Pembrolizumab: New Standard of Care in Head and Neck Cancer

Roxanne Nelson, RN, BSN

November 15, 2019

Immunotherapy with pembrolizumab (Keytruda, Merck & Co), either as monotherapy or in combination with chemotherapy, offers a new standard of care for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), say experts discussing the results from the company-sponsored KEYNOTE-48 trial.

Pembrolizumab plus chemotherapy yielded a significant survival benefit in comparison with standard therapy for both the total patient population and for patients whose tumors were positive for programmed cell death–ligand-1 (PD-L1).

Monotherapy with pembrolizumab yielded a significant overall survival benefit for patients with tumors that were PD-L1 positive; and in the total study population, overall survival was noninferior.

"Thus, pembrolizumab monotherapy is a new standard of care, first-line therapy option for patients with PD-L1-positive recurrent or metastatic HNSCC. Pembrolizumab with chemotherapy is also a new option for all patients, regardless of PD-L1 status," comment Robert L. Ferris, MD, PhD, from the University of Pittsburgh, Pennsylvania, and Lisa Licitra MD, from the University of Milan, Italy, in a commentary that accompanies article in the Lancet.

"The positive results of KEYNOTE-048 represent substantial progress for patients with recurrent or metastatic HNSCC," Ferris and Licitria add.

These comments echo the reactions from experts when the study was presented earlier this year at the annual meeting of the American Society for Clinical Oncology (ASCO), as reported by Medscape Medical News at that time.

Presenter Danny Rischin, MD, from the Peter MacCallum Cancer Center, Melbourne, Australia, said: "These data support pembrolizumab plus platinum-based CT [chemotherapy] and pembrolizumab monotherapy as new first-line standard-of-care therapies for relapsed/metastatic head and neck squamous cell carcinoma."

At the ASCO meeting, the study was highlighted as "most important" by Francis P. Worden, MD, of the University of Michigan Rogel Cancer Center, Ann Arbor. He predicted that pembrolizumab in combination with chemotherapy will replace the EXTREME regimen (cetuximab with platinum-based therapy and fluorouracil) as first-line therapy in HNSCC.

However, while agreeing that the data are practice changing, Vinita Noronha, MD, of the Tata Memorial Cancer Center in Mumbai, India, emphasized that several questions remained unanswered.

In a discussion of the paper, Noronha pointed out that the findings do not provide guidance on which patients should receive pembrolizumab alone or in combination with chemotherapy, and there are also questions as to why both the response rate and progression-free survival rate failed to improve. It was also unclear whether there was a role for sequential therapy or whether all patients should receive the combination up front. Some of these questions have been addressed in the commentary to the Lancet article.

Study Details

KEYNOTE-048 was a randomized, phase 3 study that included 882 participants with untreated locally incurable recurrent or metastatic HNSCC. It was conducted at 200 sites in 37 countries.

Patients were stratified by PD-L1 expression, p16 status, and performance status and were randomly assigned in a 1:1:1 ratio to one of three groups: pembrolizumab monotherapy at 200 mg every 3 weeks for 35 cycles; pembrolizumab 200 mg every 3 weeks for six cycles combined with a platinum and 5-fluorouracil followed by maintenance pembrolizumab 200 mg every 3 weeks for an additional 29 cycles; or cetuximab plus a platinum and 5-fluorouracil (ie, the EXTREME regimen).

Most patients (85%, n = 754) had tumors that were PD-L1 positive and had a PD-L1 combined positive score (CPS) of ≥1; 381 (43%) had a CPS of ≥20.

The final results of the study showed that pembrolizumab alone improved overall survival as compared to cetuximab with chemotherapy in the CPS ≥20 cohort (median, 14.9 vs 10.7 months; hazard ratio [HR], 0.61; P = .0007) as well as in the larger group with CPS ≥1 (12.3 vs 10.3 months; HR, 0.78; P = .0086). It also proved to be noninferior within the total patient population (11.6 vs 10.7 months; HR, 0.85).

Pembrolizumab combined with chemotherapy also improved overall survival compared to cetuximab with chemotherapy in the total patient population (13.0 vs 10.7 months; HR, 0.77; P = .0034). Combination therapy was also superior to chemotherapy in patients with CPS ≥20 (14.7 vs 11.0 months; HR, 0.60; P = .0004) and in those with CPS ≥1 (13.6 vs 10.4 months; HR, 0.65; P < .0001).

However, neither pembrolizumab alone nor pembrolizumab in combination with chemotherapy improved progression-free survival or the overall objective response rate, as compared with combination cetuximab and chemotherapy. The proportion of patients for whom progressive disease was the best response was also higher in the pembrolizumab-alone group compared with cetuximab-plus-chemotherapy group.

As for toxicity, all-cause adverse events of grade 3 or greater occurred in 164 (55%) patients in the pembrolizumab-alone group, 235 (85%) in the pembrolizumab-plus-chemotherapy group, and 239 (83%) in the cetuximab-with-chemotherapy group.

Events that led to death occurred in 25 (8%) participants in the pembrolizumab-alone group, 32 (12%) in the pembrolizumab-plus-chemotherapy group, and 28 (10%) in the cetuximab-with-chemotherapy group.

Two New Standards Available

In their commentary, Ferris and Licitra point out that although the present study was not designed to compare pembrolizumab monotherapy with pembrolizumab plus chemotherapy, "we can qualitatively evaluate the study results."

They note that median OS was similar for pembrolizumab alone and pembrolizumab with chemotherapy in the cohort with CPS ≥20 and was better for pembrolizumab with chemotherapy in the cohort with CPS ≥1 and in the total population. Objective response was higher for pembrolizumab with chemotherapy in PD-L1-positive patients and in the total population, and the duration of response was better than for pembrolizumab alone.

"In this scenario, two new standards are available for the same patients, offering the opportunity to tailor treatment for clinical and patient preferences and individual decision making," they comment. On the basis of the findings of KEYNOTE-048, the PD-L1 biomarker will now become more useful for therapy selection for patients with HNSCC

However, as with any change in standard of care, there are substantial implications for subsequent therapy, they continue. For patients who do not improve after receiving first-line pembrolizumab monotherapy, second-line standard-of-care systemic therapy options will now include platinum doublets containing cetuximab. For those who experience disease progression after receiving first-line pembrolizumab with chemotherapy, cetuximab will subsequently be offered.

The study was funded by Merck Sharp & Dohme. Several of the coauthors have disclosed multiple relationships with industry, as noted in the original article. Ferris reports multiple relationships with industry. Licitra has disclosed no relevant financial relationships.

Lancet. Published Online October 31, 2019. Abstract, Commentary

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