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SAN DIEGO -- A combination of lenvatinib (Lenvima) and pembrolizumab (Keytruda) failed to meet survival endpoints compared with chemotherapy as first-line therapy for patients with advanced or recurrent endometrial cancer, the phase III LEAP-001 trial showed.

Among an all-comer population of 842 patients, the median progression-free survival (PFS) with the combination was 12.5 months versus 10.2 months with chemotherapy (HR 0.91, 95% CI 0.76-1.09), while overall survival (OS) was 37.7 months and 32.1 months, respectively (HR 0.93, 95% CI 0.77-1.12), reported Christian Marth, MD, PhD, of Innsbruck Medical University in Austria, during the Society of Gynecologic Oncology annual meeting.

In a population of patients with proficient mismatch repair (pMMR) disease, median PFS was 9.6 months with the combination versus 10.2 months with chemotherapy (HR 0.99, 95% CI 0.82-1.21), and median OS was 30.9 months and 29.4 months, respectively (HR 1.02, 95% CI 0.83-1.26).

As background, the phase III KEYNOTE-775/Study 309 trial showed that the combination of lenvatinib and pembrolizumab significantly improved PFS and OS compared with physician's-choice chemotherapy in patients with previously treated advanced endometrial cancer, both in the overall and pMMR populations.

Thus, the objective here was to evaluate the combination versus chemotherapy in the first line.

While the trial failed to meet its primary endpoint, Marth reported that he and his team found that the combination prolonged PFS and OS in the deficient mismatch repair (dMMR) population, as well as in patients who had received prior neoadjuvant/adjuvant chemotherapy.

Median PFS with the combination was 31.8 months versus 9 months with chemotherapy (HR 0.61, 95% CI 0.40-0.92) in the dMMR population, while median OS was not reached in either arm (HR 0.57, 95% CI 0.36-0.91).

Marth also noted there was a higher overall response rate in the dMMR population: 72% versus 58% with chemotherapy, with a median duration of response not reached in the combination arm versus 11.7 months with chemotherapy.

Among the subgroup of patients with prior neoadjuvant/adjuvant chemotherapy, PFS improved in both the pMMR population, with a median PFS of 12.5 months with the combination versus 8.3 months with chemotherapy (HR 0.60, 95% CI 0.37-0.97), and among all-comers, with a median PFS of 15 months versus 8.3 months, respectively (HR 0.52, 95% CI 0.33-0.82).

ORR and duration of response were also better in both the pMMR and all-comer populations in the prior neoadjuvant/adjuvant chemotherapy subgroup.

"These data confirm that lenvatinib/pembrolizumab is an active combination for endometrial cancer, and should be regarded as an important treatment option for advanced/recurrent endometrial cancer that is pMMR with disease progression during prior systemic therapy in any setting," Marth said.

enrolled 842 patients who were randomly assigned to receive lenvatinib once a day plus pembrolizumab every 3 weeks for up to 35 cycles, or paclitaxel plus carboplatin every 3 weeks for up to 7 cycles.

Eligible patients included those with stage III, stage IV, or recurrent endometrial carcinoma, as well as those who received no prior chemotherapy, except in the neoadjuvant or adjuvant setting.

Median age was 63 in the combination arm and 64 in the chemotherapy arm, and 17.6% and 16.1%, respectively, received prior chemotherapy and/or chemoradiotherapy. About two-thirds of patients had endometrioid histology.

The median duration of treatment was 316.5 days with the combination compared with 126 days with chemotherapy.

Almost every patient in each arm experienced any-grade adverse events (AEs) and treatment-related AEs, with 71.7% and 40.9% of patients in the combination and chemotherapy arms experiencing AEs leading to treatment interruption, and 47.4% and 19.5% experiencing AEs resulting in treatment discontinuation.

Regarding AEs of special interest for pembrolizumab, Marth noted that these were relatively low in number, and low grade, with the exception of hypothyroidism and hyperthyroidism, which occurred in 62.6% and 16.4% of patients, respectively.

Marth also reported that health-related quality of life was similar between the two groups across most quality-of-life scales, but was better with the combination for neuropathy and alopecia.

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