Pembrolizumab Plus Lenvatinib and Chemo Misses OS End Point in Gastroesophageal Adenocarcinoma

Pembrolizumab (Keytruda) plus lenvatinib (Lenvima) and chemotherapy failed to elicit a statistically significant improvement in overall survival (OS) vs chemotherapy alone as frontline therapy for patients with locally advanced unresectable or metastatic HER2-negative gastroesophageal adenocarcinoma, failing to meet 1 of the dual primary end points of the phase 3 LEAP-015 trial (NCT04662710) at the final analysis.1

Prior findings from an interim analysis showed that the investigational regimen led to a statistically significant improvement in progression-free survival (PFS)—the study’s other primary end point—and objective response rate (ORR), a key secondary end point.

The safety profile of the regimen was similar to that reported in prior studies evaluating the combination. Data from the trial will be subject to review and shared 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, Global Clinical Development, Merck Research Laboratories, stated in a news release. “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.”

LEAP-015 was a randomized, open-label, phase 3 trial evaluating pembrolizumab plus lenvatinib with chemotherapy vs chemotherapy alone in the first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastroesophageal adenocarcinoma.

The study was divided into two parts: a safety run-in (part 1), results from which were presented at the 2023 Gastrointestinal Cancers Symposium,2 and the main study (part 2). In part 2, the primary end points were OS and PFS as assessed by blinded independent central review (BICR) per RECIST 1.1 criteria in patients with a PD-L1 combined positive score (CPS) of 1 or higher and in all patients.1,3 Secondary end points were ORR and duration of response according to BICR per RECIST 1.1 criteria in the same two patient populations, and safety.

In part 2, as many as 880 patients were randomly assigned 1:1 to receive pembrolizumab plus lenvatinib and chemotherapy or chemotherapy alone. As part of induction, which lasted approximately 12 weeks, patients in the investigational arm received 400 mg of intravenous (IV) pembrolizumab every 6 weeks for 2 cycles plus oral lenvatinib at 8 mg daily plus chemotherapy.

For chemotherapy in both arms, patients could have received either CAPOX in the form of oral capecitabine at 1000 mg/m2 twice daily for 14 days plus IV oxaliplatin at 130 mg/m2 every 3 weeks for 4 cycles; or mFOLFOX6 in the form of an IV bolus of 5-fluorouracil (5-FU) at 400 mg/m2, plus continuous IV 5-FU at 2400 mg/m2 and IV leucovorin at 400 mg/m2 or IV levoleucovorin at 200 mg/m2, plus IV oxaliplatin at 85 mg/m2 every 2 weeks for 6 cycles. The maximum number of chemotherapy cycles in the control arm was administered in accordance with local standards.

During the consolidation phase, patients in the investigational arm received 400 mg of IV pembrolizumab every 6 weeks for up to 16 doses plus oral lenvatinib at 20 mg daily.

“Gastric and gastroesophageal cancers continue to present challenges due to their heterogeneity and generally poor prognoses,” Corina Dutcus, MD, senior vice president, Oncology Global Clinical Development Lead at Eisai, stated 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. These results contribute to the scientific community’s collective understanding of these complex diseases and add to the body of knowledge in oncology research. We are deeply grateful to the patients, caregivers, and investigators who participated in this study.”

Merck noted that results from LEAP-015 will not affect the current approved indications for pembrolizumab plus lenvatinib or other ongoing trials from the LEAP clinical program.

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 24, 2025. https://www.merck.com/news/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-ga/
2. Eduardo Yanez P, 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.4
3. Efficacy and safety of lenvatinib (E7080/MK-7902) plus pembrolizumab (MK-3475) plus chemotherapy in participants with advanced/metastatic gastroesophageal adenocarcinoma (MK-7902-015/E7080-G000-321/LEAP-015) (LEAP-015). ClinicalTrials.gov. Updated November 18, 2024. Accessed January 24, 2025. https://www.clinicaltrials.gov/study/NCT04662710