Pembrolizumab/Lenvatinib Regimens Miss Survival End Points in Metastatic NSCLC

The first-line combination of pembrolizumab (Keytruda), lenvatinib (Lenvima), pemetrexed, and platinum-containing chemotherapy did not meet the dual primary end points of overall survival (OS) and progression-free survival (PFS) compared with pembrolizumab plus pemetrexed and platinum-containing chemotherapy in patients with metastatic, nonsquamous non–small cell lung cancer (NSCLC) in whom EGFR-, ALK- or ROS1-directed therapies were not indicated, according to data from the final analysis of the phase 3 LEAP-006 trial (NCT03829319).¹

Additionally, pembrolizumab plus lenvatinib failed to meet the coprimary end points of OS and PFS compared with docetaxel in patients with metastatic NSCLC who progressed on or after platinum-containing chemotherapy and 1 prior anti–PD-1/PD-L1 therapy in whom EGFR-, ALK- or ROS1-directed therapies were not indicated, according to data from the final analysis of the LEAP-008 trial (NCT03976375).

Safety data from the pembrolizumab plus lenvatinib–based regimens were consistent with findings from previously reported studies. Detailed data from both studies will be shared with the medical community in the future.

Findings from LEAP-006 and LEAP-008 will not affect the current approved indications for pembrolizumab plus lenvatinib or other ongoing trials from the LEAP program.

“As a leader in lung cancer research, we continue to try to advance science for our patients by building upon the standard we set several years ago with [pembrolizumab],” Gregory Lubiniecki, MD, vice president of global clinical development at Merck Research Laboratories, stated in a news release. “While these results are not what we hoped for, we are proud of the foundational role that [pembrolizumab] has established in the treatment of certain types of lung cancer, and we are committed to continuing to research how we can further improve responses to our medicines for patients with difficult-to-treat forms of the disease.”

Prior findings from interim analyses of both LEAP-006 and LEAP-008 showed that the pembrolizumab plus lenvatinib–based regimens did not demonstrate a statistically significant improvement in PFS or overall response rate (ORR), a key secondary end point.

LEAP-006 was a randomized, placebo-controlled trial that enrolled patients with histologically or cytologically confirmed stage IV nonsquamous NSCLC who have confirmation that EGFR-, ALK- or ROS1-directed therapies are not indicated.² Patients needed to have measurable disease per RECIST v1.1 criteria, a life expectancy of at least 3 months, and an ECOG performance status of 0 or 1. Patients with known untreated central nervous system metastases and/or carcinomatous meningitis were not allowed to enroll.

During the study, an estimated 748 patients were randomly assigned 1:1.1 Those in the experimental arm received 200 mg of intravenous (IV) pembrolizumab once every 3 weeks plus 8 mg of oral lenvatinib once daily, 500 mg/m2 of IV pemetrexed once every 3 weeks, and area under curve 5 mg/mL/min of carboplatin or 75 mg/m2 of cisplatin once every 3 weeks. Patients in the control arm were given the same regimen of pembrolizumab and chemotherapy plus placebo.

Pembrolizumab was administered for up to 35 cycles, and after 2 years of combination therapy, lenvatinib was allowed to be given as monotherapy until protocol-specified discontinuation criteria were met. Carboplatin or cisplatin was administered for up to 4 cycles.

Along with the primary end points of blinded independent central review (BICR)–assessed PFS per RESIST v1.1 criteria and OS, secondary endpoints included ORR, duration of response (DOR), quality of life, and safety.

LEAP-008 was a randomized, open-label trial that included patients with histologically or cytologically confirmed metastatic squamous or nonsquamous NSCLC (stage IV: M1a, M1b, M1c) who experienced progressive disease on treatment with 1 prior anti–PD-1/PD-L1 monoclonal antibody given either as monotherapy or in combination with other checkpoint inhibitors or other therapies, and progressive disease during or after platinum-doublet chemotherapy for metastatic disease.3 Confirmation that EGFR-, ALK- or ROS1-directed therapies were not indicated was required. At least 1 measurable lesion per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and a life expectancy of at least 3 months were also needed.

The trial enrolled an estimated 422 patients who were randomly assigned 4:4:1 to receive 200 mg of IV pembrolizumab once every 3 weeks plus 20 mg of oral lenvatinib once per day; 75 mg/m2 of IV docetaxel once every 3 weeks; or 24 mg of oral lenvatinib once per day. Pembrolizumab treatment lasted for up to 35 cycles or until protocol-specified discontinuation criteria were met. After 2 years of combination therapy, continued treatment with single-agent lenvatinib was permitted until protocol-specified discontinuation criteria were met.

BICR-assessed PFS and OS were the primary end points, and secondary endpoints consisted of ORR, DOR, quality of life, and safety.

“Despite great progress in recent years, unmet needs still remain in the treatment of patients with metastatic non-small cell lung cancer, particularly for those without targetable biomarkers,” Corina Dutcus, MD, senior vice president of global clinical development in oncology at Eisai, said. “[Pembrolizumab] plus [lenvatinib] has demonstrated survival benefit in advanced renal cell carcinoma and advanced endometrial carcinoma, and while we are disappointed that the final analyses of these NSCLC studies did not show the same benefit, we remain committed to applying learnings from these studies and furthering research in oncology for people with unmet needs. We thank all the patients, their families and the investigators involved.”

References

1. Merck and Eisai provide update on two phase 3 trials evaluating Keytruda (pembrolizumab) plus Lenvima (lenvatinib) in patients with certain types of metastatic non-small cell lung cancer. News release. Merck. September 22, 2023. Accessed September 22, 2023. https://www.merck.com/news/merck-and-eisai-provide-update-on-two-phase-3-trials-evaluating-keytruda-pembrolizumab-plus-lenvima-lenvatinib-in-patients-with-certain-types-of-metastatic-non-small-cell-lung-cancer/
2. Safety and efficacy study of pemetrexed + platinum chemotherapy + pembrolizumab (MK-3475) with or without lenvatinib (MK-7902/E7080) as first-line intervention in adults with metastatic nonsquamous non-small cell lung cancer (MK-7902-006/E7080-G000-315/LEAP-006). ClinicalTrials.gov. Updated August 23, 2022. Accessed September 22, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03829319
3. Efficacy and safety of pembrolizumab (MK-3475) with lenvatinib (E7080/MK-7902) vs. docetaxel in participants with metastatic non-small cell lung cancer (NSCLC) and progressive disease (PD) after platinum doublet chemotherapy and immunotherapy (MK-7902-008/E7080-G000-316/LEAP-008). ClinicalTrials.gov. Updated August 15, 2023. Accessed September 22, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03976375