Nivolumab and ISA 101 HPV vaccine in incurable HPV-16+ cancer

Abstract

Background: Vaccines directed against Human Papilloma Virus (HPV) do not generally mediate regression of invasive cancer. To test the hypothesis that the efficacy of vaccine‐induced T cells may be amplified through treatment with immune checkpoint antibodies, we conducted a phase II trial of ISA 101, a synthetic long‐peptide HPV‐16 vaccine, and nivolumab in pts with incurable HPV‐16+ cancer. Methods: Tumors were HPV‐genotype 16 by Cervista HPV16/18. Patients were ECOG PS 0‐1 with up to one prior regimen for recurrence. ISA101 100 mcgs/peptide was given Days 1, 22, 50. Nivolumab 3 mg/kg was given iv every 2 wks beginning day 8 for up to one year. Imaging was obtained baseline, 11 wks and every 6 wks thereafter. The primary objective was assessment of overall response rate (ORR) targeting 30%. Secondary objectives: tolerability, PFS, OS. A Simon two stage design required response in 2/15 first stage and 5/25 in second stage. Results: The trial accrued 24 patients; 22 with oropharynx cancer (OPC) and 1 pt each with anal and cervical cancer. 18 pts (75%) had progression within 6mos of prior platin and 1 was platin‐naïve. 12 pts (50%) had prior cetuximab. Treatment was frontline for recurrence in 10/24 and second line in 14/24. ORR is 33% (8/24): 1 CR, 7 PR (1 unconfirmed), 3(13%) SD, 13 (54%) PD. ORR in OPC pts is 36% (8/22). 6/8 pts with PR progressed within 6 mos of prior platin. Median duration of response 30.1+ wks (6‐ 49+ wks); 5/8 pts with PR remain in response. Median PFS is 2.7 mos [95% CI 2.3‐8.0 mos] and median OS is not reached with median follow up time among censored pts 8.6 mos. PFS rate at 6 mos: 33%, [16‐52%] OS rate at 6 mos 74%, [51‐87%] . Toxicity: grade 3 transaminase and grade 4 lipase elevation in 1 pt each, grade 1‐2 toxicity: fever (5 pts), injection site reaction (6 pts), transaminase elevation, fatigue, nausea (3 pts each). Conclusions: The primary endpoint was met and ORR of 36% in OPC pts compares favorably to 16% for nivolumab monotherapy in p16+ OPC pts in Checkmate 141 (Ferris RL et al N Engl J Med 2016; 375:1856). These data suggest that the efficacy of vaccine‐induced T cells can be augmented by anti‐PD‐1 therapy, mitigating the influence of an immunosuppressive microenvironment. Our findings merit confirmation in a larger randomized trial. Correlation of efficacy outcomes with immunoprofiling of tumors will be presented.