Expert Discusses Promise of Nivolumab in Head and Neck Cancer

Robert Ferris, MD, PhD

Treatment options for patients with head and neck cancer who progress after chemotherapy are limited.

“This is a setting of disease where there are really no effective systemic agents,” says Robert Ferris, MD, PhD, co-leader of the Cancer Immunology Program at the University of Pittsburgh Cancer Institute. “Creating a new standard of care has been evasive and difficult for this population of patients with very rapid progression.”

Recent data from the phase III CheckMate-141 study, in which single-agent nivolumab (Opdivo) reduced the risk of death by 30% and doubled 1-year overall survival (OS) rates compared with investigator's choice of therapy, offers significant promise for those with advanced platinum-refractory head and neck cancer, says Ferris, an investigator on the CheckMate-141 study.

“What we have seen with a randomized phase III trial is the establishment of a new standard of care,” he says. “This will come about in new approvals, new trials, and combinations and, hopefully, this will transform the way we think about head and neck cancer.”

The CheckMate-141 study demonstrated a median OS with nivolumab of 7.5 months compared with 5.1 months with investigator's choice of therapy (HR, 0.70; 95% CI, 0.51-0.96; P = .0101). Only 13.1% of patients experienced grade 3/4 adverse events with nivolumab versus 35.1% with investigator's choice.

In April 2016, nivolumab received a breakthrough therapy designation by the FDA for this patient population. Updated data from CheckMate-141 will be presented in June at the 2016 ASCO Annual Meeting.

OncLive: Can you explain the significance of Checkmate-141?

In an interview with OncLive, Ferris further explains the potential of nivolumab, its future, and its limitations in the treatment of patients with head and neck cancer.Ferris: This is the first positive randomized phase III trial in head and neck cancer in over a decade. The Checkmate-141 trial presented data using the anti—PD-1 monoclonal antibody nivolumab, which was compared in a 2:1 randomization in favor of nivolumab against standard of care, which was investigator’s choice chemotherapy. In the comparison arm, patients could receive either cetuximab or methotrexate docetaxel.

In the trial, one of the major eligibility requirements is that patients had to progress within 6 months of platinum-based therapy. That could be in the locally advanced or in the recurrent metastatic setting. Some physicians look at Checkmate-141 as a second-line trial; however, it is better perceived as a platinum-refractory population.

Whether patients progressed in the first-, second-, or third-line setting, they had to, at some point, progress within 6 months of platinum therapy. That selects for a very rapidly progressing group of patients for whom we have no effective therapies. To have an OS endpoint met, which was the primary endpoint of this study, is significant. When the study was stopped early, this permitted patients to have access and cross over to the other arm because of the OS benefit. A hazard ratio of .70 indicates a 30% reduction in risk of death.

What should community oncologists take away from these findings?

Are nivolumab combinations being explored in this setting?

In addition, a landmark analysis—indicting the percentage of individuals who were alive at 1 year—may be better than even a response rate. In this case, the nivolumab treatment arm had 36% of the patients alive at 1 year, compared with 16.5% in the control arm. There was a 20% increase in patients alive at 1 year, who were spending time with their families and enjoying holidays. This is extremely gratifying for those of us who participated in this trial.The bottom line is that 20% more patients are alive at 1 year and the grade 3/4 adverse events were only present in 13% of the nivolumab arm. Therefore, we really have a “Goldilocks”—an effective agent with one-third of the grade 3/4 adverse events than with traditional chemotherapy. This was the outcome we were hoping for. Obviously, we would like higher response rates and longer OS, but that combination is the promise of immunotherapy. Hopefully, this is just the beginning.There are a number of companies combining anti—PD-1 agents with radiotherapy and different chemotherapies in the neoadjuvant setting, the adjuvant setting, and in the locally advanced setting.

What sort of impact will immunotherapy have on the landscape of this disease?

In the locally advanced setting, we may not just improve survival but also actually give durable, overall, permanent cures. Improving cure rates in the locally advanced setting for patients with head and neck tumors is really the “holy grail.” That is going to require combinations. Those trials are not only designed, but they are are opening imminently.What we have found for 20 years is that we intensify therapy, sculpt radiotherapy to get the highest dose into the tumor, add chemotherapies, have doublets and triplets, have chemotherapy before chemotherapy and radiation, have agents during radiation, and have adjuvant treatment. All we have done is increase toxicity—not survival.

What questions remain regarding the use of nivolumab in head and neck cancer?

The only survival advantages we have seen are because we have enriched populations with HPV-positive patients. We have not actually improved with all this treatment intensification any of the survival of HPV-negative patients. Now we have an agent with toxicities that are one-third of the standard agents, and can double the number of patients alive at 1 year. That would suggest that we have the ability not just to intensify therapy with a more effective agent. We have the potential to replace some toxic systemic agents and reduce the radiotherapy dose, for once, in the history of head and neck cancer.We need to realize that this is a totally different mechanism of action than we have had in the past, so we will need new biomarkers, and we need to study the tissue of treated patients.

Let’s face it: even with the exciting data in the CheckMate-141 study, the vast majority of patients did not respond and did not benefit. There were still 65% of patients who were not alive at 1 year that we need to penetrate. The only way to do this is to understand anti—PD-1 therapy resistance, to have patients willing to donate tissue on trials, to have patients willing to slow down in the clinic, and participate in trials where we can look at resistance mechanisms. Then, we need to figure out rational combinations. As exciting as these results are, it is still sobering because we have a long way to go.

Gillison ML, Blumenschein G, Fayette J, et al. Nivolumab Versus Investigator’s Choice (IC) for Recurrent or Metastatic (R/M) Head and Neck Squamous Cell Carcinoma (SCCHN): CheckMate-141. Presented at: AACR 2016 Annual Meeting, New Orleans; April 16-20, 2016. Abstract CT099.