First-line pembrolizumab a new standard for recurrent, metastatic head and neck squamous cell carcinoma

MUNICH — Pembrolizumab prolonged survival compared with standard first-line systemic therapy for patients with recurrent or metastatic head and neck cancer, according to late-breaking study results presented at European Society for Medical Oncology Congress.

Perspective from Ezra E.W. Cohen, MD; Tanguy Seiwert, MD

The benefit — observed with pembrolizumab (Keytruda, Merck) monotherapy, as well as use of the anti-PD-1 agent with chemotherapy — represents the first advance in initial treatment for these patients in more than a decade.

The regimens should be considered as new first-line standards of care for this setting, according to study author Barbara Burtness, MD, professor of medicine (medical oncology), leader of the head and neck cancers program, and codirector of the developmental therapeutics research program at Yale Cancer Center.

“It’s really thrilling,” Burtness, a HemOnc Today Editorial Board member, said in an interview. “To see patients achieve complete responses or remain progression free long term on pembrolizumab alone is a huge change compared with what we had before.”

The EXTREME regimen serves as standard first-line treatment for recurrent or metastatic head and neck squamous carcinoma.

The treatment — given in six 3-week cycles — consists of the EGFR inhibitor cetuximab (Erbitux, Eli Lilly) plus chemotherapy. Cetuximab is administered at a loading dose of 400 mg/m², followed by 250 mg/m² weekly. The chemotherapy component includes carboplatin area under the curve (AUC) 5 or cisplatin 100 mg/m², plus 5-FU 1,000 mg/m² daily for 4 days.

The open-label, randomized phase 3 KEYNOTE-048 study included 882 patients with recurrent or metastatic HNSCC who were not curable by local therapy and had no prior systemic therapy in the recurrent or metastatic setting. All patients provided tumor samples for PD-L1 testing.

Researchers randomly assigned patients to one of three groups: standard treatment with EXTREME (n = 300); monotherapy with pembrolizumab, dosed at 200 mg every 3 weeks (n = 301); or pembrolizumab plus the same chemotherapy schedule used in EXTREME (n = 281).

Treatment continued for six cycles or 24 months, or until disease progression or unacceptable toxicity.

Primary endpoints included PFS and OS among three groups: patients with PD-L1 combined positive score (CPS) of 20 or higher, CPS score of 1 or higher, and the total population.

Interim results showed pembrolizumab monotherapy significantly extended median OS compared with the EXTREME regimen among patients with CPS 20 or higher (14.9 months vs. 10.7 months; HR = 0.61; 95% CI, 0.45-0.83), as well as among patients with CPS 1 or higher (12.3 months vs. 10.3 months; HR = 0.78; 95% CI, 0.64-0.96). In the entire cohort, OS with pembrolizumab monotherapy was noninferior to that observed with EXTREME.

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“It is important to draw attention to the 14.9-month OS in the CPS 20 population,” Burtness told HemOnc Today. “We have never had a median survival like that in head and neck cancer, so I think it changes everything.”

Approximately 45% of patients in this comparison had CPS scores 20 or higher.

“We had been thinking the ‘great responders’ would encompass about 10% to 12% of patients,” Burtness said. “It was not clear this treatment would have a survival impact on such a large group.”

Pembrolizumab monotherapy did not significantly extend PFS among patients with CPS 20 or higher. Per the analysis plan, investigators performed no additional PFS comparisons.

Confirmed objective response rates were lower among patients assigned pembrolizumab monotherapy than those assigned EXTREME (CPS 20, 23% vs. 36%; CPS 1, 19% vs. 35%; and total population, 17% vs. 36%). However, median duration of response was longer with pembrolizumab monotherapy in all three groups (CPS 20, 20.9 months vs. 4.2 months; CPS 1, 20.9 months vs. 4.5 months; and total population, 20.9 months vs. 4.5 months).

A considerably lower percentage of patients assigned pembrolizumab monotherapy than EXTREME experienced grade 3 to grade 5 drug-related adverse events (17% vs. 69%).

The pembrolizumab-chemotherapy combination significantly prolonged median OS compared with EXTREME in the total population (13 months vs. 10.7 months; HR = 0.77; 95% CI, 0.63-0.93). However, the pembrolizumab-chemotherapy combination did not significantly extend OS compared with EXTREME among patients in either of the CPS-stratified groups.

The pembrolizumab-chemotherapy combination did not significantly extend PFS compared with EXTREME. Overall response rates were the same in each group (36%), but median duration of response was longer in the pembrolizumab-chemotherapy group (6.7 months vs. 4.3 months). Rates of grade 3 to grade 5 drug-related adverse events also were comparable (71% vs. 69%).

The study will continue until a final OS analysis is performed.

The fact that the interim analysis showed pembrolizumab monotherapy significantly extended OS compared with EXTREME — despite a lower response rate and numerically shorter PFS — suggests the agent “appears to prolong life even when the cancer continues to grow.” This supports pembrolizumab’s use as first-line therapy for patients with recurrent or metastatic disease, she said.

“Whether pembrolizumab is given alone or with chemotherapy may depend on PD-L1 expression, and we are conducting analyses to answer this question,” she said. – by Mark Leiser

Reference:

Burtness B, et al. Abstract LBA8_PR. Presented at: European Society for Medical Oncology Congress; Oct. 19-23, 2018; Munich.

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Disclosures: Merck & Co. Inc. provided funding for this study. Burtness reports advisory board roles with Aduro Biotech, Amgen, AstraZeneca, Bristol-Myers Squibb, Genentech and Merck; research funding from Advaxis, Bristol-Myers Squibb and Merck; honoraria from IDDI; and travel expenses, including accommodations, from Boehringer Ingelheim.

Perspective

Ezra E.W. Cohen, MD

The KEYNOTE-048 study represents a change in therapy for patients with recurrent or metastatic head and neck squamous cell carcinoma. The evidence to use pembrolizumab in the first-line setting is compelling, both as a single agent for patients whose tumors express PD-L1 and in combination with chemotherapy if PD-L1 expression is quite low or unknown. There are still data elements that need to be reported, such as how different PD-L1-expressing cohorts fared in both experimental arms and the subsequent therapy that patients received. Nonetheless, we immediately have new standards of care in the first-line setting that extend survival.

Ezra E.W. Cohen, MD

Moores Cancer Center

UC San Diego

Disclosures: Cohen reports consultant fees from and a scientific advisory board role with Merck Sharpe & Dohme.

Perspective

Tanguy Seiwert, MD

This is the first study to show superior overall survival over the decade-old standard of care — platinum-based chemotherapy and cetuximab — and establishes PD-L1 CPS as a valid marker for head and neck cancer that should be routinely measured in these patients.

The challenge is that treatment benefit is not equally distributed but depends on a biomarker. Hence, PD-L1 CPS expression will likely inform our choice between the two new options — pembrolizumab alone, with a favorable side effect profile, and pembrolizumab combined with chemotherapy, which may be used in a larger group of patients.

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 for patients who have tumors with low or absent PD-L1 expression, where there is potentially less benefit.

The usefulness of other biomarkers to select patients for treatment, such as tumor mutational burden, should also be examined.

Tanguy Seiwert, MD

University of Chicago Medicine

Disclosures: HemOnc Today could not confirm Seiwert’s relevant disclosures at the time of reporting.