Source: www.medpagetoday.com
Author: Ian Ingram, Deputy Managing Editor, MedPage Today

Adding a tumor-specific vaccine to PD-1 checkpoint inhibition was safe and effective in HPV16-positive patients with recurrent or metastatic oropharyngeal cancer, a small phase II trial found.

Among 24 patients treated with nivolumab (Opdivo) and the ISA101 long peptide vaccine, 22 of whom had oropharyngeal cancer, 33% responded and median overall survival was 17.5 months, Cornelis Melief, PhD, of ISA Pharmaceuticals in the Netherlands, reported here at the 4th annual Cancer Immunotherapy Conference.

All eight of the responders had oropharyngeal cancer (36%), with two complete and six partial responses. The median duration of response among these patients was 10.3 months, and responses were seen in both platin- and cetuximab-refractory patients, and those refractory to both.

Melief noted that one of the partial responders had total clearance of the primary tumor, but a solitary lung metastasis remained, but was stable at 2.5 years.

Rate of overall survival at 6 and 12 months was 75% and 70%, respectively. The combination was well tolerated and safe, said Melief, with no increase in the rate of serious adverse events. A randomized trial is planned to confirm the findings.

“The results of our trial are among the first clinical data to support the general concept of combining cancer vaccination with immune checkpoint blockade to enhance efficacy of vaccine-activated T cells in the immunosuppressive tumor environment,” Melief’s group wrote in JAMA Oncology, where the findings were also published.

The findings compare favorably to outcomes in a larger group of p16-positive patients in CheckMate 141, which tested nivolumab in recurrent or metastatic, chemotherapy-refractory squamous cell head and neck cancer, and led to FDA approval in that setting.

Overall response among the 63 p16-positive patients in that trial was 15.9%, and median overall survival was 9.1 months.

Median progression-free survival (PFS) in the current study was just 2.7 months, similar to that in CheckMate 141: 2.0 months in nivolumab-treated patients, which was no different from the PFS with standard therapy at 2.3 months (HR 0.89, 95% CI 0.70-1.13, P=0.32).

“These findings are nearly double the response rate and median overall survival reported in the CheckMate 141, KEYNOTE-012, and KEYNOTE-055 trials,” said Theodoros Teknos, MD, of Seidman Cancer Center in Cleveland, calling the study an important incremental discovery in the burgeoning field of immunotherapy for head and neck cancer.

In KEYNOTE-012, the rate of overall response rate was 12% in a similar patient group (survival was not reported). In KEYNOTE-055, the rates were 20% and 8 months, respectively.

“Based on the findings reported in this study, additional investigation in the form of a larger randomized clinical trial evaluating the contribution of HPV16 vaccination to PD-L1 inhibition is warranted,” he told MedPage Today. “Nested in this trial, it would be advisable to perform robust analysis of immunologic subsets and cytokine profiling to identify biomarkers of response to this treatment approach.”

Teknos, who was not involved in the study, noted that the subgroup analysis again calls into question the use of PD-L1 as a biomarker. While 43% of the PD-L1 ≥1% group were responders, 18% of the PD-L1 < 1% group were as well.

Melief also presented data on the ISA101 vaccine in 62 late-stage HPV-positive cervical cancer patients treated with the ISA101 vaccine in combination with chemotherapy and highlighted the survival difference among those with a vaccine-induced T-cell response. Median overall survival was 22.7 months in those that had an HPV-specific response above the median versus 12.9 months for those with a response below the median (HR 0.286, 95% CI 0.149-0.551, P=0.0066).

He noted that this was not due just to immunocompetence differences between patients, as the effect was found to be independent of patients’ immune status.

The current study enrolled 24 patients from 2015 to 2016 — 20 men and four women. Outside of the oropharyngeal cancer patients, there was one patient with anal and cervical cancers each. Patients received three 100 μg doses of the subcutaneous ISA101 vaccine (days 1, 22, and 50). Starting on day 8, intravenous nivolumab was given every 2 weeks for a year or until disease progression or unacceptable toxicity.

Toxicities were of the expected variety: fever and injection site reactions with ISA101, and diarrhea, fatigue, and hepatoxicity with nivolumab. Two patients had grade 3 and 4 adverse events that led to discontinuation of nivolumab (an asymptomatic transaminase level elevation and a lipase elevation, respectively).

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