Transcript:Robert L. Ferris, MD, PhD: Recurrent metastatic head and neck cancer has essentially one standard of care, which is to combine cetuximab with platinum 5-FU. This regimen, called the EXTREME regimen, is active and leads to response rates that are pretty good, but associated with high toxicities, and sometimes this is a difficult-to-administer regimen. Furthermore, there is not always long-term durability, and so the field was looking for new agents. Immunotherapy has presented a potentially promising approach because the immune system has memory. We know that through the vaccines that we all receive early in life, the immune system can have memory for years and years down the road, particularly against viruses or bacteria. Therefore, the field of immunotherapy in cancer held promise that we could potentially, for a recurrent metastatic cancer patient, induce their immune system response against their cancer, providing long-term durability—the so-called tail of the curve—which demonstrates that the immune system could continue to recognize and control the disease.

The immune checkpoint inhibitors, particularly nivolumab and pembrolizumab, are targeting the PD-1 immune checkpoint. In a large randomized phase III trial, nivolumab was shown to double the overall survival rate at 1 year as compared to investigators’ choice single-agent chemotherapy—either cetuximab, docetaxel, or methotrexate. Since none of those agents are particularly beneficial or useful, they have been used essentially as a last resort, and they were used in this phase III trial to compare with single-agent nivolumab or the anti-PD-1 antibody. We found that 6-month progression-free survival was doubled, and as I mentioned, overall survival was also doubled.

Fortunately, the grade 3 and 4 adverse events were only one-third the rate in the nivolumab-treated patients as they were in the single-agent chemotherapy group. So, although those agents are not very effective, they were almost 3 times as toxic. This has led to a new paradigm where we can stimulate immunity against someone’s cancer, give long-term durability to a subset who respond, on the order of 15% to 20% of the patients, and do this in a way that’s quite tolerable.

Recently published were data from the CheckMate-141 study, which was the first phase III randomized immunotherapy trial in head and neck cancer. This was a trial of 360 patients randomized 2:1 in favor of nivolumab and comparing nivolumab, an anti-PD-1 antibody, versus single-agent chemotherapy of investigator’s choice, either docetaxel, cetuximab, or methotrexate. The primary endpoint was overall survival, and, indeed, overall survival was doubled in patients who received nivolumab (36%) versus the control arm of single-agent chemotherapy (which was 16.6%). So, it met its primary endpoint, and this led to the FDA approval of nivolumab for recurrent metastatic, cisplatin-refractory head and neck cancer patients.

Now, subsets of patients who appeared to respond differently were based on the 2 biomarkers of PD-L1 status—the ligand for PD-1—and patients whose tumors expressed PD-L1 had a much better outcome and a higher response rate. So, those patients had a 45% chance of being alive at 1 year instead of a 30% reduction in death. A second biomarker is human papillomavirus (HPV). HPV-positive head and neck cancer patients using the p16 surrogate biomarker to identify them, again, had a much better outcome to anti-PD-1/nivolumab than the HPV-negative patients.

Based on the data from the CheckMate-141 study, which led to the FDA approval of nivolumab, this established a new standard-of-care in platinum-refractory, recurrent metastatic head and neck cancer. With a doubling of the overall survival, patients and physicians have been asking for anti-PD-1 therapies because the toxicity profile is much more promising, the drug is much more tolerable than chemotherapy, and the survival is much improved. So, the new standard of care for platinum-refractory disease is anti-PD-1/nivolumab. Although pembrolizumab is also FDA approved, we need to acknowledge that it has not yet been subject to a randomized phase III trial. And so, we have good data from KEYNOTE-012 and KEYNOTE-055 and an ongoing randomized phase III trial for pembrolizumab, but those data are not yet available. So, the current standard-of-care is anti-PD-1, either nivolumab or pembrolizumab.

Transcript Edited for Clarity