Pembrolizumab/Lenvatinib Combo Misses OS End Points in Select Advanced Melanoma and mCRC

The phase 3 LEAP-003 (NCT03820986) and LEAP-017 (NCT04776148) trials evaluating pembrolizumab (Keytruda) plus lenvatinib (Lenvima) did not meet their primary end points of overall survival (OS) in select patients with unresectable or metastatic melanoma and metastatic colorectal cancer (mCRC), respectively.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 CRC,” Corina Dutcus, MD, senior vice president of Clinical Development, Oncology at Eisai Inc., stated in a 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].”

The randomized, placebo-controlled, LEAP-003 trial enrolled patients with unresectable stage III or stage IV melanoma who had not received treatment for advanced or metastatic disease.² Patients were required to have an ECOG performance status of 0 or 1, at least 1 measurable lesion by RECIST v1.1 criteria, and acceptable organ function.

Study participants (n = 674) were randomly assigned 1:1 to receive intravenous (IV) pembrolizumab at 300 mg on day 1 of each 3-week cycle with or without oral lenvatinib given at a daily dose of 20 mg.¹

OS and progression-free survival (PFS) by RECIST v1.1 criteria served as co-primary end points of the trial. Key secondary end points comprised objective response rate (ORR), duration of response (DOR), and safety.

Data from an earlier interim analysis of the trial indicated that the doublet significantly improved PFS over single-agent pembrolizumab in this population. However, after review of the OS findings from a planned interim analysis, and a recommendation issued by an independent data monitoring committee, Merck and Eisai have announced that the trial will be discontinued. The companies are informing study investigators of the decision and directing them to connect with study participants to further discuss treatment.

The randomized, open-label, LEAP-017 trial enrolled patients with histologically or cytologically confirmed unresectable stage IV mCRC that was not microsatellite instability high or mismatch repair deficient.³ Patients must have progressed on or following standard-of-care treatment or could not tolerate such treatment. These must have included all of the following agents if approved and available:

• Fluoropyrimidine, irinotecan, and oxaliplatin with or without an anti-VEGF monoclonal antibody like bevacizumab (Avastin) or with an anti-EGFR monoclonal antibody like cetuximab (Erbitux) or panitumumab (Vectibix) for those with RAS wild-type disease
• And a BRAF inhibitor in combination with cetuximab with or without binimetinib for those with BRAF V600E–mutated disease

They also were required to have measurable disease by RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and acceptable organ function.

A total of 480 participants were randomly assigned 1:1 to receive IV pembrolizumab at 400 mg on day 1 of each 6-week cycle plus oral lenvatinib at a once-daily dose of 20 mg or oral regorafenib at a once-daily dose of 160 mg on days 1 to 21 of each 4-week cycle or oral TAS-102 given at a twice-daily dose of 35 mg/m² on days 1 to 5 and days 8 to 12 of each 4-week cycle.¹

In addition to OS serving as the primary end point of the trial, secondary end points included PFS, ORR, and DOR by RECIST v1.1 criteria. Investigators also examined the safety and tolerability of the regimen as well as quality of life.³

Data from the final prespecified OS analysis indicated a trend toward improved OS with the doublet vs regorafenib or TAS-102, but the difference in benefit was not determined to be statistically significant. Investigators also noted a trend toward improvement in PFS, ORR, and DOR with pembrolizumab plus lenvatinib over regorafenib or TAS-102 but these results were not tested for statistical significance per the prespecified statistical analysis plan.

Data from both trials showed that the safety profile of the combination regimen was consistent with what has previously been reported.

“We are grateful to all 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,” Gregory Lubiniecki, MD, vice president of Global Clinical Development at Merck Research Laboratories, added in the press release. “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.”

According to the press release, the findings from LEAP-003 and LEAP-017, including preplanned subgroup analyses, are undergoing full evaluation. Results will be shared with the scientific community in the future.

References

1. Merck and Eisai provide update on phase 3 trials of Keytruda (pembrolizumab) plus Lenvima (lenvatinib) in certain patients with advanced melanoma (LEAP-003) and metastatic colorectal cancer (LEAP-017). News release. Merck. April 7, 2023. Accessed April 7, 2023. https://www.merck.com/news/
2. Safety and efficacy of pembrolizumab (MK-3475) combined with lenvatinib (MK-7902/E7080) as first-line intervention in adults with advance melanoma (MK-7902-003/E7080-G000-312/LEAP-003). ClinicalTrials.gov. Updated August 23, 2022. Accessed April 7, 2023. https://clinicaltrials.gov/ct2/show/NCT03820986
3. Yoshino T, Fu R, Hawk N, et al. 506TiP pembrolizumab plus lenvatinib versus standard of care for previously treated metastatic colorectal cancer (mCRC): phase III LEAP-017 study. Ann Oncol. 2021;32(suppl 5):S580. doi:10.1016/j.annonc.2021.08.1025