Efficacy of pembrolizumab in patients with advanced cancer of unknown primary (CUP): a phase 2 non-randomized clinical trial

Abstract

Background: Cancer of unknown primary (CUP) is an aggressive rare malignancy with limited treatment options. Data regarding clinical activity of immune checkpoint inhibitors in CUP is lacking. Therefore, we evaluated the efficacy of pembrolizumab, a programmed cell death-1 inhibitor, in patients with CUP.

Methods: The study was designed as a phase 2 basket trial for independent rare tumor cohorts including CUP. Adult patients with CUP who had progressed on previous systemic therapy, performance status 0/1 and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST V.1.1) were eligible. Patients received pembrolizumab (200 mg) intravenously every 21 days. Twenty-nine patients were enrolled and treated between August 2016 and June 2020. The primary endpoint was non-progression rate (NPR) at 27 weeks (NPR-27) per immune-related RECIST. Key prespecified secondary endpoints were confirmed objective response rate (ORR), safety, duration of response (DoR), progression-free survival (PFS) and overall survival (OS). Pretreatment biopsies were examined for biomarkers of response (programmed cell death ligand-1 (PD-L1) expression and tumor infiltrating lymphocytes (TILs)).

Results: Among 25 (of 29 enrolled) eligible and evaluable patients, 14 (56%) had poorly differentiated carcinoma. Patients received a median of two lines of therapy prior to enrollment. Median follow-up was 27.3 months. NPR-27 was observed in seven patients (28.0% (95% CI: 12.1 to 49.4)). ORR was 20.0% (95% CI: 6.8 to 40.7) with five patients achieving immune-related partial response with median DoR of 14.7 months (95% CI: 9.8 to 19.6). Median PFS and OS were 4.1 (95% CI: 3.1 to 5.1) and 11.3 (95% CI: 5.5 to 17.1) months, respectively. Treatment-related adverse events of any and grade ≥3 were seen in 19 (76%) and 4 (16%) patients, respectively. One (4%) patient had grade 3 immune-related acute kidney injury requiring treatment discontinuation. Neither PD-L1 nor TILs were associated with NPR-27. Both positive PD-L1 staining (44.4% vs 6.3%; p=0.040) and intense TIL infiltration (44.4% vs 6.3%; p=0.040) were associated with response.

Conclusion: Pembrolizumab showed encouraging efficacy in patients with CUP with acceptable safety profile.

Trial registration number: NCT02721732.

Keywords: immunotherapy; therapies, investigational.

Conflict of interest statement

Competing interests: KPR reports research support from Bayer, AstraZeneca, and Daiichi outside the submitted work; SAP-P reports research support from AbbVie, ABM Therapeutics, Acepodia, Alkermes, Aminex Therapeutics, Amphivena Therapeutics, BioMarin Pharmaceutical, Boehringer Ingelheim, Bristol Myers Squibb, Cerulean Pharma, Chugai Pharmaceutical Co., Curis, Daiichi Sankyo, Eli Lilly, ENB Therapeutics, Five Prime Therapeutics, Gene Quantum, Genmab A/S, GlaxoSmithKline, Helix BioPharma Corp., Incyte Corp., Jacobio Pharmaceuticals Co., Medimmune, LLC., Medivation, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals, Pieris Pharmaceuticals, Pfizer; Principia Biopharma, Puma Biotechnology, Rapt Therapeutics, Seattle Genetics, Silverback Therapeutics, Taiho Oncology, Tesaro, TransThera Bio, NCI/NIH, P30CA016672 – Core Grant (CCSG Shared Resources) outside the submitted work; DSH reports research support from AbbVie, Adaptimmune, Adlai Nortye, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Daichi-Sankyo, Eisai, Eli Lilly, EMD Sereno, Erasca, Fate Therapeutics, Genentech, Genmab, GlaxoSmithKline, Ignyta, Infinity, Kite, Kyowa, LOXO, Merck, MedImmune, Millenium, Mirati, miRNA, Molecular TeMpLaTeS, Mologen, NaVier, nci-cep, Novartis, Numab, Pfizer, Seattle Genetics, Takeda, Turning Point, Vernstam, VM Oncology, and other support from Adaptimmune, Amgen, AstraZeneca, Bayer, Genentech, GlaxoSmithKline, Infinity, Numab, Pfizer, Seattle Genetics, Alpha Insights, Acuta, Axiom, Baxter, Boxer Capital, COG, Ecor1, GLG, Group H, Guidepoint, HCW Precision, Janssen, Merrimack, Medscape, Prime Oncology, STCube, Tavistock, Trieza Therapeutics, Molecular Match, Oncoresponse, Presagia, AACR, ASCO, Celgene, Eli Lilly, SITC, and Phillips, outside of the submitted work; MO reports research support from Merck Sharp & Dohme Corp, AbbVie, Agilvax, Takeda Pharmaceuticals (Japan), Acrotech Biopharma, Janssen Research & Development LLC, Pfizer outside the submitted work; FM-B reports research support from Aileron Therapeutics, AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences, Curis, CytomX Therapeutics, Daiichi Sankyo Co., Debiopharm International, eFFECTOR Therapeutics, Genentech, Guardant Health, Klus Pharma, Millennium Pharmaceuticals, Novartis, Puma Biotechnology, Taiho Pharmaceutical Co.; consulting fees from Aduro BioTech, Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche, Genentech, IBM Watson, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer, Samsung Bioepis, Seattle Genetics, Tyra Biosciences, Xencor, Zymeworks; has served on advisory committees for Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology, Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis; receives honoraria from Chugai Biopharmaceuticals, Mayo Clinic, Rutgers Cancer Institute of New Jersey; and support for travel and accommodation from Beth Israel Deaconess Medical Center outside the submitted work; AN reports research support from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor/Millendo, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera BioSciences, TopAlliance BioSciences, Eli Lilly, Kymab, PsiOxus, Arcus Biosciences, NeoImmuneTech, ImmuneOncia, and Surface Oncology, non-financial support for travel and accommodation from ARMO BioSciences, has served as an advisory board member for Novartis, CytomX Therapeutics, Genome and Company, STCube Pharmaceuticals, OncoSec KEYNOTE-695, and Kymab, reports research funding for his spouse from Immune Deficiency Foundation, Jeffery Modell Foundation and chao physician-scientist, and Baxalta, and his spouse has served as an advisory board member for Takeda, CSL, Behring, Horizon, and Pharming outside the submitted work. BSt, DDK, DJ, DOCO, AA, AFW, BSm, RWH, GRV declare no competing interests.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Tumor response and survival outcomes on pembrolizumab in patients with cancer of unknown primary. (A) (Spider plot) shows the change in sum of target lesion diameters over time in 23 evaluable patients who were treated on the current study and underwent at least one radiological restaging evaluation (two patients had clinical progression prior to first restaging and are reported as default 20% increase). Two patients had unequivocal progression of non-target lesions and were considered as cases with progressive disease (PD). (B) (Waterfall-plot) shows the maximum per cent change from baseline as measured by immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). Partial response (PR) was defined by ≥30% decrease in tumor burden and PD was defined by ≥20% increase in tumor burden, confirmed on a consecutive scan at least 4 weeks apart. (C and D) (KapIan-Meier curves) show progression-free survival and overall survival of patients on study at the time of data cut-off measured from treatment initiation to disease progression/death and death, respectively. Data from patients without an event were censored at date of last follow-up (marks). NPR, non-progression rate.