| Title: |
Phase I/II Study of Combined BCL-xL and MEK Inhibition with Navitoclax and Trametinib in KRAS or NRAS Mutant Advanced Solid Tumors. |
| Authors: |
Corcoran, Ryan; Do, Khanh; Kim, Jeong; Cleary, James; Parikh, Aparna; Yeku, Oladapo; Xiong, Niya; Weekes, Colin; Veneris, Jennifer; Ahronian, Leanne; Mauri, Gianluca; Tian, Jun; Norden, Bryanna; Michel, Alexa; Van Seventer, Emily; Siravegna, Giulia; Camphausen, Kyle; Chi, Gary; Fetter, Isobel; Brugge, Joan; Chen, Helen; Takebe, Naoko; Penson, Richard; Juric, Dejan; Flaherty, Keith; Sullivan, Ryan; Clark, Jeffrey; Heist, Rebecca; Matulonis, Ursula; Liu, Joyce; Shapiro, Geoffrey |
| Source: |
Clinical Cancer Research, vol 30, iss 9 |
| Publisher Information: |
eScholarship, University of California |
| Publication Year: |
2024 |
| Collection: |
University of California: eScholarship |
| Subject Terms: |
Humans; Neoplasms; Sulfonamides; Aniline Compounds; Pyridones; Pyrimidinones; GTP Phosphohydrolases; Antineoplastic Combined Chemotherapy Protocols; Protein Kinase Inhibitors; Treatment Outcome; Mutation; Adult; Aged; 80 and over; Middle Aged; Female; Male; Proto-Oncogene Proteins p21(ras); bcl-X Protein |
| Description: |
PurposeMEK 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 methodsWe 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.ResultsA 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.ConclusionsNavitoclax in combination with trametinib was tolerable. Durable clinical responses were observed in patients with RAS-mutant GYN cancers, warranting further evaluation in this population. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
qt60b4j31r; https://escholarship.org/uc/item/60b4j31r; https://escholarship.org/content/qt60b4j31r/qt60b4j31r.pdf |
| DOI: |
10.1158/1078-0432.ccr-23-3135 |
| Availability: |
https://escholarship.org/uc/item/60b4j31r; https://escholarship.org/content/qt60b4j31r/qt60b4j31r.pdf; https://doi.org/10.1158/1078-0432.ccr-23-3135 |
| Rights: |
CC-BY-NC-ND |
| Accession Number: |
edsbas.D24A7250 |
| Database: |
BASE |