MEK Inhibition Is Now a Standard of Care in Recurrent Low-Grade Serous Ovarian Cancer: What Next?

April 25, 2022 12:08 pm

The following article is provided by The Clearity Foundation to support women with ovarian cancer and their families. Learn more about The Clearity Foundation and the services we provide directly to women as they make treatment decisions and navigate emotional impacts of their diagnosis.

by Rachel N. Grisham, M.D.

As summarized in this issue of The ASCO Post, the highly anticipated results of the GOG 281/LOGS study, which randomly assigned patients with recurrent low-grade serous ovarian cancer to the MEK inhibitor trametinib vs standard-of-care chemotherapy or endocrine therapy, have now been reported by Gershenson et al in The Lancet.1 Dr. Gershenson has been one of the greatest contributors to low-grade serous ovarian cancer research for decades and continues to advance the field in the development of novel treatment strategies for this rare type of ovarian cancer.

Low-grade serous ovarian cancer accounts for up to 10% of epithelial ovarian cancer cases and has been characterized as having a more indolent nature than high-grade serous ovarian cancer but lower response rates to chemotherapy. Due to the prevalence of MAP kinase alterations within this disease, with multiple studies showing that approximately one-third of patients harbor a somatic KRAS mutation, there has been considerable interest in the use of MEK inhibitors for treatment of patients with low-grade serous ovarian cancer.

‘Valuable Study Information’

This phase II/III trial randomly assigned 260 patients with recurrent, measurable, low-grade serous ovarian cancer who had received at least one prior line of platinum-based chemotherapy to single-agent trametinib or physician’s choice of intravenous (IV) pegylated liposomal doxorubicin, IV weekly paclitaxel, IV topotecan, oral letrozole, or oral tamoxifen. The primary endpoint was progression-free survival, favoring the trametinib group (median = 13 months, 95% confidence interval [CI] = 9.9–15.0 months) over the standard-of-care group (median = 7.2 months, 95% CI = 5.6–9.9 months; hazard ratio = 0.48, 95% CI = 0.36–0.64). Based on these results, trametinib is now listed in the NCCN Drugs & Biologics Compendium for the treatment of recurrent low-grade serous ovarian cancer and is considered a standard-of-care therapy for patients treated in the United States.

Rachel N. Grisham, MD
Rachel N. Grisham, MD

Prior prospective data regarding response rates to chemotherapy and endocrine therapy in low-grade serous ovarian cancer have been limited. This study provides valuable information regarding the expected response rates to chemotherapy and endocrine therapy. Of note, the response rates to both oral tamoxifen (0/27) and IV topotecan (0/8) were 0% in this study; however, the study population was heavily pretreated, with almost half of patients having received three or more regimens prior to study entry.

Prior studies have shown that patients with low-grade serous ovarian cancer harboring a MAP kinase alteration may have better outcomes overall. Similar to the phase III MILO/ENGOT-ov11 study of binimetinib vs physician’s choice of chemotherapy in patients with recurrent low-grade serous ovarian cancer,2 the GOG 281/LOGS study showed response rates were more favorable with trametinib than with standard-of-care therapy in mutation-positive patients (11of 22 [50%] vs 2 of 22 [9%]) than in mutation-negative patients (4 of 48 [8%] vs 3 of 42 [7%]), although this did not reach statistical significance. These results suggest that somatic mutation tumor testing can be helpful in counseling patients about the expected benefit of MEK inhibitor therapy and should be considered for all patients with recurrent low-grade serous ovarian cancer.

Ongoing Studies

With single-agent MEK inhibitors now accepted as a standard-of-care therapy, ongoing studies seek to build upon these results by combining MEK inhibitors with other agents. For instance, the ENGOT-ov60/GOG3052/RAMP 201 phase II study of a dual MEK/RAF inhibitor (VS-6766) with or without the focal adhesion kinase (FAK) inhibitor defactinib is currently enrolling patients with recurrent low-grade serous ovarian cancer (ClinicalTrials.gov identifier NCT04625270).

DISCLOSURE: Dr. Grisham has received personal fees from Clovis, Mateon, Regeneron, Verastem, Amgen, Medscape, Aptitude Health, PER, Signatera, and GSK.

REFERENCES

1. Gershenson DM, Miller A, Brady WE, et al: Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): An international, randomised, open-label, multicentre, phase 2/3 trial. Lancet 399:541-553, 2022.

2. Monk BJ, Grisham RN, Banerjee S, et al: MILO/ENGOT-ov11: Binimetinib versus physician’s choice chemotherapy in recurrent or persistent low-grade serous carcinomas of the ovary, fallopian tube, or primary peritoneum. J Clin Oncol 38:3753-3762, 2020.

Dr. Grisham works on the Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, and in the Department of Medicine, Weill Cornell Medical College, New York.

This article was published by The ASCO Post.

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