Trametinib Boosts PFS and Response Rates in Low-Grade Ovarian Cancer

David M. Gershenson, MD

Trametinib (Mekinist) monotherapy has emerged as a new treatment option for women with recurrent low-grade serous ovarian cancers based on improvements in survival outcomes and response rates demonstrated in a phase II/III study, according to David M. Gershenson, MD.

The findings involving the MEK inhibitor were scheduled to be presented at the 2020 Society of Gynecologic Oncology Annual Meeting on March 29 but were released electronically after the conference was canceled because of coronavirus disease 2019. In the NRG-GOG 0281 trial (NCT02101788), treatment with trametinib resulted in a 52% reduction in the risk of disease progression or death. The median progression-free survival (PFS) was 13.0 months (95% CI, 9.9-15.0) with trametinib compared with 7.2 months (95% CI, 5.6-9.9) for physician’s choice of standard-of-care (SOC) therapy (HR, 0.48; 95% CI, 0.36-0.64; 1-sided P <.0001). Median overall survival (OS) also was longer with trametinib therapy, but the results did not reach statistical significance.¹

“This was not only was the first study of trametinib in this patient population, but it also turned out to be the first positive randomized clinical trial of any targeted agent in low-grade serous carcinoma,” Gershenson, a professor of gynecologic oncology at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with OncLive^®. “It establishes trametinib as a new standard-of-care treatment option for women who have low-grade serous carcinoma.”

Low-grade serous carcinoma of the ovary or peritoneum is a rare subtype that comprises 5% to 10% of all serous cancers, Gershenson and colleagues said in their conference abstract. Most of these malignancies are diagnosed in advanced stages and more than 70% of those with stage II to IV disease will experience relapse.¹

Although chemotherapy and hormonal therapy are frequently administered to patients in the primary and recurrent disease settings², low-grade serous carcinoma also is characterized by alterations in the MAP kinase cell-signaling network, which includes MEK proteins.¹ Trametinib targets MEK 1/2 kinases and is given in combination with dabrafenib (Tafinlar), a BRAF inhibitor, in melanoma, non—small cell lung cancer, and anaplastic thyroid cancer metastases with BRAF V600 mutations.³

In NRG-GOG 0281, patients were randomized 1:1 to be treated until progression with either trametinib at 2 mg daily or 1 of 5 SOC options: paclitaxel (80 mg/m² weekly for 3 of 4 weeks), pegylated liposomal doxorubicin (40-50 mg on day 1 of 28-day cycle) , topotecan (4.0 mg/m² weekly for 3 of 4 weeks), letrozole (2.5 mg daily), or tamoxifen (20 mg twice daily). Patients who progressed on SOC were allowed to cross over to trametinib . The primary end point was PFS; secondary objectives included OS, objective response rate (ORR), and toxicity.

In all, 260 patients with a median age of 56.2 years were enrolled between February 2014 and April 2018. The primary site of malignancy was the ovary for 90.8% of participants and the peritoneum for 9.2%. Overall, 48.1% had 3 or more prior lines of therapy. Median follow-up was 31.4 months.

In addition to a significant improvement in PFS, trametinib therapy also resulted in a higher response rate than SOC. The ORR was 26.2% (95% CI, 19.0%-34.0%) with trametinib versus 6.2% (95% CI, 2.0-10.0) with SOC, which translated into an odds ratio favoring trametinib of 5.4 (95% CI, 2.4-12.2; P <.0001).

Response duration for those who received trametinib was longer compared with participants in the SOC arm; the median duration with trametinib was 13.6 months (95% CI, 8.1-18.8) versus 5.9 months (95% CI, 2.8-12.2) with SOC.

Additionally, median OS was 37.0 months (95% CI, 30.3-not estimable) with trametinib versus 29.2 months (95% CI, 23.5-51.6) with SOC, which represented a 25% reduction in the risk of death but not a statistically significant improvement (HR, 0.75; 95% CI, 0.51-1.11; 1-sided P = .054). The OS analysis in the SOC arm included patients who had crossed over to trametinib therapy after progressing on SOC. Among patients who crossed over (n = 88), the median PFS was 10.8 months (95% CI, 7.3-12.0), the ORR was 15% (95% CI, 7.0-22.0), and the duration of response was 15.9 months (95% CI, 4.2-22.1).

Treatment-emergent adverse events (AEs) were more prevalent in patients who received trametinib than in those in the SOC arm. Common all-grade AEs in the trametinib and SOC arms, respectively, were skin rash (92.1% vs 48.5%), fatigue (72.5% vs 57.8%), diarrhea (72.4% vs 33.6%), nausea (60.6% vs 50.8%), and anemia (51.9% vs 43.0%).

The principal toxicities of grade 3 or greater severity for trametinib versus SOC therapy, respectively, were hematologic (13.4% vs 9.4%), gastrointestinal (27.6% vs 29%), skin (15% vs 3.9%), and vascular (18.9% vs 8.6). AEs of special interest included decreased ejection fraction in 7.9% of patients who received trametinib compared with 0.8% with SOC and pneumonitis in 2.4% and 0% of patients, respectively. Among all participants, 35.4% in the trametinib arm discontinued treatment due to an AE or complication compared with 12.3% in the SOC arm.

“The MEK inhibitors can be tricky drugs to manage, and the [adverse] effects with trametinib are different from what you might see with conventional chemotherapy or endocrine therapies,” Gershenson said. “A number of patients in this trial did require dose reductions related to adverse events. It was moderately well tolerated but there are [adverse] effects clinicians need to be aware.”

Gershenson conducted this study of trametinib after an initial phase II study of patients with low-grade serous ovarian cancer treated with selumetinib, also a MEK1/2 inhibitor, demonstrated an ORR of 15% in this patient population. The FDA is reviewing selumetinib as a potential therapy for pediatric patients 3 years or older with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas.⁴

“We knew that a drug that targeted the MAP pathway as MEK inhibitors do certainly had the potential benefit of helping patients,” Gershenson said. “There had also been preclinical work that showed that MEK inhibitors had activity in low-grade serous carcinoma cell lines, as well.”

Although trametinib is not FDA-approved ovarian cancer, the National Comprehensive Cancer Network (NCCN) added trametinib to the guidelines as an option for platinum-sensitive and platinum-resistant recurrent low-grade serous carcinoma after findings from NRG-GOG 0281 were presented at the 2019 European Society for Medical Oncology Annual Congress.^2,5

NRG Oncology in the United States and the National Cancer Research Network in the United Kingdom collaborated on the study.

References

1. Gershenson DM, Miller A, Brady W, et al. A randomized phase II/III study to assess the efficacy of trametinib in patients with recurrent or progressive low-grade serous ovarian or peritoneal cancer. For presentation at: 2020 Society of Gynecologic Oncology Annual Meeting; March 28-31, 2020; Toronto, Canada. Abstract 42. https://sgo.confex.com/sgo/2020/meetingapp.cgi/Paper/17159.
2. NCCN Clinical Practice Guidelines: ovarian cancer, including fallopian tube cancer and primary peritoneal cancer. Version 1.2020. National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/pdf/ovarian.pdf. Updated March 11, 2020. Accessed April 6, 2020.
3. Mekinist [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2019. www.accessdata.fda.gov/drugsatfda_docs/label/2019/204114s012lbl.pdf. Accessed April 6, 2020.
4. US FDA accepts regulatory submission for selumetinib in neurofibromatosis type 1 and grants priority review [press release]. Kenilworth, NJ: AstraZeneca and Merck & Co; November 14, 2019. bit.ly/2V6auAD. Accessed April 1, 2020.
5. Trametinib improves outcomes for women with low-grade serous carcinoma of the ovary/peritoneum on NRG Oncology trial. NRG Oncology website. bit.ly/3aQG5wH. Published September 29, 2019. Accessed April 6, 2020.