Jean-Pascal Machiels, MD, PhD

Invited discussant Jean-Pascal Machiels, MD, PhD, Head of the Department of Medical Oncology at the Cliniques universitaires Saint-Luc, UCLouvain, Brussels, called the study “very important,” especially for showing that in patients with high expression of programmed cell death ligand 1 (PD-L1), “we can probably remove cisplatin and have a good outcome with immunotherapy alone.” However, Dr. Machiels cautioned, more work needs to be done to determine which patients will benefit most. The challenge now, he said, is to bring immunotherapy into the curative setting, probably in combination with chemoradiation.

“The benefit is clinically relevant in patients with a combined positive score of at least 20,” he said, “but are we taking any risks in giving pembrolizumab (Keytruda) first-line to patients with PD-L1 expression of at least 20%?” Despite the survival advantage, response rates are lower, especially in the first few months, he pointed out. The response rate was 13% higher with the EXTREME regimen, and progression-free survival favored the EXTREME regimen as well, at least at the start of therapy. A similar pattern was observed for patients with a combined positive score of at least 1. There are no data for patients with essentially no PD-L1 expression.

Clinical Implications

“If we need important tumor shrinkage for the patient at the beginning, we may choose a platinum regimen,” he suggested. For patients needing rapid tumor shrinkage whose PD-L1 status cannot be assessed, the combination of pembrolizumab plus chemotherapy should be used in the first-line setting, he added.

It is important, Dr. Machiels emphasized, to test patients for PD-L1 status, as for the 40% whose tumors have expression of at least 20%, pembrolizumab alone is the new standard of care. In the 35% to 40% of patients with PD-L1 expression between 1% and 20%, the combination of pembrolizumab plus chemotherapy is a good option, and for such patients with low-burden disease, pembrolizumab monotherapy might be considered. For the 15% of patients with no PD-L1 expression, chemotherapy with cetuximab might remain more effective, he said.

Additional Commentary

Tanguy Seiwert, MD, Head and Neck Cancer Program Director at the University of Chicago Medicine, underlined that this is the first study to show a survival benefit over the standard of care in advanced head and neck cancer. KEYNOTE-048 also establishes PD-L1 scoring “as a valid marker for head and neck cancer—one that should be routinely measured,” he said.

Tanguy Seiwert, MD

“The challenge is that treatment benefit is not equally distributed but depends on a biomarker,” explained Dr. Seiwert. “Hence, PD-L1 combined positive score expression will likely be used to inform the choice of pembrolizumab alone, with a favorable side-effect profile, or pembrolizumab plus chemotherapy, which may be used in a larger group of patients.” Dr. Seiwert continued: “Higher PD-L1 expression is associated with more benefit, but the exact cut points have to be determined, and individual patient characteristics will play an important role as well. Separate analyses are needed in patients who have tumors with low or absent expression of PD-L1, where there is potentially less benefit.” ■

DISCLOSURE: Dr. Machiels is an advisory board member or speaker for Pfizer, Roche, AstraZeneca, Bayer, Innate Pharma, Merck Serono, Boehringer Ingelheim, Bristol-Myers Squibb, Novartis, Janssen, and Incyte; has received travel expenses from Amgen, Bristol-Myers Squibb, Pfizer, and MSD; is a member of data safety monitoring boards for Debio and Nanobiotix; and is an uncompensated advisor for MSD. Dr. Seiwert has received honoraria from AstraZeneca, Bristol-Myers Squibb, and Merck; is a consultant/advisor to AstraZeneca, Bayer, Roche Molecular Diagnostics, Nanobiotix, Celgene, Innate Pharma, Merck, Bristol-Myers Squibb, and Aduro Biotech; has received institutional research funding from Merck, Bristol-Myers Squibb, and Jounce Therapeutics; and has received travel expenses from Merck, Bristol-Myers Squibb, Innate Pharma, Nanobiotix, Bayer, Roche Molecular Diagnostics, AstraZeneca, and Celgene.