MEK/PI3K Inhibitor Combo Generates Activity in RAS/BRAF-Mutant Ovarian Cancer

Aditya Bardia, MD, MPH

Aditya Bardia, MD, MPH

Continuous dosing of the MEK inhibitor binimetinib (Mektovi) plus buparlisib (BKM120), a PI3K inhibitor, demonstrated promising activity as treatment of patients with ovarian cancer harboring either aRASor BRAFmutation, according to results from a phase Ib clinical trial (NCT01363232).

“The toxicity profile of the combination regimen evaluated in this study resulted in a lower dose intensity than anticipated,” study investigators, led by Aditya Bardia, MD, MPH, wrote in their paper. “However, an encouraging signal was observed in patients with ovarian cancer.” According to the study authors, the population of patients withRAS/BRAF-mutant ovarian cancer does not have effective standard therapies.

Patients with advanced solid tumors—including lung (n = 27) and ovarian (n = 19)—who either progressed after standard therapy or had no standard therapy were given the combination regimen to determine safety and efficacy. The combination was evaluated in patients harboring aKRAS, NRAS,orBRAF mutation to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D).

In the dose-escalation phase, the MTD was determined as 90 mg buparlisib once daily/45 mg binimetinib twice daily on a continuous schedule. However, fewer dose-limiting toxicities (DLTs) were observed with the RP2D of 80 mg buparlisib/45 mg binimetinib compared with the MTD, which led to the lower doses in the RP2D. One patient out of seven who received the RP2D reported grade 3 maculopapular rash, compared with 2 out of 6 patients who received the MTD and reported DLTs of grade 3 diarrhea, grade 3 anaphylactic reaction, and grade 3 swelling face.

In the dose-expansion arm, 6 total patients (12.0%) achieved a partial response (PR) and remained on treatment from day 57 to 169. In the RP2D arm, PRs were most commonly noted in patients withRAS/BRAF-mutant ovarian cancer (27.8%). One patient withEGFR-mutant lung cancer (7.7%) also achieved a PR. The highest disease control rate (DCR) in the RP2D population was reported in the group of patients withRAS/BRAF-mutant ovarian cancer, in which the DCR was 61.1% (95% CI, 35.7%-82.7%). This population of patients with ovarian cancer also achieved the longest median progression-free survival (PFS) at 3.7 months (95% CI, 1.8-not estimable).

During the first cycle of treatment, 13 patients (20.3%) had at least 1 DLT, the most frequent of which included diarrhea (6.3%), central serous retinopathy (CSR; 3.1%), and stomatitis (3.1%). Investigators noted that all cases of CSR were grade 1 in severity, reversible, and manageable. During the dose-escalation phase, no patients experienced DLTs in the 50 mg buparlisib/45 mg binimetinib or 60 mg buparlisib/45 mg binimetinib arms.

Overall, 53 patients (59.6%) reported a grade 3/4 adverse event (AE) that required a dose interruption or change, and 54 patients (60.7%) had a grade 3/4 AE that required additional therapy for diarrhea, pneumonia, nausea, and vomiting. The most common grade 3/4 AEs among all patients included blood CPK increase (27.0%), alanine aminotransferase increase (14.6%), aspartate aminotransferase increase (13.5%), maculopapular rash (12.4%), diarrhea (7.9%), lipase increase (7.9%), and stomatitis (6.7%). One patient died while on treatment due to disease progression, and 10 additional patients died within 30 days of their last dose due to disease progression.

AEs of any grade were reported in 44 patients (89.8%) and grade 3/4 AEs in 33 patients (67.3%) who received the RP2D. The most common grade 3/4 AEs observed in the RP2D arm included blood CPK increase (30.6%), ALT increase (20.4%), AST increase (16.3%), lipase increase (12.2%), and diarrhea (10.2%).

In the multicenter, open-label study, patients received the combination of binimetinib plus buparlisib to determine the MTD and/or a recommended dose for the phase II trial. Additionally, investigators aimed to assess the safety and efficacy of this combination in patients with advanced solid tumors harboringRAS/BRAFmutations. Overall, 89 patients enrolled in the study and received at least 1 dose of the combination therapy; 1 patient withdrew consent before the first dose was given. Forty-eight patients were included in the dose-escalation phase, and 41 patients were included in the dose-expansion phase.

Baseline characteristics were similar across all cohorts of the study. Sixty-two percent of all patients were female, and the median age was 57 years (range, 30-78). The primary cancer sites included lung (30%), ovarian (21%), colon (15%), rectum (10%), triple-negative breast (7%), pancreas (7%), and melanoma (2%), among other sites (8%). The median number of prior antineoplastic regimens was 3 (range, 1-12).

Patients had to have an ECOG performance status of 0 to 2 and evaluable disease determined by RECIST version 1.1 to be included in the trial. Patients who had diabetes mellitus, impaired cardiovascular function, clinically significant cardiovascular diseases, a history of depression, or ocular disease were excluded from the study.

“Based on these data, further exploration of this combination may be warranted to define a better‐tolerated dose and/or schedule, such as alternative scheduling with noncontinuous/pulsatile dosing of either agent, which could be explored further inRAS/BRAF‐mutant tumors,” Bardia and colleagues concluded.

Reference:

Bardia A, Gounder M, Rodon J, et al. Phase Ib study of combination therapy with MEK inhibitor binimetinib and phosphatidylinositol 3-kinase inhibitor buparlisib in patients with advanced solid tumors with RAS/RAF alterations [Published Online August 8, 2019].Oncologist. 25(1):e160-e169. doi: 10.1634/theoncologist.2019-0297.