Phase I/II Study of Combined BCL-xL and MEK Inhibition with Navitoclax and Trametinib in KRAS or NRAS Mutant Advanced
Ryan B Corcoran1, Khanh T Do2, Jeong E Kim1,3
1Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
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.
Insights
The combination of navitoclax and trametinib showed tolerability in patients with RAS-mutant cancers. Durable responses were observed in gynecologic cancers, suggesting further investigation in this group.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- MEK inhibitors (MEKi) demonstrate limited efficacy as monotherapy for RAS-mutant cancers.
- BCL-2-like protein 1 (BCL-xL) is identified as a critical suppressor of apoptosis in response to MEKi treatment.
- Targeting BCL-xL offers a potential strategy to enhance MEKi efficacy.
Purpose of the Study:
- To evaluate the safety and efficacy of combining a BCL-xL inhibitor (navitoclax) with a MEK inhibitor (trametinib) in patients with RAS-mutant tumors.
- To determine the recommended phase II dose (RP2D) for this combination therapy.
- To explore the efficacy across different cancer types, including pancreatic, gynecologic (GYN), and non-small cell lung cancer (NSCLC).
Main Methods:
- A dose escalation study (NCT02079740) was conducted with navitoclax and trametinib.
- Expansion cohorts included patients with pancreatic, GYN, and NSCLC harboring KRAS/NRAS mutations.
- Paired tumor biopsies and serial cell-free DNA (cfDNA) were analyzed to assess molecular changes and treatment response.
Main Results:
- The recommended phase II dose (RP2D) was established as trametinib 2 mg daily and navitoclax 250 mg daily.
- Partial responses (PR) were observed in 16% of evaluable patients at RP2D.
- Significant efficacy was noted in GYN cancers, with 33% achieving PR and a median response duration of 8.2 months. No PRs were seen in colorectal, NSCLC, or pancreatic cancers.
- MAPK pathway inhibition and reductions in cfDNA KRAS/NRAS mutation levels correlated with clinical benefit.
Conclusions:
- The combination of navitoclax and trametinib is tolerable in patients with RAS-mutant cancers.
- Durable clinical responses were observed in patients with RAS-mutant GYN cancers.
- Further evaluation of this combination in GYN cancers is warranted.
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