Abstract CT089: Phase Ib/II of CD40 agonistic antibody APX005M in combination with nivolumab (nivo) in subjects with metastatic melanoma (M) or non-small cell lung cancer (NSCLC)

Background: Despite recent success with checkpoint inhibitors, the majority of patients with M or NSCLC have a transient response or no response to checkpoint blockade. Preclinical data suggest that activation of CD40 can be combined with PD-1 blockade to trigger effective T cell immunity. We are conducting a multi-center, open label Phase Ib/II clinical trial to evaluate the combination of APX005M with nivo in subjects with M or NSCLC. We report safety and efficacy from the completed Phase Ib portion of the study and the 1st stage of the Phase II M cohort. Methods: Phase Ib followed a 3+3 design and enrolled adult subjects with M and disease progression (PD) while receiving anti-PD-1 therapy (anti-CTLA-4 more than 3 months prior to study entry was allowed) and subjects with immunotherapy naïve NSCLC, in 3 dose levels of APX005M (0.03, 0.1 and 0.3 mg/kg) combined with a fixed dose of nivo (360mg) every 3 weeks. Primary objectives in Phase Ib were to evaluate safety and determine the Phase II dose (P2D) of APX005M. Phase II is enrolling subjects with M or NSCLC in two parallel Phase II cohorts, each following a Simon 2-stage design. Primary objective in Phase II is to evaluate the tumor response in each cohort. Phase Ib analyses were performed on dose limiting toxicity (DLT)-evaluable subjects. Phase II analyses were performed on all treated subjects. Results: Phase Ib: No DLTs were observed in the 9 subjects enrolled in Phase Ib and the P2D for APX005M is 0.3 mg/kg. Four subjects experienced Grade 3 AEs considered related to study drugs (non-DLTs, including transaminitis, hyperbilirubinemia, anemia, pneumonitis, 1 subject each) with no grade 4 AEs reported. Of the 5 subjects with M, 1 had a confirmed PR, 2 had prolonged SD (>8 months) and 2 had PD as best overall response. Of the 4 subjects with NSCLC, 1 had a robust confirmed PR, 2 had SD (on study lesion biopsies histology negative) and 1 had PD as best overall response. Phase II: The 1st stage of the M cohort enrolled 10 additional subjects. One subject experienced a Grade 3 AE considered related to study drugs with no grade 4 AEs reported. Of these 10 subjects, 2 had confirmed PR, 2 had SD, and 6 had PD as best overall response. The overall toxicity profile of the combination is consistent with the profiles of individual agents. NanoString analysis of paired tumor biopsies revealed high tumor-infiltrating lymphocytes, and increased expression of IFNγ inducible cytokines (CXCL9 and CXCL10) while on treatment. Increased tumor T cell infiltration was further confirmed by immunohistochemistry. Conclusions: APX005M + nivo demonstrated a good safety profile and promising antitumor activity in M subjects with PD while receiving anti-PD-1 therapy and potential activity in NSCLC. The study is currently enrolling subjects in the 2nd stage of the Phase II M cohort and the 1st stage of the Phase II NSCLC cohort. Clinical trial information: NCT03123783. Citation Format: Harriet Kluger, Sarah A. Weiss, Anthony J. Olszanski, Lynn Schuchter, Gerald P. Linette, Linda Garland, Nicholas O. Iannotti, Melissa Johnson, Emin Avsar, Minu K. Srivastava, Ovid C. Trifan, Martin J. Edelman. Phase Ib/II of CD40 agonistic antibody APX005M in combination with nivolumab (nivo) in subjects with metastatic melanoma (M) or non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT089.