The KEYNOTE-048 trial is practice-changing, according to its invited discussant, Vanita Noronha, MD, Professor of Oncology at Tata Memorial Centre in Mumbai, India. Although a number of questions remain to be answered, she said the take-home message is that the study “met most of its primary endpoints” and, importantly, showed that first-line pembrolizumab can prolong survival of patients with advanced head and neck cancer.

Vanita Noronha, MD

Attempting to simplify the study’s “complicated set of questions,” Dr. Noronha summarized the key findings:

• For pembrolizumab vs EXTREME, there is no benefit in terms of response and progression-free survival, but toxicity is less. Overall survival is superior in the programed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20% and CPS ≥ 1% populations and is noninferior in the total population.
• For pembrolizumab/chemotherapy vs EXTREME, there is no benefit in terms of response and progression-free survival, and toxicity is similar. Overall survival is superior in all patient populations.

The separation of the survival curves in the PD-L1–expressing populations, as compared to the convergence of the curves for the total population, points to a differential effect of pembrolizumab based upon PD-L1 expression, Dr. Noronha said.

“Of note, the response rate to pembrolizumab was lower than to ­EXTREME in all the patient populations except when pembrolizumab was combined with chemotherapy,” she added. “This is an important point to keep in mind in situations when we sometimes need a response in patients who are markedly symptomatic.”

She also observed: “Pembrolizumab alone has the concern of a lower response rate and a minimal impact on progression-free survival, but it is safe, and in combination with chemotherapy, it does not cause a major increase in toxicity.”

Practical Implications

Dr. Noronha framed how she will now use this information in the clinic in her patients with recurrent and metastatic disease who cannot undergo “radical therapy.” If the disease-free interval is < 6 months, she considers the patient to have platinum-refractory disease and to be a good candidate for immunotherapy. If the disease-free interval is > 6 months, performance status is good, comorbidities are controlled, the patient can receive platinum, and any treatment is reimbursable or affordable, she will select treatment based on the degree of symptoms.

For severely symptomatic patients, she will give pembrolizumab plus chemotherapy. If the patient has mild or moderate symptoms and a CPS ≥ 20%, she will give pembrolizumab alone; for patients with a CPS ≥ 1%, she will give pembrolizumab alone or with chemotherapy. When a patient's CPS is 0% or unknown, she will treat with the EXTREME regimen (or something similar) or pembrolizumab plus chemotherapy.

“For the patient who has a borderline performance status, has multiple comorbidities, cannot receive platinum, or has financial constraints, I would treat with single-agent intravenous chemotherapy, oral metronomic chemotherapy, single-agent targeted therapy, or best supportive care,” she said. ■

DISCLOSURE: Dr. Noronha has received institutional research funding from Amgen, Sanofi/Aventis, and Dr. Reddy’s Laboratories.