CDX-1140 Plus Capecitabine, Oxaliplatin, and Pembrolizumab in Advanced BTC

Cecilia Monge, MD, MPH

As part of the growing immunotherapy landscape in cholangiocarcinoma, Cecilia Monge, MD, MPH, presented the rationale and study design for a new phase 2 study that aims to investigate the CD40 agonist CDX-1140 in combination with capecitabine, oxaliplatin, and pembrolizumab in advanced biliary tract cancer (BTC).¹ Combination therapies have been fast evolving in BTC, especially with the addition of durvalumab to gemcitabine/cisplatin (GemCis) as the newly established frontline standard of care. A phase 2 study of 11 patients with advanced BTC treated with pembrolizumab in combination with capecitabine and oxaliplatin demonstrated a median follow-up of 34.8 months and disease control rate of 81.8%, with 3 patients experiencing a partial response and 6 with stable disease.² The median progression-free survival (PFS) was 4.1 months, and the median overall survival was 9.9 months.² The most common grade 3/4 adverse events (AEs) were lymphocytopenia (64%), anemia (36%), and thrombocytopenia (27%).² CDX-1140 is a fully human immunoglobulin G2 agonistic anti-CD40 monoclonal antibody that activates dendritic cells and B cells and has antitumor activity against CD40-expressing cancer cells.¹ CD40 has been shown to improve immune surveillance, and it has been hypothesized that combining a CD40 agonist with an anti–PD-1 antibody could overcome the immunosuppressive microenvironment of BTC.³ In preclinical mouse models, the combination therapy improved survival over either monotherapy and survival was further extended when combined with GemCis.⁴ A phase 1, dose-escalation, cohort expansion study evaluated CDX-1140 monotherapy and in combination with pembrolizumab in 20 patients.¹ The most common toxicities seen were arthralgia (42%), pyrexia (37%), fatigue (32%), and increased alanine transaminase/aspartate transaminase (ALT/AST; 20%), with 36% of patients experiencing grade 3 AEs, including ALT/AST increase, fatigue, and pneumonitis. In addition, 2 patients experienced grade 4 AEs, including encephalopathy and hypoxia.¹ This led to the development of a phase 2 study of CDX-1140 in combination with capecitabine and oxaliplatin plus pembrolizumab in advanced BTC. To be enrolled, patients must have progression through 1 line of treatment in the advanced setting. The study’s primary end point is to determine the PFS of the combination therapy. Key secondary end points include safety, tolerability and feasibility, response rate, and overall survival.¹

Sources:

1. Monge C. A phase II study of CDX-1140, a CD40 agonist, in combination with capecitabine and oxaliplatin and pembrolizumab in advanced biliary tract carcinoma. Presented at: Cholangiocarcinoma Foundation meeting, April 12-14, 2023; Salt Lake City, UT.
2. Monge C, Pehrsson EC, Xie C, et al. A phase II study of pembrolizumab in combination with capecitabine and oxaliplatin with molecular profiling in patients with advanced biliary tract carcinoma. Oncologist. 2022;27(3):e273-e285.
3. Borst J, Ahrends T, Bąbała N, Melief CJM, Kastenmüller W. CD4+ T cell help in cancer immunology and immunotherapy. Nat Rev Immunol. 2018;18(10):635-647.
4. Diggs LP, Ruf B, Ma C, et al. CD40-mediated immune cell activation enhances response to anti-PD-1 in murine intrahepatic cholangiocarcinoma. J Hepatol. 2021;74(5):1145-1154.