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Clinical Results With Combination Of Anti-CD27 Agonist Antibody, Varlilumab, With Anti-PD1 Antibody Nivolumab In Advanced Cancer Patients.

Rachel E. Sanborn, Michael J. Pishvaian, Harriet M. Kluger, Margaret K. Callahan, Amy M. Weise, Jose Lutzky, Michael Jay Yellin, Tracey Rawls, Laura Vitale, Abdel Halim, Tibor Keler, Tom Davis, Naiyer A. Rizvi

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3007 Background: A phase 1 trial to assess the safety and immunological activity of the combination of varlilumab (V) and nivolumab (N), and recommend a dose of V for the phase 2 study was conducted. Methods: The study was performed using the approved dose of N (3 mg/kg Q2W) and escalating doses of V (0.1, 1, or 10 mg/kg Q2W) in anti-PD-(L)1 naïve patients with advanced cancer. Results: A total of 36 patients (21 CRC, 8 ovarian [OVA], 4 melanoma and 3 SCCHN) were enrolled. Toxicity was consistent with the safety profile of each agent individually; no unexpected toxicities were seen with the combination. No MTD was identified. An OVA cancer patient in the 10 mg/kg cohort had a DLT: hepatitis (G4) and acute kidney injury (G3). A CRC patient in the 10 mg/kg cohort had a drug-related SAE of mixed motor sensory neuropathy (G2) and a CRC patient in the 1 mg/kg cohort had rash (G3). No additional drug related SAEs or DLTs were reported. The majority of tumors were PD-L1 negative (24/27) by IHC at baseline. For patients with post treatment biopsies, PD-L1 expression was observed in 43.5% (10/23) and correlated with increases in CD8 T cell infiltration, consistent with the generation of anti-tumor immunity. Other treatment related biomarker changes included transient increases in serum chemokine levels, and a prominent decrease in circulating Tregs. Biomarker analysis did not clearly differentiate between dose levels, or delineate an optimal V dose. Three patients had objective PR by RECIST [CRC MSI-low (1 mg/kg V), SCCHN (10 mg/kg V) and OVA (10 mg/kg V, uPR)]. The response in the CRC patient is ongoing with a 94% decrease in target lesion diameter and a PFS of 19+ months. There were also 11 patients with SD. Phase 2 cohorts are ongoing in RCC, SCCHN, OVA, CRC and GBM. The Phase 2 portion includes exploration of different dose/regimens of V, including high and low exposure, to better characterize the optimal dosing strategy for V, in combination with a fixed dose of N (240 mg Q2W). Conclusions: The combination of V and N was well tolerated, associated with strong biological signals, and has evidence of clinical activity in subsets of patients with tumor types that are typically resistant to PD-1 inhibitor monotherapy. Clinical trial information: NCT02335918.