Phase 3 LEAP-015 Study Currently Evaluating Pemrolizumb/Lenvatinib/Chemotherapy Combination in Patients with Advanced Gastroesophageal Adenocarcinoma

The global, randomized, active-controlled, open-label, 2-part, phase 3 LEAP-015 trial (NCT0466271) is actively looking at the efficacy and safety of the combination of pembrolizumab (Keytruda), Lenvatinib (Lenvima), and chemotherapy in the first-line setting for patients with advanced gastroesophageal adenocarcinoma compared with chemotherapy alone, according to a presentation at the 2021 European Society for Medical Oncology World Congress on Gastrointestinal Cancer.

Currently, the combination of chemotherapy with fluoropyrimidine and platinum therapy is recommended by the National Comprehensive Cancer Network as a first-line treatment in this patient population, but researchers have called for more effective therapies. Previous findings have shown that the PD-1 inhibitor pembrolizumab in combination with the multiple receptor tyrosine kinases inhibitor lenvatinib demonstrated synergistic antitumor activity and an acceptable safety profile in patients with advanced gastroesophageal adenocarcinoma. The LEAP-006 study (NCT03829319) also looked at pembrolizumab, lenvatinib, and platinum-doublet chemotherapy for patients with non-small cell lung cancer and showed promising results.

During the first part of the trial, patients will be given 400 mg of pembrolizumab intravenously every 6 weeks for 2 cycles along with 8 mg of lenvatinib twice daily plus the investigator’s choice of chemotherapy. If the patients tolerate treatment after a 21-day evaluation, they will move to part 2, the main part looking at efficacy outcomes, of the study with the same dosing options, depending on dose limiting toxicities. Patients that complete 18 cycles of treatment pembrolizumab and attain stable disease or better, along with patients who achieve complete response on 4 or more cycles of pembrolizumab, will be eligible for retreatment. Re-treated patients will be eligible up to 9 additional cycles of a second-course treatment of 400 mg of pembrolizumab depending on if they experience radiographic disease progression.

During the safety evaluation, less than 3 dose limiting toxicities occurred in the 6 participants in the part 1 safety run that led to part 2 enrollment. Dose limiting toxicities included grade 4 neutropenia, grade 3 or 4 thrombocytopenia, and grade 4 anemia. Non-hematological dose limiting toxicities also include hypertension and gastrointestinal perforation, but excluding grade 3 nausea, vomiting, and diarrhea that lasted more than 3 days but could be controlled by medial intervention within 72 hours. Ninety-five percent confidence intervals will be estimated between-group differences in adverse events (AEs) occurring in 10% or more of patients in either arm , grade 3 to 5 AEs occurring in 5% or more, and serious AEs occurring in the same number of patients in either treatment group.

In order to determine OS and PFS tumor imaging will be conducted in the chest, abdomen, and pelvis, and by magnetic resonance imaging for the brain, every 6 weeks until disease progression, initiation of a new anticancer treatment, withdrawal from the study, or death. Tumor response and disease progression will be assessed by BICR per RECIST v1.1, with complete or partial responses confirmed by imaging 4 weeks after initiation of treatment and until a response is observed. Patients who undergo second-course treatment will have imaging done every 12 weeks after the treatment is restarted.

Researchers began recruitment in December 2020 in clinics across the globe with over 700 patients in the trial so far. The first part of the study will look at the safety of the treatment with part 2 looking at primary end points of progression free survival and overall survival in patients on the combination therapy compared with those on standard-of-care chemotherapy. Secondary end points include objective response rate and duration of response for patients in the intent-to-treat population and those with a PD-L1 combined positive score greater than 1. Exploratory assessments include the evaluation the change from baseline to the time of deterioration in health-related quality of life.

_Reference:

_{Tabernero J, Cohen J, Cutsem E, et al. A randomized phase 3 study evaluating the efficacy and safety of first-line pembrolizumab plus lenvatinib plus chemotherapy compared with chemotherapy in patients with advanced/metastatic gastroesophageal adenocarcinoma: LEAP-015. Poster presented at: European Society for Medical Oncology World Congress on Gastrointestinal Cancer; June 30-July 3, 2021; virtual. Abstract P-154. doi:10.1016/j.annonc.2021.05.209}