Tumor Biomarker Analysis of Encorafenib + Binimetinib in Advanced Melanoma

The randomized, 2-part, multicenter, open-label, phase 3 COLUMBUS study has demonstrated that encorafenib (enco) + binimetinib (bini) and enco alone (approved in the US, EU, and other countries) improved the 5-year PFS and OS as compared to vemurafenib (vemu) in patients (pts) with BRAF V600E/K–mutant metastatic melanoma. A retrospective analysis explored the genetic and transcriptional correlates associated with response and intrinsic resistance to enco + bini. This was done through an exploratory biomarker analysis of COLUMBUS Part 1. The ACE ImmunoID NeXT whole exome and whole transcriptome sequencing assays (Personalis) were utilized to analyze the baseline (BL) tumor samples. The analysis of progression-free survival (PFS) and overall survival (OS) was conducted with a data cutoff date of September 15th, 2020. The analysis was stratified by treatment type and the presence of particular genetic or transcriptomic alterations at baseline. A high tumor mutation burden (TMB) was characterized as a TMB above the median value of 8.6 mutations (muts) per megabase.

A total of 366 tissue specimens were effectively examined. The study’s findings entail a comparison between the enco + bini arm (comprising 116 participants) and the vemu arm (comprising 130 participants). The median progression-free survival (PFS) in the enco + bini and vemu arms was 14.9 and 5.7 months, respectively, with a hazard ratio (HR) of 0.55 [95% CI: 0.40–0.76]. The median overall survival (OS) was 34.8 and 18.6 months, respectively, with an HR of 0.67 [95% CI: 0.50–0.90], comparable to the safety cohort observations. Elevated tumor mutational burden (TMB), increased programmed death-ligand 1 (PD-L1) expression, and interferon-gamma (IFNg) signature was observed to be correlated with extended progression-free survival (PFS) and overall survival (OS) in the encorafenib plus binimetinib treatment group compared to the vemurafenib treatment group.

Elevated expression of ErbB2 and mutations in the PI3KCA pathway were observed to be linked with reduced survival outcomes in patients receiving the enco + bini regimen compared to those receiving the vemu regimen. Patients exhibiting elevated immune-related signatures demonstrated a superior clinical response to the combination therapy of enco + bini compared to vemu. Elevated ErbB2 expression and mutations in the PI3KCA pathway may serve as potential resistance mechanisms to the combination of enco and bini. The incorporation of checkpoint inhibitors or targeted therapies for the PI3KCA pathway, in conjunction with enco + bini, may potentially enhance the clinical advantages for patients diagnosed with metastatic melanoma with BRAF V600E/K mutation.

Source:https://oncologypro.esmo.org/meeting-resources/esmo-congress/tumor-biomarker-analysis-from-columbus-part-1-encorafenib-binimetinib-for-braf-v600e-k-mutant-advanced-or-metastatic-melanoma

Clinical Trial:https://clinicaltrials.gov/ct2/show/NCT01909453

R. Dummer, N. Pathan, S. Deng, C. Robert, A.M. Arance Fernandez, J.W.B. de Groot, C. Garbe, H.J. Gogas, R. Gutzmer, I. Krajsova, G. Liszkay, C. Loquai, M. Mandala, D. Schadendorf, N. Yamazaki, A. di Pietro, T. Xie, P.A. Ascierto, K. Flaherty/Tumor biomarker analysis from COLUMBUS part 1: Encorafenib + binimetinib for BRAF V600E/K-mutant advanced or metastatic melanoma/ESMO Congress | OncologyPRO. (n.d.). Oncologypro.esmo.org. Retrieved May 4, 2023, from https://oncologypro.esmo.org/meeting-resources/esmo-congress/tumor-biomarker-analysis-from-columbus-part-1-encorafenib-binimetinib-for-braf-v600e-k-mutant-advanced-or-metastatic-melanoma