Results from the phase 3 KEYNOTE-062 study appear mixed for both pembrolizumab monotherapy versus chemotherapy and pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced gastric or gastroesophageal junction adenocarcinoma.
In the phase 3 KEYNOTE-062 trial (NCT02494583), pembrolizumab (Keytruda) monotherapy showed noninferiority to chemotherapy for overall survival (OS) in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma and a PD-L1 combined positive score (CPS) of 1 or higher, and a clinically meaningful benefit over chemotherapy in those with a CPS of 10 or higher, but when combined with chemotherapy, pembrolizumab was not superior to chemotherapy alone in either patient group.1
The long-term findings from the trial, which were presented during the 2022 Gastrointestinal Cancers Symposium, showed that at a median follow-up of 54.3 months (range, 46.8-66.1), pembrolizumab monotherapy resulted in a median OS of 10.6 months (95% CI, 7.7-13.8) in those with a PD-L1 CPS of 1 or higher vs 11.1 months (95% CI, 9.2-12.8) with chemotherapy (HR, 0.90; 95% CI, 0.75-1.08). In those with a PD-L1 CPS of 10 or higher, single-agent pembrolizumab resulted in a median OS of 17.4 months (95% CI, 9.1-23.1) vs 10.8 months (95% CI, 8.5-13.8) with chemotherapy (HR, 0.62; 95% CI, 0.45-0.86).
In the subset of patients with a PD-L1 CPS of 1 or higher, the median OS with pembrolizumab plus chemotherapy was 12.5 months (95% CI, 10.8-13.9) vs 11.1 months (95% CI, 9.2-12.8) with chemotherapy alone (HR, 0.85; 95% CI, 0.71-1.02). In the subset of patients with a PD-L1 CPS of 10 or higher, the median OS with pembrolizumab/chemotherapy was 12.3 months (95% CI, 9.5-14.8) vs 10.8 months (95% CI, 8.5-13.8) with chemotherapy alone (HR, 0.76; 95% CI, 0.56-1.03).
The addition of pembrolizumab to chemotherapy also failed to significantly improve progression-free survival (PFS) over chemotherapy alone in both subsets. The combination resulted in a median PFS of 6.9 months (95% CI, 5.8-7.8) vs 6.5 months (95% CI, 5.7-7.1) with chemotherapy alone in patients with a PD-L1 CPS of 1 or higher (HR, 0.84; 95% CI, 0.70-1.01). In the patient population with a CPS of 10 or higher, the median PFS with pembrolizumab plus chemotherapy was 5.8 months (95% CI, 5.6-8.2) vs 6.2 months (95% CI, 5.4-7.0) with chemotherapy alone (HR, 0.71; 95% CI, 0.52-0.96).
"With respect to the combination arms, not much has changed over the past 2 years," study author Zev A. Wainberg, MD, of UCLA Health, said in a presentation on the data. "We still see, unfortunately, and perplexingly to some extent, a negative impact of chemotherapy and pembrolizumab over chemotherapy alone. We see that in the patient population with a CPS of greater than 1. We see that as well in the patient population with a CPS greater than 10. Similarly, with respect to PFS, there was no advantage, even 2 years later, with pembrolizumab plus chemotherapy over chemotherapy alone in either [subset]."
Topline findings from KEYNOTE-062 trial showed that the study missed its primary OS end point.2 Subsequently, in July 2021, Merck announced plans to withdraw the accelerated approval indication for pembrolizumab in the third-line setting for select patients with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma with a CPS of 1 or higher, since the approval was contingent on positive findings from KEYNOTE-062 and the phase 3 KEYNOTE-061 trial (NCT02370498).3 The immunotherapy missed each trial’s primary end point of OS and PFS in those with a PD-L1 CPS of 1 or higher.
KEYNOTE-062 enrolled patients with locally advanced, unresectable, or metastatic gastric or GEJ adenocarcinoma. Patients needed to have a CPS of at least 1, HER2 neu negativity, and an ECOG performance status of 0 or 1. Patients were stratified by region, whether they had locally advanced or metastatic disease, and whether they received 5-fluorouracil (5-FU) or capecitabine.
A total of 763 patients were randomized 1:1:1 to receive pembrolizumab at 200 mg once every 3 weeks for up to 35 cycles (n = 256), pembrolizumab at the same schedule in combination with chemotherapy (n = 257), or chemotherapy alone (n = 250). Chemotherapy treatment included cisplatin at 80 mg/m2 every 3 weeks plus 5-FU at a daily dose of 800 mg/m2 for 5 days every 3 weeks or capecitabine twice daily for days 1 though 14 every 3 weeks. Treatment was continued until intolerable toxicity, disease progression, or patient or physician withdrawal.
The primary end points of the trial were OS and PFS, and the secondary end points included overall response rate and safety.
Additional data presented during the Symposium showed that in the subset of patients with a CPS of 1 or higher, the 24-month OS rate with pembrolizumab monotherapy was 26.6% vs 18.8% with chemotherapy. In the subset of patients with a CPS of 10 or higher, the 24-month OS rates with single-agent pembrolizumab and chemotherapy were 39.1% and 21.1%, respectively.
The combination of pembrolizumab and chemotherapy resulted in a 24-month OS rate of 24.5% in those with a CPS of 1 or higher, and 28.3% in those with a CPS of 10 or higher; these rates were 18.8% and 21.1% with chemotherapy alone, respectively.
Updated safety data showed that adverse effects (AEs) of any grade occurred in 95.3%, 97.6%, and 98.4% of patients in the pembrolizumab monotherapy, pembrolizumab/chemotherapy, and chemotherapy-alone arms, respectively; grade 3 or higher AEs were observed in 50.4%, 84.8%, and 82.4% of patients, respectively.
Within the pembrolizumab monotherapy arm, 11.4% of patients experienced AEs that led to treatment discontinuation and 9.8% had AEs that led to death; these rates were 34.0% and 6.8%, respectively, in the pembrolizumab/chemotherapy arm, and 23.8% and 5.3%, respectively in the chemotherapy-alone arm.
Wainberg noted that treatment with pembrolizumab alone resulted in fewer treatment-related AEs. Specifically, 54.7% of patients who received single-agent pembrolizumab experienced at least 1 treatment-related AE (TRAE) vs 94.0% and 91.8% of those in the combination and chemotherapy-alone arms, respectively. Furthermore, 17.3% of patients in the pembrolizumab group experienced grade 3 to 5 TRAEs, vs 73.2% and 69.3% of those in the combination and chemotherapy arms, respectively. Treatment-related AEs led to discontinuation in 4.3% of those on the pembrolizumab monotherapy arm and resulted in death in 1.2% of these patients; these rates were 27.6% and 2.0%, respectively, in the combination arm and 18.0% and 1.2%, respectively, in the chemotherapy arm.
The long-term follow-up safety and efficacy data from the KEYNOTE-062 trial were consistent with the final analysis, according to Wainberg.
Despite the fact that pembrolizumab plus chemotherapy did not prove to be superior to chemotherapy with regard to OS in either CPS subset, there are plans to further evaluate the combination in the first-line treatment of patients with gastric or GEJ adenocarcinoma, as part of the phase 3 KEYNOTE-859 trial (NCT03675737).
"The large, randomized, phase 3 trial has completed enrollment [and more information will] hopefully be available in the next year or so,” Wainberg concluded. “[That study] is looking at different cut offs of CPS and different end points."
1. Wainberg ZA, Shitara K, Van Cutsem E, et al. Pembrolizumab with or without chemotherapy versus chemotherapy alone for patients with PD-L1–positive advanced gastric or gastroesophageal junction adenocarcinoma: update from the phase 3 KEYNOTE-062 trial. J Clin Oncol. 2022;40(suppl 4):243. doi:10.1200/JCO.2022.40.4_suppl.243
2. Merck provides update on phase 3 KEYNOTE-062 trial evaluating KEYTRUDA (pembrolizumab) as monotherapy and in combination with chemotherapy for first-line treatment of patients with advanced gastric or gastroesophageal junction adenocarcinoma. News release. Merck; April 25, 2019. Accessed January 20, 2022. https://bit.ly/2IXZtwG
3. Merck provides update on KEYTRUDA (pembrolizumab) indication in third-line gastric cancer in the US. News release. Merck; July 1, 2021. Accessed January 20, 2022. https://bit.ly/2Uuc965