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Interim results from CLASSICAL-Lung, a phase 1b/2 study of pepinemab (VX15/2503) in combination with avelumab in advanced non-small cell lung cancer patients [Meeting Abstract]

Shafique, M; Fisher, T; Evans, E; Leonard, J; Pastore, D R; Mallow, C; Smith, E; Schroeder, A; Chin, K; Beck, J; Baumgart, M; Govindan, R; Gabrail, N; Goldman, J; Sanborn, R; Spira, A; Seetharamu, N; Lou, Y; Mansfield, A; Zauderer, M
Background Despite progress of immune checkpoint blockade therapies, many patients with non-small cell lung cancer (NSCLC) do not receive durable clinical benefit from these agents, and even in those who do respond initially, acquired resistance and tumor recurrence can develop. Pepinemab is an IgG4 humanized monoclonal antibody targeting semaphorin 4D (SEMA4D, CD100). In vivo preclinical studies demonstrated antibody blockade of SEMA4D promoted immune infiltration and reduced function and recruitment of immunosuppressive myeloid cells within the tumor [1,2]. Importantly, preclinical combinations of anti-SEMA4D with various immunotherapies enhanced T cell infiltration and activity, as well as durable tumor regression. Methods The CLASSICAL-Lung clinical trial evaluates the combination of pepinemab with anti-PD-L1 antibody avelumab to couple beneficial modifications of the immune microenvironment via pepinemab with immune activation via checkpoint inhibition. This ongoing phase 1b/2, open label, single arm, first-in-human combination study is designed to evaluate the safety, tolerability and efficacy of the combination in patients with advanced (stage IIIB/ IV) NSCLC, including a dose escalation cohort and expansion cohorts consisting of 1) 17 immunotherapy-naive patients and 2) 33 patients whose tumors progressed during or following immunotherapy (IO failure). Results The combination was well tolerated with no concerning safety signals identified to date. No patient experienced a treatment-related adverse event leading to permanent treatment discontinuation or death and the most frequent related AEs were grades 1 or 2 fatigue, pyrexia, or chills. Interim analysis focused on the IO failure cohort which included 22 evaluable patients. Two patients experienced a partial response (PR) with 49% and 37% tumor reduction on study following acquired resistance to prior treatment with pembrolizumab. In addition, stable disease of at least 8 weeks was observed in 11 patients and 4 patients have remained on study for >=20 weeks. Analysis of pre-and on-treatment lung biopsies demonstrated no or low tumor burden detected in 2 patients with PR, and interestingly no detectable tumor was observed in the biopsies from 3 of 4 patients with stable disease. Conclusions Preliminary data suggest the combination of pepinemab plus avelumab is well tolerated and shows initial signals of antitumor activity in patients with IO failure. We will present updated clinical response data, as well as additional immunophenotyping of tissue biopsies, including but not limited to activated T cells, regulatory T cells, DCs, monocytes, macrophages, and importantly myeloid-derived suppressor cells (MDSCs)
ISSN: 2051-1426
CID: 4229702

Four-year survival rates for patients with metastatic melanoma who received ipilimumab in phase II clinical trials

Wolchok, J D; Weber, J S; Maio, M; Neyns, B; Harmankaya, K; Chin, K; Cykowski, L; de Pril, V; Humphrey, R; Lebbe, C
BACKGROUND: This analysis was carried out to evaluate the long-term survival of patients with metastatic melanoma who received ipilimumab, a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte antigen-4, in clinical trials. PATIENTS AND METHODS: Patients received ipilimumab in one of three completed phase II clinical trials (CA184-008, CA184-022, and CA184-007). Previously treated patients were enrolled in all studies, and treatment-naive patients were also included in study CA184-007. Patients received ipilimumab at a dose of 10 mg/kg in studies CA184-008 and CA184-007, and at doses of 0.3, 3, or 10 mg/kg in study CA184-022. Ipilimumab was given every 3 weeks for four doses, and eligible patients could receive ipilimumab maintenance therapy every 12 weeks. In study CA184-022, patients could cross over to be retreated with ipilimumab at 10 mg/kg upon disease progression. Ongoing survival follow-up is conducted in a companion study, CA184-025. RESULTS: Four-year survival rates [95% confidence interval (95% CI)] for previously treated patients who received ipilimumab at 0.3, 3, or 10 mg/kg were 13.8% [6.1-22.5], 18.2% [9.5-27.6], and 19.7% [13.4-26.5] to 28.4% [13.9-44.2], respectively. In treatment-naive patients who received ipilimumab at 10 mg/kg, 4-year survival rates were 37.7% [18.6-57.4] to 49.5% [23.8-75.4]. CONCLUSIONS: These results demonstrate durable survival in a significant proportion of patients with metastatic melanoma who received ipilimumab therapy.
PMID: 23666915
ISSN: 1569-8041
CID: 2201322