CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study

Summary

Background

Standard chemotherapy remains inadequate in metastatic pancreatic adenocarcinoma. Combining an agonistic CD40 monoclonal antibody with chemotherapy induces T-cell-dependent tumour regression in mice and improves survival. In this study, we aimed to evaluate the safety of combining APX005M (sotigalimab) with gemcitabine plus nab-paclitaxel, with and without nivolumab, in patients with pancreatic adenocarcinoma to establish the recommended phase 2 dose.

Methods

This non-randomised, open-label, multicentre, four-cohort, phase 1b study was done at seven academic hospitals in the USA. Eligible patients were adults aged 18 years and older with untreated metastatic pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status score of 0–1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. All patients were treated with 1000 mg/m² intravenous gemcitabine and 125 mg/m² intravenous nab-paclitaxel. Patients received 0·1 mg/kg intravenous APX005M in cohorts B1 and C1 and 0·3 mg/kg in cohorts B2 and C2. In cohorts C1 and C2, patients also received 240 mg intravenous nivolumab. Primary endpoints comprised incidence of adverse events in all patients who received at least one dose of any study drug, incidence of dose-limiting toxicities (DLTs) in all patients who had a DLT or received at least two doses of gemcitabine plus nab-paclitaxel and one dose of APX005M during cycle 1, and establishing the recommended phase 2 dose of intravenous APX005M. Objective response rate in the DLT-evaluable population was a key secondary endpoint. This trial (PRINCE, PICI0002) is registered with ClinicalTrials.gov, NCT03214250 and is ongoing.

Findings

Between Aug 22, 2017, and July 10, 2018, of 42 patients screened, 30 patients were enrolled and received at least one dose of any study drug; 24 were DLT-evaluable with median follow-up 17·8 months (IQR 16·0–19·4; cohort B1 22·0 months [21·4–22·7], cohort B2 18·2 months [17·0–18·9], cohort C1 17·9 months [14·3–19·7], cohort C2 15·9 months [12·7–16·1]). Two DLTs, both febrile neutropenia, were observed, occurring in one patient each for cohorts B2 (grade 3) and C1 (grade 4). The most common grade 3–4 treatment-related adverse events were lymphocyte count decreased (20 [67%]; five in B1, seven in B2, four in C1, four in C2), anaemia (11 [37%]; two in B1, four in B2, four in C1, one in C2), and neutrophil count decreased (nine [30%]; three in B1, three in B2, one in C1, two in C2). 14 (47%) of 30 patients (four each in B1, B2, C1; two in C2) had a treatment-related serious adverse event. The most common serious adverse event was pyrexia (six [20%] of 30; one in B2, three in C1, two in C2). There were two chemotherapy-related deaths due to adverse events: one sepsis in B1 and one septic shock in C1. The recommended phase 2 dose of APX005M was 0·3 mg/kg. Responses were observed in 14 (58%) of 24 DLT-evaluable patients (four each in B1, C1, C2; two in B2).

Interpretation

APX005M and gemcitabine plus nab-paclitaxel, with or without nivolumab, is tolerable in metastatic pancreatic adenocarcinoma and shows clinical activity. If confirmed in later phase trials, this treatment regimen could replace chemotherapy-only standard of care in this population.

Funding

Parker Institute for Cancer Immunotherapy, Cancer Research Institute, and Bristol Myers Squibb.

Introduction

Pancreatic adenocarcinoma is one of the most lethal cancers worldwide with 5-year survival rates of less than 10%,¹ and is predicted to become the second leading cause of cancer-related mortality in the USA by 2030. The objective response rates for the two most common standard-of-care regimens—gemcitabine plus nab-paclitaxel and FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin)—are less than 50% for patients with metastatic pancreatic adenocarcinoma receiving first-line treatment, with short response duration and moderate toxicity.2, 3 The median progression-free survival for these therapies is approximately 6 months: 5·3–7·9 months for gemcitabine plus nab-paclitaxel and 6·2–6·4 months for FOLFIRINOX (appendix p 7). Olaparib, a poly (ADP-ribose) polymerase inhibitor used as first-line maintenance therapy, and pembrolizumab, an anti-PD1 monoclonal antibody used as second-line therapy, represent important advances in the treatment of pancreatic adenocarcinoma, but clinical benefits are limited to small subsets of patients.4, 5 Pancreatic adenocarcinoma is refractory to immunotherapy, largely because of its immunosuppressive tumour microenvironment.⁶ Orthogonal treatment combinations, such as with immune agonists, are possible solutions to overcome this immunologically cold disease.7, 8

Research in context

Evidence before this study

We searched PubMed and major congress abstracts until Aug 1, 2020, using the terms “pancreatic cancer”, “CD40”, “chemotherapy”, “checkpoint blockade” and “treatment”. No language restriction was applied. The result of this search showed that treatment of patients with advanced, microsatellite stable pancreatic cancer with standard-of-care gemcitabine and nab-paclitaxel has an objective response rate of between 21% to 48%, depending on the study, but treatment with immune checkpoint blockade has an objective response rate of less than 5%. Studies of gemcitabine and nab-paclitaxel were randomised phase 3 studies. Studies with immune checkpoint antibodies were not phase 3. Combination of gemcitabine plus nab-paclitaxel with checkpoint blockade in this patient population exhibits an objective response rate of less than 20%, although this response has not been extensively studied. Treatment of this patient population with CD40 agonist monoclonal antibodies has been minimally tested, although phase 1 single-agent studies have been completed and safe doses of multiple CD40 agonists identified. The combination of gemcitabine plus nab-paclitaxel and a CD40 agonist, with or without checkpoint blockade, has not been studied.

Added value of this study

This phase 1b study is, to our knowledge, the first to evaluate the safety and activity of combining the CD40 agonist APX005M with gemcitabine plus nab-paclitaxel, with or without the anti-PD-1 antibody nivolumab, as first-line treatment in patients with metastatic pancreatic ductal adenocarcinoma. It shows the clinical potential of this treatment combination, as evidenced by a clinically manageable safety profile and its objective response rate.

Implications of all the available evidence

These results support a randomised phase 2 study of these drugs, underway to evaluate the effect and independent roles of chemotherapy, CD40, and anti-PD-1 drugs in the treatment of this disease.

CD40, a member of the tumour necrosis factor receptor superfamily, is a novel candidate drug target for immunotherapy.⁷ Binding of CD40 by its ligand, CD154 (expressed on platelets and mature, activated CD4-positive T cells), or by an agonistic monoclonal antibody such as APX005M (sotigalimab), activates the receptor and results in the activation of antigen-presenting cells, including dendritic cells, B cells, and monocytes. In mouse pancreatic cancer models, the combination of agonistic CD40 monoclonal antibody with gemcitabine plus nab-paclitaxel triggers T-cell-dependent tumour regressions and improves survival benefit, which are further augmented by addition of an anti-PD-1 monoclonal antibody.9, 10 Mechanistically, it is hypothesised that chemotherapy-induced release of tumour antigens, coupled with antigen-presenting cell activation and T-cell priming via agonistic CD40 monoclonal antibody, can sensitise pancreatic adenocarcinoma to immunotherapy.

In a first-in-human, single-agent study¹¹ of APX005M in patients with advanced solid tumours, dose-dependent increases in antigen-presenting cells and T-cell activation were observed, consistent with CD40 engagement. Several patients exhibited prolonged stable disease and APX005M was well tolerated. Here, we report the results of the phase 1b portion of a seamless phase 1b–2 study of APX005M plus gemcitabine plus nab-paclitaxel, with or without nivolumab, as first-line treatment in patients with metastatic pancreatic adenocarcinoma.