Pembrolizumab extends benefit in subsequent therapies of HER2-negative gastric or gastro-oesophageal junction adenocarcinoma
According to a recent post-hoc analysis of the Keynote-859 study, the addition of pembrolizumab to first-line chemotherapy continues to benefit patients with locally advanced or metastatic HER2-negative gastric or gastro-oesophageal junction adenocarcinoma when evaluating the progression-free survival after next line of therapy. These data further support pembrolizumab plus chemotherapy as a new first-line treatment option in this patient population.
Previously, the phase III Keynote-859 study demonstrated that adding pembrolizumab to chemotherapy significantly improved the primary endpoint of overall survival (OS, p < 0.0001) and the secondary endpoints of progression-free survival (PFS, p< 0.0001) and objective response rate (ORR, p= 0.00009) compared with chemotherapy alone in patients with HER2-negative, previously untreated locally advanced or metastatic gastric or gastro-oesophageal junction (G/GEJ) adenocarcinoma. To further characterise the efficacy of pembrolizumab plus chemotherapy and explore the potential influence of subsequent therapy on outcomes, Prof. Wyrwicz and colleagues did a post-hoc analysis of time from randomisation to objective tumour progression on next-line therapy or death from any cause (PFS2).
Study design
In Keynote-859, a total of 1.579 patients with histologically or cytologically confirmed, locally advanced unresectable or metastatic adenocarcinoma of the stomach or GEJ were randomised in a 1:1 ratio to either pembrolizumab (200 mg, intravenously once every three week) or placebo for a maximum of 35 cycles. In addition, all patients were to receive investigator’s choice of 5-fluorouracil (5-FU) plus cisplatin or capecitabine plus oxaliplatin. Patients could not have received prior treatment, were HER2-negative and must have an ECOG performance status of 0 or 1. Patients were stratified by geographic region, PD-L1 CPS (<1 vs. ≥1) and choice of chemotherapy. Primary endpoint of the study was OS, with secondary endpoints of PFS, ORR, duration of response (DoR) and safety. Progression-free survival after next line of therapy (PFS2) was defined as the time from randomisation to objective tumour progression on next-line therapy or death from any cause, whichever occurred first.
Results
It was previously reported that OS was significantly improved in the pembrolizumab arm as compared to the control arm in the overall population (HR[95%CI]: 0.78[0.70-0.87], p< 0.0001), for patients with PD-L1 CPS ≥1 (HR[95%CI]: 0.74[0.65-0.84], p< 0.0001) and for those with PD-L1 CPS ≥10 (HR[95%CI]: 0.65[0.53-0.79], p< 0.0001). Results were consistent across all subgroups analysed. In addition, pembrolizumab also improved the secondary endpoints of PFS (6.9 vs. 5.6 months, HR[95%CI]: 0.76[0.67-0.85], p< 0.0001), ORR (51.3% vs. 42.0%, p= 0.00009) and DoR (median 8.0 vs. 5.7 months). Treatment-related adverse events of grade ≥ 3 were reported in 59.4% of patients treated with pembrolizumab, and in 51.1% of patients receiving placebo; respectively 1.0% and 2.0% of patients died as a result of TRAEs.1
After a median study follow-up of 31.0 months, 44.9% of patients in the pembrolizumab arm and 46.8% of patients in the placebo arm received at least one subsequent systemic anticancer therapy. The use of specific therapies was well balanced between arms; 42.9% in the pembrolizumab group and 43.9% in the placebo group received chemotherapy, 17.3% and 17.5% received a VEGF/VEGFR inhibitor, 8.4% and 9.1% received a PD-(L)1 inhibitor, and 11.6% and 12.2% received other systemic anticancer therapy. Median PFS2 was 11.2 months for patients receiving pembrolizumab and was 10.0 months for patients receiving placebo (HR[95%CI]: 0.76[0.68-0.85]).2
Conclusions
Pembrolizumab added to fluoropyrimidine- and platinum-containing chemotherapy provides statistically significant, clinically meaningful improvements in OS, PFS and ORR and a prolonged DoR compared to chemotherapy alone in the overall, PD-L1 CPS ≥1 and PD-L1 CPS ≥10 populations. Furthermore, the benefit of adding pembrolizumab to first-line chemotherapy was maintained when evaluating PFS2. Together with an expected safety profile, results of the Keynote-859 study support pembrolizumab plus chemotherapy as a new treatment option for this patient population.
References
1. Rha SY, et al. Pembrolizumab (pembro) plus chemotherapy (chemo) as first-line therapy for advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) cancer: phase III KEYNOTE-859 study. Ann Oncol 2023;34:319-20.
2. Wyrwicz L, et al. Additional data from the KEYNOTE-859 study of pembrolizumab plus chemotherapy versus placebo plus chemotherapy for advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) cancer. Presented at ESMO WCGIC 2023; Abstract O-3.
