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Welcome to this second in a series of 4 CME/CE/CPE-certified educational ClinicalThought™ commentaries on the optimal management of patients with head and neck cancers. In this commentary, Barbara Burtness, MD, reviews the data behind current best practice with immune checkpoint inhibitors nivolumab and pembrolizumab for patients with metastatic recurrent head and neck cancer.
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The use of immunotherapy as a standard of care in metastatic recurrent squamous cell carcinoma of the head and neck is now clearly established. Based on data from the phase I KEYNOTE-012 trial with pembrolizumab and the phase III CheckMate-141 trial with nivolumab, these immunotherapies were approved by the FDA in 2016 for patients with platinum‑refractory head and neck cancer, with the subsequent phase III KEYNOTE-040 trial also demonstrating benefit with pembrolizumab. Based on this evidence, the patient in our case would be best treated with one of these immunotherapies as he was clearly platinum refractory with rapid progression upon treatment discontinuation.
Durvalumab—The EAGLE Trial
The PD-L1–targeted monoclonal antibody, durvalumab, also has activity in head and neck cancer. In the randomized phase III EAGLE trial, durvalumab with or without the anti–CTLA-4 monoclonal antibody tremelimumab was compared with standard-of-care chemotherapy in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). In this trial, there was no significant difference in OS with immunotherapy vs the investigator's choice standard-of-care options. However, with longer follow-up, a survival benefit emerged for patients who received durvalumab monotherapy, so this was an interesting outcome.
CPS vs PD-L1 in HNSCC
Taken together, these data established clear evidence that immunotherapy is active in patients with head and neck cancer, with nivolumab and pembrolizumab integrated into standard clinical practice. Then, in correlative analyses of the KEYNOTE‑040 trial, a new biomarker began to emerge: combined positive score (CPS). CPS measures PD-L1 expression on both tumor cells and immune cells (lymphocytes and macrophages). CPS is generated by counting the number of PD-L1‑positive tumor and immune cells, dividing it by the total number of viable tumor cells in the field, and multiplying by 100. It became clear that CPS is a better predictor of response to PD-1 blockade, such that patients with a low CPS were less likely to benefit from pembrolizumab.
Pembrolizumab in First‑line HNSCC
Consistent activity of these agents immediately raised the question of whether it would be possible to give immunotherapy in the first‑line setting. Given that PD-1–directed antibodies have ORRs of approximately 18% and standard-of-care chemotherapy with cetuximab has a response rate of approximately 35%, there was some question about how best to structure a comparison of immunotherapy with standard of care in the first‑line setting.
To this end, the phase III KEYNOTE‑048 trial took a novel approach by comparing pembrolizumab with or without chemotherapy to a single control arm of the EXTREME regimen (platinum agent with 5‑fluorouracil and cetuximab). The trial analysis was done in a biomarker‑directed fashion, such that we first analyzed patients with the highest PD-L1 expression (CPS ≥ 20), followed by those with CPS ≥ 1, and then the total population. There was a clear advantage for the use of pembrolizumab, whether it was given alone or together with chemotherapy, over standard of care. In the biomarker‑directed analyses there was an OS advantage for pembrolizumab alone or pembrolizumab plus chemotherapy in patients with CPS ≥ 1. Among those with CPS < 1, pembrolizumab plus chemotherapy was advantageous, but pembrolizumab alone was not. In the total population, pembrolizumab alone was noninferior to the EXTREME regimen.
Among patients who responded to pembrolizumab monotherapy, the median duration of response was remarkable at approaching 21 months. Response rates were higher with pembrolizumab plus chemotherapy than with pembrolizumab alone and comparable to chemotherapy plus cetuximab. Of note, the response rate with pembrolizumab plus chemotherapy was 43% among patients with CPS ≥ 20, which was better than the EXTREME regimen (38%). These data led to the approval of first‑line pembrolizumab without chemotherapy for patients with CPS ≥ 1, or pembrolizumab plus chemotherapy for all patients.
Patients who received pembrolizumab alone experienced fewer toxicities than those in the EXTREME arm, while those who received pembrolizumab plus chemotherapy experienced similar rates of toxicities as patients in the EXTREME arm. More immune‑related adverse events occurred in the pembrolizumab arms, but there were fewer infusion reactions and less rash.
Will Immunotherapy Work in the Curative Setting?
With solid evidence that immunotherapy should be a standard treatment for patients with recurrent metastatic disease, including in the first‑line setting for patients with PD-L1 expression, the question was raised whether these agents could be incorporated into the curative setting. The phase III JAVELIN 100 head and neck trial (NCT02952586) compared the anti-PD-L1 monoclonal antibody avelumab plus chemoradiotherapy to standard of care chemoradiotherapy in patients with previously untreated, locally advanced head and neck cancer; results showed that adding avelumab offered no benefit in the primary endpoint of progression-free survival, and the trial was discontinued. The larger phase III KEYNOTE-412 trial (NCT03040999) was designed to compare chemoradiation with or without pembrolizumab followed by pembrolizumab maintenance in patients with locally advanced disease. This trial is fully accrued and we anticipate results within the next year.
One question that will be important to answer with data from the JAVELIN 100 head and neck and KEYNOTE-412 trials is whether giving an immune checkpoint inhibitor during chemoradiation increases toxicity in a manner that compromises benefit. An alternate strategy to try to avoid that possibility would be to incorporate immunotherapy following chemoradiation, which is the strategy being pursued in the ECOG‑ACRIN EA3161 trial (NCT03811015). In this phase II/III trial, all patients complete chemoradiation as standard of care for locally advanced, high‑risk P16‑positive oropharynx cancer, and then are randomized to nivolumab or observation.
Additional research is investigating the intriguing suggestion that even a single dose of preoperative immunotherapy can lead to dramatic response. KEYNOTE‑689 (NCT03765918) is a large randomized phase III trial examining neoadjuvant pembrolizumab previous to surgery, followed by risk‑based postoperative therapy with pembrolizumab or standard of care adjuvant therapy in patients with newly diagnosed resectable disease. In addition, Schoenfeld and colleagues reported high response rates for nivolumab with ipilimumab in the preoperative setting, and the Netherlands Cancer Institute has pursued a similar strategy.
In brief, there is no mature evidence yet that immune checkpoint inhibitors belong in the curative setting for patients with head and neck cancer, but there are a lot of interesting strategies under study.
Combination Strategies With Immunotherapy
Finally, it has been hypothesized that the benefit of immunotherapy could be enhanced by combination with novel immunotherapies that improve the activity of immune checkpoint inhibitors, either by activating costimulatory molecules or by affecting the tumor microenvironment. To this end, trials are ongoing evaluating combinations with injectable stimulator of interferon gene agonists and antiangiogenics such as bevacizumab and lenvatinib, which may downregulate the function of myeloid‑derived suppressor cells. Indeed, current clinical trial opportunities for patients with head and neck cancer are truly remarkable.
In my own practice, I have been fortunate to work with immunotherapy since the phase 1b trials. We participated in KEYNOTE‑012 and had patients from around the country enroll. It was a remarkable experience to see patients respond from scan to scan with steady decreases in target lesions with very little toxicity. Moreover, they were remaining well for 2 years or longer. Clearly, patients understand that this is an exciting new way to manage cancer and they are very open to receiving immunotherapies and to participating in trials of immunotherapy. When a patient has a response to immunotherapy, even if they experience toxicity requiring treatment, they can frequently live with their cancer for a very long time. I have a number of patients who were treated with immunotherapies who are now completely disease free and have been off treatment for several years. It feels quite different than treating metastatic recurrent head and neck cancer in the past, and it is exciting to watch the field continue to move forward.