Pembrolizumab With or Without Chemotherapy Continues to Show Survival Benefit Over Cetuximab Plus Chemotherapy in Recurrent/Metastatic HNSCC

Kevin J. Harrington, MD, PhD

Following a 4-year follow-up, patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) displayed a continued survival benefit when treated with pembrolizumab (Keytruda) or pembrolizumab plus chemotherapy compared with cetuximab (Erbitux) in combination with chemotherapy, according to findings from the phase 3 KEYNOTE-048 (NCT02358031) trial.¹

The results, which were published in the Journal of Clinical Oncology, showed that at a median follow-up of 45.0 months (interquartile range, 41.0-49.2), patients with a PD-L1 combined positive score(CPS) of at least 20 who received pembrolizumab (n = 133) experienced a median overall survival (OS) of 14.9 months (95% CI, 11.5-20.6) compared with 10.8 months (95% CI, 8.8-12.8) among 122 patients who received cetuximab plus chemotherapy (HR, 0.61; 95% CI, 0.46-0.81; P = .00034).

Patients with a PD-L1 CPS of at least 1 achieved a median OS of 12.3 months (95% CI, 10.8-14.8) vs 10.4 months (95% CI, 9.0-11.7) in the pembrolizumab (n = 257) and cetuximab arms (n = 255), respectively (HR, 0.74; 95% CI, 0.61-0.89; P = .0008). The median OS in the overall population was 11.5 months (95% CI, 10.3-13.5) vs 10.7 months (95% CI, 9.3-12.1) for patients in the pembrolizumab (n = 301) and cetuximab arms (n = 300), respectively (HR, 0.81; 95% CI, 0.68-0.97; P = .00994).

Additionally, patients with a PD-L1 CPS who were treated with pembrolizumab plus chemotherapy (n = 126) experienced a median PFS of 14.7 months (95% CI, 10.3-19.3), improving upon what was observed with the cetuximab/chemotherapy combination (HR, 0.62; 95% CI, 0.46-0.84; P = .00082). The median PFS for patients with a PD-L1 CPS of at least 1 who received the pembrolizumab-containing combination (n = 242) was 13.6 months (95% CI, 10.7-15.5), again besting what was reported with cetuximab/chemotherapy among patients with the same PD-L1 CPS parameters (HR, 0.64; 95% CI, 0.53-0.78; P = .00001). The median PFS for patients in the overall cohort that received pembrolizumab plus chemotherapy (n = 281) was 13.0 months (95% CI, 10.9-14.7), which exceeded that of the cetuximab/chemotherapy population (HR, 0.71; 95% CI, 0.59-0.85; P = .00008).

“With long-term follow-up of KEYNOTE-048, first-line pembrolizumab alone and pembrolizumab-chemotherapy showed enduring survival benefits compared with cetuximab-chemotherapy in R/M HNSCC,” wrote Kevin J. Harrington, MD, PhD, of the Institute of Cancer Research, and co-investigators, in the study. “With an almost 4-year follow-up, 48-month OS rates were higher for pembrolizumab and pembrolizumab-chemotherapy in all populations.”

In June 2019, initial findings from KEYNOTE-048 previously supported the FDA’s decision to approve pembrolizumab for the frontline treatment of patients withmetastatic or unresectable HNSCC. These findings showed a 22% reduction in the risk of disease progression or death with single-agent pembrolizumab, compared with standard treatments with cetuximab plus chemotherapy.2,3

KEYNOTE-048 enrolled adult patients with treatment-naïve recurrent/metastatic HNSCC. Patients were randomly assigned 1:1:1 to receive pembrolizumab monotherapy, pembrolizumab plus platinum and 5-fluorouracil, or cetuximab plus platinum and fluorouracil. Enrolled patients were stratified based on PD-L1 expression (TPS≥ 50% vs TPS < 50%), p16 status (positive vs negative), and performance status (0 vs 1).2

In the monotherapy arm, patients were given pembrolizumab at a dose of 200 mg once every 3 weeks. Patients in the pembrolizumab plus chemotherapy arm received pembrolizumab at the same dosing schedule as those in the monotherapy arm in combination with 6 cycles of cisplatin 100 mg/m2 once every 3 weeks or carboplatin area under the curve (AUC) 5 once every 3 weeks and fluorouracil 1000 mg/m2 per day via a 4-day infusion once every 3 weeks. In the chemotherapy arm, patients were treated with cetuximab at a loading does of 400 mg/m2 and then 250 mg/m2 per week plus 6 cycles of cisplatin 100 mg/m2 once every 3 weeks or carboplatin AUC 5 once every 3 weeks and fluorouracil 1000 mg/m2 per day, 4-day infusion once every 3 weeks.

The dual primary end points were OS and progression-free survival (PFS). Secondary end points included objective response rate (ORR) and safety. Duration of response (DOR) represented an exploratory end point.

Additional updated results showed that pembrolizumab monotherapy was favored in terms of OS compared with chemotherapy plus cetuximab in most patient subgroups that were examined by investigators. The most pronounced benefit was observed among patients who never smoked (HR, 0.72; 95% CI, 0.49-1.05), those with metastatic disease (HR, 0.73; 95% CI, 0.60-0.90), and those who were not from Europe or North America (HR, 0.73; 95% CI, 0.57-0.95). Additionally, pembrolizumab plus chemotherapy was favored across all examined subgroups compared with chemotherapy plus cetuximab, including among patients aged at least 65 years (HR, 0.52; 95% CI, 0.38-0.71), those from Europe (HR, 0.58; 95% CI, 0.42-0.81), and those who were current smokers (HR, 0.64; 95% CI, 0.40-1.00).1

In terms of PFS, patients with a PD-L1 CPS of at least 20 who received the pembrolizumab-containing combination achieved a median figure of 5.8 months (95% CI, 4.7-7.6) compared with 5.3 months (95% CI, 4.9-6.4) among patients who were given chemotherapy plus cetuximab (HR, 0.76; 95% CI, 0.57-1.02; P = .03273). Patients with a PD-L1 of at least 1 who were treated with pembrolizumab plus chemotherapy experienced a median PFS of 5.1 months (95% CI, 4.7-6.2) vs 5.0 months (95% CI, 4.8-6.0) in the chemotherapy plus cetuximab arm (HR, 0.86; 95% CI, 0.71-1.04; P = .06497). The median PFS was similar to, but did not exceed, that of chemotherapy plus cetuximab among patients in all other PD-L1 CPS subgroups.

Treatment with pembrolizumab plus chemotherapy improved the ORR compared with chemotherapy plus cetuximab among patients with a PD-L1 CPS of at least 20 (43.7% vs 38.2%) and in patients with a PD-L1 CPs of at least 1 (37.2% vs 35.7%). Patients who received pembrolizumab monotherapy did not experience a benefit in terms of ORR compared with chemotherapy plus cetuximab.

The median DOR was 23.4 months (95% CI, 5.7-35.9) in the pembrolizumab monotherapy arm compared with 4.5 months (95% CI, 2.9-7.2) in the with chemotherapy plus cetuximab arm. In the pembrolizumab combination arm, the median DOR was 6.7 months (95% CI, 3.9-13.2). Median DOR did not significantly vary due to PD-L1 CPS status in any of the arms.

Updated safety findings showed that any grade treatment-related adverse effects (TRAEs) occurred at a rate of 58.3%, 95.7%, and 96.9% in the pembrolizumab monotherapy, pembrolizumab plus chemotherapy, and chemotherapy plus cetuximab groups, respectively. TRAEs of at least grade 3 severity were present in 17.0%, 71.7%, and 69.3% of patients, respectively.

Reference

1. Harrington KJ, Burtness B, Greil R, et al. Pembrolizumab with or without chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma: updated results of the phase III KEYNOTE-048 study. J Clin Oncol. 2023;41(4):790-802. doi:10.1200/JCO.21.02508
2. FDA approves pembrolizumab for first-line treatment of head and neck squamous cell carcinoma. FDA. Updated June 10, 2019. Accessed February 2, 2023. bit.ly/2wP4Oz8
3. Burtness B, Harrington KJ, Greil R, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019;394(10212):1915-1928. doi:10.1016/S0140-6736(19)32591-7.