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Two first-line trials involving pembrolizumab (Keytruda)-based combinations for the treatment of recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) delivered mixed results.

While first-line pembrolizumab plus lenvatinib (Lenvima) significantly improved progression-free survival (PFS) and overall response rate (ORR) compared with pembrolizumab alone in patients with recurrent or metastatic HNSCC with PD-L1 combined positive score ≥1, it failed to improve overall survival (OS), reported Lisa Licitra, MD, of the University of Milan.

However, in the other study, a pembrolizumab-based regimen that replaces the chemotherapy backbone of platinum and fluorouracil with carboplatin and paclitaxel achieved results "consistent with other first-line regimens in this patient population including the standard-of-care combination of pembrolizumab plus platinum and fluorouracil," said Marcin Dzienis, MD, of Gold Coast University Hospital in Brisbane, Australia.

Both studies were presented at the Multidisciplinary Head and Neck Cancers Symposium in Phoenix.

LEAP-010

The phase III randomized 511 patients to pembrolizumab plus lenvatinib or pembrolizumab plus placebo.

With a median follow-up of 11.5 months, the first interim analysis showed that the median PFS was 6.2 months with the combination versus 2.8 months with pembrolizumab alone (HR 0.64, 95% CI 0.50-0.81, P=0.0001). The 12-month PFS rates were 28.5% and 19.2%, respectively.

The ORR was 46.1% with the combination and 25.4% with pembrolizumab alone (P=0.00003).

However, in a second interim analysis at a median follow-up of 21.3 months, median OS was just 15 months with the combination versus 17.9 months with pembrolizumab alone (HR 1.15, 95% CI 0.91-1.45, P=0.882), with 24-month OS rates of 36% and 40%, respectively.

As for safety, 61.4% of patients in the combination arm had grade ≥3 treatment-related adverse events (TRAEs) compared with 17.8% in the pembrolizumab-alone arm, with 28% and 8%, respectively, discontinuing treatment due to TRAEs.

There were 10 treatment-related deaths -- seven in the combination arm and three in the pembrolizumab-alone arm.

The results suggest that first-line pembrolizumab as monotherapy or in combination with chemotherapy "remains the standard of care for first-line treatment for patients with recurrent/metastatic HNSCC," Licitra concluded.

Based on these OS results, the study's sponsors .

When asked how the negative results from LEAP-010 might effect (which is evaluating pembrolizumab plus lenvatinib versus chemotherapy in patients with recurrent or metastatic HNSCC following progression after platinum-based chemotherapy and immunotherapy), Licitra noted that some of the LEAP trials -- such as those involving other diseases including non-small cell lung cancer, urothelial cancer, and melanoma -- were also positive in terms of PFS and ORR, but not in OS.

"This is something that is making us think about the fact that this combination is probably not the best way to go," she said.

KEYNOTE-B10

In explaining the rationale behind the single-arm phase IV trial, Dzienis suggested that there is a need for alternative chemotherapy regimens considering that the standard of care (based on the ) includes fluorouracil, which is associated with unfavorable toxicity, as well as extra costs and inconvenience related to the need for a 4-day infusion with an indwelling catheter.

This study included 101 patients (median age 64 years) with previously untreated recurrent/metastatic HNSCC irrespective of their PD-L1 status.

At a median follow-up of 18.9 months, the confirmed objective response rate (ORR) by blinded independent central review was 48.5%, with 6.9% of patients achieving a confirmed complete response, and 41.6% achieving a partial response. The median duration of response was 5.5 months.

Median PFS was 5.6 months, with a 12-month PFS rate of 12.1%, and median OS was 13.1 months, with a 12-month OS rate of 52.3%.

Any-grade TRAEs occurred in 95% of patients, while grade 3-5 TRAEs occurred in 75.2%, most commonly decreased neutrophil count (44.6%) and anemia (19.8%).

The study "demonstrated durable antitumor activity with pembrolizumab plus carboplatin plus paclitaxel," Dzienis concluded. This regimen can be used "as an additional first-line treatment option in patients with recurrent/metastatic HNSCC, irrespective of PD-L1 status," he added.