Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study

Abstract

Purpose: Pembrolizumab and pembrolizumab-chemotherapy demonstrated efficacy in recurrent/metastatic head and neck squamous cell carcinoma in KEYNOTE-048. Post hoc analysis of long-term efficacy and progression-free survival on next-line therapy (PFS2) is presented.

Methods: Patients were randomly assigned (1:1:1) to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Efficacy was evaluated in programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20, CPS ≥ 1, and total populations, with no multiplicity or alpha adjustment.

Results: The median study follow-up was 45.0 months (interquartile range, 41.0-49.2; n = 882). At data cutoff (February 18, 2020), overall survival improved with pembrolizumab in the PD-L1 CPS ≥ 20 (hazard ratio [HR], 0.61; 95% CI, 0.46 to 0.81) and CPS ≥ 1 populations (HR, 0.74; 95% CI, 0.61 to 0.89) and was noninferior in the total population (HR, 0.81; 95% CI, 0.68 to 0.97). Overall survival improved with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.62; 95% CI, 0.46 to 0.84), CPS ≥ 1 (HR, 0.64; 95% CI, 0.53 to 0.78), and total (HR, 0.71; 95% CI, 0.59 to 0.85) populations. The objective response rate on second-course pembrolizumab was 27.3% (3 of 11). PFS2 improved with pembrolizumab in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.84) and CPS ≥ 1 (HR, 0.79; 95% CI, 0.66 to 0.95) populations and with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.86), CPS ≥ 1 (HR, 0.66; 95% CI, 0.55 to 0.81), and total (HR, 0.73; 95% CI, 0.61 to 0.88) populations. PFS2 was similar after pembrolizumab and longer after pembrolizumab-chemotherapy on next-line taxanes and shorter after pembrolizumab and similar after pembrolizumab-chemotherapy on next-line nontaxanes.

Conclusion: With a 4-year follow-up, first-line pembrolizumab and pembrolizumab-chemotherapy continued to demonstrate survival benefit versus cetuximab-chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma. Patients responded well to subsequent treatment after pembrolizumab-based therapy.

Trial registration: ClinicalTrials.gov NCT02358031.

FIG 1.

Trial profile for the total KEYNOTE-048 population.^{,c a}Enrollment in the pembrolizumab-chemotherapy arm was temporarily paused after three deaths occurred in the first 14 patients enrolled in the pembrolizumab-chemotherapy arm. Enrollment was later resumed on the advice of the safety monitoring committee. Patients allocated to cetuximab-chemotherapy during this time were excluded from the efficacy analysis population for pembrolizumab-chemotherapy versus cetuximab-chemotherapy analyses. ^bReasons for discontinuation are provided in the Data Supplement. ^cReprinted from the study by Burtness et al. ITT, intention-to-treat.

FIG 2.

Kaplan-Meier estimates of OS. Pembrolizumab alone versus cetuximab with chemotherapy in the (A) PD-L1 CPS ≥ 20, (B) PD-L1 CPS ≥ 1, and (C) total populations at long-term follow-up and pembrolizumab with chemotherapy versus cetuximab with chemotherapy in the (D) PD-L1 CPS ≥ 20, (E) PD-L1 CPS ≥ 1, and (F) total populations. ^aFrom the product-limit (Kaplan-Meier) method for censored data. ^bOn the basis of a Cox regression model with the Efron method of handling ties with treatment as a covariate stratified by ECOG PS, HPV status, and PD-L1 status. In case the event count in any stratum was < 5, stratification factors were eliminated in the order of ECOG PS > HPV status > PD-L1 status until the event count in every stratum was ≥ 5. ^cNominal one-sided P values were calculated using a log-rank test stratified by ECOG PS, HPV status, and PD-L1 status. In case the event count in any stratum was < 5, stratification factors were eliminated in the order of ECOG PS > HPV status > PD-L1 status until the event count in every stratum was ≥ 5. CPS, combined positive score; ECOG PS, Eastern Cooperative Oncology Group performance status; HPV, human papillomavirus; OS, overall survival; PD-L1, programmed death ligand 1.

FIG 3.

Subgroup analysis of OS. (A) Pembrolizumab alone versus cetuximab with chemotherapy in the total population and (B) pembrolizumab with chemotherapy versus cetuximab with chemotherapy in the total population at long-term follow-up. ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio.

FIG 4.

Kaplan-Meier estimates of DOR in patients with a best objective response of CR or PR. Pembrolizumab alone versus cetuximab with chemotherapy in the (A) PD-L1 CPS ≥ 20, (B) PD-L1 CPS ≥ 1, and (C) total populations at long-term follow-up and pembrolizumab with chemotherapy versus cetuximab with chemotherapy in the (D) PD-L1 CPS ≥ 20, (E) PD-L1 CPS ≥ 1, and (F) total populations. ^aFrom the product-limit (Kaplan-Meier) method for censored data. CPS, combined positive score; CR, complete response; DOR, duration of response; IQR, interquartile range; ORR, objective response rate; PD-L1, programmed death ligand 1; PR, partial response.

FIG 5.

Pembrolizumab second-course response characteristics.^a-c Each bar represents one patient who received a second course of pembrolizumab. Shown here are first-course first objective response per RECIST v1.1 by BICR, progressive disease after stopping first course per RECIST v1.1 by investigator review, and second-course objective response per RECIST v1.1 by investigator review. Eligibility for second course and response during second course were assessed by the investigator (not by BICR). ^aAt data cutoff, patients 1 and 8 did not have available last scan on second-course pembrolizumab. ^bPatients 2, 4, 5, 6, 7, and 8 received first-course treatment of pembrolizumab alone. Patients 1, 3, 9, 10, and 11 received first-course pembrolizumab-chemotherapy. ^cPatient 1 discontinued first-course pembrolizumab-chemotherapy with CR before PD occurred. At the time of PD, the patient's lesions were smaller than 1 cm and the patient did not have any symptoms of progression. Therefore, the investigator's plan, as agreed on by the study sponsor, was to repeat scans per the protocol schedule and start second-course pembrolizumab once lesions were larger than 1 cm. BICR, blinded independent central review; CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.

FIG 6.

Kaplan-Meier estimates of progression-free survival on the next line of therapy. Pembrolizumab alone versus cetuximab with chemotherapy in the (A) PD-L1 CPS ≥ 20, (B) PD-L1 CPS ≥ 1, and (C) total populations at long-term follow-up and pembrolizumab with chemotherapy versus cetuximab with chemotherapy in the (D) PD-L1 CPS ≥ 20, (E) PD-L1 CPS ≥ 1, and (F) total populations. ^aFrom the product-limit (Kaplan-Meier) method for censored data. ^bOn the basis of a Cox regression model with the Efron method of handling ties with treatment as a covariate stratified by ECOG PS, HPV status, and PD-L1 status. In case the event count in any stratum was < 5, stratification factors were eliminated in the order of ECOG PS > HPV status > PD-L1 status until the event count in every stratum was ≥ 5. ^cNominal one-sided P values were calculated using a log-rank test stratified by ECOG PS, HPV status, and PD-L1 status. In case the event count in any stratum was < 5, stratification factors were eliminated in the order of ECOG PS > HPV status > PD-L1 status until the event count in every stratum was ≥ 5. CPS, combined positive score; ECOG PS, Eastern Cooperative Oncology Group performance status; HPV, human papillomavirus; PD-L1, programmed death ligand 1; PFS2, progression-free survival on the next line of therapy.