Credit: David A Litman | stock.adobe.com

New data released from the Phase III LEAP-015 trial (NCT04662710) show that Keytruda (pembrolizumab) combined with Lenvima (lenvatinib) and chemotherapy improved progression-free survival (PFS) and objective response rate (ORR) in patients with advanced HER2-negative gastroesophageal adenocarcinoma, but fell short of statistical significance in overall survival (OS). With PFS and OS being the trial’s dual primary endpoints, the mixed results will inform further research into this difficult-to-treat disease, according to investigators.^1,2

“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 Inc, said in a press release. “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 Keytruda plus Lenvima 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.”¹

The Keytruda plus Lenvima combination has been approved for advanced renal cell carcinoma and for patients with advanced endometrial carcinoma that is mismatch repair proficient or not microsatellite instability-high. Studies are ongoing evaluating the combination in hepatocellular carcinoma and esophageal cancer as part of the LEAP clinical program.

To date, more than 1600 trials are evaluating Keytruda across a range of cancer types and treatment settings. Keytruda also has approved indications in melanoma; non-small cell lung cancer; head and neck squamous cell cancer; classical Hodgkin lymphoma; primary mediastinal large B-cell lymphoma; urothelial carcinoma; gastric cancer; microsatellite instability-high or mismatch repair deficient cancer; microsatellite instability-high or mismatch repair deficient colorectal cancer; esophageal cancer; cervical cancer; hepatocellular carcinoma; Merkel cell carcinoma; renal cell carcinoma; endometrial carcinoma; tumor mutational burden-high cancer; cutaneous squamous cell carcinoma; and triple-negative breast cancer.

Trial Design

The randomized, open-label, LEAP-015 trial compared Keytruda plus Lenvima combined with chemotherapy vs. chemotherapy alone in the first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastroesophageal adenocarcinoma. Part one of the two-part study is a safety run-in and part two is the main study.

The primary endpoints of part two are OS and PFS as evaluated by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) in all patients and in those with tumors expressing PD-L1 (Combined Positive Score [CPS] ≥1).

The trial’s secondary endpoints are ORR and duration of response as evaluated by BICR per RECIST v1.1 in patients with tumors expressing PD-L1 (CPS ≥1) and the total patient population, as well as safety.

In part two of the trial, up to 880 patients were randomly assigned in a 1:1 ratio to receive Keytruda plus Lenvima plus chemotherapy in the induction phase for approximately 12 weeks at doses of Keytruda 400 mg administered intravenously (IV) every six weeks (Q6W) for two cycles with daily oral Lenvima 8 mg plus chemotherapy of CAPOX or mFOLFOX6. In the consolidation phase, IV Keytruda was administered a dose 400 mg Q6W, for less than or equal to 16 doses, plus daily oral Lenvima 20 mg; or chemotherapy with either the CAPOX regimen or mFOLFOX6 regimen.

Full results from the trial will be presented at an upcoming medical meeting as data analysis is ongoing, according to Merck and Eisai. In terms of safety, reports of adverse events were consistent the previously established safety profile of the combination.

“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, said in the 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.”¹

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. 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://clinicaltrials.gov/study/NCT04662710