As part of our coverage of the American Association for Cancer Research [AACR] annual conference, being held April 16th to the 20th in New Orleans, we are speaking today with Dr. Robert Ferris, MD, PhD, an head and neck surgical oncologist and cancer immunologist at the University of Pittsburgh Cancer Institute, where he is also the co-leader of the Cancer Immunology Program. Dr. Ferris is one of the senior authors of an abstract [CT099] presented at the meeting, on the results of the phase III CheckMate-141 study which investigated the efficacy of the anti-PD-1 antibody, nivolumab in patients with head and neck cancer.
—Interviewed by Anna Azvolinsky, PhD
OncoTherapy Network: Dr. Ferris, can you tell us the design of this study?
Dr. Ferris: Sure. This was a randomized phase III trial comparing the anti-PD-1 monoclonal antibody, nivolumab [Opdivo], against the current standard of care systemic therapy. This was a trial specifically selecting a very poor prognosis group of patients who had progressed after platinum therapy within 6 months and that could have been either in the locally advanced setting or in the recurrent metastatic setting. In head and neck cancer, the so-called platinum-refractory group that progresses within 6 months has a very poor prognosis and there are not really any systemic therapies that are affective. And so this trial was designed to target this group of patients with a novel immunotherapeutic approach, comparing single-agent nivolumab, targeting the PD-1 pathway against investigator’s choice systemic therapy consisting of either docetaxel or cetuximab [Erbitux] or methotrexate as the alternatives. In this randomized phase III study, we were able to analyze the primary endpoint of overall survival and there were additional secondary endpoints of response rates, progression-free survival and correlative biomarkers. But the data for overall survival being positive was the reason why the trial was stopped early.
OncoTherapy Network: What are some of the key results of the study? You mentioned that patients treated with nivolumab had an overall survival benefit.
Dr. Ferris: Right. A preplanned interim analysis after a data lock was performed at the end of December 2015. At the end of January 2016, the data safety monitoring committee reviewed the results of the primary endpoint of overall survival and this demonstrated a more than doubling of patients alive at one year; approximately 36% in the nivolumab arm versus about 16.5% in the investigator’s choice, systemic chemotherapy arm. So as the primary endpoint, this had sufficient power and in fact, exceeded the preplanned power based on the number of events. So they stopped the trial early, I think appropriately to make nivolumab available for crossover for the control arm and to report these results publically. So that was quite impressive. There was a hazard ratio of 0.7, so a 30% reduction of risk of death in the nivolumab arm and, as I mentioned, a greater than doubling in the individuals alive at 12 months. Now, that would be impressive in it of itself, but the grade 3 and 4 adverse events were about one-third in the nivolumab arm. So the combination of more than doubling of those alive at 12 months plus the dramatically lower adverse event rate in the nivolumab arm was a very compelling topline result generating the enthusiasm for this trial.
OncoTherapy Network: Can you comment on the differences in overall survival between those patients with PD-L1 positive tumors compared to those whose tumors did not express PD-L1? How significant was that?
Dr. Ferris: Right. It should be stated that although as exciting as the data are of the clinical results I just mentioned, it’s true that the majority of patients still progressed and many of them did not derive benefit. So therefore, the field of oncologists want to know: can we enrich, can we select for patients most likely or more likely to benefit? And then can we understand some biomarkers of resistance or to target those individuals with different agents now that we know that immunotherapy works and that head and neck cancer is an immunotherapy-responsive disease. Based on data that many of us know from melanoma, and more recently from non-small cell lung cancer, the expression of the ligand, PD-L1, for the receptor PD-1 that is targeted by nivolumab has been proposed as an enrichment biomarker, not necessarily as a binary selection biomarker. Indeed, PD-L1-positive tumors appeared to have an overall higher response rate than PD-L1-negative tumors. Interestingly, there was still efficacy that was apparent in the nivolumab arm even for PD-L1-negative tumors. And so, clearly, nivolumab is efficacious, as we would say, regardless of PD-L1 status, but clearly one has a better likelihood of the overall survival benefit if the patient’s tumor is PD-L1-positive.
OncoTherapy Network: Another biomarker that the study analyzed was the HPV [human papillomavirus] status in patients’ tumors. Can you tell us about those results?
Dr. Ferris: Yes, the human papilloma virus is responsible for increasing proportion of head and neck squamous cell carcinomas. It’s been rising at about a 5% rate annually for the past 20 or 30 years. For overall, about a 250% increase and so this is a big subset of head and neck cancers that are HPV-driven. Interestingly, because HPV-positive patients appear to do better for many therapies, it is less common to have them in the recurrent metastatic setting. But in the CheckMate-141 trial, approximately 25% of the patients enrolled were HPV-positive using the surrogate biomarker of p16 immunohistochemistry. And so that was a big subset that we were anxious to see whether HPV-positive patients in particularly benefited from anti-PD-1 nivolumab. There were some data that suggested roughly equivalent response rates from a pembrolizumab [Keytruda] trial at a previous ASCO [meeting]. So this was a subset that was analyzed. Interestingly, nivolumab in the CheckMate-141 study was effective regardless of HPV status. But HPV positivity did portend a greater benefit for overall survival enhancement with nivolumab over the investigator’s choice chemotherapy. So both PD-L1 positivity and HPV positivity appeared to be biomarkers for greater improvement in benefit with nivolumab, although the PD-L1-negative and HPV-negative patients still benefited, still derived some benefit although less from nivolumab in this trial.
OncoTherapy Network: Just lastly, how significant are these results in the context of currently available treatment options for head and neck cancer patients?
Dr. Ferris: Well, head and neck cancer can be a devastating disease. And in some situations it is curable in the locally advanced setting. When it reoccurs, in the first- or second-line setting, often it is incurable, particularly when we select out very aggressively and rapidly growing cisplatin-refractory population that recur within 6 months of platinum therapy. So, these are results that are significant because really, we have no effective therapies for the platinum-resistant population and a good proportion of patients in the CheckMate-141 study had recurred within 6 months of locally advanced therapy of a cisplatin-containing regimen. So now we have an agent that is efficacious, we demonstrate that head and neck cancer is indeed an immunotherapy-responsive tumor type. So this opens up a so-called fourth therapeutic modality that can be used as a single-agent and is actively under investigation in combination with chemotherapies, with biological therapies such as the EGFR-targeted antibody cetuximab, with radiotherapy in locally advanced disease, and this now opens up now a really great new opportunity for new therapies for such a devastating disease that often leads to disfigurement, difficulty in breathing, speaking, swallowing, and demonstrates not only an overall survival benefit, but in the context of much lower toxicities than the current standard. I think that is why the field is enthusiastic. We have not had an FDA-approved agent for head and neck cancer for a number of years and we now have the potential to adding immunotherapy into the standard-of-care regimens for this difficult disease.
OncoTherapy Network: Thank you so much for discussing these results with us, Dr. Ferris.
Dr. Ferris: My pleasure.