Upfront Pembrolizumab With or Without Chemo Approved for HNSCC by FDA

Pembrolizumab has been approved by the FDA as monotherapy for newly diagnosed patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma whose tumors express PD-L1 and for use in combination with platinum and fluorouracil for this patient population, irrespective of PD-L1 expression.

Pembrolizumab (Keytruda) has been approved by the FDA as monotherapy for newly diagnosed patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma whose tumors express PD-L1 (composite positive score [CPS] ≥1) and for use in combination with platinum and fluorouracil (FU) for this patient population, irrespective of PD-L1 expression.

The decision is based on findings from the phase III KEYNOTE-048 trial, in which single-agent pembrolizumab led to a 22% reduction in the risk of disease progression or death compared with the standard EXTREME regimen, which comprises cetuximab (Erbitux) with carboplatin or cisplatin plus FU, in patients with PD-L1—positive tumors (HR, 0.78; 95% CI, 0.64-0.96;P= .0171). When in combination with chemotherapy in the overall KEYNOTE-048 population, the PD-1 inhibitor led to a 23% reduction in the risk of disease progression or death (HR, 0.77; 95% CI, 0.63-0.93; P= .0067).

"This approval is a very exciting milestone in the treatment of head and neck cancer and has the potential to transform the way we treat patients with this debilitating disease by offering important new therapeutic options," Barbara Burtness, MD, professor of medicine, Yale School of Medicine and co-director, Development Therapeutics Research Program, Yale Cancer Center, stated in a press release. "Metastatic or recurrent head and neck cancer has been an area of significant unmet need, so it is encouraging to have immunotherapy regimens available for patients in the first-line setting."

The open-label, randomized, phase III KEYNOTE-048 study evaluated whether pembrolizumab could prolong survival and slow disease progression versus the EXTREME regimen—platinum-based chemotherapy with cisplatin or carboplatin, 5-FU, and cetuximab (Erbitux)—in the recurrent or metastatic setting. A total 882 patients were randomized in a 1:1:1 ratio to either standard EXTREME treatment (cetuximab at 400 mg/m2loading dose followed by 250 mg/m2weekly, plus cisplatin at 100 mg/m2or carboplatin AUC 5 every 3 weeks, plus 5-FU at 1000 mg/m2daily on day 1 through 4 of each 3-week cycle for a maximum of 6 cycles; n = 300); single-agent pembrolizumab at 200 mg every 3 weeks for 2 years (n = 301); or a combination of pembrolizumab and platinum-based chemotherapy with 5-FU (n = 281). Treatment was administered until unacceptable toxicity or progressive disease.

Patients enrolled on the study had squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx; had not received prior chemotherapy or systemic therapy for their recurrent or metastatic disease; and had good ECOG performance status with tissue available for PD-L1 testing. Patients were stratified by PD-L1 expression, p16 status, and ECOG performance status.

The primary endpoints were progression-free survival (PFS) and OS in patients with a PD-L1 CPS ≥20, ≥1, and in all patients enrolled. The data cutoff date was June 13, 2018, with a minimum follow-up of 17 months.

Results of the study, which were presented at the 2018 ESMO Congress, showed that in patients with PD-L1 CPS ≥20 (n = 255), the median OS was 14.9 months versus 10.7 months in those who received pembrolizumab alone versus EXTREME (HR, 0.61; 95% CI, 0.45-0.83;P= .0007), respectively, and the 2-year OS rate was 38% versus 22%. There was no difference in PFS between the 2 arms (HR, 0.99; 95% CI, 0.75-1.29;P= .5).

Moreover, the ORRs were 23.3% and 36.1% with pembrolizumab and standard therapy, respectively; however, the median DOR was longer with the PD-1 inhibitor at 20.9 months versus 4.5 months.

For patients with a PD-L1 CPS ≥1 (n = 512), the results were similar, in which the median OS for pembrolizumab monotherapy versus EXTREME was 12.3 months versus 10.3 months, respectively (HR, 0.78; 95% CI, 0.64-0.96;P= .0086); the 2-year OS rates were 30% versus 19%. The ORR was 19.1% with pembrolizumab and 34.9% with standard therapy, yet the median DOR was again longer with pembrolizumab at 20.9 months and 4.5 months, respectively. There was no difference in PFS between the 2 groups (HR, 1.16; 95% CI, 0.75-1.29).

In the overall population (N = 559), treatment with pembrolizumab added to chemotherapy (n = 281) versus the EXTREME regimen (n = 278) led to a median OS of 13.0 months versus 10.7 months, respectively (HR, 0.77; 95% CI, 0.63-0.93;P= .0034); the 2-year OS rates were 29% versus 19%, respectively. Additionally, the ORRs were 35.6% and 36.3% with pembrolizumab/chemotherapy versus EXTREME therapy, and the DOR was 6.7 months versus 4.3 months, respectively. There was no PFS difference between the 2 groups (HR, 0.92; 95% CI, 0.77-1.10; P= .2).

Additionally, the OS improvement with the combination of pembrolizumab/chemotherapy versus EXTREME in those with PD-L1 CPS ≥20 and CPS ≥1 was not statistically significant, Burtness explained.

Single-agent pembrolizumab was also examined against EXTREME treatment in the overall population. The ORR for pembrolizumab alone in this group was 17% versus 36% with EXTREME. The OS for single-agent pembrolizumab was noninferior to EXTREME in this population; superiority will be evaluated at the final analysis of the trial.

Regarding safety, pembrolizumab was well tolerated with a safety profile that was consistent with prior studies. The combination of pembrolizumab and chemotherapy had a comparable safety profile to EXTREME. The rates of grade 3 to 5 treatment-related adverse events (TRAEs) were 17% for those treated with pembrolizumab monotherapy and 69% for patients who received standard treatment. In the pembrolizumab/chemotherapy group, the rate of grade 3 to 5 TRAEs was 71%.

"Head and neck squamous cell carcinoma has historically presented many challenges to physicians and patients, including limited treatment options and physical and functional issues caused by the disease and its treatment," Jonathan Cheng, MD, vice president, clinical research, Merck Research Laboratories, the developer of pembrolizumab, stated in the press release. "This approval is an important advance in the management of this devastating cancer. The results of KEYNOTE-048, which support this approval, demonstrated that KEYTRUDA monotherapy for patients whose tumors expressed PD-L1 CPS greater than or equal to one and KEYTRUDA in combination with chemotherapy regardless of PD-L1 expression significantly prolonged survival for patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma in the first-line setting."


  1. FDA Approves Two New Indications for Merck's KEYTRUDA(pembrolizumab). Merck. Published June 11, 2019. https://bit.ly/2WwH4dw. Accessed June 11, 2019.
  2. Burtness B, Harrington KJ, Greil R, et al. KEYNOTE-048: Phase III study of first-line pembrolizumab (P) for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA8_PR.