Overall, these data support the use of pembrolizumab and pembrolizumab plus chemotherapy as first-line treatment of patients with relapsed and/or metastatic HNSCC.
Patients with PD-L1-positive relapsed/refractory head and neck squamous cell carcinoma (HNSCC) who were treated in the KEYNOTE-048 trial experienced and improvement in progression-free survival after subsequent therapy (PFS2) with pembrolizumab (Keytruda) compared with the EXTREME regimen. The PFS2 benefit was consistent in patients who received pembrolizumab alone and those who received added chemotherapy.1
In findings presented at the 2020 ASCO Virtual Scientific Meeting, lead author Kevin J. Harrington, MBBS, PhD, added that the combination of pembrolizumab plus chemotherapy also extended PFS2 for the total study population.
Among the total population, the 24-month PFS2 rate was 19.7% among those assigned to pembrolizumab (n = 301) compared with 11.4% in the EXTREME arm (n = 300). The median PFS2 was 9.0 months for both groups (HR, 0.90; 95% CI, 0.75-1.07).
For those in the total population assigned to pembrolizumab/chemotherapy (n = 281), the 24-month PFS2 rate was 21.4% versus 10.5% in favor of the experimental arm. Similarly, the median PFS2 was superior in the pembrolizumab/chemotherapy arm (n = 278) 10.3 vs 9.0 months; HR, 0.74; 95% CI, 0.62-0.88).
“Overall, these data support the use of pembrolizumab and pembrolizumab plus chemotherapy as first-line treatment of patients with relapsed and/or metastatic HNSCC,” he said.
In the phase 3 KEYNOTE-048 (NCT02358031), 882 patients with metastatic HNSCC were randomly assigned to pembrolizumab, pembrolizumab plus platinum-based chemotherapy and 5-fluorouracil (5-FU), or the EXTREME regimen consisting of cetuximab (Erbitux) plus platinum-based chemotherapy and 5-FU.
In this subsequent analysis, Harrington et al sought to evaluate outcomes for subsequent therapy in patients who progressed following first-line treatment. Eligible patients had never received systemic therapy for metastatic or recurrent disease and were considered incurable by local therapies. PFS2 was defined as time from randomization to objective tumor progression on next-line therapy or death from any cause.
Overall, investigators compared 301 patients assigned to pembrolizumab alone to 300 patients assigned to EXTREME. A total of 281 patients were assigned to pembrolizumab/chemotherapy versus 278 assigned to EXTREME.
Patients were assessed for PD-L1–positivity at a combined positive score (CPS) greater than or equal to 20 (³20) and CPS greater than or equal to 1 (³1).
Among patients with CPS ≥20, PFS2 at 24 months was 27.0% for pembrolizumab monotherapy (n = 133) compared with 12.5% for EXTREME (n = 122). The median PFS2 was 11.7 versus 9.4 months in favor of the pembrolizumab arm (HR, 0.64; 95% CI, 0.48-0.84).
For patients with CPS ≥20 assigned to pembrolizumab/chemotherapy, the 24-month PFS2 rate was 28.9% pembrolizumab combination (n = 126) compared with 12.0% for EXTREME n = 110). The median PFS2 was 11.3 versus 9.7 months in favor of the pembrolizumab arm (HR, 0.63; 95% CI, 0.47-0.84).
For patients with CPS ≥1 assigned to pembrolizumab monotherapy, the 24-month PFS2 rate was 22.0% pembrolizumab combination (n = 257) compared with 9.9% for EXTREME (n = 255). The median PFS2 was 9.4 versus 8.8 months in favor of the pembrolizumab arm (HR, 0.80; 95% CI, 0.66-0.96).
Among the CPS ≥1 population, the 24-month PFS2 rate assigned for those assigned to pembrolizumab/chemotherapy was 23.7% pembrolizumab combination (n = 242) compared with 9.0% for EXTREME (n = 235). The median PFS2 was 10.3 versus 8.9 months in favor of the pembrolizumab arm (HR, 0.66; 95% CI, 0.54-0.80).
Harrington concluded with an overview of the first subsequent therapies selected by investigators for their patients who developed progressive disease. Approximately half of all patients received any new cancer treatment in the total population of each arm: 49.5% in the pembrolizumab monotherapy arm, 40.9% in the pembrolizumab/chemotherapy arm, and 53.0% in the EXTREME arm. The largest number of patients received chemotherapy as their next line of treatment (44.9%, 31.3%, and 34.0%, respectively).
“As anticipated, patients who had not received the EXTREME regimen in the first line were more likely to receive EGFR inhibitor therapy, and conversely those who had not received an immune checkpoint inhibitor in the first line were more likely to receive [an immune checkpoint inhibitor] as their next treatment,” said Harrington.
Treatment with an EGFR inhibitor were 19.6%, 13.2%, and 6.3% for the pembrolizumab, pembrolizumab/chemotherapy, and EXTREME arms, respectively. Subsequent treatment with an immune checkpoint inhibitor were 2.0%, 4.3%, and 16.7%, respectively.
Based on previous data from KEYNOTE-048, the FDA approved pembrolizumab in June 2019 for the first-line treatment of patients with metastatic or unresectable recurrent HNSCC as monotherapy in patients with CPS ≥1 or in combination with platinum and FU irrespective of PD-L1 expression.
Single-agent pembrolizumab induced a 22% reduction in the risk of disease progression or death compared with the standard EXTREME regimen in patients with PD-L1–positive tumors (HR, 0.78; 95% CI, 0.64-0.96; P =.0171).2 When combined with chemotherapy, the PD-1 inhibitor led to a 23% reduction in the risk of disease progression or death (HR, 0.77; 95% CI, 0.63-0.93; P = .0067) in the overall population.
1. Harrington KJ, Rischin D, Greil R, et al. KEYNOTE-048: progression after the next line of therapy following pembrolizumab (P) or P plus chemotherapy (P+C) vs EXTREME (E) as first-line (1L) therapy for recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). J Clin Oncol. 38:2020(suppl 15; abstr 6505). doi:10.1200/JCO.2020.38.15_suppl.6505
2. FDA approves pembrolizumab for first-line treatment of head and neck squamous cell carcinoma. FDA. Accessed May 30, 2020. bit.ly/3djbOIf