Phase Ib/II study of the efficacy and safety of binimetinib (MEK162) plus panitumumab for mutant or wild-type RAS metastatic colorectal cancer Journal Article
| Authors: | Van Cutsem, E.; Yaeger, R.; Delord, J. P.; Tabernero, J.; Siu, L. L.; Ducreux, M.; Siena, S.; Elez, E.; Kasper, S.; Zander, T.; Steeghs, N.; Murphy, D.; Edwards, M.; Wainberg, Z. A. |
| Article Title: | Phase Ib/II study of the efficacy and safety of binimetinib (MEK162) plus panitumumab for mutant or wild-type RAS metastatic colorectal cancer |
| Abstract: | Introduction: Activating RAS gene mutations occur in approximately 55% of patients with metastatic colorectal cancer (mCRC) and are associated with poorer clinical outcomes due to epidermal growth factor receptor (EGFR) blockade resistance. Combined EGFR and mitogen-activated protein kinase (MEK) inhibition may extend response to EGFR inhibition and overcome acquired resistance. This phase Ib/II dose escalation trial evaluated the safety and activity of dual inhibition with binimetinib (MEK1/2 inhibitor) and panitumumab (EGFR inhibitor [EGFRi]) in patients with RAS mutant or BRAF wild type (WT)/RAS WT mCRC. Methods: Phase Ib dose escalation started with binimetinib 45 mg twice daily plus panitumumab 6 mg/kg administered every 2 weeks. In the phase II study, patients with measurable mCRC were enrolled into 4 groups based on previous anti-EGFR monoclonal antibody therapy and RAS mutational status. Results: No patients in the phase Ib portion (n=10) had a response; 70% of patients had stable disease. In the phase II portion (n=43), overall response rate (ORR, confirmed) was 2.3% with one partial response in the RAS WT group, DCR was 30.2%, and median progression-free survival was 1.8 months (95%CI, 1.6-3.3). All patients experienced ≥1 adverse event, with the most common being diarrhea (71.7%), vomiting (52.8%), nausea (50.9%), fatigue (49.1%), dermatitis acneiform (43.4%), and rash (41.5%). Most patients required treatment interruption or dose reduction due to difficulties tolerating treatment. Conclusions: The combination of binimetinib and panitumumab had substantial toxicity and limited clinical activity for patients with mutant or WT RAS mCRC, independent of EGFRi treatment history. © 2023 The Author(s). |
| Keywords: | mitogen activated protein kinase; adult; human tissue; middle aged; gene mutation; major clinical study; somatic mutation; genetics; clinical trial; constipation; fatigue; diarrhea; drug dose reduction; drug efficacy; drug safety; drug withdrawal; skin toxicity; nuclear magnetic resonance imaging; antineoplastic agent; colorectal cancer; metastasis; progression free survival; computer assisted tomography; multiple cycle treatment; phase 2 clinical trial; bayes theorem; nausea; stomatitis; vomiting; antineoplastic combined chemotherapy protocols; incidence; epidermal growth factor receptor; colonic neoplasms; creatinine blood level; pathology; histology; irinotecan; monoclonal antibody; panitumumab; abdominal pain; asthenia; drug dose escalation; fever; hypomagnesemia; pneumonia; rash; colorectal neoplasms; maculopapular rash; multicenter study; colorectal tumor; colon tumor; prophylaxis; acne; phase 1 clinical trial; intestine obstruction; toxicity; disease control; oxaliplatin; dry skin; rectal neoplasms; rectum tumor; protein p21; proto-oncogene proteins p21(ras); fluoropyrimidine; b raf kinase; disease exacerbation; oncogene ras; benzimidazole derivative; benzimidazoles; antidiarrheal agent; decreased appetite; metastatic colorectal cancer; loose feces; demographics; contrast; overall response rate; erbb receptors; response evaluation criteria in solid tumors; Common Terminology Criteria for Adverse Events; humans; human; male; female; article; ras mutation; binimetinib; treatment interruption; ecog performance status; ras wild type; dermatitis acneiform |
| Journal Title: | The Oncologist |
| Volume: | 28 |
| Issue: | 12 |
| ISSN: | 1083-7159 |
| Publisher: | Oxford University Press |
| Date Published: | 2023-12-01 |
| Start Page: | e1209 |
| End Page: | e1218 |
| Language: | English |
| DOI: | 10.1093/oncolo/oyad210 |
| PUBMED: | 37597246 |
| PROVIDER: | scopus |
| PMCID: | PMC10712701 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- Source: Scopus |
