Abstract CT137: Combination of agonistic CD40 monoclonal antibody CP-870,893 and anti-CTLA-4 antibody tremelimumab in patients with metastatic melanoma

Abstract

Purpose: Combining immunostimulatory monoclonal (mAb) and checkpoint inhibition may improve response rates and overall survival in patients with metastatic melanoma. CP-870,893 is an agonistic fully human IgG2 mAb targeting the immune stimulatory molecule CD40 (αCD40). Tremelimumab (treme) is a fully human IgG2 mAb targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA4), a negative co-stimulatory molecule found on T cells. Methods: Patients with metastatic melanoma were enrolled on a single-arm open-label phase I study. αCD40 and treme were dosed i.v. every 3 weeks and 12 weeks, respectively. Dose escalation followed a 3 + 3 strategy with alternating increases of αCD40 and treme in each cohort. Outcomes were scored using the Common Terminology Criteria for Adverse Events v3.0 and RECIST 1.0. Flow cytometric analysis of baseline blood samples was compared to samples obtained at least 3 weeks after the last dose of αCD40 and treme. Results: Toxicity: Twenty-four patients were enrolled and treated at 4 different dose levels. Two patients were replaced per protocol due to rapid, symptomatic progression of disease; these patients were not evaluated for response but were included in toxicity analysis. Dose-limiting toxicities (DLT), considered to be likely due to treatment, were colitis (n = 1) and hypophysitis (n = 1) and uveitis (n = 1). Cytokine release syndrome (CRS), grade 1-2, occurring within 24 hours of CP administration, was the most common treatment-related toxicity occurring in 19 (79.2%) patients. CRS symptoms were controlled with standard supportive care. All episodes of CRS resolved within 24 hours of αCD40 administration. The estimated maximum tolerated dose was 0.2 mg/kg of αCD40 and 10 mg/kg of treme. Outcomes: Overall objective response rate (ORR) was 27.3% (best response): two patients (9.1%) had complete responses to treatment and four (18.2%) patients had partial responses. The median follow-up was 22 months with a median progression free survival of 2.5 months and a median overall survival (OS) of 26.1 months. Correlative studies: Flow cytometric analysis of peripheral blood lymphocytes revealed changes in CD8+ T cell phenotypes. Double positive granzyme B+ and Ki-67+ cells increased from 0.56 ± 0.17% (mean ± standard error) for all CD8+ T cells at baseline to 1.01 ± 0.23% post-treatment (p = 0.03). CD8+ T cells expressing both programmed cell death 1 and eomesodermin were also higher after treatment, increasing from 7.7 ± 1.1% to 10.4 ±1.8% (p = 0.04) of all CD8+ T cells. Conclusion: Combination therapy with αCD40 and treme was well-tolerated in patients with metastatic melanoma, with rates of CRS and other toxicity similar to previously reported rates for αCD40 or treme treatments alone. Overall ORR was 27.3%, with median OS of 26.1 months. Given the tolerability, antitumor activity, and biomarker evidence of immune activation, expanded study of this combination should be pursued. Citation Format: David L. Bajor, Rosemarie Mick, Matthew J. Riese, Lee P. Richman, Xiaowei Xu, Drew A. Torigian, Erietta Stelekati, Martha Sweeney, Brendan Sullivan, Lynn M. Schuchter, Ravi Amaravadi, E. John Wherry, Robert H. Vonderheide. Combination of agonistic CD40 monoclonal antibody CP-870,893 and anti-CTLA-4 antibody tremelimumab in patients with metastatic melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT137. doi:10.1158/1538-7445.AM2015-CT137

Combination cancer immunotherapy and new immunomodulatory targets

“…Preclinical programmes include agonist antibodies from Alligator Biosciences and several other companies. A Phase I trial combining the CD40-specific agonist CP-870893 (developed by Pfizer) and the CTLA4-specific antibody tremelimumab (NCT01103635) found colitis, hypophysitis and uveitis to be the dose-limiting toxicities 93 . The most common treatment-related toxicity was grade 1-2 cytokine release syndrome, which occurred within 24 hours of administration of the CD40-specific agonist in 79.2% patients with metastatic melanoma (n = 22); the objective response rate was 27.3%.…”

Combination Approaches with Immune-Checkpoint Blockade in Cancer Therapy

“…A 27.3% response rate was obtained with anti-CD40 (CP-870893) plus anti-CTLA-4 (tremelimumab) in a phase I study in melanoma patients (NCT01103635) (89). As anti-CD40 has been shown to upregulate PD-L1 in a mouse model (90), higher response rates might be obtained with anti-CD40 plus anti-PD-1.…”

Cancer immunotherapy: activating innate and adaptive immunity through CD40 agonists

“…In addition, CD40 agonists are being combined with inhibitors of immune checkpoint molecules such as CTLA-4 (NCT01103635) and PD-1/PD-L1 (NCT02304393, NCT2706353) blocking antibodies. A phase I study investigating CP-870,893 in combination with tremelimumab, a fully human IgG2 mAb targeting CTLA-4, showed clinical activity with a response rate of 27.3% in patients with metastatic melanoma [85]. Further studies, though, are required to discern whether this activity is superior to that previously seen with single agent treatment of CP-870,893 (RR 27%) [23] or tremelimumab (11%) [86] in patients with metastatic melanoma.…”