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New Data Clarify Role of First-Line Keytruda in Head and Neck Ca

CHICAGO — Final analysis of KEYNOTE-048 could help guide pembrolizumab (Keytruda) use in first-line for patients with recurrent or metastatic head and neck cancer, a researcher reported here.

While previous data from the trial showed that pembrolizumab with or without chemotherapy topped standard of care in most, the new findings revealed that the PD-1 inhibitor alone was only superior in patients with PD-L1 expression levels of ≥1%, according to Danny Rischin, MD, of Peter MacCallum Cancer Centre in Melbourne, Australia.

Median overall survival (OS) with pembrolizumab alone was 11.5 months versus 10.7 months with EXTREME, a non-significant difference, Rischin said at the American Society of Clinical Oncology (ASCO) annual meeting.

Co-author Barbara Burtness, MD, of Yale Cancer Center in New Haven, Connecticut, told MedPage Today, that while the monotherapy arm failed to show superiority over EXTREME in the total population, the OS number was still “quite good,” and given that response rates and progression-free survival were not improved, suggested a durable effect on the natural history of the disease.

Danny Rischin, MD, presenting the final analysis of KEYNOTE-048

KEYNOTE-048 compared pembrolizumab alone or pembrolizumab plus chemotherapy (carboplatin or cisplatin and 5-fluorouracil) against the EXTREME regimen (cetuximab with carboplatin or cisplatin plus 5-fluorouracil [5-FU]) in patients with recurrent or metastatic recurrent head and neck squamous cell carcinoma.

Burtness presented the initial survival data at the 2018 European Society for Medical Oncology meeting in Munich, which showed that pembrolizumab plus chemotherapy improved OS in all patients, with the best outcomes seen in those with higher PD-L1 combined positivity score (CPS) ≥1 and ≥20. At the time, pembrolizumab alone significantly improved median OS for the CPS ≥1 and ≥20 populations, and demonstrated non-inferiority in the total patient population.

“That was the first evidence that pembrolizumab could prolong survival in the first-line setting and those data are now before the FDA,” said Burtness. “We don’t have an approval there, but it would be surprising if one didn’t come.”

Rischin said the safety profile was comparable between the pembrolizumab combination arm and EXTREME, while the safety profile in the monotherapy arm was favorable.

“The data from KEYNOTE-048 supports pembrolizumab plus platinum-based chemotherapy and pembrolizumab monotherapy as new first-line standard of care therapies for recurrent head and neck squamous cell carcinoma,” he said.

Response rates between pembrolizumab monotherapy compared with EXTREME, respectively, were 23.3% versus 36.1% in the CPS ≥20 group, 19.1% versus 34.9% in the CPS ≥1 group, and 16.1% versus 36.0% in the overall population.

For the pembrolizumab combination compared with EXTREME, response rates were 42.9% versus 38.2% in the CPS ≥20 group, 36.4% versus 35.7% in the CPS ≥1 group, and 35.6% versus 36.3% in the overall population.

“There was a much higher response rate for chemotherapy plus pembrolizumab, so given that many patients with head and neck cancer have a lot of symptoms, and given also that we worry about the consequences of early progression in HPV-negative patients, seeing that you could get to a 42% response rate with pembro-chemo was very illuminating,” said Burtness. “People are likely to be quite comfortable using pembrolizumab alone in the CPS ≥20 population, and yet understand that if they have a patient who’s got pain or has an airway at risk, then adding chemotherapy will add a much higher response rate.”

Burtness noted that while the trial was not designed to compare the two investigational arms, when looking at median OS and the hazard ratios, there did not appear to be any added benefit of chemotherapy for the CPS ≥20 population. Median OS was 14.7 months with the pembrolizumab combination in this group (HR 0.60) and 14.8 months with pembrolizumab alone in this group (HR 0.61).

“It looks like there is a differential effect of pembrolizumab based upon the expression of PD-L1,” noted ASCO session discussant Vanita Noronha, MD, of Tata Memorial Hospital in Mumbai, India.

“I wonder how much of the benefit of pembrolizumab in the CPS ≥1 population was driven by the CPS ≥20 population,” she said, noting that roughly half of the CPS ≥1 group consisted of these patients.

For patients with mild or moderate symptoms, Noronha recommended pembrolizumab monotherapy for CPS ≥20; pembrolizumab with or without chemo for CPS ≥1 patients; and either EXTREME (or similar regimen) or pembrolizumab plus chemotherapy for patients with PD-L1-negative disease or whose status is unknown.

KEYNOTE-048 was supported by Merck.

Rischin disclosed relevant relationships with from Amgen, Bristol-Myers Squibb (BMS), Genentech/Roche, GlaxoSmithKline (GSK), Merck, and Regeneron. Co-authors disclosed multiple relevant relationships with industry.

Burtness disclosed relevant relationships with Aduro Biotech, Alligator Biosciences, Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Cue Biopharma, Debiopharm Group, Genentech/Roche, GSK, Maverick Therapeutics, MedImmune, Merck, and VentiRx.

Noronha disclosed relevant relationships (institutional) with Amgen and Sanofi/Aventis.