Trametinib Shows Promising Benefit for Low-Grade Serous Ovarian Cancer

Results of a phase II/III clinical trial in women with low-grade serous ovarian cancer demonstrated greater survival outcomes for those treated with MEK inhibitor therapyversus standard-of-care (SOC) options in the recurrent setting.

David M. Gershenson, MD, discussed the findings for trametinib (Mekinist) monotherapy in aninterview with Targeted Therapies in Oncology. “This was not only 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,” he said. “It establishes trametinib as a new standard-of-care treatment option for women who have low-grade serous carcinoma.”

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 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

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 settings,² lowgrade serous carcinoma is also characterized by alterations in the MAP kinase cell-signaling network, which includes MEK proteins.¹ Trametinib targets MEK1/2 kinases and is given in combination with the BRAF inhibitor dabrafenib (Tafinlar) in patients with melanoma, non–small cell lung cancer, and anaplastic thyroid cancer metastases with BRAF V600 mutations.³

In NRG-GOG 0281, patients were randomized to receive 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 each 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% underwent 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

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 severity or higher 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.

Gershenson, who is a professor of gynecologic oncology at The University of Texas MD Anderson Cancer Center in Houston, conducted this study of trametinib after an initial phase II study of patients with low-grade serous ovarian cancer treated with selumetinib, also an MEK1/2 inhibitor, demonstrated an ORR of 15% in this patient population.⁴ The FDA approved selumetinib as a therapy for pediatric patients 3 years or older with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas.⁵

Although trametinib is not FDA approved for ovarian cancer, the National Comprehensive Cancer Network added trametinib to the guidelines as an option for patients with platinum-sensitive and platinum-resistant recurrent low-grade serous carcinoma after findings from NRG-GOG 0281 were presented at the European Society for Medical Oncology 2019 Congress (TABLE).^2,6

NRG Oncology and the National Cancer Research Network 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. Presented at: 2020 Society of Gynecologic Oncology Annual Meeting; March 28-31, 2020; Toronto, Canada. Abstract 42. bit.ly/2XFKxdP}

_{2. NCCN Clinical Practice Guidelines: ovarian cancer, including fallopian tube cancer and primary peritoneal cancer. Version 1.2020. National Comprehensive Cancer Network website. Updated March 11, 2020. Accessed April 6, 2020. bit.ly/2VcFsIh}

_{3. Mekinist. Package insert. Novartis Pharmaceuticals Corporation; 2019. Accessed April 6, 2020. bit.ly/2Vx2Yil}

_{4. Farley J, Brady WE, Vathipadiekal V, et al. Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. Lancet Oncol. 2013;14(2):134-140. doi:10.1016/S1470-2045(12)70572-7}

_{5. FDA approves selumetinib for neurofibromatosis type 1 with symptomatic, inoperable plexiform neurofibromas [news release]. Silver Spring, MD: CDER Office of Communications. April 10, 2020.https://bit.ly/2yp2iEj. Accesssed May 6, 2020.}

_{6. Trametinib improves outcomes for women with low-grade serous carcinoma of the ovary/peritoneum on NRG Oncology trial. NRG Oncology website. Published September 29, 2019. Accessed April 6, 2020. bit.ly/3aQG5wH}