Phase I/II Study of Combined BCL-xL and MEK Inhibition with Navitoclax and Trametinib in KRAS or NRAS Mutant Advanced Solid Tumors

Abstract

Purpose: MEK inhibitors (MEKi) lack monotherapy efficacy in most RAS-mutant cancers. BCL-xL is an anti-apoptotic protein identified by a synthetic lethal shRNA screen as a key suppressor of apoptotic response to MEKi.

Patients and methods: We conducted a dose escalation study (NCT02079740) of the BCL-xL inhibitor navitoclax and MEKi trametinib in patients with RAS-mutant tumors with expansion cohorts for: pancreatic, gynecologic (GYN), non-small cell lung cancer (NSCLC), and other cancers harboring KRAS/NRAS mutations. Paired pretreatment and day 15 tumor biopsies and serial cell-free (cf)DNA were analyzed.

Results: A total of 91 patients initiated treatment, with 38 in dose escalation. Fifty-eight percent had ≥3 prior therapies. A total of 15 patients (17%) had colorectal cancer, 19 (11%) pancreatic, 15 (17%) NSCLC, and 32 (35%) GYN cancers. The recommended phase II dose (RP2D) was established as trametinib 2 mg daily days 1 to 14 and navitoclax 250 mg daily days 1 to 28 of each cycle. Most common adverse events included diarrhea, thrombocytopenia, increased AST/ALT, and acneiform rash. At RP2D, 8 of 49 (16%) evaluable patients achieved partial response (PR). Disease-specific differences in efficacy were noted. In patients with GYN at the RP2D, 7 of 21 (33%) achieved a PR and median duration of response 8.2 months. No PRs occurred in patients with colorectal cancer, NSCLC, or pancreatic cancer. MAPK pathway inhibition was observed in on-treatment tumor biopsies. Reductions in KRAS/NRAS mutation levels in cfDNA correlated with clinical benefit.

Conclusions: Navitoclax in combination with trametinib was tolerable. Durable clinical responses were observed in patients with RAS-mutant GYN cancers, warranting further evaluation in this population.

Figure 1.

Study design. A, Study schema for part 1 dose escalation and CONSORT diagram. Specific dose levels, dosing schedule, and patients enrolled are shown. B, Study schema for part 2 dose expansion cohorts and CONSORT diagram. Specific tumor types and patients enrolled are shown.

Figure 2.

Clinical efficacy. A, Best tumor response by RECIST in all patients at all dose levels, shown by tumor type. B, Best tumor response by RECIST in patients treated at the RP2D, shown by tumor type. C–F, Best tumor response by RECIST in patients treated at all dose levels with (C) colorectal cancer, (D) pancreatic ductal adenocarcinoma (PDAC), (E) NSCLC, and (F) GYN cancers. Patients treated at the RP2D are indicated with a red diamond.

Figure 3.

Time on treatment and PFS and OS. A, Swim plot of patients showing time on treatment by tumor type. Time of first response is indicated by a black triangle and patients still ongoing on treatment at the time of the data cut are indicated with an arrow. B and C, Kaplan–Meyer curves for (B) PFS and (C) OS are shown for patients with GYN versus non-GYN tumor types with associated P values.

Figure 4.

Serial ctDNA analysis and MAPK pathway inhibition in paired tumor biopsies. A, Percent change in KRAS or NRAS mutant allele-fraction in ctDNA after 4 weeks of treatment, relative to pre-treatment levels, in patients achieving clinical benefit (defined as PR or SD) versus PD on first restaging scan. B, PFS and OS for patients who achieved a 30% or greater decrease in ctDNA levels by 4 weeks, relative to pretreatment levels, compared with patients who did not. C and D, Examples of patients with (C) ovarian cancer and (D) cervical cancer who achieved durable partial responses. Serial monitoring of tumor-specific NRAS or KRAS mutation allele fraction in ctDNA throughout treatment is shown, along with CT scans from baseline, response nadir, and progression with lesions indicated. E, The degree of MAPK pathway suppression was assessed by measurement of MAPK-regulated transcript levels in each patient's day 15 tumor biopsy relative to the paired pretreatment biopsy. Patients from this study were compared with similar paired pre- and on-treatment tumor biopsies obtained from BRAF^V600 mutant melanoma treated with BRAF inhibitor therapy with or without MEK inhibitor. F, The degree of MAPK pathway suppression achieved by day 15 of treatment was compared between patients achieving PR or SD versus PD on first restating scan, with individual tumor types indicated.