Dataset Information

A Phase Ib/II Trial of Combined BRAF and EGFR Inhibition in BRAF V600E Positive Metastatic Colorectal Cancer and Other Cancers: The EVICT (Erlotinib and Vemurafenib In Combination Trial) Study.

ABSTRACT:

Purpose

BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While compelling preclinical data have highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy has not been investigated in clinical studies.

Patients and methods

We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib.

Results

Thirty-two patients with BRAF V600E positive metastatic colorectal cancer (mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960 mg twice daily with erlotinib 150 mg daily selected as the recommended phase II dose. Among 31 evaluable patients with mCRC and 7 with other cancers, overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43% (3/7), respectively, with clinical benefit rates of 65% and 100%. Early ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA monitoring revealed distinct patterns of convergent genomic evolution associated with acquired treatment resistance, with frequent emergence of MAPK pathway alterations, including polyclonal KRAS, NRAS, and MAP2K1 mutations, and MET amplification.

Conclusions

The Erlotinib and Vemurafenib In Combination Trial study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in understanding potential mechanisms of resistance.

SUBMITTER: Tan L

PROVIDER: S-EPMC10011885 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

A Phase Ib/II Trial of Combined BRAF and EGFR Inhibition in BRAF V600E Positive Metastatic Colorectal Cancer and Other Cancers: The EVICT (Erlotinib and Vemurafenib In Combination Trial) Study.

Tan Lavinia L Tran Ben B Tie Jeanne J Markman Ben B Ananda Sumi S Tebbutt Niall C NC Michael Michael M Link Emma E Wong Stephen Q SQ Chandrashekar Sushma S Guinto Jerick J Ritchie David D Koldej Rachel R Solomon Benjamin J BJ McArthur Grant A GA Hicks Rodney J RJ Gibbs Peter P Dawson Sarah-Jane SJ Desai Jayesh J

Clinical cancer research : an official journal of the American Association for Cancer Research 20230301 6

<h4>Purpose</h4>BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While compelling preclinical data have highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy has not been investigated in clinical studies.<h4>Patie ...[more]

PMID: 36638198

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Project description:Interventions: Tarceva (erlotinib) and Zelboraf (vemurafenib) are the intervention being studied. Both are provided in tablet form and are taken orally everyday until disease progression or unacceptable toxicity (anticipated this will be for approximately 6 months). There will be 3 dose levels: a) Dose level D-1 = erlotinib (100 mg/day) and vemurafenib (720 mg twice a day) b) Dose level D1 = erlotinib (100 mg/day) and vemurafenib (960 mg twice a day) c) Dose level D2 = erlotinib (150 mg/day) and vemurafenib (960 mg twice a day). Please note; this is a dose escalation study in the first phase, proceeding to dose expansion in the second phase. Strategies used to monitor adherence will be via a patient diary, where patients are asked to complete a daily diary entry recording drug use, as well as, standard drug tablet return and accountability logs. Primary outcome is to determine the safety of the combination of vemurafenib and erlotinib in the first 4 weeks of treatment in BRAF V600E mutant metastatic CRC and identify the dosing regimen to be evaluated in Phase II. This outcome will be assessed via the incidence of dose-limiting toxicities (DLTs) reported within the first 4 weeks of treatment with the combination of erlotinib and vemurafenib in a cohort of 3 patients. After each cohort of 3 patients completes the DLT observation period, a clinical synthesis of the available toxicity information will be reviewed by the trials safety monitoring committee.[Post first 4 weeks of treatment.];Secondary primary outcome is to evaluate the clinical efficacy of the combination of vemurafenib and erlotinib in BRAF V600E mutant metastatic CRC as measured by the proportion of patients achieving a complete or partial response (CR or PR) within the first 24 weeks of treatment. This outcome will be assessed using the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 within the first 24 weeks of treatment with the combination of erlotinib and vemurafenib.[Post the first 24 weeks of treatment.] Study Design: Purpose: Treatment; Allocation: Non-randomised trial; Masking: Open (masking not used);Assignment: Single group;Type of endpoint: Safety/efficacy

Project description:BackgroundGenetics-based basket trials have emerged to test targeted therapeutics across multiple cancer types. However, while vemurafenib is FDA-approved for BRAF-V600E melanomas, the non-melanoma basket trial was unsuccessful, suggesting mutation status is insufficient to predict response. We hypothesized that proteomic data would complement mutation status to identify vemurafenib-sensitive tumors and effective co-treatments for BRAF-V600E tumors with inherent resistance.MethodsReverse Phase Proteomic Array (RPPA, MD Anderson Cell Lines Project), RNAseq (Cancer Cell Line Encyclopedia) and vemurafenib sensitivity (Cancer Therapeutic Response Portal) data for BRAF-V600E cancer cell lines were curated. Linear and nonlinear regression models using RPPA protein or RNAseq were evaluated and compared based on their ability to predict BRAF-V600E cell line sensitivity (area under the dose response curve). Accuracies of all models were evaluated using hold-out testing. CausalPath software was used to identify protein-protein interaction networks that could explain differential protein expression in resistant cells. Human examination of features employed by the model, the identified protein interaction networks, and model simulation suggested anti-ErbB co-therapy would counter intrinsic resistance to vemurafenib. To validate this potential co-therapy, cell lines were treated with vemurafenib and dacomitinib (a pan-ErbB inhibitor) and the number of viable cells was measured.ResultsOrthogonal partial least squares (O-PLS) predicted vemurafenib sensitivity with greater accuracy in both melanoma and non-melanoma BRAF-V600E cell lines than other leading machine learning methods, specifically Random Forests, Support Vector Regression (linear and quadratic kernels) and LASSO-penalized regression. Additionally, use of transcriptomic in place of proteomic data weakened model performance. Model analysis revealed that resistant lines had elevated expression and activation of ErbB receptors, suggesting ErbB inhibition could improve vemurafenib response. As predicted, experimental evaluation of vemurafenib plus dacomitinb demonstrated improved efficacy relative to monotherapies.ConclusionsCombined, our results support that inclusion of proteomics can predict drug response and identify co-therapies in a basket setting.

Dataset Information

A Phase Ib/II Trial of Combined BRAF and EGFR Inhibition in BRAF V600E Positive Metastatic Colorectal Cancer and Other Cancers: The EVICT (Erlotinib and Vemurafenib In Combination Trial) Study.

Purpose

Patients and methods

Results

Conclusions

Publications

A Phase Ib/II Trial of Combined BRAF and EGFR Inhibition in BRAF V600E Positive Metastatic Colorectal Cancer and Other Cancers: The EVICT (Erlotinib and Vemurafenib In Combination Trial) Study.

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