Department of Investigational Cancer Therapeutics (Phase I Program), University of Texas MD Anderson Cancer Center, Houston, TX
David S. Hong , Van Karlyle Morris II, Siqing Fu , Michael J. Overman , Sarina Anne Piha-Paul , Bryan K. Kee , Ralph Zinner , David R. Fogelman , Reena Mistry , Funda Meric-Bernstam , Scott Kopetz , Imad Shureiqi
Background: BRAF V600 mutations, present in 5-10% of patients (pts) with metastatic colorectal cancer (mCRC), are considered poor prognostic markers, and <10% of BRAF-mutated mCRC pts respond to a combination of cetuximab (C) and irinotecan (I). Vemurafenib (V), an oral kinase inhibitor to the mutated V600 isoform of BRAF, demonstrated a 5% response rate in a phase I trial with BRAF-mutated mCRC. In vitro data in CRC cell lines has shown that blockade of mutated BRAF by vemurafenib triggers compensatory activation of EGFR. Inhibition of EGFR combined with vemurafenib results in synergistic cytotoxicity in preclinical models, further augmented by irinotecan. The safety and efficacy of the combination in pts with BRAF-mutated advanced malignancies have not been studied. Methods: In this 3+3 phase I study, pts with refractory BRAF-mutated cancer received escalating doses of vemurafenib in combination with cetuximab and irinotecan over a 14-day cycle. Radiographic responses were evaluated every 4 cycles by RECIST 1.1. Adverse events (AEs) were assessed by CTCAE 4.0. Results: Through 1/2014, 10 pts have been enrolled: 7 at dose level 1(DL) (V- 480mg PO BID, C-250 mg/m2 weekly and I- 180mg/m2 every 14 days) and three at DL 2 (increased to V-720mg PO BID). One dose-limiting toxicity was observed at DL1 (grade 3 arthralgia) and resolved with dose reduction. The most common AEs were rash, nausea, and diarrhea. Of the 6 evaluable pts treated at DL 1, 5 had mCRC and 1 had appendiceal adenocarcinoma. Four of the 5 mCRC pts (80%) achieved a partial response. For the 5 mCRC pts, median best response was a reduction of -44% (range, 0% to -70%) with duration of responses of 5, 5+, 8+, 12+, and 14+ cycles. The appendiceal carcinoma pt had disease progression. PK and PD analysis is planned. Conclusions: The combination of vemurafenib with irinotecan and cetuximab seems well tolerated in pts with BRAF-mutated mCRC. Even with a low vemurafenib dose, PRs were seen in 4 of 5 evaluable mCRC pts in the first cohort. Additional pts continue to be enrolled at higher dose levels of vemurafenib. A US cooperative group randomized phase II trial of this combination in BRAF-mutated mCRC (SWOG1406) is planned. Clinical trial information: NCT01787500.
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Abstract Disclosures
2015 ASCO Annual Meeting
First Author: David S. Hong
2023 ASCO Gastrointestinal Cancers Symposium
First Author: Yungchang Chen
2021 ASCO Annual Meeting
First Author: Scott Kopetz
2022 ASCO Gastrointestinal Cancers Symposium
First Author: Scott Kopetz