Pembrolizumab + chemo emerging as first-line SoC in advanced oesophageal cancer

Pembrolizumab in combination with chemotherapy significantly improves overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) vs chemotherapy alone in patients with previously untreated, locally advanced unresectable or metastatic oesophageal cancer, according to results of the phase III KEYNOTE-590 study presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.

The statistically significant and clinically meaningful improvements in outcomes, along with manageable safety profile, have led the investigators to conclude that pembrolizumab plus chemotherapy should be a new standard of care (SoC) in first-line treatment of patients with locally advanced unresectable or metastatic oesophageal cancer. [Kato K, et al, ESMO 2020, abstract LBA8_PR]

In the study, 749 patients with locally advanced unresectable or metastatic oesophageal adenocarcinoma (EAC) or oesophageal squamous cell carcinoma (ESCC) or advanced/metastatic oesophagogastric junction (EGJ) Siewert type 1 adenocarcinoma were randomized (1:1) to receive pembrolizumab (200 mg intravenously [IV] Q3W; n=373; median age, 64 years; male, 82 percent) or placebo (n=376; median age, 62 years; male, 84.8 percent) for ≤35 cycles, on top of chemotherapy (5-FU 800 mg/m² for days 1–5 Q3W for ≤35 cycles plus cisplatin 80 mg/m² IV Q3W for ≤6 cycles). The study’s dual primary endpoints were OS and PFS, while ORR was a secondary endpoint.

At baseline, about half (52.5 percent in the pembrolizumab group vs 52.4 in the placebo group) of the patients were from Asia, and 59.8 percent in each group had an Eastern Cooperative Oncology Group (ECOG) performance status of 1. A majority of patients (73.5 percent vs 72.9 percent) had squamous cell carcinoma, while 26.5 percent vs 27.1 percent had adenocarcinoma. About half (49.9 percent vs 52.4 percent) of the patients had a PD-L1 combined positive score (CPS) of ≥10.

“After a median follow-up of 10.8 months, pembrolizumab plus chemotherapy demonstrated superior OS and PFS vs chemotherapy alone,” said investigator Dr Ken Kato of National Cancer Hospital, Tokyo, Japan.

Median OS was 12.4 months for pembrolizumab plus chemotherapy vs 9.8 months for chemotherapy alone (hazard ratio [HR], 0.73; 95 percent confidence interval [CI], 0.62 to 0.86; p<0.0001) among all patients included in the trial, while 24-month OS rate was 28 percent vs 16 percent.

In patients with ESCC, median OS was 12.6 months vs 9.8 months (HR, 0.72; 95 percent CI, 0.60 to 0.88; p=0.0006) and 24-month OS rate was 29 percent vs 17 percent overall. In ESCC patients with PD-L1 CPS ≥10, median OS was 13.9 months vs 8.8 months (HR, 0.57; 95 percent CI, 0.43 to 0.75; p<0.0001), while 24-month OS rate was 31 percent vs 15 percent.

Among patients with PD-L1 CPS ≥10, median OS was 13.5 months vs 9.4 months (HR, 0.62; 95 percent CI, 0.49 to 0.78; p<0.0001), while 24-month OS rate was 31 percent vs 15 percent.

Median PFS was 6.3 months vs 5.8 months (HR, 0.65; 95 percent CI, 0.55 to 0.76; p<0.0001) among all patients, 6.3 months vs 5.8 months (HR, 0.65; 95 percent CI, 0.54 to 0.78; p<0.0001) in patients with ESCC, and 7.5 months vs 5.5 months (HR, 0.51; 95 percent CI, 0.41 to 0.65; p<0.0001) in patients with PD-L1 CPS ≥10. At 18 months, PFS rates were 16 percent vs 6 percent, 17 percent vs 6 percent, and 21 percent vs 5 percent, respectively.

“The OS and PFS benefits with pembrolizumab plus chemotherapy were generally consistent across key subgroups of patients,” said Kato.

“ORR was likewise superior in the pembrolizumab vs placebo group, at 45 percent vs 29.3 percent among all patients included in the trial [p<0.0001]. The median duration of response was 8.3 months vs 6 months,” he noted.

Rates of grade ≥3 treatment-related adverse events (AEs) were similar between the two groups (71.9 percent vs 67.6 percent), while grade ≥3 immune-related AEs and infusion reactions were more common with pembrolizumab plus chemotherapy vs chemotherapy alone (7 percent vs 2.2 percent). No new safety signals were detected.

“Results of KEYNOTE-590 are potentially practice-changing. The addition of pembrolizumab to platinum-based chemotherapy is a new standard of care [in this patient population],” commented study discussant Professor Andrés Cervantes of University of Valencia, Spain.

“While the results are independent of PD-L1 CPS status, patients with squamous histology and those with PD-L1 CPS ≥10 appeared to obtain maximum benefit from pembrolizumab plus chemotherapy,” he added.