Trametinib Represents a New Standard-of-Care Option in Recurrent Low-Grade Serous Ovarian Carcinoma

David Gershenson, MD

The MEK inhibitor trametinib (Mekinist) reduced the risk of disease progression or death by 52% compared with current standard-of-care (SOC) therapies in patients with relapsed or persistent low-grade serous ovarian carcinoma, making it the potential new SOC for this patient population, according to data from a phase 2/3 trial (NCT02101788) published in The Lancet.^1,2

At a median follow-up of 31.5 months (interquartile range [IQR], 18.1-43.3) for the trametinib arm and 31.3 months (IQR, 15.7-41.9) for the SOC arm, the median investigator-assessed progression-free survival (PFS) with trametinib was 13.0 months (95% CI, 9.9-15.0), vs 7.2 months (95% CI, 5.6-9.9) in the SOC group (hazard ratio [HR], 0.48; 95% CI, 0.36-0.64; one-sided P < .0001) among 260 patients.

“We believe this study represents a major advancement in the treatment of women with low-grade serous carcinoma, particularly since the treatment options are limited,” lead study investigator David Gershenson, MD, of The University of Texas MD Anderson Cancer Center, said in an interview with OncLive®. “We hope we can build on this. This trial has also allowed us to learn more about the mutations associated with low-grade serous carcinoma, and a little bit more about the biology of the MAPK pathway.”

Low-grade serous carcinoma is a relatively rare form of cancer, accounting for 5% of all cases of epithelial ovarian cancers.3 The disease is characterized by a younger age at the time of diagnosis and longer survival than those with high-grade serous disease. Notably, most patients with low-grade disease are diagnosed in the advanced stages, and more than 70% will relapse.

Notably, low-grade serous ovarian carcinomas have a distinct developmental pathway than that of high-grade serous disease. Low-grade serous ovarian carcinomas are known to have a high frequency of activating mutations in the MAPK pathway. In the largest unselected cohort of patients with low-grade serous carcinomas sequenced to date, 27% of patients were found to have KRAS mutations, 13% had BRAF mutations, and 9% had NRAS mutations.4

The current frontline treatment for patients with low-grade serous ovarian carcinoma consists of chemotherapy followed by aromatase inhibitor therapy, although this subtype is relatively resistant to platinum-based chemotherapy, further underscoring the need for more effective targeted approaches.

The current open-label, multicenter phase 2/3 trial included patients who were at least 18 years of age who had recurrent low-grade serous carcinoma of the ovary or peritoneum, and measurable disease, as defined by RECIST v1.1 criteria. To be eligible for enrollment, patients had to have received at least 1 prior platinum-based chemotherapy regimen, although they could not have received all 5 current SOC drugs: paclitaxel, pegylated liposomal doxorubicin, topotecan, letrozole, and tamoxifen.

Notably, patients were permitted to have received an unlimited number of prior regimens, including chemotherapy or hormonal therapy. Those with serous borderline tumors or tumors containing low-grade serous and high-grade serous carcinoma were excluded.

A total of 260 patients were randomized 1:1 to receive trametinib (n = 130) or 1 of the 5 SOC options (n = 130). Patients in the investigative arm received oral trametinib at a once-daily dose of 2 mg. Those in the SOC arm received 1 of the following: intravenous (IV) paclitaxel at 80 mg/m2 by body surface area on days 1, 8, and 15 of every 28-day cycle; intravenous pegylated liposomal doxorubicin at a dose ranging from 40 mg/m2 to 50 mg/m2 by body surface area on day 1 every 4 weeks; IV topotecan at 4 mg/m2 by body surface area on days 1, 8, and 15 of every 28-day cycle; oral letrozole at a once-daily dose of 2.5 mg; or oral tamoxifen at a twice-daily dose of 20 mg.

The primary end point of the trial was investigator-assessed PFS, and key secondary end points included toxicity, objective response rate (ORR), quality of life; the predictive and prognostic effect of MAPK pathway activation on response or PFS, the prognostic effect of phosphorylated ERK expression, and overall survival (OS). Exploratory end points included PFS and ORR following crossover.

The median ages of patients in the trametinib and SOC arms were 56.6 years (range, 44.6-63.3) and 55.3 years (range, 42.4-65.6), respectively. Most patients across the investigative and control arms had disease located in the ovary (92% and 90%, respectively), had stage III disease (74% and 72%), and had an ECOG performance status of 0 (72% in both). Moreover, most patients across the arms had received 3 or more prior lines of therapy (48% and 49%), had received 1 line of prior chemotherapy (48% and 42%), and received 1 prior line of hormonal therapy (58% and 52%). At the time of data cutoff, 60% and 53% of the patients in the trametinib and SOC arms, respectively, were alive.

Additional data from the trial showed that trametinib induced an ORR of 26%, which compared favorably with the ORR achieved in the SOC arm overall, which was 6% (odds ratio, 5.4; 95% CI, 2.4-12.2; P <.0001). In the investigative and control arms, 59% and 71% of patients, respectively, had stable disease for a minimum of 8 weeks. The ORRs achieved with the individual SOC therapies were 9% with paclitaxel, 3% with pegylated liposomal doxorubicin, 0% with topotecan, 14% with letrozole, and 0% with tamoxifen.

The median duration of response observed in the trametinib arm was 13.6 months (95% CI, 8.1-18.8), vs 5.9 months (95% CI, 2.8-12.2) in the SOC arm.

At the time of the data cutoff, a total of 260 patients comprised the analysis for OS; 43% of these patients had died (n = 51/130, trametinib arm; n = 60/130, SOC arm). The median OS in the investigative arm was 37.6 months (95% CI, 32.0–not evaluable) compared with 29.2 months (95% CI, 23.5-51.6) in the control arm. The HR for death was 0.76 (95% CI, 0.51-1.12; P = .056). The analysis included the effect of 68% of those in the SOC arm who crossed over to trametinib following disease progression.

Patients who crossed over from the SOC arm to the trametinib arm following disease progression (n = 88) experienced a median PFS of 10.8 months (95% CI, 7.3-12.0), and an ORR of 15% (95% CI, 7%-22%). Of the patients who progressed or died after crossing over to trametinib (n = 66), 65% had a longer time to disease progression than they had on preceding SOC therapy.

Notably, mutation status in the SOC group was not found to be a significant prognostic factor for PFS (HR, 0.58; 95% CI, 0.30-1.10; P = .19) or ORR (odds ratio, 1.67; 95% CI, 0.30-9.28).

The most frequent treatment-emergent adverse effects (TEAEs) of any grade reported in the trametinib arm included fatigue (73%), diarrhea (73%), acneiform rash (63%), nausea (61%), and anemia (52%). In the SOC arm, the most common TEAEs were fatigue (58%), nausea (51%), and anemia (43%).

The most frequent grade 3 or 4 TEAEs related to trametinib were skin rash (13%), anemia (13%), hypertension (12%), diarrhea (10%), nausea (9%) and fatigue (8%). In the SOC group, the most frequent grade 3 or 4 AEs were abdominal pain (17%), nausea (11%), anemia (10%) and vomiting (8%). Notably, no treatment-related deaths occurred in either arm.

Overall, grade 3 or higher gastrointestinal disorders occurred in 29% of patients in the trametinib arm and 28% of those in the SOC arm. Small intestine obstruction was observed in 13% of those in the investigative arm vs 7% of those in the control arm; colon obstruction occurred in 1% and 5% of patients, respectively.

The median number of cycles of trametinib received was 8 (IQR, 3-16). Dose reductions occurred in 11% of all trametinib cycles, and 70% of patients required at least 1 dose reduction of trametinib. Additionally, 38% required 2 dose reductions, and within that subset of patients, 14 withdrew from the trial due to disease progression, 17 withdrew due to AEs, and 2 withdrew for other reasons. Overall, 36% of patients discontinued trametinib due to toxicity vs 30% of those in the SOC arm. Four percent of patients remained on treatment at the time of data cutoff.

Gershenson and colleagues noted that the findings from this trial raised the question of how to sequence chemotherapy, hormonal therapy, and trametinib in patients with low-grade serous carcinoma. They suggested trametinib would be the most favorable option at first relapse for in patients administered chemotherapy followed by aromatase inhibitor in the frontline setting.

The use of a MEK inhibitor such as trametinib in patients who have not received a previous aromatase inhibitor should lead to a discussion between physician and patient based on the agent’s efficacy and safety profile, according to the study investigators. Preclinical data suggest that MEK inhibition could promote hormone sensitivity in ovarian cancer cells.

“We will hopefully conduct future trials with the drug, possibly in combination with other drugs,” Gershenson concluded. “There is preclinical evidence that MEK inhibitors and endocrine drugs, like aromatase inhibitors, may be synergistic, so it would make sense to consider a clinical trial with the combination, for instance, of letrozole and trametinib.”

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. 2022;399(10324):541-553. doi:10.1016/S0140-6736(21)02175-9
2. Trametinib represents potential new standard-of-care for patients with recurrent low-grade serous ovarian carcinoma. News release. The University of Texas MD Anderson Cancer Center; February 3, 2022. Accessed February 10, 2022. https://bit.ly/3oDN1q0
3. Cheasley D, Nigam A, Zethoven M, et al. Genomic analysis of low-grade serous ovarian carcinoma to identify key drivers and therapeutic vulnerabilities. J Pathol. 2021;253(1):41-54. doi:10.1002/path.5545