LEAP-010 Trial Discontinued After OS Projection With Pembrolizumab/Lenvatinib in Metastatic HNSCC

The combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) demonstrated a statistically significant improvement in progression-free survival (PFS) and objective response rate (ORR) but failed to improve overall survival (OS) compared with pembrolizumab plus placebo as frontline therapy for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) whose tumors express PD-L1, according to 2 planned interim analyses of the phase 3 LEAP-010 trial (NCT04199104).^1,2

The Data Monitoring Committee conducted both analyses over 11 months, the first of which evaluated PFS and ORR. In the second analysis, Merck and Eisai, developers of the agents, determined that the likelihood of reaching the protocol-specified threshold for statistical significance for OS was low. Based on this, the study will be closed.

The safety profile of the combination was in line with previously reported adverse effects with pembrolizumab plus lenvatinib. A complete assessment of the data, including preplanned subgroup analyses, is ongoing despite the closure. The companies will partner with investigators to share the results with the medical community.

“With the LEAP-010 trial, we aimed to explore whether this combination could improve upon options already available with KEYTRUDA-based regimens for appropriate patients with metastatic or with unresectable, recurrent HNSCC,” Gregory Lubiniecki, MD, vice president of Global Clinical Development at Merck Research Laboratories, stated in a news release. “Although the PFS results from this study were encouraging, unfortunately, the combination did not result in an OS benefit for patients. We will apply lessons from this trial to help continue advancing research of this combination.”

The combination of pembrolizumab and lenvatinib is currently indicated for the treatment of patients with advanced renal cell carcinoma and advanced endometrial cancer in the United States, the European Union, and Japan, among other countries.

The combination was evaluated in the randomized, placebo-controlled, double-blinded, phase 3 LEAP-010 trial to establish efficacy in patients with recurrent or metastatic HNSCC whose tumors express PD-L1.

To be eligible for enrollment, patients had to have pathologically confirmed recurrent or metastatic HNSCC of the oral cavity, oropharynx, hypopharynx, and/or larynx that is not eligible for curative-intent therapy. Patients must have received prior therapy with platinum and an anti–PD-(L)1 inhibitor, demonstrated documented disease progression on at least 2 pre-study images per RECIST v1.1 criteria, and have measurable disease.³

They were also required to have an ECOG performance status of 0 or 1, adequately controlled blood pressure without antihypertensive agents, and adequate organ function. Hepatitis B surface antigen positivity and hepatitis C virus (HCV) infection did not preclude patients from enrollment as long as they had received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and demonstrated undetectable HBV and HCV viral load, respectively.³

Approximately 511 patients were randomly assigned 1:1 to receive 200 mg of intravenous pembrolizumab on day 1 of every 3-week cycle plus 20 mg of oral lenvatinib once daily, or 200 mg of IV pembrolizumab on day 1 of every 3-week cycle plus matched placebo.

In both arms, pembrolizumab was administered for up to 35 cycles, equating to approximately 2 years, or until protocol-specified discontinuation criteria were met. After 2 years of combination therapy, patients were allowed to continue lenvatinib monotherapy until protocol-specified discontinuation criteria were met.

The primary end points of the study were OS, PFS, and ORR. PFS and ORR were evaluated by blinded independent central review (BICR) per RECIST v1.1 criteria, modified to follow up to 10 target lesions and up to 5 target lesions per organ. Secondary end points included duration of response and safety.³

“While we were initially encouraged to see that [pembrolizumab] plus [lenvatinib] met two of its three primary endpoints at an earlier interim analysis, unfortunately the combination did not meet the threshold for the third primary end point of OS,” Corina Dutcus, MD, senior vice president, Global Clinical Development, Oncology at Eisai Inc., stated in the release. “Our clinical program is designed to help accelerate our efforts to tackle difficult-to-treat, advanced cancers, and while the outcome may not always be what we anticipate, we know that this is part of clinical development, and we remain committed to scientific exploration in pursuit of improving care for patients.”

Notably, the decision will not affect current approvals for pembrolizumab and lenvatinib or other ongoing trials from the LEAP program, including the phase 2 LEAP-009 trial (NCT04428151), which is evaluating pembrolizumab plus lenvatinib vs chemotherapy in patients with recurrent or metastatic HNSCC following progression after platinum-based chemotherapy and immunotherapy.

References

1. Merck and Eisai provide update on phase 3 LEAP-010 trial evaluating KEYTRUDA (pembrolizumab) plus LENVIMA (lenvatinib) in patients with certain types of recurrent or metastatic head and neck squamous cell carcinoma. News release. Merck. August 25, 2023. Accessed August 25, 2023. https://www.merck.com/news/merck-and-eisai-provide-update-on-phase-3-leap-010-trial-evaluating-keytruda-pembrolizumab-plus-lenvima-lenvatinib-in-patients-with-certain-types-of-recurrent-or-metastatic-head-and-ne/
2. Siu LL, Burtness B, Cohen EEW, et al. Phase III LEAP-010 study: first-line pembrolizumab with or without lenvatinib in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). J Clin Oncol. 2020;38(suppl 15):TPS6589. doi:10.1200/JCO.2020.38.15_suppl.TPS6589
3. Lenvatinib (E7080/MK-7902) in combination with pembrolizumab (MK-3475) vs. standard chemotherapy and lenvatinib monotherapy in participants with recurrent/metastatic head and neck squamous cell carcinoma that progressed after platinum therapy and immunotherapy (MK-7902-009/E7080-G000-228/LEAP-009). ClinicalTrials.gov. Updated August 24, 2023. Accessed August 25, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04428151