Add-on pembrolizumab ups survival in advanced HER2-negative G/GEJ cancer

Adding pembrolizumab to chemotherapy significantly improved survival outcomes and response rate compared with chemo alone in patients with locally advanced or metastatic HER2-negative gastric or gastroesophageal junction (G/GEJ) adenocarcinoma, according to the updated results of the KEYNOTE-859 study presented at ESMO WCGIC 2023.

The study met the primary endpoint of overall survival (OS) and all secondary endpoints across all populations, with increased expression of PD-L1 status, said lead author Dr Lucjan Wyrwicz from Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw, Poland.

At a median follow-up of 31 months, patients treated with pembrolizumab plus chemo achieved a significantly longer median OS compared with placebo plus chemo in the overall population (12.9 vs 11.5 months; hazard ratio [HR], 0.78, p<0.0001). [ESMO WCGIC 2023, abstract O-3]

The OS benefit with the pembrolizumab-chemo regimen was sustained irrespective of PD-L1 expression status (13.0 vs 11.4 months; HR, 0.74; p<0.0001 [PD-L1 CPS* ≥1] and 15.7 vs 11.8 months; HR, 0.65; p<0.0001 [PD-L1 CPS ≥10]).

Moreover, a higher 24-month OS rate was observed among patients on pembrolizumab plus chemo than those on placebo plus chemo, both in the overall cohort (28.2 percent vs 18.9 percent) and the PD-L1 CPS ≥1 (26.6 percent vs 17.7 percent) and PD-L1 CPS ≥10 subgroups (37.9 percent vs 20.9 percent).

Secondary endpoints

Median progression-free survival (PFS) was significantly prolonged with pembrolizumab plus chemo vs placebo plus chemo arm across all populations (6.9 vs 5.6 months; HR, 0.76 [overall], 6.9 vs 5.6 months; HR, 0.72 [PD-L1 CPS ≥1], and 8.1 vs 5.6 months; HR, 0.62 [PD-L1 CPS ≥10]; p<0.0001 for all).

The 12-month PFS rate was also higher among those treated with pembrolizumab plus chemo compared with placebo plus chemo in the overall (17.8 percent vs 9.4 percent), PD-L1 CPS ≥1 (19.5 percent vs 7.9 percent), and PD-L1 CPS ≥10 populations (25.4 percent vs 7.7 percent).

Pembrolizumab plus chemo recipients also achieved a significantly higher objective response rate (ORR) than the placebo plus chemo recipients across all populations (51.3 percent vs 42.0 percent; p=0.00009 [overall], 52.1 percent vs 42.6 percent; p=0.00041 [PD-L1 CPS ≥1], and 60.6 percent vs 43.0 percent; p=0.00002 [PD-L1 CPS ≥10]). Median duration of response (DOR) in the respective cohorts were of 8.0, 8.3, and 10.9 months.

Post hoc analysis

A post hoc analysis was conducted to evaluate the impact of subsequent therapy on outcomes. In this analysis, almost half of the participants have received ≥1 subsequent systemic therapy – 42.9 percent of patients in the pembrolizumab arm and 43.9 percent in the placebo arm were receiving chemotherapy.

PFS2, defined as the PFS after the next line of therapy, was longer in the pembrolizumab plus chemo arm vs the placebo plus chemo arm (median 11.2 vs 10.0 months), and 24-month PFS2 rate was higher (24.2 percent vs 13.3 percent).

The benefit of adding pembrolizumab to first-line chemo was maintained when evaluating PFS2 given the similar HRs observed for PFS and PFS2 (0.76 for both).

A new treatment alternative?

This double-blind, phase III trial involved 1,579 patients with HER2-negative, locally advanced or metastatic G/GEJ adenocarcinoma and a known PD-L1 status. Participants were randomly assigned to receive either pembrolizumab 200 mg IV Q3W (n=790) or placebo (n=789) for ≤35 cycles in addition to standard chemotherapy (FP* or CAPOX**).

In terms of safety, 59.4 percent of patients on pembrolizumab plus chemo and 51.1 percent of patients on placebo plus chemo experienced grade 3–5 treatment-related adverse events, with only one event leading to death in each arm.

“Overall, pembrolizumab added to fluoropyrimidine- and platinum-containing chemotherapy provided statistically significant, clinically meaningful improvements in OS, PFS, and ORR and prolonged DOR compared with chemo alone in the overall, PD-L1 CPS ≥1, and PD-L1 CPS ≥10 populations,” said Wyrwicz.

“Together with an expected safety profile, results of KEYNOTE-859 support pembrolizumab plus chemo as a new treatment option for this patient population,” he added.