Immuno-Oncology Resource Center

Immuno-Oncology Resource Center

December 29, 2019
4 min read

Pembrolizumab changes standard of care for recurrent, metastatic head and neck squamous cell carcinoma

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Barbara Burtness, MD
Barbara Burtness

Pembrolizumab in combination with platinum-based chemotherapy appeared to be a safe and effective first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma, according to results of the randomized phase 3 KEYNOTE-048 study published in The Lancet.

Researchers also deemed first-line monotherapy with pembrolizumab (Keytruda, Merck) to be appropriate for patients with PD-L1-positive recurrent or metastatic HNSCC, based on safety and efficacy data.

“I do believe the results of this study have already changed the standard of care,” Barbara Burtness, MD, professor of medicine at Yale University School of Medicine and Yale Cancer Center, and HemOnc Today Editorial Board Member, told Healio. “The FDA approved pembrolizumab in the first line in June, so pembrolizumab monotherapy for patients with PD-L1 expression, as well as pembrolizumab plus chemotherapy for all patients, is now the standard of care.”

Combining chemotherapy with immune checkpoint inhibitors makes sense in HNSCC because it disrupts tumor architecture that can reduce immune exclusion, results in antigen shedding and encourages rapid disease control, Burtness and colleagues wrote.

Researchers conducted the current trial to determine whether the PD-1 inhibitor pembrolizumab, as monotherapy or in combination with chemotherapy, improves OS compared with the EGFR inhibitor cetuximab (Erbitux, Eli Lilly) and chemotherapy among patients with recurrent or metastatic HNSCC.

The investigators randomly assigned 882 patients with previously untreated recurrent or metastatic HNSCC to pembrolizumab monotherapy (n = 301), pembrolizumab with carboplatin or cisplatin and 5-FU (n = 281), or cetuximab with carboplatin or cisplatin and 5-FU (n = 300).

Among all patients, 754 (85%) had a PD-L1 combined positive score (CPS) of 1 or more and 381 (43%) had a CPS of 20 or more.

OS and PFS served as the study’s primary endpoints. Secondary endpoints included safety and tolerability.

Median follow-up was 11.5 months in the pembrolizumab monotherapy group, 13 months in the pembrolizumab-chemotherapy group and 10.7 months in the cetuximab-chemotherapy group.

Results of the second interim analysis showed pembrolizumab alone improved OS compared with cetuximab plus chemotherapy among patients with a CPS of 20 or more (median, 14.9 months vs. 10.7 months; HR = 0.61; 95% CI, 0.45-0.83) and among those with a CPS of 1 or more (median, 12.3 months vs. 10.3 months; HR = 0.78; 95% CI, 0.64-0.96). OS with pembrolizumab monotherapy appeared noninferior to that of cetuximab and chemotherapy among the total population (median, 11.6 months vs. 10.7 months; HR = 0.85; 95% CI, 0.71-1.03).


Researchers observed significant improvement in OS with pembrolizumab plus chemotherapy vs. cetuximab and chemotherapy among all patients (median, 13 months vs. 10.7 months; HR = 0.77; 95% CI, 0.63-0.93) at the second interim analysis. They also reported a significant OS benefit at final analysis among patients with a CPS of 20 or more (median, 14.7 months vs. 11 months; HR = 0.6; 95% CI, 0.45-0.82) and those with a CPS of 1 or more (13.6 months vs. 10.4 months; HR = 0.65; 95% CI, 0.53-0.8).

Neither pembrolizumab monotherapy nor pembrolizumab plus chemotherapy improved PFS at second interim analysis.

Grade 3 or worse all-cause adverse events occurred among 55% (n = 164) of patients treated with pembrolizumab monotherapy, 85% (n = 235) of patients who received pembrolizumab plus chemotherapy, and 83% (n = 239) of those who received cetuximab plus chemotherapy. Adverse events that led to death occurred among 8% (n = 25) of patients in the pembrolizumab monotherapy group, 12% (n = 32) of the pembrolizumab-chemotherapy group, and 10% (n = 28) of the cetuximab-chemotherapy group.

Inconsistent access to second-line PD-1 and PD-L1 inhibitors across countries that enrolled participants, the lack of statistical power to compare outcomes in the pembrolizumab monotherapy and pembrolizumab-chemotherapy groups, and the open-label design of the study served as limitations.

“There have been several completed trials of checkpoint inhibitors in combination with chemoradiation, but these have not been reported yet,” Burtness said. “As well, there is some evidence for activity in the preoperative setting. I anticipate that there will be some indications for the immune checkpoint inhibition in the definitive setting in the future.”

The change in standard of care has substantial implications on subsequent therapy, according to an accompanying editorial by Robert L. Ferris, MD, PhD, FACS, director of UPMC Hillman Cancer Center, Hillman professor of oncology and associate vice chancellor for cancer research at University of Pittsburgh, and Lisa Licitra, MD, PhD, interim director of medical oncology in the head and neck cancer department at Istituto Nazionale Tumori in Milan.

“Notably, a higher than expected response was seen with cytotoxic chemotherapy in patients who had not improved on previous anti-PD-1 or PD-L1 monoclonal antibodies, first in non-small-cell lung cancer and more recently in HNSCC, which could be mediated by the long half-life of these antibodies,” Ferris and Licitra wrote. “These findings need to be prospectively validated, including an investigation into what cytotoxic agents or combinations provide the most efficacy post-failure of PD-1-based immunotherapy. There is also an urgent need for new immunotherapeutic approaches for patients who have not improved on previous immunotherapy.”– by John DeRosier

For more information:

Barbara Burtness, MD, can be reached at Smilow Cancer Hospital Care Center at Yale New Haven, 35 Park St., Ste. NP-4 New Haven, CT, 06511; email:

Disclosures: Merck Sharp & Dohme funded this study. Burtness reports honoraria, institutional funding and travel expenses from Boehringer Ingelheim and Merck Sharp & Dohme, and fees for advisory roles from Aduro Biotech, Alligator Biosciences, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Cure Biosciences, Debiopharm, Genentech/Roche, GlaxoSmithKline, Maverick Therapeutics and VentiRx. Please see the study for all other authors’ relevant financial disclosures. Ferris reports advisory/consultant roles with Aduro Biotech, Amgen, AstraZeneca, Bain Capital Life Sciences, Eli Lilly, GlaxoSmithKline, Iovance Biotherapeutics, Merck Sharp & Dohme, Nanobiotix, Numab Therapeutics, Oncorus, Regeneron, Tesaro, Torque Therapeutics and VentiRx. Licitra reports consultant/advisory roles with AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene International Eisai, Exelixis, Hoffmann-La Roche, IRX Therapeutics, Medpace, Pfizer, Novartis and Roche.