Pembrolizumab Plus Chemotherapy Combination Improves Survival in Esophageal Squamous Cell Carcinoma

Patients with previously untreated esophageal squamous cell carcinoma experienced an improvement in survival after being treated with pembrolizumab (Keytruda) and chemotherapy compared with placebo plus chemotherapy, according to the results of the phase 3 KEYNOTE-590 trial (NCT03189719) published in in The Lancet Oncology.

Patients with esophageal squamous cell carcinoma and PD-L1 combined positive score (CPS) of 10 or more who received the combination achieved a median overall survival (OS) of 13.9 months compared with 8.8 months in the placebo arm (HR, 0.57; 95% CI, 0.43-0.75; P< .0001). Patients in the pembrolizumab arm experienced a median progression-free survival (PFS) of 6.3 months compared with 5.8 months among those in the placebo arm (HR, 0.65; 95% CI, 0.54-0.78; P< .0001).

“To our knowledge, this is the first study to show a significant survival benefit with immunotherapy plus chemotherapy in the first-line setting for esophageal cancer. These data support the recent US Food and Drug Administration approval of pembrolizumab plus chemo- therapy in first-line therapy for advanced or metastatic esophageal or gastroesophageal junction cancer,” investigators of the study wrote.

The study enrolled 749 patients, 373 of whom were randomized to the pembrolizumab group and 376 were randomized to the placebo group. In total, 73% (n = 548) of patients had esophageal squamous cell carcinoma, 52% (n = 286) of whom had a PD-L1 CPS of 10 or more. Additionally, 27% (n = 201) had adenocarcinoma, 12% (n = 91) of whom had Siewert type 1 gastroesophageal junction adenocarcinoma. Patients received 200 mg of pembrolizumab intravenously every 3 weeks along with standard of care. Patients in the placebo group received the placebo to pembrolizumab intravenously every 3 weeks along with standard of care.

The median duration of follow-up was 22.6 months. A total of 4% (n = 15) of patients in the pembrolizumab group and less than 1% (n = 1) in the placebo group completing the 35 treatment cycles. The mean exposure to treatment was 7.7 months in the pembrolizumab group and 5.8 months in the placebo group.

The OS for patients with esophageal squamous cell carcinoma was 12.6 months in the pembrolizumab group and 8.8 months in the placebo groups (HR, 0.72; 95% CI, 0.60-0.88; P = .0006). The OS for those with PD-L1 CPS of 10 or more was 13.5 months in the pembrolizumab group and 9.4 months in the placebo group (HR, 0.62; 95% CI, 0.49-0.78; P < .0001), while the OS for all randomized patients was 12.4 months in the pembrolizumab group and 9.8 months in the placebo group (HR, 0.73; 95% CI, 0.62-0.86; P < .0001).

The 24-month OS rate in the pembrolizumab group was 31% compared with 15% in the placebo group. Moreover, in patients with esophageal squamous cell carcinoma who had a PD-L1 CPS of 10 or more, the 24-month OS rate was 29% in the pembrolizumab group and 17% in the placebo group. Among those with esophageal squamous cell carcinoma, the rate was 31% in the pembrolizumab group vs 15% in the placebo group for those with a PD-L1 CPS of 10 or more. It was also reported that the 24-month OS rate was 28% in the pembrolizumab group compared with 16% in the placebo group for all randomized patients.

PFS for patients with PD-L1 CPS of 10 or more was 7.5 months (95% CI, 6.2-8.2) in the pembrolizumab group and 5.5 months (95% CI, 4.3-6.0) in the placebo group (HR, 0.51; 95% CI, 0.41-0.65; P< .0001). Additionally, pembrolizumab yielded a median PFS of 6.3 months (95% CI, 6.2-6.9) compared with 5.8 months (95% CI, 5.0-6.0) in the placebo group (HR, 0.65; 95% CI, 0.55-0.76; P< .0001) in the population of randomized patients.

The overall response rate in all randomized patients in the pembrolizumab group was 45.0% (95% CI, 39.9-50.2) compared with 29.3% (95% CI, 24.7-34.1) in the placebo group. The median duration of response in the pembrolizumab group was 8.3 months and 6.0 months in the placebo group. In total, 18% of patients in the pembrolizumab group had response durations lasting 24 months or longer compared with 6% of those in the placebo group.

All patients had adverse effects (AEs) in the pembrolizumab group vs 99% (n = 368) in the placebo group. AEs of grade 3 or higher occurred in 86% (n = 318) in the pembrolizumab group and 83% (n = 308) in the placebo group. The most notable AEs in the pembrolizumab and placebo cohorts, respectively, were decreased neutrophil count (24% vs 17%), anemia (17% vs 22%), and neutropenia (15% vs 16%).

A total of 24% (n = 90) of patients in the pembrolizumab group and 20% (n = 74) in the placebo group discontinued treatment due to of AEs. Eight percent (n = 28) of patients in the pembrolizumab arm and 10% (n = 38) in the placebo arm died due to of AEs.

Investigators reported that 98% (n = 364) of patients in the pembrolizumab group and 97% (n = 360) in the placebo group had treatment-related AEs (TRAEs). Additionally, 72% (n = 266) of patients in the pembrolizumab group and 68% (n = 250) in the placebo group had a grade 3 of higher TRAE. Two percent (n = 9) of patients in the pembrolizumab group and 1% (n = 5) in the placebo group died due to TRAEs.

Patients also experienced immune-mediated AEs and infusion reactions, including 26% (n = 95) in the pembrolizumab group and 12% (n = 43) in the placebo group. The most common immune-mediated AEs in the pembrolizumab and placebo groups, respectively, were hypothyroidism (11% vs 7%), pneumonitis (6% vs 1%), and hyperthyroidism (6% vs 1%). Grade 3 or higher immune-mediated AEs occurred in 7% (n = 26) of patients in the pembrolizumab group and 2% (n = 8) in the placebo group.

Reference

Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet. 2021;398(10302):759-771. doi:10.1016/S0140-6736(21)01234-4