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