Safety and efficacy of AMG 820, an anti-colony-stimulating factor 1 receptor antibody, in combination with pembrolizumab in adults with advanced solid tumors

Abstract

Background: To determine the safety and efficacy of the anti-colony-stimulating factor 1 receptor (anti-CSF1R) monoclonal antibody AMG 820 in combination with pembrolizumab in patients with select solid tumors.

Patients and methods: Patients had advanced, refractory mismatch repair-proficient colorectal cancer, pancreatic cancer, or non-small cell lung cancer (NSCLC) with low (<50%) programmed cell death-ligand 1 (PD-L1) expression and were naïve to anti-programmed cell death-1 (PD-1)/PD-L1 or had relapsed/refractory NSCLC after anti-PD-1/PD-L1 treatment with low or high (≥50%) PD-L1 expression; all were anti-CSF1/CSF1R naïve. Patients received 1100 mg or 1400 mg AMG 820 plus 200 mg pembrolizumab intravenously every 3 weeks. The primary endpoints were incidence of dose-limiting toxicities (DLTs) and adverse events (AEs) and objective response rate per immune-related Response Evaluation Criteria in Solid Tumours at the recommended combination dose.

Results: Overall, 116 patients received ≥1 dose of AMG 820 plus pembrolizumab (18 at 1400 mg AMG 820; 98 at 1100 mg AMG 820). Most patients (64%) were male; the median age was 64 (range 30-86) years. Seven patients had DLTs (1 at 1400 mg AMG 820; 6 at 1100 mg AMG 820). Almost all patients (99.1%) had AEs, 87.9% with grade ≥3 AEs. The most common AEs were increased aspartate aminotransferase (59.5%), fatigue (48.3%), periorbital/face edema (48.3%), and rash/maculopapular rash (37.1%). The best response was immune-related partial response in 3 patients (3%; duration of response 9.2, 10.0, 12.5 months) and immune-related stable disease in 39 patients (34%). None of the completed phase II cohorts met the predefined threshold for efficacy. Post-treatment there was accumulation of serum colony-stimulating factor 1 (CSF1) and interleukin-34, reduction in CSF1-dependent CD16-expressing monocytes, and increased PD-L1 expression and CD4 and CD8 cell numbers in tumor biopsies.

Conclusions: The recommended combination dose of 1100 mg AMG 820 plus 200 mg pembrolizumab had an acceptable safety profile. Although pharmacodynamic effects were observed, antitumor activity was insufficient for further evaluation of this combination in selected patient populations.

Trial registration number: NCT02713529.

Keywords: clinical trials as topic; drug therapy, combination; gastrointestinal neoplasms; immunotherapy; lung neoplasms.

Conflict of interest statement

Competing interests: ARAR reports research support from Amgen and Merck, during the conduct of the study. JMC reports grants from AstraZeneca, Merck, and Tesaro, outside the submitted work; personal fees from Bristol Myers Squibb, outside the submitted work; and other from Roche, outside the submitted work. VM reports personal fees from Bayer, Bristol Myers Squibb, Janssen, and Pieris, outside the submitted work. MB reports grants from Amgen, during the conduct of the study; grants from Ascentage Pharma, AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Oncomed, and Pfizer, outside the submitted work; personal fees from AstraZeneca, outside the submitted work; and non-financial support from AstraZeneca and Merck Sharp & Dohme, outside the submitted work. ECA reports grants from AbbVie, Amcure, Amgen, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Boehringer Ingelheim, CytomX, Eli Lilly, H3, Incyte, Janssen, Kura, Loxo, Macrogenics, Menarini, Merck Serono, Merck, Merus, Millennium, Nanobiotix, Nektar, Novartis, Pfizer, PharmaMar, Principia, PsiOxus, Puma, Rigontec, Roche/Genentech, Sanofi, START, Taiho, and Tesaro, outside the submitted work; and other from AbbVie, Amcure, AstraZeneca, Celgene, Cerulean Pharma, EUSA, GLG, Guidepoint Global, HM Hospitals Group, International Cancer Consultants, Janssen-Cilag, Nanobiotix, Novartis, NPO Foundation Intheos (Investigational Therapeutics in Oncological Sciences), Oncoart Associated, Pfizer, Pierre Fabre, PsiOxus Therapeutics, Roche/Genentech, Seattle Genetics, Servier, and START, outside the submitted work. WE has nothing to disclose. JT reports other funding from Amgen, during the conduct of the study. RDH reports grants from Amgen and Merck, during the conduct of the study. AR reports honoraria for public speaking and advisory board meetings for Roche, Bristol Myers Squibb, Novartis, Pierre Fabre, and Sanofi. MAS reports grants from Merck, during the conduct of the study. AJO reports personal fees from Merck, during the conduct of the study; and personal fees from Array, Bristol Myers Squibb, Novartis, and Pfizer, outside the submitted work. DJ has nothing to disclose. NL reports other from Amgen, during the conduct of the study; personal fees from Innovent Biologics, outside the submitted work; and other from Alexion, ALX Therapeutics, Apexian, Asana BioSciences, Ascentage, BeiGene, Cerulean Pharma, Constellation, CytomX, Formation Biologics, Forty Seven, Ikena, Incyte, InhibRx, Innovent Biologics, Jounce Therapeutics, Livzon, Loxo, MacroGenics, Merck, Northern Biologics, Odonate Therapeutics, Pfizer, Regeneron, Symphogen, and TaiRx, outside the submitted work. DPR reports equity in Acworth Pharmaceuticals and MPM Capital and is an advisor for 28/7 Therapeutics, Gritstone Oncology, Maverick Therapeutics, MPM Capital, and Oncorus, outside the submitted work. ER is an employee and stockholder of Amgen. GJ is an employee and stockholder of Amgen. HW is an employee and stockholder of Amgen. NS is an employee and stockholder of Amgen. M-ADS is an employee of Amgen. DN is an employee and stockholder of Amgen. KPP reports funding to START for conduct of this clinical trial from Amgen; funding to START for conduct of clinical trials from 3D Medicines, AbbVie, ADC Therapeutics, ArQule, Calithera Biosciences, Curegenix, Daiichi Sankyo, EMD Serono, Formation Biologics, Incyte, Jounce Therapeutics, MabSpace Biosciences, MedImmune, Merck, Mersana, OncoMed, Peloton Therapeutics, Regeneron, Sanofi, and Syros Pharmaceuticals, outside the submitted work; and advisory board fees from ArQule, Basilea, and Bayer, outside the submitted work.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Flow of patients through the study.

Figure 2

Best response by patient, based on change from baseline in the sum of the longest diameters of lesions. CRC, colorectal cancer; irPD, immune-related progressive disease; irPR, immune-related partial response; irSD, immune-related stable disease; NSCLC, non-small cell lung cancer; SLD, sum of the longest diameter.

Figure 3

Levels of CSF1 (A), IL-34 (B), and CD14+ CD16+ monocytes (C) in the peripheral blood of patients before and after dosing with AMG 820 plus pembrolizumab. CSF1, colony-stimulating factor 1; D, day; IL-34, interleukin-34; pre, predose; W, week.