Barbara Burtness, MD
Frontline pembrolizumab (Keytruda) monotherapy showed an improvement in overall survival (OS) and duration of response (DOR) versus standard therapy in patients with PD-L1–positive recurrent or metastatic head and neck squamous cell carcinoma (HNSCC); however, there was not a similar improvement in progression-free survival (PFS) or overall response rate (ORR) with the PD-1 inhibitor, according to interim findings from the phase III KEYNOTE-048 trial presented at the 2018 ESMO Congress.
Moreover, pembrolizumab in combination with chemotherapy was associated with a significant improvement in OS versus the standard regimen in the overall study population. In HNSCC, standard frontline therapy is the EXTREME regimen: platinum-based chemotherapy with cisplatin or carboplatin, 5-fluorouracil (5-FU), and cetuximab (Erbitux).
“Pembrolizumab alone and pembrolizumab given with a platinum and 5-flourouracil should represent new standards of care for first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma,” said lead study author Barbara A. Burtness, MD, professor of medicine (medical oncology); Disease Aligned Research Team leader, Head and Neck Cancers Program; co-director, Developmental Therapeutics Research Program, of Yale Cancer Center.
Pembrolizumab was granted an accelerated approval in August 2016 as a treatment for patients with recurrent or metastatic HNSCC following progression on a platinum-based chemotherapy.
The open-label, randomized, phase III KEYNOTE-048 study evaluated whether pembrolizumab could prolong survival and slow disease progression versus the EXTREME regimen 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 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 PFS and OS in patients with a PD-L1 combined positive score (CPS) ≥20, ≥1, and in all patients enrolled. The data cutoff date was June 13, 2018, with a minimum follow-up of 17 months.
In patients with PD-L1 CPS ≥20 (n = 255), the median OS was 14.9 months versus 10.7 months in patients who received single-agent pembrolizumab 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 treatment, respectively; however, the median DOR was longer with the PD-1 inhibitor at 20.9 months versus 4.5 months.
Results were similar for patients with a PD-L1 CPS ≥1 (n = 512), 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
Moreover, 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, Burtness said.