Encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mutated metastatic colorectal cancer: real-life data from an Italian multicenter experience

Boccaccino, Alessandra; Borelli, Beatrice; Intini, Rossana; Antista, Maria; Bensi, Maria; Rossini, Daniele; Passardi, Alessandro; Tamberi, Stefano; Antonuzzo, Lorenzo; Noto, Leonardo; Roviello, Giandomenico; Zichi, Clizia; Salati, Massimiliano; Puccini, Alberto; Noto, C.; Parisi, Alessandro; Rihawi, Karim; Persano, Mara; Crespi, Veronica; Libertini, Michela; Giordano, Mirella; Moretto, Roberto; Cremolini, Chiara

doi:10.1016/j.esmoop.2022.100506

Cited by 16 publications

(10 citation statements)

References 20 publications

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“…Adverse events were slightly higher in the three-drug regimen as compared to the two-drug regimen and were similar to side effects seen with previous trials on BRAF , EGFR , and MEK inhibitors. A real-world study by Boccaccino et al returned the same response results for the three-drug regimen vs. the two-drug regimen as seen in the BEACON trial [ 25 ]. However, in the long-term updated results of the BEACON trial by Tabernero et al, response rates were slightly better with the three-drug regimen vs. two-drug regimen (27% vs. 20%), but there was no difference in median OS among the two groups (9.3 months vs. 9.3 months).…”

Section: Discussionmentioning

confidence: 92%

BRAF Inhibitors in BRAF-Mutated Colorectal Cancer: A Systematic Review

Aiman,

Ali,

Jumean

et al. 2023

JCM

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Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths globally. BRAF mutation is present in about 10% of CRC patients and is associated with a poor response to chemotherapy. These patients have a relatively poor prognosis. This review aims to assess the efficacy and safety of BRAF inhibitors in BRAF-mutated CRC patients. A literature search was performed on PubMed and Embase, and clinical trials relevant to BRAF inhibitors in CRC were included. Data were extracted for efficacy and safety variables. Two randomized clinical trials (n = 765) and eight non-randomized trials (n = 281) were included based on inclusion criteria. In RCTs, an overall response was reported in 23% of the patients treated with BRAF inhibitor-based regimens compared to 2.5% with control regimens. The hazard ratio of overall survival was also significantly better with triplet encorafenib therapy at 0.52 (95% CI = 0.39–0.70). In single-arm trials, ORR was 17% and 34% in two-drug and three-drug regimens, respectively. BRAF inhibitor-based regimens were safe and effective in the treatment of BRAF-mutated CRC. Large-scale randomized trials are needed to find a suitable population for each regimen. PROSPERO registration No. CRD42023471627.

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Section: Discussionmentioning

confidence: 92%

BRAF Inhibitors in BRAF-Mutated Colorectal Cancer: A Systematic Review

Aiman,

Ali,

Jumean

et al. 2023

JCM

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“…It is worth noting that only 10% of the patients that participated in BEACON had MSI high cancers compared with a prevalence of MSI exceeding 50% in BRAF mutant colorectal cancers of the TCGA and DFCI cohorts. Similarly, in a “real life” cohort of BRAF mutant metastatic colorectal cancers treated with targeted therapies as used in the BEACON trial in several Italian centers, the prevalence of MSI or Mismatch Repair deficiency was 15% [ 34 ]. This suggests that MSS cancers are enriched in the metastatic setting and that MSI-associated BRAF mutated cancers progress less often to a metastatic stage.…”

Section: Discussionmentioning

confidence: 99%

The Genomic Environment of BRAF Mutated and BRAF/PIK3CA Double Mutated Colorectal Cancers

Voutsadakis

2022

JCM

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Background: Colorectal cancer represents the most prevalent gastrointestinal malignancy. Prognosis of metastatic disease has improved in recent years with the introduction of effective systemic therapies, but mean survival remains in the range of two to three years. Targeted therapies based on specific molecular alterations in sub-sets of colorectal cancers have the potential of contributing to therapeutic progress. BRAF and PIK3CA are oncogenic kinases commonly mutated in colorectal cancers and can be targeted through small molecule kinase inhibitors. Methods: Clinical and genomic data from two extensive series of colorectal cancers were interrogated to define the molecular characteristics of cancers with BRAF mutations with and without concomitant mutations in PIK3CA. Results: Colorectal cancers that are BRAF and PIK3CA double mutants represent a small minority of about 5% of colorectal cancers in the two examined series of mostly localized disease. They also represent about one third of all BRAF mutated colorectal cancers. Most mutations in BRAF are classic V600E mutations. A high prevalence of MSI and CIMP is observed in BRAF mutated colorectal cancers with or without PIK3CA mutations. Mutations in tumor suppressors FBXW7 and ATM display a higher prevalence in BRAF mutated cancers. The prognosis of BRAF mutated colorectal cancers with or without PIK3CA mutations is not significantly different than counterparts with wild type BRAF. This contrasts with the known adverse prognostic effect of BRAF in metastatic disease and relates to the different prevalence of MSI in mutant BRAF localized versus metastatic colorectal cancers. Conclusions: BRAF mutations are the defining molecular alterations in double mutant BRAF and PIK3CA colorectal cancers as determined by increased MSI and CIMP in BRAF subsets with and without PIK3CA mutations. Moreover, BRAF mutated cancers with and without PIK3CA mutations are characterized by the absence of KRAS mutations and a lower prevalence of APC mutations than BRAF wild type counterparts. Mismatch-repair-associated gene mutations display higher frequencies in BRAF mutated colorectal cancers. Despite the absence of prognosis implications of BRAF mutations in the studied cohorts of mostly localized cancers, such mutations could be prognostic in certain subsets. The presence of mutations in other genes, such as ATM and high MSI status present opportunities for combination therapies.

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“…However, despite application of strict eligibility criteria in the trial, the guideline recommendation is generalized to all patients with pretreated BRAF V600E mutated mCRC, and does not elaborate on the uncertainty of benefit in patients who were not represented in the BEACON trial [ 39 , 40 ]. Boccacino and colleagues found that patients treated with encorafenib-cetuximab in an Italian nominal use program had approximately 2 months shorter median OS [ 41 ]. As this nominal use program applied eligibility criteria closely resembling those of BEACON, an additional population-based study was conducted in the Netherlands which discovered that over a third of all patients treated with encorafenib-cetuximab in routine clinical care would have been ineligible for the BEACON trial [ 42 ].…”

Section: Using Rwd For Treatment Effect Evaluationmentioning

confidence: 99%

Harnessing the Potential of Real-World Evidence in the Treatment of Colorectal Cancer: Where Do We Stand?

van Nassau,

Bol,

van der Baan

et al. 2024

Curr. Treat. Options in Oncol.

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Opinion statementTreatment guidelines for colorectal cancer (CRC) are primarily based on the results of randomized clinical trials (RCTs), the gold standard methodology to evaluate safety and efficacy of oncological treatments. However, generalizability of trial results is often limited due to stringent eligibility criteria, underrepresentation of specific populations, and more heterogeneity in clinical practice. This may result in an efficacy-effectiveness gap and uncertainty regarding meaningful benefit versus treatment harm. Meanwhile, conduct of traditional RCTs has become increasingly challenging due to identification of a growing number of (small) molecular subtypes. These challenges—combined with the digitalization of health records—have led to growing interest in use of real-world data (RWD) to complement evidence from RCTs. RWD is used to evaluate epidemiological trends, quality of care, treatment effectiveness, long-term (rare) safety, and quality of life (QoL) measures. In addition, RWD is increasingly considered in decision-making by clinicians, regulators, and payers. In this narrative review, we elaborate on these applications in CRC, and provide illustrative examples. As long as the quality of RWD is safeguarded, ongoing developments, such as common data models, federated learning, and predictive modelling, will further unfold its potential. First, whenever possible, we recommend conducting pragmatic trials, such as registry-based RCTs, to optimize generalizability and answer clinical questions that are not addressed in registrational trials. Second, we argue that marketing approval should be conditional for patients who would have been ineligible for the registrational trial, awaiting planned (non) randomized evaluation of outcomes in the real world. Third, high-quality effectiveness results should be incorporated in treatment guidelines to aid in patient counseling. We believe that a coordinated effort from all stakeholders is essential to improve the quality of RWD, create a learning healthcare system with optimal use of trials and real-world evidence (RWE), and ultimately ensure personalized care for every CRC patient.

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Encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mutated metastatic colorectal cancer: real-life data from an Italian multicenter experience

Cited by 16 publications

References 20 publications

BRAF Inhibitors in BRAF-Mutated Colorectal Cancer: A Systematic Review

BRAF Inhibitors in BRAF-Mutated Colorectal Cancer: A Systematic Review

The Genomic Environment of BRAF Mutated and BRAF/PIK3CA Double Mutated Colorectal Cancers

Harnessing the Potential of Real-World Evidence in the Treatment of Colorectal Cancer: Where Do We Stand?

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