The safety run-in of the LEAP-014 trial showed acceptable toxicity and antitumor responses in patients with metastatic esophageal cancer receiving pembrolizumab, lenvatinib, and chemotherapy consisting of cisplatin plus either paclitaxel or 5-fluororacil.
Lenvatinib (Lenvima) and pembrolizumab (Keytruda) combined with chemotherapy showed acceptable safety and tolerability as well as antitumor activity in patients with metastatic esophageal squamous cell carcinoma (mESCC), according to results from the LEAP-014 study (NCT04949256) presented in a poster at the 2023 ESMO Congress.1
In 13 patients enrolled in the safety run-in of the trial, all 7 patients who received lenvatinib/pembrolizumab plus 5-fluororacil (5-FU) and cisplatin (FP) had a grade 3 or 4 treatment-related adverse event (TRAE), 3 of which were serious. Two out of 6 patients who received lenvatinib/pembrolizumab plus paclitaxel and cisplatin (TP) had grade 3 or 4 TRAEs. No dose-limiting toxicities (DLTs) were reported in the patients who received TP, whereas a DLT of grade 3 acute kidney injury associated with increased creatinine level and another of grade 3 hypokalemia were reported in the group that received FP.
Pembrolizumab plus 5-FU and cisplatin is a standard-of-care frontline treatment for locally advanced or metastatic esophageal cancer. The phase 3, randomized, open-label LEAP-014 study is designed to compare lenvatinib, pembrolizumab, and chemotherapy with pembrolizumab plus chemotherapy. Part 1 of the study is a safety run-in, and part 2 will randomly assign patients to either regimen on a 1:1 basis.
The primary end point of part 1 was the safety and tolerability of lenvatinib/pembrolizumab plus chemotherapy, with secondary end points including objective response rate (ORR) and duration of response (DOR) by RECIST v1.1 by blinded independent central review (BICR).
Patients enrolled in both parts of the trial must have mESCC with measurable disease per RECIST v1.1, an ECOG performance status (PS) of 0 or 1. In part 1, 6 patients located in China, South Korea, Taiwan, or Hong Kong received lenvatinib/pembrolizumab plus TP per local standards, whereas the other 7 received lenvatinib/pembrolizumab plus FP. Patients were evaluated for 21 days after the first dose of lenvatinib/pembrolizumab plus FP or TP for DLTs. Enrollment for part 2 could begin if fewer than 3 DLTs were reported in either cohort.
Patients in part 1 received 400 mg of intravenous pembrolizumab every 6 weeks for 2 cycles, 8 mg lenvatinib orally daily, and 4 cycles of FP or TP every 3 weeks. Afterward, they received pembrolizumab at the same dose every 6 weeks until at least 16 doses, and lenvatinib 20 mg daily until disease progression or unacceptable toxicity.
The median age of patients was 64 for receiving lenvatinib/pembrolizumab plus FP and 66 for those receiving lenvatinib/pembrolizumab plus TP. All 13 patients were male. In the lenvatinib/pembrolizumab plus FP group, 5 (71%) had an ECOG PS of 1 and 4 (57%) had a PD-L1 combined positive score (CPS) of at least 10, whereas in the lenvatinib/pembrolizumab plus TP group, 5 (83%) had an ECOG PS of 1 and 3 (50%) had a PD-L1 CPS of at least 10. In the lenvatinib/pembrolizumab plus FP group, 5 (71%) were located in East Asia, with 1 (14%) in North American/Western Europe and 1 (14%) in the rest of the world. The lenvatinib/pembrolizumab plus TP group were all located in East Asia.
At a data cutoff of February 2, 2023, all 13 patients had received at least 1 dose of their assigned regimen, and 2 of 7 who received lenvatinib/pembrolizumab plus FP and 3 of 6 who received lenvatinib/pembrolizumab plus TP were still receiving study treatment. The median time from first dose to the data cutoff was 16.6 months (range, 15.9 to 17.3) in the lenvatinib/pembrolizumab plus FP cohort and 5.6 months (range, 4.6-6.2 months) in the lenvatinib/pembrolizumab plus TP cohort.
The median duration of treatment in the lenvatinib/pembrolizumab plus FP cohort was 13.5 months (range, 1.5-17.2), and 4.5 months (range, 1.0-5.7) in the lenvatinib/pembrolizumab plus TP cohort.
The ORR by BICR was 86% in the lenvatinib/pembrolizumab plus FP cohort, including 1 complete response and 5 partial responses. No patients had stable disease. The median DOR was 11.7 months (range, 2.3-13.8+) with an ongoing response. The median time to response was 1.6 months (range, 1.4-3.0).
The ORR by BICR was 33% in the lenvatinib/pembrolizumab plus TP cohort, with 2 partial responses. One patient had stable disease, and another had no assessment due to no postbaseline imaging assessment. The median DOR was 4.2 months (range, 2.2+ to 4.2). The median time to response was 1.5 months (range, 1.4-1.5).
One hundred percent of patients in both groups had AEs of any cause, with 7 (100%) in the lenvatinib/pembrolizumab plus FP cohort and 4 (67%) having grade 3 to 5 AEs. One death occurred in the lenvatinib/pembrolizumab plus TP arm due to cardiac arrest that was determined to be unrelated to study treatment.
In the lenvatinib/pembrolizumab plus FP cohort, dose interruption was needed in 6 patients for pembrolizumab (86%), 4 (57%) for lenvatinib, 3 (43%) for both, and 6 (86%) for FP, with 3 (43%) patients needing dose interruption for all drugs. Dose reduction was needed in 2 patients (29%). Four patients (57%) discontinued at least 1 treatment, but none discontinued all treatments.
In the lenvatinib/pembrolizumab plus TP cohort, dose interruption was needed in 1 patient for pembrolizumab (17%), 3 (50%) for lenvatinib, 1 (17%) for both, and 2 (33%) for FP, with 1 (17%) patients needing dose interruption for all drugs. Dose reduction was needed in 1 patient (17%). Two patients (33%) discontinued at least 1 treatment and 1 patient (17%) discontinued all study treatments. Only 1 of these 2 discontinued treatment due to a TRAE, and the patient who discontinued all study treatment was not due to a TRAE.
There were no grade 3 or 4 immune-mediated AEs or infusion reactions reported in either cohort; however, 1 patient receiving pembrolizumab/lenvatinib plus FP discontinued treatment due to immune-mediated AE or infusion reaction.
The most commonly reported AEs in the lenvatinib/pembrolizumab plus FP cohort included nausea in 71%, neutrophil count decreased in 71%, decreased appetite, hypothyroidism, fatigue, hypertension, and stomatitis in 57% each, and palmar-plantar erythrodysesthesia in 43%. In the lenvatinib/pembrolizumab plus TP cohort, the most commonly reported AEs included anemia in 67%, hyponatremia, neutrophil count decreased, white blood cell count decreased in 50% each, and hypokalemia, hypothyroidism, rash, and vomiting in 33% each.
Reported immune-mediated AEs from any cause were hypothyroidism in 4 (58%), adrenal insufficiency in 1 (14%), hyperthyroidism in 1 (14%), and pneumonitis in 1 (14%) in the lenvatinib/pembrolizumab plus FP cohort, and hypothyroidism in 2 (33%) in the lenvatinib/pembrolizumab plus TP cohort.
Based on the low number of DLTs, lenvatinib/pembrolizumab plus chemotherapy was considered to have a manageable safety profile and part 2 was initiated. Part 2 randomly assigned approximately 850 patients to receive pembrolizumab plus chemotherapy with or without lenvatinib. The primary end points for part 2 are overall survival for up to approximately 49 months and progression-free survival for up to approximately 41 months.2 In part 2, they may receive FP or TP chemotherapy or mFOLFOX (5-FU plus leucovorin plus oxaliplatin) every 2 weeks for 6 cycles.1
“LEAP-014 part 2 is ongoing and will be used to evaluate the efficacy and safety of lenvatinib plus pembrolizumab plus chemotherapy compared with pembrolizumab plus chemotherapy as first-line treatment of patients with mESCC,” the investigators concluded in their poster.