Squamous cancers of the head and neck are either caused by high risk Human Papilloma Virus (HPV), or by mutations promoted by smoking. Therapeutic vaccines directed against HPV, despite efficacy in pre-malignancy, do not generally mediate regression of invasive cancer. To test the hypothesis that the efficacy of vaccine-induced T cell responses may be amplified through immune checkpoint antibodies, we conducted a phase II trial of a synthetic long-peptide (SLP) HPV-16 vaccine (ISA101) and nivolumab, a PD-1 inhibitor, in pts with incurable HPV-16+ cancer.
Tumors were confirmed HPV-genotype 16. Patients were ECOG performance status 0-1 and had 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. Baseline biopsies were mandatory. The primary objective was assessment of overall response rate (ORR) targeting 30%. Secondary objectives included tolerability, PFS, OS and HPV-specific immune response.
The trial accrued 24 patients in one year; 22 with oropharynx cancer (OPC) and 1 pt each with anal and cervical cancer. Eighteen pts (75%) had progression within 6 mos of prior platinum and 1 was platinum-naïve. Twelve pts (50%) had prior cetuximab treatment. Study 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). Duration of response median 30.1+ wks (6- 49+ wks), 6/11 pts with PR/SD remain without progression. Of 8 pts with PR, 6 had progressed within 6 mos of prior platinum, 5 within 6 mos of prior cetuximab, and 5 were treated in second line. Median PFS is 2.7 mos and median OS is not reached with median follow up time among censored pts 8.6 mos. PFS rate at 6 mos: 33%, OS rate at 6 mos 74%.
The ORR of 36% in OPC pts compares favorably to the ORR of 16% for nivolumab monotherapy in p16+ OPC pts in Checkmate 141 (Ferris RL et al N Engl J Med 2016). These data suggest that the efficacy of vaccine-induced T cells can be augmented by anti-PD-1 therapy. Our findings should be confirmed in a larger randomized trial. In patients with HPV- H&N cancer we aim to apply a similar combination treatment, but the vaccine in that case will consist of a mix of SLP’s containing selected neo-epitopes generated by mutations in the cancer cells. The process of identifying optimal neo-epitopes and producing a personalized vaccine as well as the timelines involved will be discussed.