What Women Should Know About the FDA's Endometrial Cancer Combination Approval

Women with endometrial cancer that is not categorized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who are not eligible for curative surgery or radiation, and whose disease has progressed after previous systemic therapy now have a new, and much needed, treatment option.

Last week, the Food and Drug Administration (FDA) approved the combination use of Lenvima (lenvatinib) and Keytruda (pembrolizumab) for this patient population.

“While the majority of endometrial cancer is early stage and potentially curable, metastatic recurrent endometrial cancer rarely is. Our treatment options for women with advanced and recurrent endometrial cancer are limited by a ‘shallow bench’ of treatment options,” Dr. Amelia Jernigan, a gynecologic oncologist with the LSU Health Sciences Center Department of Obstetrics and Gynecology, explained in an interview with CURE.

Therapeutic Need

While many women will respond initially to front-line chemotherapy (about 50% to 60%), Jernigan noted that these responses are rarely durable and eventual recurrence or progression through treatment is the rule. In addition, second-line treatments have been shown to induce a much lower response rate (about 14% to 16%).

“As endometrial cancer is the most common gynecologic cancer in the US, we often find ourselves trying to figure out what to do after front-line therapy fails,” she added.

In addition, there is a need for treatment of women whose tumors are not categorized as MSI-H or dMMR — features of cancer’s genetic coding, which result in it behaving and “looking” a certain way on a microscopic level.

“MSI-H or dMMR tumors are tumors that have broken cellular machinery to fix mismatches in the DNA of a cell and the presence of this can be tested on tumor specimens,” said Jernigan, who is also an active member of the Society of Gynecologic Oncology and serves on the Communications Committee.

However, 70% of women’s endometrial cancers are not MSI-H or dMMR. “Therefore, most women in desperate need of a promising second-line therapy were still at a loss,” she said.

KEYNOTE-146 Trial

The FDA based its decision on data from the multi-cohort, multicenter, open-label, single-arm phase 2 KEYNOTE-146/Study 111 trial — designed to evaluate Keytruda in combination with Lenvima among 108 patients with metastatic endometrial carcinoma that had progressed following at least one prior systemic therapy in any setting. In particular, the agency focused on data from 94 patients in the study whose tumors were not MSI-H or dMMR.

A little over one-third of whom had a response to the regimen that lasted up to six months.

“The nearly 40% response rate in all comers in this trial is exciting because it allows for women who fail front-line chemotherapy to have a higher chance of responding to treatment,” Jernigan said.

Project Orbis

The FDA’s decision was also made under a new initiative of the FDA Oncology Center of Excellence, known as Project Orbis, which is designed to allow international partners to concurrently submit oncology drugs for review. In addition to the FDA, the Australian Therapeutic Goods Administration and Health Canada collaborated on the review of the combination, leading to simultaneous approvals in all three countries.

“With attempts to maximize safety, understand value and efficacy of new drugs, and variable administrative processes for new drug approval from country to country, patients can often experience considerable delays in access to novel and cutting-edge cancer treatments due to regulatory hold up,” Jernigan explained, adding that because of this, Project Orbis seems to be a success.

As part of the initiative, the agency was able to approve the novel combination three months ahead of the Prescription Drug User Fee Act date.

“The hope is to maintain a safe and thorough approval process but cut through some of the red tape and cut out some of the inefficiency,” Jernigan said. “This will hopefully minimize the number of patients who do not get access to the latest cancer treatment options because of regulatory hold up.”

Moving Forward

Moving forward, Jernigan sees the oncology field embracing more targeted therapies like the combination use of Keytruda and Lenvima. With this, the goal is also to aim for an increased use of targeted treatment options with improved toxicity and more durable responses for women with endometrial cancer.

“Endometrial cancer represents a diverse group of cancers and we’ve embraced carboplatin and paclitaxel as front-line therapy for advanced and recurrent disease. However, in select patient populations, we’ve found that using a targeted therapy either alone or in combination with systemic chemotherapy can improve outcomes,” she added. “I think we will begin to be able to more specifically identify targets that are actionable in this diverse group of tumors.”

Read CURE’s original coverage of the FDA’s approval of Keytruda in combination with Lenvima.