Neither the LEAP-003 nor LEAP-017 studies study showed survival benefit with pembrolizumab plus lenvatinib for patients with melanoma or colorectal cancer.
The phase 3 LEAP-003 trial (NCT03820986) of pembrolizumab (Keytruda) plus lenvatinib (Lenvima) as first-line treatment for adults with unresectable or metastatic melanoma has been discontinued due to a lack of improvement in overall survival (OS), one of the trials primary end points.1
LEAP-017 (NCT04776148), a phase 3 trial also evaluating pembrolizumab plus lenvatinib, showed a trend toward improvement in survival, but did not meet statistical significance per the pre-specified statistical analysis plan, according to the final pre-specified analysis of OS in patients with unresectable and metastatic colorectal cancer that is mismatch repair proficient (pMMR) or not microsatellite instability-high (MSI-H).
While neither study showed promise for their respective patient populations, the safety profile of the combination was consistent with previously reported data in both trials. Now, there is an ongoing, full evaluation of the data from these studies, including pre-planned key subgroup analyses, and the companies plan to work with investigators to share the results with the scientific community.
“We are grateful to all the investigators, patients, and their families for their participation in these studies, and we will continue to evaluate [pembrolizumab] plus [lenvatinib] across different types of cancer where additional treatment options are needed. We remain fully committed to building on existing treatments as part of our efforts to help as many appropriate patients with cancer as we can,” said Gregory Lubiniecki, MD, vice president, global clinical development, Merck Research Laboratories, in the press release.
The combination of pembrolizumab plus lenvatinib is approved in the United States, Europe, Japan, and other countries for the treatment of advanced renal cell carcinoma (RCC) and some types of advanced endometrial carcinoma. Updated data from the LEAP-003 and LEAP-017 trials do not affect the current approved indications for the combination.
Through the LEAP clinical program, Merck and Eisai are investigating the combination in more than 10 clinical trials across multiple tumor types, including endometrial carcinoma, hepatocellular carcinoma, melanoma, non-small cell lung cancer, RCC, head and neck cancer, colorectal cancer, gastric cancer, esophageal cancer, and more.
In the randomized, placebo-controlled phase 3 LEAP-003 trial, investigators evaluated pembrolizumab plus lenvatinib compared with pembrolizumab alone as a first-line treatment for adult patients with unresectable or metastatic melanoma.
A total of 674 patients were randomized in a 1:1 ratio to receive either pembrolizumab 200 mg via intravenous infusion (IV) on day 1 of each 3-week cycle plus lenvatinib 20 mg orally once daily, or pembrolizumab 200 mg IV on day 1 of each 3-week cycle plus placebo. Pembrolizumab was administered to patients for approximately 2 years at up to 35 cycles, or until protocol-specified discontinuation criteria were met. After patients received 2 years of combination therapy, lenvatinib could have been administered as a single agent until protocol-specified discontinuation criteria were met.
Those enrolled in the study had histologically or cytologically confirmed melanoma or unresectable stage III or stage IV melanoma and must have been untreated for advanced or metastatic disease. Patients were required to have documentation of BRAF V600-activating mutation status or consent to BRAF V600mutation testing during the screening period, have an ECOG performance status of 0-1, have the presence of ≥1 measurable lesion by CT or MRI per RECIST 1.1, have resolved from all toxic effect(s) of the most recent prior therapy to grade 1 or less, have adequately controlled blood pressure with or without antihypertensive medications, and have adequate organ function.2
The dual primary end points of the study included OS and progression-free survival (PFS), as assessed by RECIST v1.1. The key secondary end points were overall response rate (ORR) and duration of response (DOR), both as assessed by RECIST v1.1, and safety.
While 1 of the study’s primary end points, OS, was not met, an earlier interim analysis showed that the trial’s other dual primary end point of PFS led to a statistically significant improvement among patients given the combination of pembrolizumab plus lenvatinib arm vs the pembrolizumab plus placebo.1
Then in the randomized, open-label, phase 3 LEAP-017 trial, pembrolizumab plus lenvatinib was compared with regorafenib (Stivarga) or TAS-102 for patients with unresectable and metastatic colorectal cancer that is pMMR or not MSI-H who have received and progressed on or after, or became intolerant to, prior treatment. Those enrolled in the study had to have been previously treated for colorectal cancer and have shown disease progression as defined by RECIST v1.1 on or after, or could not tolerate, standard treatment.
The primary end point of the study was OS with the key secondary end points of PFS, ORR, and DOR, according to RECIST v1.1 per blinded independent central review.
The study enrolled 480 patients with a histologically or cytologically confirmed diagnosis of unresectable and metastatic colorectal adenocarcinoma who had measurable disease per RECIST 1.1, as assessed by the investigator, an ECOG performance status of 0-1, a life expectancy of at least 3 months, and adequately controlled blood pressure with or without antihypertensive medications.3
Patients were randomized 1:1 to receive pembrolizumab 400 mg IV on day 1 of each 6-week cycle plus lenvatinib 20 mg orally once daily, or regorafenib 160 mg given orally once daily on days 1-21 of each 4-week cycle, or TAS-102 35mg/m2 given orally twice a day on days 1-5 and days 8-12 of each 4-week cycle. Treatment with pembrolizumab was given to patients for up to 18 cycles and for approximately 2 years, or until protocol-specified discontinuation criteria were met. After 2 years of combination therapy was completed, lenvatinib may have been given to patients as a single agent until protocol-specified discontinuation criteria were met.1
“With the LEAP-003 and LEAP-017 trials, we set out to help improve outcomes for patients with two difficult-to-treat advanced cancers, melanoma and colorectal cancer,” said Corina Dutcus, MD, senior vice president, clinical development, oncology at Eisai Inc, in the press release. “While these results are different from our initial expectation, insights from both studies will help contribute to our understanding of [pembrolizumab] plus [lenvatinib]. We remain confident in [lenvatinib] as a pillar of Eisai’s oncology portfolio and will continue to evaluate its potential in ongoing trials within the LEAP program.”