FDA Grants Breakthrough Status to Lenvatinib/Pembrolizumab for Endometrial Cancer

Roy Baynes, MD, PhD

The FDA has granted a breakthrough therapy designation to the combination of lenvatinib (Lenvima) and pembrolizumab (Keytruda) for the treatment of patients with advanced and/or metastatic non—microsatellite instability high (MSI-H)/proficient mismatch repair endometrial carcinoma who have progressed after ≥1 prior systemic therapy.

The designation, which will expedite the development and review of the combination in this setting was based on interim data from the phase Ib/II basket Study 111/KEYNOTE-146 trial, which were presented at the 2018 ASCO Annual Meeting. In the 53-patient endometrial cancer cohort, the objective response rate (ORR) at week 24 per independent radiology review was 45.3% (95% CI, 31.6-59.6). The overall ORR was 47.2% (n = 25; 95% CI, 33.3-61.4), including 3 complete responses and 25 partial responses.

“We designed Study 111 to learn as much as we could about the Lenvima/Keytruda combination as efficiently as possible, driven by a sense of urgency to bring forward a potential new treatment option for patients in need,” Takashi Owa, PhD, vice president and chief medicine creation officer, Oncology Business Group, Eisai, the company codeveloping the combination with Merck (MSD), said in a statement.

“We are encouraged by the continued activity seen in patients with endometrial carcinoma, and the latest breakthrough therapy designation for Lenvima and Keytruda has strengthened our commitment, as part of our human healthcare mission, to expedite the path to ultimately benefitting patients living with endometrial carcinoma as quickly as possible.”

The Study 111 cohort the FDA assessed included 53 patients with metastatic endometrial carcinoma who had received no more than 2 prior systemic therapies. Patients received 20 mg of oral lenvatinib daily plus pembrolizumab at 200 mg IV every 3 weeks. Beyond the primary endpoint of ORR at 24 weeks, secondary outcome measures included overall ORR, duration of response, progression-free survival (PFS), and overall survival.

The median patient age was 63.7 years and 83% of patients were white. Twenty patients had an ECOG performance status of 0 and 33 patients had a status of 1. Twenty-two patients had received 1 prior systemic treatment regimen, 22 had received 2, and 9 had received ≥3.

Four patients had MSI-H status, 45 were microsatellite stable, and 4 had unknown status. Of the 24 patients tested for PD-L1 status, 13 were positive and 11 were negative.

The median PFS with the combination was 7.4 months (95% CI, 5.0-NE). Nineteen patients had stable disease and 5 had progressive disease. The median duration of response was not estimable (range, 1.2+ months to 23.4+ months). Overall, 79.3% of patients had a duration of response ≥12 months.

Seventy percent (n = 37) of patients experienced grade 3 treatment-related adverse events (TRAEs) with the combination, including hypertension (34%), diarrhea (8%), fatigue (6%), and palmar-plantar erythrodysesthesia (6%). There were no grade 4 TRAEs and 30% of patients had serious TRAEs. Overall, there were 5 patient deaths in the study; however, only 1 patient death (due to intracranial hemorrhage) was considered by the investigator to be related to the study treatment.

The FDA previously granted a breakthrough therapy designation to the lenvatinib/pembrolizumab combination in January 2018 for the treatment of patients with advanced and/or metastatic renal cell carcinoma.

“This second breakthrough therapy designation for the Lenvima/Keytruda combination represents another step forward in our collaboration with Eisai and supports the continued evaluation of this combination in more than 11 types of cancer,” Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said in a statement. “We will continue to work closely with Eisai to build on the robust data for the Lenvima/Keytruda combination in advanced endometrial carcinoma in an effort to offer a new option for these patients and potentially help address a critical unmet need.”

Makker V, Rasco DW, Vogelzang NJ, et al. Lenvatinib + pembrolizumab in patients with advanced endometrial cancer: Updated results. J Clin Oncol. 2018;36 (suppl; abstr 5596).