The European Medicines Agency's Committee for Medicinal Products for Human Use has recommended approval of pembrolizumab as a monotherapy or in combination with platinum and 5-FU as frontline treatment for patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma and PD-L1 expression on their tumors.
Jonathan Cheng, MD
The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has recommended approval of pembrolizumab (Keytruda) as a monotherapy or in combination with platinum and 5-FU as frontline treatment for patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) and PD-L1 expression (composite positive score [CPS] ≥1) on their tumors.1
The CHMP based its positive opinion on findings from the phase III KEYNOTE-048 trial,2,3 in which single-agent pembrolizumab led to a 22% reduction (HR, 0.78; 95% CI, 0.64-0.96; P = .0171) 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. When used in combination with chemotherapy in the overall KEYNOTE-048 population, the PD-1 inhibitor led to a 23% (HR, 0.77; 95% CI, 0.63-0.93; P = .0067) reduction in the risk of disease progression or death.
“Head and neck cancer remains a devastating disease with poor long-term outcomes and advances in survival have been difficult to achieve for more than 10 years” Jonathan Cheng, MD, vice president, clinical research, Merck Research Laboratories, said in a press release. “The positive EU CHMP opinion further validates the potential of KEYTRUDA, as monotherapy and in combination with chemotherapy, to help patients and address the high unmet need in this aggressive form of head and neck cancer.”
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/m2 loading dose followed by 250 mg/m2 weekly, plus cisplatin at 100 mg/m2 or carboplatin AUC 5 every 3 weeks, plus 5-FU at 1000 mg/m2 daily 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.
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%.