neoplasms with high proliferative activity. Front. Oncol. 9, 343 (2019).

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Acknowledgements

We would like to thank all the patients who participated in this study voluntarily. Previous presentations: Abstracts at ASCO annual meeting 2018 and NANETS annual meeting 2018.

Author information

Affiliations

Authors

Contributions

N.V.: Study concepts, study design, data collection and patient recruitment, data analysis and interpretation, quality control of data and algorithms, manuscript preparation/editing and review, figures and tables. A.D.: study concepts, study design, data collection and patient recruitment, data analysis and interpretation, quality control of data and algorithms, manuscript preparation/editing and review. M.D.: statistical analysis, manuscript preparation/editing and review, figures and tables. S.L.: statistical analysis, manuscript review. T.A.: data collection and patient recruitment, manuscript review. R.K.A.: data analysis and interpretation, manuscript review. E.D.: data collection and patient recruitment, manuscript editing/review. M.J.H.: data collection and patient recruitment, manuscript editing/review. N.M.R.: data collection and patient recruitment, manuscript review. M.M.R.: data collection and patient recruitment, manuscript review. C.S.D.: data collection and patient recruitment, manuscript editing/review. D.M.H.: data collection and patient recruitment, manuscript editing/review. S.J.C.: study concept/design, manuscript editing/review. P.F.E.: study concept/design, manuscript editing/review. J.R.S.: study concepts, study design, data collection and patient recruitment, data analysis and interpretation, quality control of data and algorithms, manuscript preparation/editing and review.

Corresponding author

Correspondence to Namrata Vijayvergia.

Ethics declarations

Ethics approval and consent to participate

This study has been conducted according to the principles of the declaration of Helsinki 2008. Ethical approval has been granted from Institutional Review Boards at Fox Chase Cancer Center, MD Anderson Cancer Center and H. Lee Moffitt Cancer Center (University of South Florida). All patients signed an informed consent for participating in this trial, including the option of publication of the data.

Consent to publish

Not applicable

Data availability

The data are available for all study authors. The datasets used and analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

N.V.: Research funding from Merck, Bayer. A.D.: Consulting fee from Novartis, Ipsen, Voluntis, Abbvie, Crinetics, Hutchison Pharma and Research funding from Novartis, Eisai, Ipsen, Hutchison Pharma. D.H.: Consulting fee from Lexicon, Ipsen, Advanced Accelarator Applications; Research funding from Genentech, Tarveda, ThermoFisher Scientific. C.D.: Personal fees from Exelixis Astellas, BeiGene, Bayer, Bristol Myer Squibb, Merck, Eli Lilly & Co, EMD Serono; Research funding from Merrimack Pharmaceuticals, Advaxis, Astra Zeneca, Eli Lilly & Co, Roche/Genentech, Amgen, Sanofi Aventis, BeiGene, Lycera, Macrogenics, Agios Pharmaceuticals, Zymeworks, outside the submitted work. M.J.H.: Research funding from Merck, Astra Zeneca. E.D.: Honararia from Pfizer, Boston Medical; Consulting fee from ARMO Biosciences; Research funding from Pfizer, Bayer, Boston Biomedical, Merck, Medimmune, GSK and Eli Lilly Co. J.S.: Consultant fee from Novartis, Speakers bureau for Lexicon and Ipsen.

Funding information

The study was supported by research grant MISP# 53956 from Merck, and NCI Comprehensive Cancer Center Support Grant CA06927.

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Vijayvergia, N., Dasari, A., Deng, M. et al. Pembrolizumab monotherapy in patients with previously treated metastatic high-grade neuroendocrine neoplasms: joint analysis of two prospective, non-randomised trials. Br J Cancer 122, 1309–1314 (2020). https://doi.org/10.1038/s41416-020-0775-0

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