Barbara Burtness, MD

An overall survival advantage has now been shown for first-line immunotherapy in recurrent or metastatic head and neck cancer, researchers reported at the European Society for Medical Oncology (ESMO) 2018 Congress.¹

In the phase III KEYNOTE-048 trial, treatment with the anti–programmed cell death protein 1 (PD-1) pembrolizumab (Keytruda) alone extended overall survival by 39% over the standard-of-care EXTREME regimen in patients with tumors with at least 20% expression of programmed cell death ligand 1 (PD-L1). In patients with PD-L1 expression of at least 1%, the increase was 22%, according to Barbara Burtness, MD, of Yale School of Medicine and Yale Cancer Center, New Haven, Connecticut.

Additionally, in all comers, the addition of pembrolizumab to platinum-based chemotherapy proved superior to the EXTREME regimen. The anti–PD-1 antibodies pembrolizumab and nivolu-mab (Opdivo) are already approved for the second-line treatment of advanced head and neck cancer. The new data suggest pembrolizumab may be a new first-line option for some of these patients.

Simply put, said Dr. Burtness, “Patients with advanced head and neck cancer who have PD-L1 expression live longer when they have initial treatment with pembrolizumab.”

The current treatment standard is the EXTREME regimen, which includes a platinum, fluorouracil (5-FU), and cetuximab (Erbitux). Around 35% of patients respond to this treatment, which leads to a median survival of just over 10 months.

“This is the first time in 10 years that we have shown an improvement in survival for this group of patients,” commented ESMO expert Jean-Pascal Machiels, MD, PhD, Head of the Department of Medical Oncology at the Cliniques universitaires Saint-Luc, UCLouvain, Brussels, at a press briefing.

Dr. Burtness predicted the findings could have a large impact on patients with recurrent or metastatic disease who have high PD-L1 expression and are not highly symptomatic. “Patients are not enthusiastic about the toxicities of platinum-based chemotherapy,” she commented. “They may prefer to be able to receive pembrolizumab alone.”

Study Details

KEYNOTE-048 randomly assigned 882 patients to 1 of 3 first-line treatments: pembrolizumab alone, pembrolizumab plus cisplatin- or carboplatin-based chemotherapy, or the EXTREME regimen. Patients had squamous cell carcinoma of the oropharynx, oral cavity, hypopharynx, or larynx that was incurable with local therapies and was recurrent or metastatic.

PD-L1 expression was measured using the combined positive score and tumor proportion score. A combined positive score of at least 20 indicated high PD-L1 expression, whereas a combined positive score of at least 1 was the lower threshold of positivity. Assessment of human papillomavirus virus type 16 found 21% of patients to be positive.

The treatment doses and schedules follow:

• Pembrolizumab monotherapy: pembrolizumab at 200 mg every 3 weeks for up to 35 cycles
• Pembrolizumab plus chemotherapy: pembrolizumab at 200 mg plus carboplatin AUC 5 or cisplatin at 100 mg/m² and 5-FU at 1,000 mg/m²/d for 4 days, for 6 cycles every 3 weeks, followed by single-agent pembrolizumab at 200 mg every 3 weeks for up to 35 cycles total
• EXTREME regimen: cetuximab at 250 mg/m² weekly plus carboplatin AUC 5 or cisplatin at 100 mg/m² plus 5-FU at 1,000 mg/m² for 4 days, for 6 cycles every 3 weeks, followed by cetuximab at 250 mg/m² weekly.

Tale of Two Comparisons

At the ESMO Congress, Dr. Burtness reported on two comparisons:

• Pembrolizumab alone (n = 310) vs EXTREME (n = 300) in patients stratified for PD-L1 expression
• Pembrolizumab plus chemotherapy (n = 281) vs EXTREME (n = 270) in patients with any PD-L1 status.

The median follow-up was 11.7 months for the pembrolizumab monotherapy arm, 13.0 months for the pembrolizumab/chemotherapy arm, and 10.7 months for the EXTREME arm. The pembrolizumab monotherapy arm was not compared with the pembrolizumab/chemotherapy arm.

Compared with the EXTREME regimen, pembrolizumab significantly improved overall survival in patients with a PD-L1 combined positive score of at least 20 (hazard ratio [HR] = 0.61; P = .0007) and a PD-L1 combined positive score of at least 1 (HR = 0.78; P = .0086). The median overall survival for high PD-L1 expressers was 14.9 months with pembrolizumab and 10.7 months with standard treatment, whereas for lower PD-L1 expressers, it was 12.3 months and 10.3 months, respectively.

In the other comparison, which involved all comers regardless of PD-L1 status, the combination of pembrolizumab plus chemotherapy extended overall survival by a significant 23% compared with the EXTREME regimen. The median survival was 13.0 months in the pembrolizumab arm vs 10.7 months in the standard chemotherapy arm (HR = 0.77; P = .0034).

Fewer Responses but ‘More Durable’

Of note, in both comparisons, progression-free survival was not improved with immunotherapy, and response rates were lower. However, the responses that did occur with pembrolizumab were more durable, reported Dr. Burtness.

Among patients with PD-L1 expression, the median progression-free survival was 3.4 months with pembrolizumab and 5.0 months with EXTREME (HR = 0.99) in the subgroup with a combined positive score of at least 20 and 3.2 months and 5.0 months, respectively, in the subgroup with a combined positive score of at least 1 (HR = 1.16). Objective response rates were 23.3% and 36.1%, respectively, in the subgroup with a combined positive score of at least 20 and 19.1% and 34.9%, respectively, in the subgroup with a combined positive score of at least 1.

The opposite scenario was observed for the median duration of response, which was almost 30 months with pembrolizumab and less than 5 months with the EXTREME regimen in both populations with a combined positive score of at least 20 and at least 1.

Pembrolizumab appears to prolong life even when the cancer continues to grow.

— Barbara Burtness, MD

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In the overall population, the response rate was approximately 36% in both the pembrolizumab/chemotherapy and EXTREME arms, but the median duration of response was 6.7 months and 4.3 months, respectively. “Although pembrolizumab yielded lower objective response rates and shorter progression-free survival, those responses were substantially more durable,” Dr. Burtness said. “Pembrolizumab appears to prolong life even when the cancer continues to grow.”

The occurrence of treatment-related adverse events of any grade, as well as grades 3 to 5, was lower in the pembrolizumab arms, as were adverse events leading to treatment discontinuation. The safety profiles of all regimens were as expected, she noted.

Dr. Burtness maintained that pembrolizumab should be a first-line option in advanced head and neck cancer. Whether to give it alone or with chemotherapy may depend on PD-L1 expression, she added. The investigators are conducting further correlative studies—assessing biomarkers and looking for clinical predictors—to further refine its use. ■

DISCLOSURES: The study was funded by Merck. Dr. Burtness is a consultant/advisor to Merck, MedImmune, Boehringer Ingelheim, Amgen, Debiopharm Group, VentiRx, AstraZeneca, Bristol-Myers Squibb, Alligator Bioscience, Genentech/Roche, and Aduro Biotech; has received research funding from Merck, Advaxis, and Bristol-Myers Squibb; honoraria from the International Drug Development Institute; and travel expenses from Boehringer Ingelheim. See the Expert Point of View (page 19) for Dr. Machiels’ disclosure.

REFERENCE

1. Burtness B, Harrington K, Greil R, et al: KEYNOTE-048: Phase 3 study of first-line pembrolizumab for recurrent/metastatic head and neck squamous cell carcinoma. 2018 ESMO Congress. LBA8_PR. Presented October 22, 2018.