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MUNICH -- Patients with metastatic or recurrent head and neck cancer lived longer if they received the anti-PD-1 drug pembrolizumab (Keytruda), with or without chemotherapy, compared with standard treatment, according to a randomized trial reported here.

Median survival for patients with PD-L1-positive (PD-L1+) tumors improved by 2 to 4 months with pembrolizumab alone, and adding the drug to chemotherapy improved median and 2-year overall survival (OS) irrespective of PD-L1 status, reported Barbara Burtness, MD, of Yale Cancer Center in New Haven, Connecticut, at the European Society for Medical Oncology congress.

"Pembrolizumab alone and pembrolizumab given with a platinum and 5-fluorouracil should represent new standards of care for first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma (HNSCC)," Burtness said. "Further analysis of biomarker and clinical predictors may optimally guide the choice of whether to administer pembrolizumab [alone] or with chemotherapy in individual patients."

Pembrolizumab alone was less toxic than standard chemotherapy, and combining the drug with chemotherapy resulted in toxicity that was similar to currently used chemotherapy regimens, she said.

The trial results established two "firsts" for the treatment of recurrent and metastatic HNSCC, said Tanguy Seiwert, MD, of the University of Chicago.

"This is the first study to show superior OS over the decade-old standard of care, platinum-based chemotherapy, and cetuximab (Erbitux), and it establishes PD-L1 CPS (Combined Positivity Score) as a valid marker for head and neck cancer that should be routinely measured in these patients," he said.

"The challenge is that treatment benefit is not equally distributed, but depends on a biomarker," Seiwert continued. "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."

The prognosis for recurrent or metastatic HNSCC remains poor, associated with a median survival of 6 to 12 months. For more than a decade, standard of care has been the EXTREME regimen, consisting of cisplatin or carboplatin plus 5-fluorouracil and cetuximab (Erbitux).

The PD-1 inhibitors pembrolizumab and nivolumab (Opdivo) prolonged survival of recurrent/metastatic HNSCC in clinical trials of second-line therapy, Burtness noted. Across multiple tumor types, a positive test for PD-L1 expression has been associated with increased sensitivity to PD-1/PD-L1 inhibitors.

Investigators in the randomized, phase III KEYNOTE-048 trial investigated pembrolizumab, alone and in combination with chemotherapy, as first-line therapy for recurrent/metastatic HNSCC. Patients who could not be cured by local therapy and had no prior exposure to systemic treatment were randomized to pembrolizumab alone, pembrolizumab plus cisplatin-5 fluorouracil chemotherapy, or the EXTREME regimen. Results in the two pembrolizumab arms were compared separately with results for patients randomized to EXTREME.

Burtness reported findings from a median follow-up of about 17 months. The analysis included 882 patients randomized to the three treatment groups. The trial had a primary endpoints of progression-free survival (PFS) and OS.

The analysis showed that neither pembrolizumab alone nor pembrolizumab with chemotherapy prolonged PFS versus EXTREME in patients with a CPS score ≥1 or ≥20. No further analyses of PFS will be performed, said Burtness.

Analyses of OS revealed statistically significant advantages for both pembrolizumab arms of the trial, but the advantage varied by PD-L1 expression.

In the subgroup of patients with CPS ≥20, patients treated with pembrolizumab monotherapy had a median survival of 14.7 months versus 10.7 months in the EXTREME arm and a 2-year survival of 38% versus 22% (HR 0.61, 95% CI 0.45-0.83, P=0.0007).

For patients with a CPS ≥1, pembrolizumab was associated with a median OS of 12.3 months versus 10.3 months with EXTREME, and a 2-year survival of 30% versus 19% (HR 0.78, 95% CI 0.64-0.96, P=0.0086).

Pembrolizumab did not significantly improve survival versus EXTREME in the total population. An upcoming final survival analysis will include a test for noninferiority, said Burtness.

The pembrolizumab-chemotherapy arm improved OS in the total study population, improving median survival from 10.7 months with EXTREME to 13.0 months and 2-year survival from 19% to 29% (HR 0.77,, 95% CI 0.63-0.93, P=0.0034).

"Neither pembrolizumab nor pembrolizumab plus chemotherapy improved response rate over the EXTREME regimen, but both pembrolizumab regimens were associated with a longer duration of response," said Burtness.

Pembrolizumab alone was associated with a better safety profile than EXTREME, and pembrolizumab plus chemotherapy had a safety profile comparable to that of EXTREME, she added.

In response to a question, Burtness said the investigators did not have an explanation for the disconnect between PFS and OS, but that they have not finished analyzing the data.

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