Ribociclib Plus Letrozole Has Activity in Recurrent Low-Grade Serous Ovarian Cancer

Although the activity of ribociclib (Kisqali) plus letrozole was found to be comparable to previously investigated regimens for patients with advanced, recurrent low-grade serous ovarian cancer (LGSOC), the increased durability of responses seen with the doublet highlights its potential as an active option in this population, according to Brian M. Slomovitz, MD.¹

Findings from the phase 2 GOG 3026 trial (NCT03673124), presented atthe 2023 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer, showed that among 48 patients, the combination elicited an overall response rate of 23% (90% CI, 13.4%-35.1%); all responders (n = 11) had partial responses to treatment.¹ The clinical benefit rate achieved with the doublet was 79% (90% CI, 67.2%-88.2%). The median DOR in these patients was 19.1 months (range, 4.8-35.8) and the median progression-free survival (PFS) was 19.1 months. The safety profile of the regimen was consistent with what has previously been reported.

“The combination of a CDK4/6 inhibitor with letrozole, as demonstrated here, is very compelling. It could be a gamechanger,” said Slomovitz, who is the director of Gynecologic Oncology and co-chair of the Cancer Research Committee at Mount Sinai Medical Center, as well as a professor of Obstetrics and Gynecology at Florida International University, Miami Beach, FL. “…This regimen may] help our patients live longer, which is ultimately why we do what we do.”

In an interview with OncLive^®, Slomovitz explains the importance of developing specific, effective treatment options in this disease subtype, key efficacy and safety data seen with ribociclib and letrozole in the GOG 3026 trial, and planned efforts to identify associated biomarkers and pursue FDA approval for the combination in LGSOC.

OncLive^®: What was the rationale for evaluating the addition of ribociclib to letrozole in patients with LGSOC?How might this regimen address unmet needs in this population?

Slomovitz: The study was done in patients with low-grade serous ovarian cancer, [which is] a rare subtype of ovarian cancer. Unfortunately, the treatment options [for these patients] are limited. Unlike high-grade [ovarian] cancer, which responds favorably to chemotherapy, the response rates to chemotherapy [with low-grade serous ovarian cancer] are 0% to 15%. The response rates to hormonal therapy are [also] limited [in this population].

Low-grade serous ovarian cancers are often estrogen receptor [ER]–positive tumors. A lot of our strategies are borrowed from other diseases, like ER-positive breast cancers. CDK4/6 inhibition works to overcome hormonal resistance. Within the cell, it is more active in patients who have loss of p16 expression. We know that loss of p16 occurs in about 75% in women with low-grade serous ovarian cancer. Additionally, we know that the combination of ribociclib with letrozole [also] helps to overcome hormonal resistance and augments the response of letrozole [alone].

What efficacy and safety data were reported at this year’s meeting?

This was an open-label, investigator-initiated, single-arm phase 2 trial, looking at the combination of letrozole with ribociclib in women with advanced, recurrent, low-grade serous ovarian carcinoma. The trial was sponsored by the GOG Foundation with support from Novartis.

The efficacy data were quite compelling. [The] ORR was 23%, which is comparable to MEK inhibition, which have also been shown to work [well] in this disease. What was very exciting is that the PFS and DOR were both about 19 months; that’s about 6 months greater than what we’ve seen with our best therapies in the past. [Although] the ORRs are similar [between the combination and previously investigated agents], the DOR makes this drug more exciting.

In general, the two drugs are very well tolerated. Grade 3 toxicities were limited, [with] the more common [adverse effects (AEs)] being a decrease in neutrophils and white blood cells. However, overall, it was very well tolerated and aligned with the [known] AE [profile] for these agents.

What next steps are planned for this research?

The next steps are crucial here. We have pathology slides and formalin-embedded slides for our patients. We are going to proceed with a translational component of the trial to further [understand] the mechanism of response, and hopefully [identify] some prognostic and predictive markers. Based on the results, we do feel that an FDA indication would be warranted, and we’re going to pursue that route.

What are the clinical implications of these findings?

We know that LGSOCs are not typical ovarian cancers; they need to be treated differently, and more likely, like ER-positive breast cancers. Chemotherapy does not work well in this disease, and [there is] an unmet need for better treatment options…

We’re very excited about this research, [especially because] it's always difficult to [conduct] clinical trials in rare tumors. Working through the GOG Foundation, we demonstrated that we could bring together our network of highly accruing sites and [successfully complete] studies, even in the rare tumor setting.

Do you feel any presentations at this year’s meeting will be particularly practice-changing within gynecologic cancers?

There [were] game-changing presentations at this year's SGO Annual Meeting. Immunotherapy [was] introduced as an additional systemic therapy for women with advanced recurrent endometrial cancer in the [phase 3] Ruby [NCT03981796] and NY-GY018 [NCT03914612] trials. [Mansoor R. Mirza, MD, of Copenhagen University Hospital,] presented the RUBY trial, and [Ramez Eskander, MD, of University of San Diego's Moore Cancer Center] presented the NY-GY018 study. [Data] from previously reported press releases [have indicated] that the addition of immunotherapy to standard chemotherapy will help women with advanced endometrial cancer not only have a longer PFS, but hopefully live longer.

Editor’s Note: Dr Slomovitz reports serving in a consultory or advisory role for AstraZeneca, Eisai, Genentech, Genmab, GOG Foundation, GSK, Karyopharm, Imvax, Incyte, Merck, Myriad, Onconova, Seagen; he received research funding from Novartis.

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Reference

Slomovitz BM, Deng W, Killion J, et al. GOG 3026: A phase II trial of letrozole + ribociclib in women with recurrent low-grade serous carcinoma of the ovary, fallopian tube or peritoneum (LGSOC): A GOG Foundation study. Presented at: 2023 SGO Annual Meeting on Women’s Cancer; March 25-28, 2023; Tampa, Florida.