Pembro Ups Survival in PD-L1–positive HNSCC

First-line treatment with the PD-1 inhibitor pembrolizumab (Keytruda; Merck) dramatically improved survival compared with standard of care in patients whose head and neck tumors expressed high levels of PD-L1, according to phase III trial data presented at the European Society for Medical Oncology 2018 Congress in October.

The KEYNOTE-048 study included 882 patients with head and neck squamous cell carcinoma (HNSCC) that recurred or metastasized following radiation or surgery. Participants received pembrolizumab alone, pembrolizumab plus platinum-based chemotherapy, or the standard-of-care EGFR inhibitor cetuximab (Erbitux; Eli Lilly) plus platinum-based chemotherapy.

The anti–PD-1 drug offered only modest benefits in the overall study population. Pembrolizumab monotherapy was less toxic than standard treatment, but led to more rapid disease progression and yielded a noninferior median overall survival (OS). The safety profile and median progression-free survival time of the immuno–chemotherapy combination were both comparable to the cetuximab regimen, yet offered a significant uptick in median OS—to 13 months from 10.7 months for standard of care—and the 2-year survival rate was also superior at 29% versus 19%.

Where pembrolizumab shined, says trial leader Barbara Burtness, MD, of the Yale University School of Medicine in New Haven, CT, was among patients with a tumor microenvironment in which at least 20% of the cancer and stromal cells expressed PD-L1. In this group, single-agent pembrolizumab produced a median OS of 14.9 months, and 38% of individuals were still alive after 2 years versus 22% in the control arm. Responders experienced disease control for a median of 20.9 months, compared with less than 5 months for the cetuximab–chemotherapy regimen.

“That is huge,” says Maura Gillison, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, who led phase III testing of another PD-1 inhibitor, nivolumab (Opdivo; Bristol-Myers Squibb), in patients with HNSCC. “There is a subset of patients who respond to the immunotherapy alone and have deep and durable responses,” with reduced side effects and improved quality of life.

However, response rates to pembrolizumab were still modest in this PD-L1–high cohort—23% compared with 36% for standard treatment. “If there's a limitation to single-agent pembrolizumab, it is the lower response rate,” says Ezra Cohen, MD, of the University of California, San Diego, who helped test it as a second-line therapy in patients with HNSCC.

Gillison says that lack of predictive power undermines the clinical utility of PD-L1 testing, especially because patients who don't respond to first-line immunotherapy tend to experience more rapid disease progression than those who receive chemotherapy. “There's probably something better that we can figure out to identify those patients,” she says.

One possibility may be a joint biomarker combining tumor mutational burden, a tumor-intrinsic measure of antigenicity, and T cell–inflamed gene expression profile, a measure of immune activation. As reported earlier this year, responses to single-agent pembrolizumab in patients with HNSCC were greatest among those with high scores for both measures—approximately 40%.

Still, even the lower odds, as defined by high PD-L1 levels, are probably strong enough for many patients to choose single-agent immunotherapy, says Laura Chow, MD, of the University of Washington in Seattle, who was not involved in the trial. “It will be a preference,” she says, “but why not take the chance that you could be one of those long-term survivors with very little toxicity?” –Elie Dolgin