Reference Detail

Ref Type

PMID

Authors

Scott Kopetz, Takayuki Yoshino, Tae Won Kim, Jayesh Desai, Rona Yaeger, Eric Van Cutsem, Fortunato Ciardiello, Harpreet Singh Wasan, Tim Maughan, Yuanyuan Zhang, Tiziana Usari, Chin-Hee Chung, Xiaosong Zhang, and Josep Tabernero

Title

BREAKWATER safety lead-in (SLI): Encorafenib + cetuximab (EC) ± chemotherapy for first-line (1L) treatment (tx) of BRAF V600E-mutant (BRAFV600E) metastatic colorectal cancer (mCRC).

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of Clinical Oncology	40	Supplement 4

URL

https://ascopubs.org/doi/10.1200/JCO.2022.40.4_suppl.134

Abstract Text

Background: Currently, there are no 1L tx options indicated specifically for patients (pts) with BRAFV600E mCRC. Based on results of BEACON CRC (NCT02928224), BRAF inhibitor encorafenib + EGFR inhibitor cetuximab was approved for tx of previously treated pts with BRAFV600E mCRC. BREAKWATER (NCT04607421), an ongoing, open-label, global, multicenter, randomized phase 3 study, evaluates 1L EC ± chemotherapy for tx of pts with BRAFV600E mCRC. Here we present preliminary data on safety and pharmacokinetics (PK) from the BREAKWATER SLI, which aimed to identify the chemotherapy backbone for EC for the phase 3 portion of BREAKWATER. Methods: SLI inclusion criteria were BRAFV600E mCRC (determined using tumor tissue or blood); evaluable disease (RECIST v1.1); ≤1 prior systemic tx for mCRC; European Cooperative Oncology Group performance status (ECOG PS) 0/1; and adequate bone marrow, hepatic, and renal function. Pts previously treated with BRAF/EGFR inhibitors or both oxaliplatin and irinotecan were excluded. Pts received encorafenib 300 mg daily + cetuximab 500 mg/m2 every 2 weeks (Q2W) + either FOLFIRI Q2W or mFOLFOX6 Q2W in 28-day cycles. The primary endpoint was frequency of dose-limiting toxicities (DLTs). PK were a secondary endpoint. Data cutoff date: Sep 13, 2021. Results: 57 pts were enrolled (EC + FOLFIRI, n = 30; EC + mFOLFOX6, n = 27). Median (range) age was 57 (28–78) years; 25% were Asian; 65% had ECOG PS 0; 37% had ≥3 organs involved; 58% were treatment naive. At cutoff date, tx was ongoing in 45 (79%) pts. Median (range) duration of tx for encorafenib in EC + FOLFIRI and EC + mFOLFOX6 was 15 (0–31) and 14 (0–27) weeks, respectively. One DLT was observed: grade 4 neutropenia in 1 pt in EC + FOLFIRI. Tx-emergent all-cause serious adverse events (AEs) occurred in 20% and 19% and grade ≥3 AEs in 33% and 56% of pts in EC + FOLFIRI and EC + mFOLFOX6, respectively. The table shows frequent (all grade in ≥30% pts or grade ≥3 in ≥10% with either tx) tx-emergent all-cause AEs. One pt died due to disease progression. In EC + FOLFIRI, in the presence of steady-state encorafenib, AUCinf of irinotecan and its active metabolite, SN-38, significantly decreased ̃25% and ̃40%, respectively, compared with values in the absence of encorafenib. In EC + mFOLFOX6, oxaliplatin PK was not significantly altered by steady-state encorafenib. Conclusions: Based on these data, BREAKWATER phase 3 will compare EC ± mFOLFOX6 with mFOLFOX6/FOLFOXIRI/CAPOX ± bevacizumab. Clinical trial information: NCT04607421.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	colorectal cancer	sensitive	Cetuximab + Encorafenib + Fluorouracil + Leucovorin + Oxaliplatin	FDA approved - On Companion Diagnostic	Actionable	In a Phase III trial (BREAKWATER) that supported FDA approval, Braftovi (encorafenib) in combination with Erbitux (cetuximab) and mFOLFOX6 (n=27) or FOLFIRI (n=30) were tolerated and resulted in a median duration of treatment of 14 and 15 weeks, respectively, in patients with metastatic colorectal cancer harboring BRAF V600E, with treatment ongoing in 79% (45/57) of the patients at data cutoff date (J Clin Oncol Vol 40, Number 4 Suppl (Feb 2022); NCT04607421).	detail... detail... detail... detail...