Activity of combination trametinib/navitoclax in patients with RAS-mutated gynecologic (GYN) cancers in a Phase 1/2 study (LBA 12)

Abstract

<b>Objectives:</b> Preclinical data suggest that concurrent MEK and BCLxL inhibition can be synergistic. Mechanistically, inhibition of RAS signaling upregulates BIM, "priming" cells for apoptosis with BCLxL inhibition. A Phase 1 trial of the MEK inhibitor trametinib with the BCLxL inhibitor navitoclax was conducted to establish the recommended phase 2 dose (RP2D) and activity in select <i>RAS</i>-mutated tumors. We report the activity of this combination in patients (pts) with <i>RAS</i>-mutated GYN cancers. <b>Methods:</b> Pts with <i>RAS</i>-mutated GYN cancers were enrolled at the Dana-Farber Cancer Institute and Massachusetts General Hospital. Pts had RECIST 1.1 measurable disease and had progressed after at least one prior line of systemic chemotherapy. Eligible pts had cancers with activating mutations affecting codons 12, 13, 61, or 146 in <i>KRAS</i> or <i>NRAS</i>. Pts received combination trametinib and navitoclax either in dose escalation (7 pts) or in a dose expansion (24 pts) at the RP2D of navitoclax 250mg days 1-28 and trametinib 2mg days 1-14, following a lead-in cycle of navitoclax 150mg days 1-7 and 250mg days 8-28 with trametinib 2mg days 1-14 in 28-day cycles. <b>Results:</b> Between 1-22-2015 and 9-21-2021, 31 pts with GYN cancers (15 ovarian, 10 endometrial, 5 cervical, 1 mullerian) were enrolled. Data cutoff was 11-1-2021. Median follow-up is 4.9 mos. The median number of prior lines was 3 (range 1-7). Overall, 6 pts (19.4%; CI 7.5-37.5%) had a confirmed response. These included 3 ovarian cancers (1 low grade serous, 1 mucinous, 1 endometrioid), 1 endometrial (adenocarcinoma NOS), 1 cervical (mixed adenocarcinoma and neuroendocrine tumor), and 1 mullerian cancer (endometrioid). 9 pts stopped treatment before their disease was re-evaluated, and 1 pt's post baseline scan was deemed nonevaluable. Among 21 pts with at least one evaluable restaging scan, the response rate was 28.6% (95% CI 11.3-52.2%). Figure 1 shows the waterfall plot of best responses in these 21 pts. Median PFS time was 3.9 mos (95% CI 3.7-13.4) and 6-mo PFS was 37.7% (95% CI 17.5-57.9). In the 6 pts with response, the median duration for response was 9.5 mos (range 3.9-27.6). The most frequently observed adverse events included LFT changes, thrombocytopenia, diarrhea, nausea, and rash. <b>Conclusions:</b> Combined MEK and BCLxL inhibition with trametinib and navitoclax had clinical activity in pts with <i>RAS</i>-mutated GYN cancers, with a response rate in all pts of 19.4%. Among pts with at least one evaluable reassessment, the response rate was 28.6%. Further studies of combined MEK and BCLxL inhibition in pts with RAS-activated GYN cancers are warranted.Fig. 1