The LEAP-001 study failed to meet its primary endpoint, but lenvatinib/pembrolizumab still showed efficacy in a specific subgroup of endometrial cancer. The highly anticipated ENGOT-en9/LEAP-001 clinical trial for endometrial cancer failed to meet its two primary endpoints. At the 2024 Society of Gynecologic Oncology (SGO) annual meeting, the research team reported that for first-line treatment of advanced or recurrent endometrial cancer, lenvatinib in combination with pembrolizumab did not significantly improve progression-free survival (PFS) or overall survival (OS) in the overall patient population or in patients with normal mismatch repair (pMMR) tumors. However, significant efficacy was still observed in patients with mismatch repair deficient (dMMR) tumors [1]. The news that the study failed to meet its primary endpoint was initially announced by the pharmaceutical company in December 2023. At the SGO meeting, Dr. Christian Marth from the Medical University of Innsbruck, Austria, further analyzed the data and pointed out: "In specific subgroups, lenvatinib/pembrolizumab prolonged progression-free survival and overall survival compared to paclitaxel/carboplatin." He specifically mentioned that patients with dMMR and those who had received neoadjuvant or adjuvant chemotherapy had better response rates and duration of response than the chemotherapy group. "Lenvatinib/pembrolizumab demonstrated survival benefits in subgroups and should be considered an important option for patients with advanced pMMR who have experienced disease progression after systemic treatment." — Dr. Christian Marth Dr. Marth emphasized that in the phase III KEYNOTE-775/Study 309 trial, lenvatinib combined with pembrolizumab significantly improved PFS and OS in previously treated patients, both in the overall population and in pMMR patients[2]. Based on these results, this combination has become the standard therapy for advanced or recurrent endometrial cancer after failure of previous treatment. Recent trials, RUBY[3] and NRG-GY018[4], have shown that immune checkpoint inhibitors combined with chemotherapy can improve efficacy in first-line treatment. LEAP-001, on the other hand, directly compares the efficacy of lenvatinib/pembrolizumab with paclitaxel/carboplatin in first-line treatment.
ENGOT-en9/LEAP-001 Trial Details
This Phase III study enrolled 842 patients from 22 countries, including those who had relapsed more than 6 months after treatment-naïve or neoadjuvant/adjuvant chemotherapy. Patients were randomized to:
Experimental group: pembrolizumab every 3 weeks + lenvatinib 20 mg daily (maximum 35 cycles)
Control group: paclitaxel/carboplatin (maximum 7 cycles)
The primary endpoints were PFS and OS in the intention-to-treat (ITT) population and pMMR patients. After a median follow-up of 38.4 months, results showed:
Lenvatinib/pembrolizumab did not significantly improve OS or PFS in the overall population or the pMMR population (Table 1).
Objective response rates (ORR) ranged from 50% to 55% in both groups.
Efficacy Still Observed in Specific Subgroups
Although the primary analysis did not meet the target, lenvatinib/pembrolizumab showed a significant advantage in the dMMR subgroup (200 patients):
Median PFS: 31.8 months vs 9.0 months (HR=0.61; 95% CI=0.40–0.92)
Median OS: Not reached vs Not reached (HR=0.57; 95% CI=0.36–0.91)
24-month OS rate: 82.9% vs 62.6%
ORR: 72.0% vs 58.0%
Duration of response: Not reached vs 11.7 months
In addition, improvements in PFS and OS were also observed in patients who had previously received chemotherapy (including the pMMR subgroup):
PFS in the general population: 15.0 months vs 8.3 months (HR=0.52)
pMMR subgroup PFS: 12.5 months vs 8.3 months (HR=0.60)
Safety and Quality of Life
The two groups had similar quality of life scores, but different adverse reaction profiles:
Lenvatinib/pembrolizumab group: Higher incidence of hypertension, hypothyroidism, diarrhea, and proteinuria.
Chemotherapy group: More common neuropathy, nausea, anemia, and hair loss.
Expert Opinion: Unsolved Mysteries and Future Directions
Dr. Robert L. Coleman of the Texas Cancer Center (SGO Invited Commentator) points out that although the primary endpoint was not met, the immunotherapy signal in the dMMR subgroup is noteworthy: "The curves were similar during chemotherapy, but PFS and OS began to diverge after 6 months. Even though 31% of patients in the control group received crossover immunotherapy, OS still improved."
He raises key questions:
Is maintenance therapy after chemotherapy a better strategy?
Does a history of chemotherapy exposure in pMMR patients affect the efficacy of immunotherapy?
Currently, the GOG-3064 (pembrolizumab) and DOMENICA (dostarlimab) trials are exploring the feasibility of replacing chemotherapy with monotherapy in dMMR patients, while maintenance therapy regimens for pMMR patients are also under evaluation.
Disclosure of Interests: Dr. Marth reported on collaborations with Eisai and Merck; Dr. Coleman disclosed financial dealings with multiple pharmaceutical companies.
Source: https://ascopost.com/issues/june-10-2024/study-misses-endpoints-but-still-shows-benefit-for-lenvatinibpembrolizumab-in-endometrial-cancer-subsets/