Pembrolizumab Combo Does Not Meet OS End Point in Advanced Gastric Cancer

Pembrolizumab plus lenvatinib showed a safety profile consistent with previous reports evaluating the combination.

The randomized, open-label, phase 3 LEAP-015 trial (NCT04662710) evaluating pembrolizumab (Keytruda) in combination with lenvatinib (Lenvima) and chemotherapy as a frontline treatment for patients with locally advanced unresectable or metastatic HER2-negative gastroesophageal adenocarcinoma did not meet its dual primary end point of overall survival (OS) at the final analysis, according to a news release from the developer, Merck.¹

Previous LEAP-015 interim analysis results revealed that the combination did meet the other dual primary end point for progression-free survival (PFS), as well as eliciting a clinically significant improvement in objective response rate (ORR), a key secondary end point.

Pembrolizumab plus lenvatinib showed a safety profile consistent with previous reports evaluating the combination. Merck and Eisai, lenvatinib’s developer, are conducting an ongoing evaluation of the study data, and the results will be presented at an upcoming medical meeting.

“Locally advanced unresectable or metastatic gastroesophageal adenocarcinoma remains a challenging disease to treat and a leading cause of cancer death worldwide,” Gregory Lubiniecki, MD, vice president of Global Clinical Development at Merck Research Laboratories, said in the press release.¹ “These study results add to our understanding of this combination and will inform our future research as we strive to improve outcomes for more patients with cancer.”

The phase 3 LEAP-015 trial was divided into a safety run-in portion and the main study. Results from the safety run-in were presented at the 2023 ASCO Gastrointestinal Cancers Symposium, in which 15 patients received at least 1 dose of pembrolizumab plus lenvatinib with chemotherapy.² Safety analysis from the study revealed that 93% of patients experienced at least 1 treatment-related adverse event (TRAE), with grade 3 TRAES occurring in 53%.

Additionally, treatment discontinuation with at least 1 drug occurred in 27% of patients, yet no treatment discontinuations encompassing all treatment drugs were observed. No patients died due to a treatment-related AE, and no grade 3 or higher immune-mediated AEs or infusion reactions occurred. Furthermore, the disease control rate was 93% (95% CI, 68%-100%) in this patient population.

In the main study, up to 880 patients were randomly assigned 1:1 to receive either pembrolizumab, lenvatinib, and chemotherapy or chemotherapy alone. During the induction phase, patients in the investigational arm received 400 mg of intravenous pembrolizumab every 6 weeks for 2 cycles plus 8 mg of oral lenvatinib every day plus either CAPOX or mFOLFOX6. CAPOX consisted of 1000 mg/m² of twice daily oral capecitabine for 14 days plus 130 mg/m² of intravenous oxaliplatin every 3 weeks for 4 cycles. mFOLFOX6 consisted of 400 mg/m² of bolus intravenous 5-fluorouracil (5-FU) plus 2400 mg/m² of continuous intravenous 5-FU plus 400 mg/m² of intravenous leucovorin or 200 mg/m² of intravenous leucovorin plus 85 mg/m² of intravenous oxaliplatin every 2 weeks for 6 cycles.

During the consolidation phase, patients in the investigational arm received 400 mg of intravenous pembrolizumab every 6 weeks for up to 16 doses plus 20 mg of lenvatinib once daily. Furthermore, patients assigned to only chemotherapy received a comparable CAPOX or mFOLFOX6 regimen at maximum cycles per local standards.

“Gastric and gastroesophageal cancers continue to present challenges due to their heterogeneity and generally poor prognoses,” Corina Dutcus, MD, senior vice president and Oncology Global Clinical Development Lead at Eisai Inc., said in the news release.¹ “While the LEAP-015 trial did not show a statistically significant increase in [OS], we were pleased to observe an improvement in [PFS] and [ORR] for patients treated with [pembrolizumab] plus [lenvatinib] in combination with chemotherapy.”

Of note, the results from the final analysis of the phase 3 LEAP-105 trial do not impact currently approved indications for the combination therapy or other ongoing LEAP clinical program trials.

References

1. Merck and Eisai provide update on phase 3 LEAP-015 trial evaluating KEYTRUDA (pembrolizumab) plus LENVIMA (lenvatinib) in combination with chemotherapy in patients with certain types of gastroesophageal adenocarcinoma. News release. Merck. January 24, 2025. Accessed January 27, 2025. https://tinyurl.com/2hdp3s35
2. Yanez PE, Ben-Aharon I, Rojas C, et al. First-line lenvatinib plus pembrolizumab plus chemotherapy versus chemotherapy in advanced/metastatic gastroesophageal adenocarcinoma (LEAP-015): safety run-in results. J Clin Oncol. 2023;41(suppl 4):411. doi:10.1200/JCO.2023.41.4_suppl.411