A First in Uterine Cancer: Immunotherapy Plus a Targeted Drug Receives FDA Approval

Advanced endometrial carcinoma (uterine cancer) combination treatment with immunotherapy pembrolizumab (Keytruda) and targeted cancer drug lenvatinib (Lenvima) received US Food and Drug Administration (FDA) accelerated approval on 17 September 2019. For this new combination to be used in uterine cancer, patients must:

• microsatellite instability-high (MSI-H) must not be present,
• mismatch repair deficiency (dMMR) must not be present,
• Have disease progression after previous systemic chemotherapy,
• And be unsuitable for curative surgery or radiotherapy.

The review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. It provides a framework for simultaneous oncology drug submission and review among international partners. FDA, the Australian Therapeutic Goods Administration and Health Canada collaborated, enabling simultaneous decisions in all three countries.

Efficacy of pembrolizumab plus lenvatinib in uterine cancerwas investigated after progression following at least one systemic chemotherapy line in metastatic endometrial carcinoma patients, numbering 108, in a single-arm, multicenter, open-label, multicohort clinical trial known as Study 111 / KEYNOTE-146.

Patients were treated every 3 weeks with intravenous pembrolizumab 200 mg combined with once-daily oral lenvatinib 20 mg, until acceptable side effects or disease progression.

Of 108 patients, 94 had tumors without MSI-H or dMMR, 11 had MSI-H or dMMR tumors, and 3 had unknown status. Tumor MSI was determined using a polymerase chain reaction test. Tumor dMMR was determined by immunohistochemistry.

The main efficacy outcomes, determined by an independent radiological review committee, were objective response rate and response duration in the study.

Study Results

• Among 94 patients whose tumors were not MSI-H or dMMR, objective response comprised 10 complete responses (10.6%) and 26 partial responses (27.7%), totaling 38.3%.
• Median response duration had not been reached at analysis, and 25 patients (69% of responders) continued responding for at least 6 months.

Before this approval, standard 2nd-line advanced uterine cancer treatment involved various chemotherapies, with reported response rates of 7-15%. Responses approaching 40% with pembrolizumab plus lenvatinib were regarded as a striking oncology success.

In endometrial carcinoma, the most common side effects of lenvatinib and pembrolizumab (≥20%) were fatigue, hypertension, musculoskeletal pain, diarrhea, reduced appetite, hypothyroidism, nausea, stomatitis, vomiting, weight loss, abdominal pain, headache, urinary tract infection, dysphonia (hoarseness), hemorrhagic events (bleeding), hypomagnesemia (low blood magnesium), palmar-plantar erythrodysesthesia (hand-foot rash), dyspnea, cough and body rash.

For endometrial carcinoma, the recommended doseis given every 3 weeks as a 30-minute intravenous infusion of pembrolizumab 200 mg, combined with once-daily oral lenvatinib 20 mg.

Below are the immune checkpoint-type immunotherapiesand the cancer types for which they have received FDA approval to date: