Pembrolizumab Improves OS, but Not PFS and ORR in Frontline HNSCC

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 = .2).

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.

Jean-Pascal Machiels, MD, PhD, head, Department of Medical Oncology at the Cliniques Universitaires Sain-Luc, Brussels, Belgium, shared his perspective on KEYNOTE-048 at a press briefing during the meeting.

“This is the first time in 10 years that we show an improvement in survival for this group of patients,” said Machiels. “For a group of patients with high expression of PD-L1, we can probably remove cisplatin. We have still some work to do to better characterize the group of patients who could benefit, and also see how we can bring this active drug to the curative setting.”

Regarding tolerability, 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%.

Further analyses of biomarker and clinical predictors may optimally guide the choice to administer pembrolizumab monotherapy or in combination with chemotherapy in individual patients.

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.

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