Purpose: Combining therapeutic activation of immune cells and checkpoint inhibition may improve response rates and overall survival in patients with metastatic melanoma. CP-870,893 (αCD40) is an agonistic fully human IgG2 mAb targeting the immune stimulatory molecule CD40. 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 histologically confirmed metastatic melanoma, measurable disease by RECIST 1.0, and no history of autoimmune diseases or previous treatments targeting CD40 or CTLA-4 were enrolled on a single-arm open-label dose escalation phase 1 study. αCD40 and treme were dosed i.v. every 3 weeks and 12 weeks, respectively , for a potential total of 16 doses of αCD40 and 4 doses of treme. Dose escalation followed a 3 + 3 strategy with alternating increases of αCD40 (range 0.1-0.2 mg/kg) and treme (range 6-15 mg/kg) in each cohort. Patient outcomes were scored using the Common Terminology Criteria for Adverse Events v3.0. 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 were compared by paired t test.
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. Patients had received a median of 1 (range 0-5) prior treatments for metastatic disease prior to enrollment. Dose-limiting toxicities (DLT), considered to be likely due to treatment, were colitis (n=1) and hypophysitis (n=1) at 0.2mg/kg αCD40 and 15mg/kg treme and uveitis (n=1) at 0.2mg/kg αCD40 and 10mg/kg treme. 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 and typically involving chills and fever. CRS symptoms were controlled with standard supportive care in the chemotherapy infusion suite and with instructed use of antipyretics and antihistamines at home. 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 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 (95% CI: 2.0–3.1 months) and a median overall survival (OS) of 26.1 months (95% CI: 13.1–39.1 months). Two patients remain disease free for more than 18 months after study completion without further medical treatment. 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 objective response rate was 27.3%, with median OS of 26.1 months including two patients still disease-free. This antitumor activity, and biomarker evidence of immune activation, provides a rationale for expanded study.
Citation Format: David L. Bajor, Rosemarie Mick, Matthew J. Riese, Richman P. Lee, Xiaowei Xu, Drew A. Torigian, Erietta Stelekati, Martha Sweeney, Brendan J. Sullivan, Lynn M. Schuchter, Ravi Amaravadi, E John Wherry, Robert H. Vonderheide. Phase I study of combination immunotherapy with agonistic CD40 monoclonal antibody (mAb) CP-870,893 (αCD40) and anti-CTLA-4 antibody tremelimumab (treme) in patients with metastatic melanoma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A38.