Σάββατο, 16 Μαΐου 2020

MEK INHIBITORS FOR LOW GRADE OVARIAN CANCER?-A CLOSE CALL

Two MEK inhibitors were tested against recurrent low-grade serous carcinomas of the ovaries, fallopian tubes, or peritoneum, but only one inhibitor offered clinical benefit over standard care, investigators from two randomized trials reported.

Trametinib improved progression-free survival (PFS) when compared with standard care, while binimetinib conferred no PFS benefit.

In a phase 2/3 trial, the median PFS was 13 months for patients treated with trametinib and 7.2 months for patients who received an aromatase inhibitor or chemotherapy (P < .0001).

"Our findings suggest that trametinib represents a new standard-of-care treatment option for women with recurrent low-grade serous carcinoma," said investigator David M. Gershenson, MD, of the University of Texas MD Anderson Cancer Center in Houston.

In contrast, in the phase 3 MILO/ENGOT-ov11 trial, there was no significant difference in PFS between patients treated with binimetinib and those who received physician's choice of chemotherapy. The median PFS was 11.2 months with binimetinib and 14.1 months with chemotherapy (P = .752).

"Although this study did not meet its primary endpoint, binimetinib showed activity in low-grade serous ovarian cancer across the efficacy endpoints evaluated, with a response rate of 24% and a median PFS of 11.2 months on updated analysis. Chemotherapy responses were better than predicted, based on historical retrospective data," said investigator Rachel N. Grisham, MD, of Memorial Sloan Kettering Cancer Center in New York.

The binimetinib trial and the trametinib trial were both discussed during a webinar on rare tumors covering research slated for presentation at the Society of Gynecologic Oncology's Annual Meeting on Women's Cancer. The meeting was canceled because of the COVID-19 pandemic.

Chemoresistant Cancers

Low-grade serous ovarian or peritoneal cancers are rare, accounting for only 5% to 10% of all serous cancers, Dr. Gershenson noted.

"[Low-grade serous cancers are] characterized by alterations in the MAP kinase pathway, as well as relative chemoresistance, and prolonged overall survival compared to high-grade serous cancers. Because of this subtype's relative chemoresistance, the search for novel therapeutics has predominated over the last decade or so," he said.

MEK inhibitors interfere with the MEK1 and MEK2 enzymes in the MAPK pathway. Alterations in MAPK, especially in KRAS and BRAF proteins, are found in 30%-60% of low-grade serous carcinomas, providing the rationale for MEK inhibitors in these rare malignancies.

Trametinib Study

In a phase 2/3 study, Dr. Gershenson and colleagues enrolled 260 patients with recurrent, low-grade serous carcinoma of the ovary or peritoneum. Patients were randomized to receive either trametinib at 2 mg daily continuously until progression (n = 130) or standard care (n = 130).

Standard care consisted of one of the following: letrozole at 2.5 mg daily; pegylated liposomal doxorubicin at 40-50 mg IV every 28 days; weekly paclitaxel at 80 mg/m2 for 3 out of 4 weeks; tamoxifen at 20 mg twice daily; or topotecan at 4 mg/m2 on days 1, 8, and 15 every 28 days. Patients randomized to standard care could be crossed over to trametinib at progression.

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All patients had at least one prior line of platinum-based chemotherapy, and nearly half had three or more prior lines of therapy. The median age was 56.6 years in the trametinib arm and 55.3 years in the control arm.

At a median follow-up of 31.4 months, median PFS, the primary endpoint, was 13 months with trametinib vs. 7.2 months with standard care. The hazard ratio (HR) for progression on trametinib was 0.48 (P < .0001).

The overall response rates were 26.2% in the trametinib arm and 6.2% in the standard care arm. The odds ratio for response on trametinib was 5.4 (P < .0001).

For 88 patients who crossed over to trametinib, the median PFS was 10.8 months, and the overall response rate was 15%.

Trametinib was also associated with a significantly longer response duration, at a median of 13.6 months, compared with 5.9 months for standard care (P value not shown).

The median overall survival was 37 months with trametinib and 29.2 months with standard care, with an HR favoring trametinib of 0.75, although this just missed statistical significance (P = .054). Dr. Gershenson pointed out that the overall survival in the standard care arm included patients who had been crossed over to trametinib.

Grade 3 or greater adverse events included hematologic toxicities in 13.4% of patients on trametinib and 9.4% on standard care; gastrointestinal toxicity in 27.6% and 29%, respectively; skin toxicities in 15% and 3.9%, respectively; and vascular toxicities in 18.9% and 8.6%, respectively.

Binimetinib Study 

The phase 3 MILO/ENGOT-ov11 study enrolled 341 patients with low-grade serous carcinomas of the ovaries, fallopian tubes, or peritoneum. Patients were randomized on a 2:1 basis to receive either binimetinib at 45 mg twice daily (n = 228) or physician's choice of chemotherapy (n = 113). Chemotherapy consisted of pegylated liposomal doxorubicin at 40 mg/m2 on day 1 of each 28-day cycle; paclitaxel at 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle; or topotecan at 1.25 mg/m2 IV on days 1-5 of each 21-day cycle.

The efficacy analysis included 227 patients assigned to binimetinib and 106 assigned to chemotherapy.

A planned interim analysis was performed in 2016 after the first 303 patients were enrolled. At that time, the median PFS by blinded central review was 9.1 months in the binimetinib arm and 10.6 months in the physician's choice arm (HR, 1.21; P = .807), so the trial was halted early for futility. Patients on active treatment at the time could continue until progression and were followed by local radiology.

At the interim analysis, secondary endpoints were also similar between the arms. The overall response rate was 16% in the binimetinib arm and 13% in the chemotherapy arm.

The most common grade 3 or greater adverse events with binimetinib were blood creatinine phosphokinase increase (26%) and vomiting (10%).

Dr. Grisham also reported updated follow-up results through January 2019.

The median PFS in the updated analysis was 11.2 months with the MEK inhibitor and 14.1 months with chemotherapy, a difference that was not statistically significant (HR, 1.12; P = .752). Updated overall response rates were the same in both arms, at 24%.

A post hoc molecular analysis of 215 patients suggested a possible association between KRAS mutation and response to binimetinib.

Two MEKs, One 'Meh' 

Discussant Jubilee Brown, MD, of the Levine Cancer Institute at Atrium Health in Charlotte, N.C., said that "with a 2% to 5% chance of response in patients with low-grade serous ovarian cancer, there is a low bar for any compound to demonstrate success."

Regarding the MILO/ENGOT-ov11 trial, she noted that "this study did not meet its primary endpoint, but perhaps the endpoint is not reflective of the importance of the study."

A different outcome might have occurred had investigators stratified patients by KRAS status upfront, comparing patients with KRAS mutations treated with binimetinib to KRAS wild-type patients treated with either a MEK inhibitor or physician's choice of care, Dr. Brown said.

She agreed with the assertion by Dr. Gershenson and colleagues that improved PFS qualifies trametinib to be considered a new option for standard care, "especially in a rare tumor setting with limited options. This is a huge win for patients."

The trametinib study was sponsored by NRG Oncology and the UK National Cancer Research Institute. Dr. Gershenson disclosed relationships with NRG Oncology, Genentech, Novartis, Elsevier, and UpToDate, as well as stock in several companies.

The binimetinib study was sponsored by Pfizer. Dr. Grisham disclosed relationships with Clovis, Regeneron, Mateon, Amgen, AbbVie, OncLive, PRIME, MCM, and Medscape. MDedge News and Medscape are owned by the same parent organization.

Dr. Brown disclosed consulting for Biodesix, Caris, Clovis, Genentech, Invitae, Janssen, Olympus, OncLive, and Tempus.

SOURCE: Gershenson DM et al. SGO 2020, Abstract 42; Grisham RN et al. SGO 2020, Abstract 41.

This article originally appeared on MDedge.com.

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