The FDA has granted an accelerated approval to the combination of pembrolizumab and lenvatinib for the treatment of patients with advanced endometrial cancer who have disease progression following prior systemic therapy. The indication applies to patients who are not candidates for curative surgery or radiation and who have disease that is not microsatellite instability–high or mismatch repair deficient.
The FDA has granted an accelerated approval to the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) for the treatment of patients with advanced endometrial cancer who have disease progression following prior systemic therapy. The indication applies to patients who are not candidates for curative surgery or radiation and who have disease that is not microsatellite instabilityhigh (MSI-H) or mismatch repair deficient (dMMR).1,2
Under Project Orbis, an initiative of the FDA Oncology Center of Excellence, the FDA, Australian Therapeutic Goods Administration, and Health Canada all collaborated on the review of the application for the doublet, leading to simultaneous approvals in all 3 countries.
“We are pleased to be working alongside our Australian and Canadian colleagues to help make potentially life-changing treatments available to patients as quickly as possible while still ensuring the FDA’s high standards of safety and effectiveness,” Acting FDA Commissioner Ned Sharpless, MD, said in a statement. He suggested that the project could be expanded to include other countries as well to overcome potential delays in access to newer drugs for patients globally.
The review also went through the FDA’s Real-Time Oncology Review program, which is aiming to review application submissions in a more efficient way.
“In addition to the international collaboration with Australia and Canada, this review used the Real-Time Oncology Review [RTOR] pilot program, which can streamline the submission of data prior to the completion and submission of the entire clinical application,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. “RTOR, and its accompanying Assessment Aid, facilitated discussions among the regulatory agencies, expediting the approval in the 3 countries. These applications were approved 3 months prior to the FDA goal date.” The Assessment Aid program focuses the FDA review on critical assessment and increases review efficiency and consistency, thereby reducing review time concerned with administrative tasks such as formatting.
The approval was supported by findings from the single-arm, multicenter, open-label, multi-cohort phase Ib/II Study 111/KEYNOTE-146 trial (NCT02501096), which evaluated 108 patients with previously treated metastatic endometrial cancer treated with lenvatinib and pembrolizumab.2Patients received 20 mg lenvatinib orally once daily plus 200 mg pembrolizumab given intravenously every 3 weeks until disease progression or unacceptable toxicity.
Overall, 87% of patients had nonMSI-H/dMMR tumors, whereas 10% did, and the remaining patients had unknown MSI/MMR status. Tumor MSI status was determined through polymerase chain reaction testing, and MMR status was assessed with immunohistochemistry testing.
The objective response rate (ORR), as assessed by independent radiologic review committee using RECIST 1.1 criteria, was 38.3% (95% CI, 29%-49%) in the patients with nonMSI-H/dMMR tumors. The complete response rate was 10.6% and the partial response rate was 27.7%. The median duration of response (DOR) was not reached at the time of data cutoff; 69% of responders had DORs of at least 6 months.
The most common adverse events (≥20%) observed with the pembrolizumab/lenvatinib combination in patients with endometrial cancer were fatigue, hypertension, musculoskeletal pain, diarrhea, decreased appetite, hypothyroidism, nausea, stomatitis, vomiting, decreased weight, abdominal pain, headache, constipation, urinary tract infection, dysphonia, hemorrhagic events, hypomagnesemia, palmar-plantar erythrodysesthesia, dyspnea, cough, and rash.
In a prior interim analysis of the study published inLancet Oncologyof 53 evaluable patients at a median of 13.3 months of follow-up, the ORR by investigator review was 39.6% (95% CI, 26.5%-54.0%) at 24 weeks. By independent review, the ORR at 24 weeks was 45.3% (95% CI, 31.6%-59.6%).3
Patients in the interim analysis population had a mean age of 64 years and 62% had an ECOG performance status of 1. The histology was endometrioid adenocarcinoma in 41% and serous adenocarcinoma in 38%. Most patients had received either 1 or 2 prior systemic therapies (43% each), but 13% had received at least 3 prior regimens. Prior chemotherapy consisted of a platinum-based doublet for 98% of patients and 57% of patients also received prior radiotherapy. Twenty-five percent of patients had PD-L1positive tumors, whereas the status was unknown in 55%; 85% of patients had microsatellite stable tumors and 8% had MSI-H tumors.
By investigator review, 64.5% of patients had responses lasting at least 12 months compared with 79.3% by independent review. The median time to response was 2.7 months by investigator review and 2.6 months by independent review.
The most common treatment-related adverse events (TRAEs) of any grade included hypertension (58%), fatigue (55%), diarrhea (51%), and hypothyroidism (47%). The most common grade 3 TRAEs were hypertension in 34% of patients and diarrhea in 8%. No grade 4 TRAEs were observed.
Immune-mediated adverse events were observed in 55.6% of patients, including skin, endocrine, gastrointestinal, pulmonary, hepatic, and renal events. Ten percent of these patients required high-dose glucocorticoids.
Serious TRAEs were reported in 30% of patients, and one patient died from treatment-related intracranial hemorrhage. The other 4 deaths that occurred in the study were considered to be due to progressive disease. Nine percent of patients discontinued treatment due to TRAEs.