BRAFV600E Metastatic Colorectal Cancer Research Articles

Real-world evaluation of clinical outcomes and long-term survivors in patients with BRAF-V600E metastatic colorectal cancer.

166 Background: BRAF-V600E mutant metastatic colorectal cancer (BRAF-V600E mCRC) is associated with poor prognosis but confers response to combination BRAF/EGFR blockade. The goal of this study is to evaluate the clinicopathologic features and natural history of BRAF-V600E mCRC in the era prior to combination BRAF/EGFR inhibitors. Methods: This is a retrospective study of patients treated at the Ottawa Hospital Cancer Centre with BRAF-V600E mCRC who did not receive combination BRAF/EGFR therapy. Patients diagnosed with colorectal cancer prior to March 31, 2021, were included. Demographic, clinical, pathologic and cancer characteristics were abstracted from electronic medical records. Outcomes of interest included duration of therapy, as a surrogate of progression free survival, and overall survival (OS). Long-term survivor was defined as OS greater than 2 years. Results: 74 patients were included. Median age was 70 years (IQR=61-78), and 39 (53%) patients were female. There were 17 (23%) patients alive at the end of the follow-up period. 31 (42%) patients had poorly differentiated grade and 26 (35%) were mismatch repair deficient (dMMR). Locations of metastases included liver (40, 54%), peritoneum (30, 41%), lung (18, 24%), bone (5, 7%) and brain (5, 7%). Overall, 64 (86%) patients received first line systemic therapy, 19 (26%) second line, and 5 (7%) third line (see Table). Median duration of therapy in the first line was 4.3 months (IQR=2.0-9.6), second line was 2.9 months (IQR=1.4-4.1), and third line 1.0 months (IQR=1.0-1.9). Overall survival in the entire cohort was 13.2 months (IQR=4.6-25.4). Importantly, 21 (28%) patients were long-term survivors, of which 8 (11%) were dMMR. Conclusions: Patients with BRAF-V600E mCRC generally have poor clinical outcomes with traditional systemic therapies. In this study, we identified approximately 25% of patients who are long-term survivors (OS >2 years). This reflects the real-world heterogeneity of clinical outcomes for patients with BRAF-V600E mCRC who did not receive BRAF/EGFR targeted therapy.[Table: see text]

SWOG S2107: Randomized phase II trial of encorafenib and cetuximab with or without nivolumab for patients with previously treated, microsatellite stable, BRAFV600E metastatic and/or unresectable colorectal cancer.

TPS234 Background: Patients with microsatellite stable (MSS), BRAFV600E metastatic colorectal cancer (mCRC) experience poor survival outcomes. Treatment with the BRAF inhibitor encorafenib (E) and anti-EGFR antibody cetuximab (C) is an approved treatment combination, with a reported overall response rate (ORR) of 20% and median progression-free survival (PFS) of 4.1 months. Anti-PD-1 antibodies like nivolumab (N) are ineffective as monotherapy for patients with MSS, BRAFV600E mCRC. In preclinical models of MSS, BRAFV600E CRC, inhibition of BRAF and EGFR induces a loss of expression of mismatch repairs genes and promotes a microsatellite instability-high phenotype, which may prime these tumors for response to immunotherapy. In support of these findings, a single-institution clinical trial of E + C + N for 26 participants with MSS, BRAFV600E mCRC reported an ORR of 50% and median PFS of 7.2 months. We hypothesize that the addition of N to E + C will improve PFS for participants with MSS, BRAFV600E mCRC. Methods: In this prospective phase II clinical trial (N=75), participants with previously treated MSS, BRAFV600E mCRC will be randomized 2:1 into 2 arms, respectively: experimental treatment (E + C + N) or standard treatment (E + C). No prior BRAF, EGFR, or immunotherapy agents are allowed. All participants will receive E (300 mg PO daily) and C (500 mg/m2 IV every 14 days), and participants in the experimental arm will receive N (480 mg IV every 28 days). The primary endpoint is PFS. Secondary endpoints include overall survival, best overall response, duration of response, and safety/tolerability. Using a one-sided α= .10 and power 80%, we target an improvement in median PFS from 4.2 to 7.3 months and a hazard ratio of 0.57. Additional participants specimens will be collected for exploratory correlative research. As of 9/2023, 37 of 75 planned participants have been enrolled. Clinical trial information: NCT05308446 .

Randomized phase II trial of encorafenib and cetuximab with or without nivolumab for patients with previously treated, microsatellite stable, BRAFV600E metastatic and/or unresectable colorectal cancer: SWOG S2107.

TPS265 Background: Patients with microsatellite stable (MSS), BRAFV600E metastatic colorectal cancer (mCRC) experience poor survival outcomes. Treatment with the BRAF inhibitor encorafenib (E) and anti-EGFR antibody cetuximab (C) is an approved treatment combination, with a reported overall response rate (ORR) of 20% and median progression-free survival (PFS) of 4.1 months. Anti-PD-1 antibodies like nivolumab (N) are ineffective as monotherapy for patients with MSS, BRAFV600E mCRC. In preclinical models of MSS, BRAFV600E CRC, inhibition of BRAF and EGFR induces a loss of expression of mismatch repair genes and promotes a microsatellite instability-high phenotype, which may prime these tumors for response to immunotherapy. In support of these findings, a single-institution clinical trial of E + C + N for 26 patients with MSS, BRAFV600E mCRC reported an ORR of 50% and median PFS of 7.2 months. We hypothesize that the addition of N to E + C will improve median PFS for patients with MSS, BRAFV600E mCRC. Methods: In this prospective phase II clinical trial (N = 75), patients with previously treated MSS, BRAFV600E mCRC will be randomized 2:1 into 2 arms, respectively: experimental treatment (E + C + N) or standard treatment (E + C). No prior BRAF, EGFR, or immunotherapy agents are allowed. All patients will receive E (300 mg PO daily) and C (500 mg/m2 IV every 14 days), and patients in the experimental arm will receive N (480 mg IV every 28 days). The primary endpoint is PFS. Secondary endpoints include overall survival, best overall response, duration of response, and safety/tolerability. Using a one-sided α = .10 and power 80%, we target an improvement in median PFS from 4.2 to 7.3 months and a hazard ratio of 0.57. Additional patient specimens will be collected for exploratory correlative research. The study activated across the United States in June 2022 and as of September 2022 has enrolled 2 of 75 planned participants. Funding: NIH/National Cancer Institute grants U10CA180888, U10CA180819, U10CA180820, U10CA180821, U10CA180868; and in part by The Hope Foundation for Cancer Research STrS award. Clinical trial information: NCT05308446 .

Monitoring tumour resistance to the BRAF inhibitor combination regimen in colorectal cancer patients via circulating tumour DNA.

This study aimed to identify mechanisms of drug resistance to the combination of vemurafenib, irinotecan, and cetuximab (VIC) in BRAFV600E metastatic colorectal cancer (mCRC). Forty-one patients with BRAFV600E mCRC from July 2018 and June 2020 were evaluated, with tissue and/or plasma samples collected. We profiled tissue and plasma samples using whole-exome sequencing and targeted sequencing of 425 cancer-relevant genes. Clinical cohort analysis from published studies was performed to consolidate our findings. BRAF mutant in baseline plasma and its dynamics are significantly associated with VIC-related response, and concurrent RNF43 mutation significantly sensitises tumour to VIC treatment. VIC resistance frequently involves genes in PI3K, MAPK pathway, and several novel resistance mechanisms such as TGFBR2 and SMAD4 mutations, and copy-number gains in PTK2, MYC, and GATA6 have been identified. We also firstly describe acquired altered genes in DNA damaging repair pathway, occurring in 33% of patients after VIC treatment, and particularly, patients with this pre-treatment resistance subclones developed inferior responses, along with higher tumour mutation burden both at baseline and progression plasma. Analysis of ctDNA can provide novel insights into molecular resistance mechanisms to VIC in BRAFV600E mCRC patients, allowing accurate guidance for clinicians in personalised treatment strategies.

Abstract B028: Changes in exosomal RNA expression associate with treatment response to BRAF + EGFR + PD-1 blockade in MSS, BRAFV600E colorectal cancer: A liquid biopsy approach

Abstract Introduction: BRAF + EGFR inhibition induces decreased expression of mismatch repair (MMR) genes in preclinical models of microsatellite stable (MSS), BRAFV600E metastatic colorectal cancer (mCRC) but has not been reported in patients. We evaluated exosomal RNA (exoRNA) isolated from serial blood specimens collected from patients (pts) with MSS, BRAFV600E mCRC treated with encorafenib (E) + cetuximab (C) + nivolumab (N) as a novel blood-based approach to compare differences in gene expression according to treatment response. Methods: Pts with refractory MSS, BRAFV600E mCRC were treated with E (300 mg daily), C (500 mg/m2 q2 weeks), and N (480 mg q4 weeks) on an IRB-approved clinical trial at MD Anderson. Responses to treatment were assessed every 8 weeks (RECIST v1.1). ExoRNA isolated from pretreatment and on-treatment (week 8) blood samples were sequenced (SMART-seq) and deconvoluted (DeMix) in order to estimate cancer-specific gene expression. Previously validated MAPK and interferon (IFN)-γ gene expression signatures were used for measuring transcriptomic changes following treatment with E+C+N. Scores between responders and non-responders were compared by unpaired t-tests. For Gene Set Enrichment Analysis (GSEA), an adjusted false discovery rate (FDR) < 0.25 was applied to find significantly enriched pathways between on-treatment and pretreatment samples separately for responders and non-responders. Results: 26 pts were treated with E+C+N, and 24 were evaluable for response. Overall response rate was 50% (95% confidence interval (CI), 29-71), and median progression-free survival was 7.4 months (95% CI, 6.0-NA). Four pts remained on study > 12 months. Between responders vs non-responders (N=12 each), mean changes in MAPK signature score was decreased (-0.63 vs 0.15, respectively; p=.13). Both patients with response > 18 months demonstrated dramatic increases in IFN-γ score following treatment with E+C+N (+13.1 and +14.6), a trend not observed in all other patients (range, -18.0 to 3.6). Among responders to E+C+N, GSEA analysis demonstrated dynamic pathway changes in normalized enrichment score (NES) for DNA repair (NES -2.3; p-adj=.008), IL6/JAK/STAT3 (NES -2.1, p-adj=.02), and IFN-α response (NES -2.0, p-adj=.03). For non-responders, relative increases in NES were observed for angiogenesis (NES 2.1, p-adj=.02) and IL-2/STAT5 (NES 2.0, p-adj= .02). Conclusions: Transcriptome analysis using exoRNA isolated from serial blood samples is feasible for assessing treatment response in pts with mCRC. Decreased MAPK score in exoRNA may be associated with treatment response to E+C+N in pts with MSS, BRAFV600E mCRC. Changes in immune NES scores following treatment may distinguish responders from non-responders to MAPK + PD-1 blockade and highlight targets for novel immune-mediated combinations for MSS, BRAFV600E mCRC. Citation Format: Van Karlyle Morris, Kimal I. Rajapakshe, Vahid Bahrambeigi, Christine M. Parsehgian, Benny Johnson, Kanwal P. Raghav, Arvind Dasari, Ryan W. Huey, Michael J. Overman, Jason Willis, Michael S. Lee, Robert A. Wolff, Bryan K. Kee, Phat Le, Paola A. Guerrero, Scott Kopetz, Anirban Maitra. Changes in exosomal RNA expression associate with treatment response to BRAF + EGFR + PD-1 blockade in MSS, BRAFV600E colorectal cancer: A liquid biopsy approach [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B028.

RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer

Anti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAFV600E colorectal cancer (mCRCBRAF-V600E). However, a large fraction of patients do not respond, underscoring the need to identify molecular determinants of treatment response. Using whole-exome sequencing in a discovery cohort of patients with mCRCBRAF-V600E treated with anti-BRAF/EGFR therapy, we found that inactivating mutations in RNF43, a negative regulator of WNT, predict improved response rates and survival outcomes in patients with microsatellite-stable (MSS) tumors. Analysis of an independent validation cohort confirmed the relevance of RNF43 mutations to predicting clinical benefit (72.7% versus 30.8%; P = 0.03), as well as longer progression-free survival (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.12–0.75; P = 0.01) and overall survival (HR, 0.26; 95% CI, 0.10–0.71; P = 0.008), in patients with MSS-RNF43mutated versus MSS-RNF43wild-type tumors. Microsatellite-instable tumors invariably carried a wild-type-like RNF43 genotype encoding p.G659fs and presented an intermediate response profile. We found no association of RNF43 mutations with patient outcomes in a control cohort of patients with MSS-mCRCBRAF-V600E tumors not exposed to anti-BRAF targeted therapies. Overall, our findings suggest a cross-talk between the MAPK and WNT pathways that may modulate the antitumor activity of anti-BRAF/EGFR therapy and uncover predictive biomarkers to optimize the clinical management of these patients.

Phase I/II trial of encorafenib, cetuximab, and nivolumab in patients with microsatellite stable (MSS), BRAFV600E metastatic colorectal cancer.

3598 Background: Treatment with encorafenib (E) and cetuximab (C) offers response and survival benefit for patients (pts) with MSS, BRAFV600E metastatic colorectal cancer (CRC). BRAF + EGFR inhibition induced a transient MSI-H phenotype in preclinical models of MSS, BRAFV600E CRC and may prime these tumors for response to immunotherapy with anti-PD-1 antibodies like nivolumab (N). Methods: In this single-arm, single-institution, phase I/II clinical trial, pts with treatment-refractory MSS, BRAFV600E metastatic CRC were eligible. No prior BRAF, MEK, or ERK inhibitors, anti-EGFR antibody, or immunotherapy was permitted. Pts received E (300 mg PO daily), C (500 mg/m2 IV q14 days), and N (480 mg IV q28 days). The primary endpoints were best overall response (RECIST 1.1) and safety/tolerability (CTCAE v5). A Simon two-stage design (H0: p≤.22; Ha: p≥.45, where p = percentage of pts with radiographic response) was employed using a one-sided α =.05 and β =.20. Median progression-free survival (PFS) and overall survival (OS) were estimated via Kaplan-Meier. To measure ex vivo treatment responses with an E-slice assay (EMPIRI), 300 µm fresh tissue slices from core biopsies were generated and cultured in serum-free media with E, C, and N. Longitudinal changes in viability were measured at days 4, 8, and 12 and compared to baseline viability in each tissue. Ex vivo “response” was defined if < 1X baseline tumor cell viability. Results: With a data cutoff of 2/8/2022, all pts are enrolled: 26 evaluable for toxicity and 23 for response. Median age is 60 years (range, 32-85), and 16 (62%) are female. Grade 3-4 treatment-related adverse events (AE) have occurred in 5/26 (19%) patients: colitis, maculopapular rash, leukocytosis, and myositis/myocarditis (all N = 1); asymptomatic elevated amylase/lipase (N = 2). Overall response rate is 48% (95% CI, 27-69), and disease control rate is 96% (95% CI, 78-100). Median PFS is 7.4 months (95% CI, 5.6-NA). For the 11 pts with responses, median duration of response is 7.7 months (95% CI, 4.5-NA). Median OS is 15.1 months (95% CI, 7.7-NA). E-slices showed concordance between pts with radiographic responses and reduction in cell viability, and between non-responders and increase in cell viability. Final results will be presented. Conclusions: E + C + N appears to be effective and well-tolerated for pts with MSS, BRAFV600E metastatic CRC. Ex vivo analysis of pretreatment tissue predicted eventual clinical response in matched patients. A follow-up randomized phase II trial (SWOG 2107) to evaluate encorafenib/cetuximab with or without nivolumab in pts with MSS, BRAFV600E metastatic CRC will activate in 2022. Clinical trial information: NCT04017650.

P-36 Real-world outcomes in BRAFV600E metastatic colorectal cancer – the Glasgow experience

Approximately 8 - 10% of metastatic colorectal cancers (mCRC) have a BRAF V600E mutation. BRAF V600E mutant mCRC represents a distinct clinical subset with a poor prognosis. Previous treatment guidelines have been derived from subgroup analyses of non-designated BRAF V600E trials. Real world studies have shown that outcomes and treatment practices can vary widely. Here, we report on our regional practices and outcomes. We undertook a retrospective analysis of all mCRC patients with confirmed BRAF V600E mCRC diagnosed in NHS Greater Glasgow and Clyde Health Board (Scotland, UK) between 01/01/2015 - 31/12/2020. Clinical and pathological features were obtained from electronic records. Univariate analysis of prognostic factors was performed using Kaplan Meier analysis and log-rank test. Multivariate analysis was performed using Cox regression. A total of 139 patients were identified for study with 1 excluded for missing follow up information. Median age at metastatic diagnosis was 69 years, with a female preponderance (59% female, 41% male). 31% of tumours also had deficient mismatch repair (dMMR) or high levels of microsatellite instability (MSI-H). Primary tumour site was mostly right-sided (n=102, 74%), with less left-sided (n=20, 15%) and rectal (n=15, 11%) tumours. 1 patient had 2 synchronous primaries (1 right colon and 1 rectal). 64% presented with de novo metastatic disease. For those with initial loco-regional disease, the median time to metastatic progression was 10 months. The most common metastatic sites were liver (54%), peritoneal (33%), lymph node (31%), and lung (28%). 36% of patients did not receive any systemic treatment, 36% received 1 line, and 28% received 2 or more lines of treatment. Most (69%) received a cytotoxic chemotherapy doublet as first-line treatment, and 6% received triplet cytotoxic chemotherapy. 7% received immunotherapy. Among the treated patients, only 19% received some form of targeted therapy over their full treatment course, usually a combination containing an anti-EGFR inhibitor. The median overall survival was poor at 7.2 months. Features significantly associated with shorter survival were performance status (PS) of 2 or worse (p < 0.01), the presence of lymph node metastasis (p = 0.010) and peritoneal metastasis (p < 0.01), a higher modified Glasgow Prognostic Score (GPS) of 2 (p = 0.035) and a high neutrophil-lymphocyte ratio >5 (p = 0.032). Primary tumour site was also significantly associated with survival (p < 0.01), with worse survival for right-sided tumours (6.6 months), compared to 14.0 months for left-sided/rectal tumours. Using multivariate analysis, independent prognostic markers were PS, presence of lymph node metastasis, presence of peritoneal metastasis and right-sided primary tumour location. This is a representative cohort of BRAF V600E metastatic colorectal cancer patients, which confirms previously known clinical features. Of the common metastatic sites, peritoneal or lymph node metastases confer a poorer prognosis. There was not widespread adoption of more intensive triplet chemotherapy over the study time period. Overall survival is poor, and changed treatment strategies facilitated by recent clinical trial advances with targeted therapies may improve outcomes in this poor prognostic group.

Quality of life with encorafenib plus cetuximab with or without binimetinib treatment in patients with BRAF V600E-mutant metastatic colorectal cancer: patient-reported outcomes from BEACON CRC

BackgroundIn the BEACON CRC study (NCT02928224), encorafenib plus cetuximab with binimetinib {9.3 versus 5.9 months; hazard ratio (HR) [95% confidence interval (CI)]: 0.60 [0.47-0.75]} or without binimetinib [9.3 versus 5.9 months; HR (95% CI): 0.61 (0.48-0.77)] significantly improved overall survival (OS) compared with the previous standard of care (control) in patients with BRAF V600E metastatic colorectal cancer (mCRC). Quality of life (QoL) was a secondary endpoint, assessed using validated instruments.Patients and methodsBEACON CRC was a randomized, open-label, phase III study comparing encorafenib plus cetuximab with or without binimetinib and the investigator’s choice of irinotecan plus cetuximab or FOLFIRI plus cetuximab (chemotherapy control) in patients with previously treated BRAF V600E mCRC. Patient-reported QoL assessments included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC) and Functional Assessment of Cancer Therapy—Colorectal (FACT-C). The primary outcome for these tools was time to definitive 10% deterioration.ResultsEncorafenib plus cetuximab, both with and without binimetinib, was associated with longer median times to definitive 10% deterioration versus the control group in the EORTC Global Health Status scale [HR (95% CI): 0.65 (0.52-0.80) versus 0.61 (0.49-0.75), respectively] and the FACT-C functional well-being subscale [HR (95% CI): 0.62 (0.50-0.76) versus 0.58 (0.47-0.72), respectively]. Consistent results were observed across all subscales of the EORTC and FACT-C instruments. QoL was generally maintained during treatment for the global EORTC and FACT-C scales.ConclusionsIn addition to improving OS, encorafenib plus cetuximab with or without binimetinib delays QoL decline in previously treated patients with BRAF V600E-mutant mCRC.

Phase I/II trial of encorafenib, cetuximab, and nivolumab in patients with microsatellite stable, BRAFV600E metastatic colorectal cancer.

12 Background: Encorafenib (E) and cetuximab (C) offers short-lived response and survival benefit for patients (pts) with MSS, BRAFV600E metastatic colorectal cancer (CRC). BRAF + EGFR inhibition induced a transient MSI-H phenotype in preclinical models of MSS, BRAFV600E CRC and may prime these tumors for response to immunotherapy with anti-PD-1 antibodies like nivolumab (N). Methods: In this single-arm, single-institution, phase I/II clinical trial, pts with treatment-refractory MSS, BRAFV600E metastatic CRC were eligible. No prior BRAF inhibitors, anti-EGFR antibody, or immunotherapy was permitted. Pts received E (300 mg PO daily), C (500 mg/m2 IV q14 days), and N (480 mg IV q28 days). The primary endpoints were best overall response (RECIST 1.1) and safety/tolerability (CTCAE v5). A Simon two-stage design (H0: p≤.22; Ha: p≥.45, where p= percentage of pts with radiographic response) was employed using a one-sided α=.05 and β=.20. In the first stage, ≥ 4/15 responses were needed in order for the trial to enroll 11 additional pts. Median progression-free survival (PFS) and overall survival (OS) were estimated via Kaplan-Meier. Results: All 26 pts have been enrolled - 23 patients treated, and 21 evaluable for response so far. Median age is 59 years (range, 32-85), and 14 (54%) are female. No dose-limiting toxicities occurred. Grade 3-4 treatment-related adverse events (AE) occurred in 4/22 (18%) patients. Grade 3 AEs included colitis, maculopapular rash, leukocytosis, and elevated amylase/lipase (all N=1). Grade 4 AEs in a single patient were myositis/myocarditis. Overall response rate is 45% (95% CI, 23-68), and disease control rate is 95% (95% CI, 75-100). Median PFS is 7.3 months (95% CI, 5.5-NA). Median OS is 11.4 months (95% CI, 7.6-NA). For the 9 pts thus far with responses, median duration of response is 8.1 months (95% CI, 7.3-NA). Updated results will be presented. Conclusions: E + C + N is effective and well-tolerated for pts with MSS, BRAFV600E metastatic CRC. The E+C+N regimen met its predefined efficacy endpoint and suggests a role for immunotherapy as a novel combination approach for this specific subpopulation of MSS metastatic CRC. A follow-up randomized phase II trial (SWOG 2107) to evaluate encorafenib/cetuximab with or without nivolumab in pts with MSS, BRAFV600E metastatic CRC will activate in early 2022. Clinical trial information: NCT04017650.

The Prognostic Value of Locoregional Interventions for BRAF V600E Metastatic Colorectal Cancer: A Retrospective Cohort Analysis.

The prognostic heterogeneity in patients with BRAF V600E metastatic colorectal cancer (mCRC) remains poorly defined. Real-world data of 93 BRAF V600E mCRC patients from Sun Yat-sen University Cancer Center were evaluated using the prognostic factors affecting overall survival (OS). Treatment of metastases served as an independent prognosticator, where curative locoregional interventions (LRIs) were associated with superior clinical outcomes (adjusted hazard ratio (HR): 0.46, 95% confidence interval (CI): 0.22–0.98; p = 0.044). The LRIs group showed an improved median OS of 49.4 months versus 18.3 months for the palliative treatments (PTs) group. The median OS of patients with colorectal liver metastasis (CRLM) was significantly prolonged after undergoing LRIs (42.4 vs. 23.7 months; HR: 0.11, 95% CI: 0.01–1.22; p = 0.030), and patients in the LRIs plus liver-limited or lung-limited metastasis (LLM) group benefited more than those in the LRIs plus non-LLM group when compared to the PTs group (LLM from LRIs vs. PTs, HR: 0.16, 95% CI: 0.04–0.68; p = 0.006. Non-LLM from LRIs vs. PTs, HR: 0.47, 95% CI: 0.21–1.05; p = 0.074). In conclusion, we confirmed the positive prognostic value of LRIs in BRAF V600E mCRC, particularly in patients with CRLM or LLM.

LBA-3 Integrated analysis of cell-free DNA (cfDNA) BRAF mutant allele fraction (MAF) and whole exome sequencing in BRAFV600E metastatic colorectal cancer (mCRC) treated with BRAF-antiEGFR +/- MEK inhibitors

The combination of encorafenib and cetuximab has led to a paradigm change in BRAFV600E mCRC with significant improved outcomes over the standard of care. Our group previously reported that BRAFV600E mCRC patients treated with BRAF/EGFR+/-MEK inhibitors could be split into three different prognostic subgroups according to tumor load surrogates. Here, we integrate the analysis of BRAFV600E MAF in cell-free DNA (cfDNA) and whole exome sequencing data to unveil predictive/prognostic profiles. An international, prospective, multicentric cohort included 59 BRAFV600E mutated mCRC patients from Vall d'Hebron and Università della Campania L. Vanvitelli, Naples that received encorafenib-cetuximab +/- binimetinib. Basal plasma samples were extracted from 40 patients and BRAF MAF by ddPCR was performed baseline. Moreover, samples for plasma Whole Exome Sequence (plWES) were also extracted baseline from 23 patients. All patients received BRAF/EGFR+/-MEK inhibitors. Responses were evaluated every 8 weeks. The primary endpoint is to correlate BRAF MAF with overall survival and overall response rate. Secondary endpoints included the identification of a WES driving signature that could predict clinical outcomes. Event rates over time will be estimated within each treatment group using the Kaplan-Meier method. In total, 70 patients were included in the analysis. Median age was 61y (33-83), 56% female, 34% right-sided tumors, and 56% received 2 or more prior chemotherapy lines. Overall, median PFS was 5.2 months (m) (CI 95% 4.1-8.5) and median OS (mOS) was 10.3 m (CI 95% 6.5-20.2). BRAF MAF was >5% in 14 pts (35%), <5% in 10 pts (25%), and undetectable in 16 pts (40%) with a mOS of 4.2 m, 17.1 m (HR 0.21, p<0.001), and 17.5 m (HR 0.15, p<0.001), respectively. In the multivariate analysis the most parsimonious model included five factors: ECOG, presence of liver metastases, CEA, NLR levels, and BRAF MAF. We stratified patients into three risk prognostic groups based on their number of presenting risk factors. These three prognostic groups showed differentiated OS outcomes, with a median OS of 5.1 m, 8.4 m (HR 0.26, p<0.001), and 21.8 m (HR 0.05, p<0.005), respectively. Added to this, WES analysis showed a clinical benefit of targeted therapy in those tumors with a BRAF/EGFR gain as well as an enrichment of response in RNF43 mutated tumors. Our preliminary data suggest that cfDNA BRAF MAF may constitute a significant tumor load surrogate with correlation with overall survival. cfDNA BRAF MAF and WES could help to identify three subgroups of patients with different prognostic and predictive features that could potentially have therapeutic implications.

BRAF, MEK and EGFR inhibition as treatment strategies in BRAF V600E metastatic colorectal cancer.

Introduction:BRAF driver mutations are found in up to 15% of patients with colorectal cancer (CRC) and lead to constitutive activation of BRAF kinase and sustained RAS/RAF/MEK/ERK pathway signaling. BRAF mutations define a sub-population characterized by a poor prognosis and dismal median survival. Following successful outcomes with BRAF inhibition in BRAF mutant metastatic melanoma, this approach was evaluated in metastatic colorectal cancer (mCRC). The development and combination of targeted therapies against multiple signaling pathways has proved particularly successful, with improved survival and response rates.Areas covered:This review addresses the development of therapeutic strategies with inhibitors targeting MAPK/ERK and EGFR signaling in BRAF V600E mutated mCRC, focusing on encorafenib, binimetinib and cetuximab. A pharmacological and clinical review of these drugs and the therapeutic approaches behind their optimization are presented.Expert opinion:Exploiting knowledge of the mechanisms of resistance to BRAF inhibitors has been crucial to developing effective therapeutic strategies in BRAF-V600E mutant mCRC. The BEACON trial is a successful example of this approach, using encorafenib and cetuximab with or without binimetinib in patients with previously treated BRAF V600E mutant mCRC, showing an impressive improvement in clinical outcomes and tolerable toxicity compared with chemotherapy, establishing a new standard of care in this setting.

Encorafenib plus cetuximab with or without binimetinib for BRAF V600E metastatic colorectal cancer: Updated survival results from a randomized, three-arm, phase III study versus choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC).

4001 Background: BEACON CRC is a randomized, phase 3 study which evaluated the triplet of encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) and the doublet of ENCO + CETUX vs. investigator’s choice of irinotecan + CETUX or FOLFIRI + CETUX in patients (pts) with BRAFV600E metastatic colorectal cancer (mCRC) whose disease had progressed after 1-2 prior regimens in the metastatic setting. Primary endpoints were overall survival (OS) and objective response rate (ORR; by blinded central review) for triplet vs control. In a previous interim analysis, triplet and doublet improved OS and ORR versus standard of care. Here we report on an updated analysis. Methods: Updated analysis includes 6 months of additional follow-up and response data for all randomized pts. The study is ongoing. Results: Pts received triplet (n=224), doublet (n=220), or control (n=221). Median OS was 9.3 months (95% confidence interval [CI]:8.2, 10.8) for triplet and 5.9 months (95% CI:5.1-7.1) for control (hazard ratio [HR] (95% CI): 0.60 (0.47-0.75)). Median OS for doublet was 9.3 months (95% CI: 8.0-11.3) (HR vs. control: 0.61 (0.48-0.77). Confirmed ORR was 26.8% (95% CI: 21.1%-33.1%) for triplet, 19.5% (95% CI: 14.5%-25.4%) for doublet, and 1.8% (95% CI: 0.5%-4.6%) for control. Retrospective subgroup analyses suggested some pts may benefit more from triplet than doublet therapy (Table). Both triplet and doublet showed improved OS compared to control in all subgroups. Adverse events were consistent with prior analysis, with grade ≥3 adverse events in 65.8%, 57.4%, and 64.2% for triplet, doublet and control, respectively. Conclusions: The updated analysis of the BEACON CRC study confirmed that encorafenib + cetuximab with or without binimetinib improved OS and ORR in previously treated pts with BRAF V600E mCRC compared with standard chemotherapy. Clinical trial information: NCT02928224 . [Table: see text]

Encorafenib plus cetuximab with or without binimetinib for BRAF V600E-mutant metastatic colorectal cancer: Quality-of-life results from a randomized, three-arm, phase III study versus the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC).

4039 Background: In the BEACON CRC study, the triplet regimen of encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) significantly improved overall survival (OS, HR:0.52, P &lt; 0.0001) and objective response rates (ORR, 26% vs 2%, P &lt; 0.0001) in patients (pts) with BRAFV600E metastatic colorectal cancer (mCRC) compared with current standard of care. This analysis focuses on the patient-reported quality of life (QOL) assessments from this study. Methods: The BEACON CRC study was a randomized, open-label, 3-arm, phase 3 global study which evaluated triplet (ENCO+BINI+CETUX) or doublet (ENCO+CETUX) vs. investigator’s choice of irinotecan + CETUX or FOLFIRI + CETUX in pts with BRAFV600E mCRC. QOL assessments (secondary endpoints in the trial) included the EORTC QOL Questionnaire (QLQ C30), Functional Assessment of Cancer Therapy Colon Cancer (FACT C), EuroQol 5D 5L, and Patient Global Impression of Change (PGIC). The primary assessment for the QOL variables was the time to definitive 10% deterioration. The study is ongoing. Results: 665 pts were randomly assigned to receive either triplet (n = 224), doublet (n = 220), or control (n = 221). Reduction in the risk of QOL deterioration was an estimated 45% (HR 0.55, 95% CI: 0.43, 0.70) and 52% (HR 0., 9485% CI: 0.38, 0.62) in EORTC QLQ C30 and FACT C assessments, respectively, in favor of the triplet regimen over control. For the doublet vs. control, reduction in risk of QOL deterioration was an estimated 46% (HR 0.54, 95% CI: 0.43, 0.69) and 54% (HR 0.46, 95% CI: 0.36, 0.59) in EORTC QLQ C30 and FACT C, respectively in favor of the doublet. Similar results were observed in EuroQol 5D 5L and PGIC assessments. There were no overall differences in QOL between triplet and doublet across the 4 instruments. Conclusions: In BEACON CRC, triplet and doublet demonstrated substantial improvement in patient-reported QOL assessments over the current standard of care in pts with BRAFV600E-mutant metastatic CRC whose disease had progressed after 1 or 2 prior regimens. Clinical trial information: NCT02928224 .

Encorafenib plus cetuximab with or without binimetinib for BRAF V600E-mutant metastatic colorectal cancer: Quality-of-life results from a randomized, three-arm, phase III study versus the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC).

8 Background: In the BEACON CRC study, the triplet regimen of encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) significantly improved overall survival (OS, HR:0.52, P &lt; 0.0001) and objective response rates (ORR, 26% vs 2%, P &lt; 0.0001) in patients (pts) with BRAF V600E metastatic colorectal cancer (mCRC) compared with current standard of care. This analysis focuses on the patient-reported quality of life (QOL) assessments from this study. Methods: The BEACON CRC study was a randomized, open-label, 3-arm, phase 3 global study which evaluated triplet (ENCO+BINI+CETUX) or doublet (ENCO+CETUX) vs. investigator’s choice of irinotecan + CETUX or FOLFIRI + CETUX in pts with BRAFV600E mCRC. QOL assessments (secondary endpoints in the trial) included the EORTC QOL Questionnaire (QLQ C30), Functional Assessment of Cancer Therapy Colon Cancer (FACT C), EuroQol 5D 5L, and Patient Global Impression of Change (PGIC). The primary assessment for the QOL variables was the time to definitive 10% deterioration between arms. Results: 665 pts were randomly assigned to receive either triplet (n = 224), doublet (n = 220), or control (n = 221). Reduction in the risk of QOL deterioration was an estimated 45% (HR 0.55, 95% CI: 0.43, 0.70) and 44% (HR 0.56, 95% CI: 0.44, 0.71) in EORTC QLQ C30 and FACT C assessments, respectively, in favor of the triplet regimen over control. For the doublet vs. control, reduction in risk of QOL deterioration was an estimated 46% (HR 0.54, 95% CI: 0.43, 0.69) and 43% (HR 0.57, 95% CI: 0.45, 0.72) in EORTC QLQ C30 and FACT C, respectively in favor of the doublet. Similar results were observed in EuroQol 5D 5L and PGIC assessments. There were no overall differences in QOL between triplet and doublet across the 4 instruments. Conclusions: In BEACON CRC, triplet and doublet demonstrated substantial improvement in patient-reported QOL assessments over the current standard of care in pts with BRAF V600E-mutant metastatic CRC whose disease had progressed after 1 or 2 prior regimens. Clinical trial information: NCT02928224.

LBA32 - Encorafenib plus cetuximab with or without binimetinib for BRAF V600E–mutant metastatic colorectal cancer: Expanded results from a randomized, 3-arm, phase III study vs the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC)

LBA32 - Encorafenib plus cetuximab with or without binimetinib for BRAF V600E–mutant metastatic colorectal cancer: Expanded results from a randomized, 3-arm, phase III study vs the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC)

Characteristics of BRAFV600E Mutant, Deficient Mismatch Repair/Proficient Mismatch Repair, Metastatic Colorectal Cancer: A Multicenter Series of 287 Patients.

BRAFV600E mutations occurring in about 10% of metastatic colorectal cancers (mCRCs) are usually associated with a poor outcome. However, their prognostic factors are unknown. We built a multicenter clinico-biological database gathering data from patients with BRAFV600E -mutant mCRC treated in one of the 16 French centers from 2006 to 2017. The primary endpoint was to identify prognostic factors using a Cox model. We included 287 patients (median age, 67 years [28-95]; female, 57%). Their median overall survival was 20.8 months (95% confidence interval [CI], 17.97-27.04), and median progression-free survival in the first-line setting was 4.34 months (95% CI, 3.81-5.03). Chemotherapy regimen and biological agents (antiangiogenic or anti-epidermal growth factor receptor) were not associated with overall and progression-free survival. Stage IV disease (synchronous metastases) and absence of curative-intent surgery were statistically associated with poor overall survival. Among the 194 patients with mismatch repair (MMR) status available, overall survival was significantly longer in patients with deficient MMR tumors compared with those with proficient MMR tumors (adjusted hazard ratio = 0.56; p = .009). Despite that BRAFV600E -mutant mCRCs are associated with poor overall and progression-free-survival, patients with deficient MMR tumors and/or resectable disease experienced a longer survival. These results highlight the importance of MMR testing and resectability discussion in patients with BRAFV600E mCRC in day-to-day practice. Mismatch repair (MMR) testing and resectability discussion in patients with BRAFV600E metastatic colorectal cancer (mCRC) should be performed in day-to-day practice to steer treatment decision making in patients with BRAFV600E -mutant mCRC.

Systemic Therapy in BRAF V600E-Mutant Metastatic Colorectal Cancer: Recent Advances and Future Strategies.

This review seeks to detail the clinical and pathologic features specific to BRAF V600E colorectal cancer. Application of novel preclinical findings translated into the clinic for the development of new therapeutic options for patients with BRAF V600E metastatic colorectal cancer will be detailed. While BRAF inhibitors in monotherapy do not have the same clinical activity for colorectal cancer relative to other solid tumors harboring an oncogenic BRAF V600E mutation, combination approaches targeting BRAF + MEK +EGFR hold promise for patients BRAF V600E colorectal cancer. Simultaneous targeting of multiple drivers along the MAPK pathway improve clinical outcomes for patients with BRAF V600E colorectal cancer. Targeted therapies and immunotherapy hold great promise in the years to come for patients with this subtype of colorectal cancer.

Antitumor activity of panRAF inhibition in BRAF V600E metastatic colorectal cancer.

616 Background: BRAF V600E mutations, present in &lt;10% of patients with metastatic colorectal cancer (mCRC), are associated with low responses to chemotherapy and poor survival outcomes. Targeted therapies against BRAF and EGFR have shown promising clinical activity. The panRAF inhibitor (PRI) LSN3074753 inhibits dimerization of all RAF isoforms to impede downstream MEK activation, with no reflexive MAPK reactivation common with other BRAF inhibitors. Anti-tumor activity of PRI has not been compared to BRAF + EGFR inhibition in patient-derived xenograft (PDX) models of BRAF V600E mCRC. Methods: Two PDX models of BRAF V600E mCRC (B1003 and C0999) were generated. C0999 featured a concomitant KRAS G12D mutation following resistance to the BRAF V600E kinase inhibitor vemurafenib. Mice were treated daily with oral PRI or with the combination of vemurafenib + intraperitoneal cetuximab. Tumor volumes were measured twice weekly. B1003 and C0999 cell cultures were established to test the interaction between PRI and palbociclib or BYL319 (PI3K inhibitor). Results: PRI was tolerated at a dose of 60 mg/kg and demonstrated a reduced tumor volume in the B1003 model after 28 days when compared to untreated controls (P=.03). No difference in tumor volume was seen between PRI and vemurafenib + cetuximab (P=.08). Assessment of anti-tumor activity by PRI in the vemurafenib-resistant BRAF V600E/KRAS G12D C0999 model will be reported. Cell culture from both the B1003 and C0999 models demonstrated synergism for PRI with palbociclib (ED50 .41 and .62 for the 2 models, respectively) and with BYL319 (ED50 .48 and .86, respectively). Conclusions: panRAF inhibition demonstrates similar anti-tumor activity to BRAF + EGFR inhibition in PDX models of BRAF V600E and represents a promising treatment strategy for further combination studies targeting additional critical signaling pathways in mCRC.