Alexander M. Castellino, PhD

April 19, 2016

NEW ORLEANS — Immunotherapy with nivolumab (Opdivo, Bristol-Myers Squibb Company) once again records a success — this time in platinum-refractory, recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).

Patients who received nivolumab — a programmed cell death protein–1 (PD-1) checkpoint inhibitor — had a significant 30% reduction in risk for death compared with patients who received standard chemotherapy, according to data from CheckMate-141 presented here at the American Association for Cancer Research (AACR) 2016 Annual Meeting.

"These are extraordinary data," presenter Maura L. Gillison, MD, PhD, Jeg Coughlin Chair of Cancer Research at the Ohio State University Comprehensive Cancer Center, in Columbus, told Medscape Medical News. "For the first time we have a drug that improves survival in this treatment-refractory patient population."

Since the approval of cetuximab (Erbitux, Eli Lilly and Company) for head and neck cancer 10 years ago, there have been no new agents for these patients, she said.

"Approximately 600,000 people in the world are diagnosed with HNSCC, and most present with advanced stage III/IV disease. Initial therapy may include combinations of surgery, radiation, and platinum-based chemotherapy," she said.

Dr Maura Gillison

HNSCC that recurs within 6 months of platinum chemotherapy given as part of initial treatment or as palliation for recurrent, metastatic disease is associated with a particularly dismal prognosis, she pointed out. "Average survival for these patients is less than 6 months," she said.

"Nivolumab is the first systemic therapy to improve survival in this patient population and therefore fulfills a huge, unmet need," she said.

"I have been treating patients for 20 years," she said. "The disease is devastating, with patients having significant issues with speech, swallowing, and breathing. Now for the first time in my career I have an option that will make a difference to the quality of life of my patients," she added.

"This study provides convincing evidence that overall survival was better than that seen on a reasonable control arm," David G. Pfister, MD, chief of the Head and Neck Oncology Service, Memorial Sloan Kettering Cancer Center, New York City, told Medscape Medical News.

He was referring to the fact that the control arm provided treatment on the basis of the investigator's choice of methotrexate, docetaxel, or cetuximab, which are standard treatments in the setting of advanced, recurrent HNSCC.

The randomized nature of the study reduced potential bias, and the trial provided a high level of evidence, he added.


Patients in the CheckMate-141 trial had advanced HNSCC that had progressed within 6 months of administration of platinum-based therapy.

"These patients have the worst prognosis of all patients we see in the clinic," Dr Gillison said.

Dr Pfister agreed. "Clearly, patients whose disease has progressed in a short time frame despite having received a go-to agent will have a worrisome prognosis," he said.

Patients were randomly assigned in a 2:1 ratio to the nivolumab arm (n = 240) or the control arm of the study. Nivolumab was administered at a dose of 3 mg/kg every 2 weeks. Patients in the control group (n = 121) received standard therapy — weekly therapy of the investigator's choice of methotrexate 40-60 mg/m2, docetaxel 30-40 mg/m2, or cetuximab 400 mg/m2 loading dose followed by 250 mg/m2 weekly.

Patients were allowed to continue receiving nivolumab after disease progression if there was evidence of clinical benefit.

The trial was stopped early because, at interim analysis, the Data Monitoring Safety Board determined that CheckMate-141 had met its primary endpoint and that patients in the control group could cross over to the nivolumab arm of the study.

"The investigators need to be congratulated on an important study in HNSCC," said discussant Lillian L. Siu, MD, senior medical oncologist at Princess Margaret Cancer Centre and professor of medicine at the University of Toronto, Canada.

It validates the notion that PD1/PD-L1 inhibition is relevant in these patients and opens up opportunities for immune checkpoint inhibitors in HNSCC, she pointed out.

She noted that survival was also reported to be improved with pembrolizumab (Keytruda, Merck Sharp & Dohme Corp) in a similar population of patients, but those survival data come from an exploratory analysis. Those data come from the KEYNOTE-012 study and were presented at the 2015 European Cancer Congress.

Significant Survival, Better for Some

For the 361 patients in the study, the median age was 60 years; 76.4% were current or former smokers; 54.8% had received two or more lines of chemotherapy; and 91.4% had received prior radiation therapy. Patients were well balanced across the two groups.

After a median follow-up of only 5.1 months, median overall survival (OS) was 7.5 months for patients receiving nivolumab and 5.1 months for patients receiving standard therapy. With a hazard ratio (HR) of 0.70, patients receiving nivolumab had a 30% reduced risk for death (97.73% confidence interval [CI], 0.51 - 0.96; P = .010). At 12 months, 36% of patients were alive, compared with 16.6% for patients in the control group.

For comparison, Dr Siu pointed out previous data for a similar patient population treated with pembrolizumab in the KEYNOTE-012 trial. Data for pembrolizumab showed a 1-year survival rate of 47% and median survival of 9.6 months.

Dr Siu also highlighted the fact that the survival data seen in CheckMate-141 parallel those seen with agents used as first-line treatment for HNSCC.

In a first-line study of HNSCC, cetuximab in combination with chemotherapy (5-fluoracil and carboplatin or cisplatin) was associated with a 2.7-month gain in OS compared with a 2.4-month gain with single-agent nivolumab in patients with refractory, recurrent HNSCC.

Dr Gillison noted that in CheckMate-141, an exploratory analysis showed that the reduction in risk for death was greater for patients whose tumors were positive for human papillomavirus (HPV) and for tumors with expression of PD-L1≥1%.

The evaluation of clinical benefit based on HPV status was important, inasmuch as certain types of HNSCC, such as those arising in the oropharynx, are associated with HPV infections. Patients with HPV-positive disease had a 44% reduced risk for death (median OS, 9.1 months vs 4.4 months for control) compared with a 27% reduced risk for death for patients with HPV-negative disease (median OS, 7.5 months vs 5.8 months for control). All comparisons were with respect to similar patients in the control arm of the study.

Given the benefit seen in a subpopulation of patients, Dr Pfister pointed out that clinical trial designs are now using such information to stratify patients on the basis of HPV status.

Patients with tumors with PD-L1≥1% had a 45% reduced risk for death (median OS, 8.7 months vs 4.6 months for control), compared with an 11% reduced risk for death for patients with PD-L1<1% tumors (median OS, 5.7 months vs 5.8 months for control).

However, in her discussion of the presentation, Dr Siu indicated that PD-L1 may not be an ideal biomarker because patients with PD-L1-negative tumors also responded to therapy.

Toxicities of any grade were seen in 59% of patients receiving nivolumab and in 78% of patients receiving chemotherapy. Grade 3/4 toxicities were also lower: 13% in patients receiving nivolumab, and 35.1% for patients receiving chemotherapy.

"We did not see any new or unusual side effects in this heavily pretreated population of patients with HNSCC," Dr Gillison told Medscape Medical News. "Toxicities were mild or moderate, and treatment-related grade 3-5 events were less frequent on nivolumab compared with the control group," she said.

"The toxicities for nivolumab and pembrolizumab are remarkably similar," Dr Siu commented. In the pembrolizumab study, toxicities of any grade and of grade 3/4 were reported in 61% and 13% of patients, respectively.

Noting that overall response rates were not presented, Dr Siu said: "Median overall survival may not be the best efficacy readout due to the dynamics of the antitumor activity with immune checkpoint inhibitors."

In this landmark analysis, 1-year survival may better reflect the benefits of nivolumab, she indicated.

Immunotherapy Coming Soon?

Currently, neither nivolumab nor pembrolizumab is approved for the treatment of patients with refractory, recurrent HNSCC. However, patients with advanced HNSCC may soon have two immunotherapeutic options.

Last week, the US Food and Drug Administration agreed to review the supplemental biologics license application for pembrolizumab, granting it a priority review. The Prescription Drug User Fee Act date is set for August 9, 2016.

Dr Siu was not drawn into a discussion of whether nivolumab is better than pembrolizumab or vice versa. "Both are important drugs, and we are at a good point in clinical practice to be able to have these options," she said.

Given that the median survival for patients in CheckMate-141 was less than 1 year, Dr Pfister stressed that more needs to be done for these patients. "While these data are exciting for this agent in this setting compared with other available treatment options, there is room for improvement and a need to build upon this strategy," he said.

"The activity of current immunotherapies in the setting of advanced HNSCC has spawned a plethora of studies," Dr Gillison said. There is active recruitment of patients to test PD-1 inhibitors in the first-line recurrent or metastatic setting and to determine whether the combination of a PD-1 inhibitor with CTLA-4 inhibition provides even better responses.

Dr Siu indicated that there is now an opportunity to study immune checkpoint inhibitors across a spectrum of HNSCC disease — locoregionally advanced disease and postoperatively.

Although immunotherapy provides improved efficacy, disease still progresses in many patients. "How do we rescue these patients?" Dr Pfister asked. He believes that improvement in therapeutic choices will come from insights gained with molecular sequencing of tumors, which will provide mutational profiles and help in understanding drivers of HNSCC that can be targeted.

"New approaches are urgently required to further improve outcomes," he said.

The study was funded by Bristol-Myers Squibb. Dr Gillison was funded in part by the Oral Cancer Foundation and is a consultant for Bristol-Myers Squibb, Eli Lilly and Company, and Merck. Dr Pfister receives clinical trial support from Merck, MedImmune/AstraZeneca, and Bristol-Myers Squibb. Dr Siu reported relationships with several pharmaceutical companies.

American Association for Cancer Research (AACR) 2016 Annual Meeting: Abstract CT099, presented April 19, 2016.


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