Ciardiello, Fortunato

LBA3500 Background: BREAKWATER (NCT04607421) is an open-label, global, randomized, phase 3 study evaluating first-line (1L) encorafenib + cetuximab (EC) ± chemotherapy (chemo) vs standard of care (SOC; chemo ± bevacizumab) in BRAF V600E-mutant metastatic colorectal cancer (mCRC). The study previously met one of its dual primary endpoints (EPs) demonstrating clinically meaningful and statistically significant improvement in confirmed objective response rate (ORR) by blinded independent central review (BICR) in the ORR subset. These results were the basis for the FDA accelerated approval of EC+mFOLFOX6 for BRAF V600E-mutant mCRC, including in the 1L, under Project Frontrunner. Here, we report the primary analysis of progression-free survival (PFS) by BICR, updated interim analysis of OS, updated safety, and other analyses. Methods: Eligible patients (pts) with untreated BRAF V600E-mutant mCRC were randomized 1:1:1 to receive EC, EC+mFOLFOX6, or SOC; EC arm enrollment was closed after a protocol amendment. Dual primary EPs: ORR and PFS by BICR (EC+mFOLFOX6 vs SOC); key secondary EP: OS (EC+mFOLFOX6 vs SOC). Results: 637 pts were randomized to EC, EC+mFOLFOX6, or SOC. Baseline demographics and disease characteristics were generally balanced between arms. EC+mFOLFOX6 (data cutoff: Jan 6, 2025) demonstrated a clinically meaningful and statistically significant PFS improvement vs SOC, meeting the other dual primary EP; HR=0.53 (95% CI 0.407, 0.677; P<0.0001); median PFS 12.8 vs 7.1 mo. OS was clinically meaningful and statistically significant vs SOC; HR=0.49 (95% CI 0.375, 0.632; P<0.0001); median OS 30.3 vs 15.1 mo. Median PFS and OS in the EC arm were 6.8 and 19.5 mo. These data and response data for all randomized pts are shown in the table. Serious treatment-emergent adverse events occurred in 30%, 46%, and 39% of pts in the safety analysis set. Safety was consistent with that known for each agent. Conclusions: BREAKWATER demonstrated clinically meaningful and statistically significant PFS and OS improvements with EC+mFOLFOX6 vs SOC and manageable toxicities. EC+mFOLFOX6 is potentially practice changing as the new SOC. Clinical trial information: NCT04607421 . ECn=158 EC+mFOLFOX6n=236 SOCn=243 EC+mFOLFOX6vs SOCHR (95% CI)P-value a Median PFS b , mo (95% CI) 6.8(5.7, 8.3) 12.8(11.2, 15.9) 7.1(6.8, 8.5) 0.53 (0.407, 0.677) <0.0001 Median OS, mo (95% CI) 19.5(17.6, 22.5) 30.3(21.7, NE) 15.1(13.7, 17.7) 0.49 (0.375, 0.632)<0.0001 ORR, b % (95% CI) 45.6(38.0, 53.3) 65.7(59.4, 71.4) 37.4(31.6, 43.7) Median DOR b , mo (95% CI) c 7.0 (4.2, 11.6) 13.9 (10.9, 18.5) 10.8 (7.6, 13.4) DOR b ≥6 mo, n (%) c 29 (40.3) 110 (71.0) 38 (41.8) DOR b ≥12 mo, n (%) c 15 (20.8) 54 (34.8) 16 (17.6) Median time to response, b wk (range) c 6.6(4.3-86.4) 7.0(5.1-103.6) 7.3 (5.4-48.0) a 1-sided stratified log rank test. b By BICR. c Responders: n=72, n=155, and n=91. DOR, duration of response.

Abstract This position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for chronic myeloid leukaemia targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies.

627 Background: The SLI of the BEACON CRC phase 3 study assessed the safety and efficacy of the combination of the BRAF inhibitor encorafenib (ENCO) + MEK inhibitor binimetinib (BINI) + anti-EGFR antibody cetuximab (CETUX) in pts with BRAFV600E-mutant mCRC after 1 or 2 prior regimens. CEA and CA19-9 are tumor markers that are widely used to monitor the effectiveness of systemic therapies for mCRC; here we report on the association of CEA and CA19-9 changes while on treatment with clinical outcomes in pts from the SLI. Methods: Pts in the SLI received the triplet of ENCO 300 mg QD + BINI 45 mg BID + CETUX 400 mg/m2 (initial dose) then 250 mg/m2 QW in 28-day cycles. Pts were evaluated for safety, radiographic response, and change in tumor markers CEA and CA19-9. Results: 30 pts were treated. The triplet was generally well tolerated, and adverse events were consistent with known BRAF, MEK, and EGFR inhibitor toxicities. The rate of severe skin toxicities (grade 3/4) was lower than generally observed for CETUX in mCRC. Of the 29 pts with a BRAFV600E mutation, the median time on study treatment was 5.6 mo (range, 1.0–9.3 mo), and 22 (76%) remained on study treatment at the time of data cutoff. The confirmed overall response rate (ORR) was 41%, with 1 complete and 11 partial responses. In addition, 9 pts had prolonged stable disease (SD) up to 9.3 mo.CEA and CA19-9 were analyzed in 28 pts. CEA and CA19-9 decreased in 96% and 82% of these pts, respectively. Among 15 pts with treatment duration ≥5.6 mo, median/mean % decreases were 97%/79% for CEA and 92%/82% for CA19-9 in confirmed responders (n=6). Respective decreases in pts with prolonged SD (n=9) were similar: 84%/68% for CEA and 89%/68% for CA19-9. Updated safety, efficacy, and tumor marker results will be provided. Conclusions: ENCO + BINI + CETUX is generally well tolerated and has encouraging clinical activity in BRAFV 600E mCRC, with a confirmed ORR of 41%. In pts with study treatment duration ≥5.6 mo, the tumor markers CEA and CA19-9 decreased markedly and to the same degree in responders vs pts with prolonged SD, providing additional evidence of the meaningful clinical activity of this regimen. Clinical trial information: NCT02928224.

TPS3622 Background: BRAF mutations are found in ≈10% of mCRC cases. Pts with BRAFV600E mCRC have a poor prognosis, with shorter progression-free survival (PFS) and overall survival (OS) than pts with BRAFwt mCRC (Van Cutsem et al 2011; Modest et al 2012; Sorbye et al 2015). The benefits of combined BRAF + EGFR inhibition in mCRC have been demonstrated in vitro (Corcoran et al 2012; Prahallad et al 2012; Yang et al 2012), and preclinical evidence suggests that adding MEK signaling inhibition improves antitumor activity. Early clinical data indicate that BRAF + EGFR + MEK inhibition has greater activity than BRAF + EGFR inhibition in pts with BRAFV600E mCRC (Van Cutsem et al 2016). Our study will examine the combination of BINI (a MEK inhibitor) + ENCO (a selective BRAF kinase inhibitor) + CTX (an anti-EGFR antibody) and of ENCO + CTX in pts with BRAFV600E mCRC. Methods: BEACON CRC (NCT02928224) is enrolling pts with BRAFV600E mCRC whose disease has progressed after 1 or 2 prior regimens in the metastatic setting. A safety lead-in phase (≈30 pts) will determine the safety and tolerability of oral ENCO 300 mg QD + oral BINI 45 mg BID + intravenous CTX 400 mg/m2 followed by 250 mg/m2 QW. In the phase 3 portion, ≈615 pts will be randomized 1:1:1 to triplet (ENCO + BINI + CTX), doublet (ENCO + CTX), or control (investigator’s choice of IRI/CTX or FOLFIRI/CTX) arms. Pts will be treated in 28-day cycles until disease progression, unacceptable toxicity, withdrawal of consent, initiation of subsequent anticancer therapy, or death. The primary endpoint is OS (triplet vs control). Secondary endpoints include OS (doublet vs control), confirmed investigator-assessed objective response rate according to RECIST version 1.1 (triplet or doublet vs control; triplet vs doublet), PFS (triplet or doublet vs control), duration of response, time to response, pharmacokinetics, and pt-reported outcomes. Safety will be summarized using standard adverse event reporting. Clinical trial information: NCT02928224.