Conference Coverage

Immunotherapy may be path forward in HPV oropharyngeal cancer


 

FROM SITC 2022

In human papillomavirus (HPV)-positive, locally advanced oropharyngeal squamous cell carcinoma, an immune checkpoint blockade regimen combined with radiotherapy led to good survival with a reduction in radiation exposure.

First-line therapy for HPV-positive oropharynx cancer is generally high-dose cisplatin combined with high-dose radiotherapy, but this regimen is associated with significant acute and long-term toxicity.

In previous studies among patients with recurrent or metastatic squamous cell carcinoma, nivolumab (Opdiva, Bristol Myers Squibb) improved survival when combined with platinum-based chemotherapy, and pembrolizumab (Keytruda, Merck) improved survival in recurrent disease compared with chemotherapy plus cetuximab.

Those precedents predicted success for HPV-positive oropharynx cancer, according to Maura Gillison, MD, PhD, who presented the results at a press briefing held in November in advance of the Society for Immunotherapy of Cancer’s 37th Annual Meeting. “Given that HPV-positive oropharynx cancers are characterized by an inflamed tumor microenvironment and HPV oncoproteins are omnipresent, required for cancer survival, and are ideal tumor-specific antigens – we hypothesized that induction and concurrent CTLA-4 and PD-1 immune checkpoint blockade, followed by volume- and dose-adapted IMRT (intensity-modulated radiotherapy), would be an effective alternative to the current standard of care,” said Dr. Gillison, who is a professor of medicine at the University of Texas MD Anderson Cancer Center, Houston.

Anti–PD-L1 therapy is approved for head and neck cancer, but the frontier is moving it into the locally advanced setting in combination with CTLA-4 inhibitors, according to Robert Ferris, MD, PhD, who moderated the press briefing and was lead author of the nivolumab in metastatic squamous cell carcinoma study. He added that recent trial data suggest this approach should be more effective and create more durable responses.

The new data support the approach. “The trial provides compelling data to support a new approach for treating newly diagnosed HPV-positive head and neck cancers. Our goal is to treat this cancer with immunotherapy alone. The results of this trial make me optimistic that this will be achievable,” Dr. Gillison said.

The study details

The researchers conducted a phase 2 clinical trial, enrolling 35 patients with newly diagnosed HPV-positive oropharynx cancer who were positive for PD-L1 expression.

Patients received 1 mg/kg ipilimumab (Yervoy, Bristol Myers Squibb) and 3 mg/kg nivolumab over a 6-week cycle, followed by a second cycle that was accompanied by 40-44 Gy radiotherapy for patients with a complete response in their primary tumor, and a boost to 50-66 based on postinduction treatment volume. The protocol reduced dose to the neck from 52 to 36 Gy. The radiation was delivered to only one nodal echelon beyond the involved node. Standard care delivers radiotherapy to essentially the entire neck, Dr. Gillison said.

Grade 3 or higher adverse events occurred in 66% of patients, the majority of which were attributable to radiotherapy. The complete response rate was 94% at 6 months as assessed by PET scan, and 2-year progression-free survival was 86%. After a median follow-up of 14.9 months, all patients were alive and cancer-free.

Overall response rate was 14% following induction, but 96% showed a histologic treatment effect. Tumor viability was less than 5% in 48% of patients, and a molecular complete response was observed in 30% as measured by plasma cell-free HPV. Patients received 36% less radiation than typical of standard of care, and the dose to critical areas was reduced by 50%.

At the press conference, Dr. Ferris asked Dr. Gillison whether the researchers observed a spike in cell-free HPV DNA before the decline occurred, suggesting evidence of tumor death and DNA release.

“We did see in a remarkable number of patients within 2 weeks of the first dose, a very strong peak in the cell-free HPV DNA, followed by a rapid decline. In those patients who still have viable tumor at the end of induction immunotherapy, we saw a second robust peak in cell-free HPV DNA at the start of radiation, with rapid clearance. So that gave us confidence that (among) those patients who had cell-free HPV clearance by the end of induction, followed by no further detection through radiation, that it’s an excellent surrogate for tumor control,” Dr. Gillison said.

Dr. Gillison has financial relationships with Eisai, Exilixis, Caladrius, iTeos, Istari, Seagen, Sensei, Bicara, Mirati, Coherus, Debiopharm, Kura, Shattuck, Nektar, Ipsen, EMD Serono, Gilead, LXS, BioNTech, Merck, Bristol Myers Squibb, Bayer, Roche, Genocea, NewLink Genetics, Aspyrian, TRM Oncology, Amgen, AstraZeneca, Celgene, and Agenus. Dr. Ferris has financial relationships with Bristol Myers Squibb, AstraZeneca/MedImmune, Merck, and Celgene.

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