Allele Fractions Reliable Surrogate for Tumor Burden Following BRAFi in CRC

Plasmatic BRAF allele fraction prognosticated tumor burden in BRAF V600E–mutant metastatic colorectal cancer (CRC) following treatment with a BRAF inhibitor plus anti-EGFR therapy with or without a MEK inhibitor, highlighting which patients may benefit most from treatment intensification, according to findings from a prospective study published in Annals of Oncology.

"These results suggest that plasmatic BRAF [allele fraction] has a survival impact and can be used to identify potentially longer [survival]," according to the authors of a study published in Annals of Oncology.

With a median follow-up of 24.1 months in a discovery cohort of 47 patients, the median progression-free survival (PFS) and overall survival (OS) were 4.4 months (95% CI, 3.6-8.0) and 10.1 months (95% CI, 6.5-17.5), respectively. Additionally, patients with high BRAF allele fraction of at least 2% (n = 23) had a median OS of 4.6 months, and patients with low BRAF allele fraction of lower than 2% (n = 24) had a median OS of 17.5 months (HR, 3.28; 95% CI, 1.58-6.81; P = .001). Median PFS in each respective group was 3.3 months vs 8.3 months (HR, 2.97; 95% CI, 1.55-5.69; P = .001).

With a median follow-up of 21.8 months in a validation cohort of 29 patients, the median OS and median PFS, respectively, were 7.3 months (95% CI, 6.3-11.3) and 4.8 months (95% CI, 4.0-6.4). Consistent with the data reported in the discovery cohort, a high allele fraction in patients (n = 12) correlated with worse PFS compared with a low allele fraction (n = 17; HR, 3.83; 95% CI, 1.60-9.17; P = .003).

Additionally, the median OS was 6.4 months for patients with a high allele fraction vs 8.8 months for patients with a low allele fraction, indicating a trend toward worse OS in the high allele fraction group that was not statistically significant (HR, 1.86; 95% CI, 0.80-4.34; P = .15).

“These results suggest that plasmatic BRAF [allele fraction] has a survival impact and can be used to identify potentially longer [survival],” the study authors stated. “While our analysis did not validate the results in the validation cohort in terms of OS, there is a clear tendency toward shorter OS among patients with high [allele fraction] in our population.”

Investigators of this study evaluated outcomes in patients with BRAF V600E–mutated metastatic CRC who received treatment at the Vall d’Hebdron University Hospital between 2015 and 2020, and included them in the discovery cohort. The external validation cohort included data from patients treated between 2018 and 2021 in 3 additional treatment centers from Italy and Spain.

Efficacy end points included PFS and OS. Investigators analyzed plasmatic BRAF V600E mutation samples with droplet digital polymerase chain reaction (ddPCR). Additionally, an evaluation of liquid biopsy aimed to identify a subgroup of patients who may derive benefit from doublet or triplet combination therapy including a MEK inhibitor.

Patients with a tissue-confirmed BRAF V600E mutation, available clinicopathological data, and an available plasma sample prior to beginning treatment with a combination including a BRAF inhibitor were eligible for inclusion in the study.

Investigators included a total of 76 patients with BRAF V600E–mutant metastatic CRC. In the discovery and validation cohorts, respectively, 49% and 41% had a high baseline BRAF allele fraction.

Compared with those who had a low allele fraction, more patients with a high allele fraction in the discovery cohort had an ECOG performance status of at least 2 (17% vs 0%), at least 2 tumor sites (43% vs 29%), and liver metastases (78% vs 17%). Similar trends in terms of these baseline characteristics occurred in high allele fraction and low allele fraction patients in the validation cohort.

Overall, 70% of patients in the discovery cohort and 72% in the validation cohort received doublet therapy. In the discovery cohort, the most common baseline genomic alterations included PTEN mutations (5.7%), AKT1 mutations (2.9%), KRAS amplification (2.9%), and EGFR amplification (2.9%). In the validation cohort, common alterations included GNAS mutations (14%), MET amplification (6.9%), KRAS mutations (3.4%), ARAF mutations (3.4%), ERBB2 mutations (3.4%), and EGFR mutations (3.4%).

In a multivariate analysis, factors that had statistically significant impact on OS included an ECOG performance status of 1 or more (HR, 5.21; 95% CI, 1.66-16.31; P = .005) and having 3 or 4 metastatic sites (HR, 2.94; 95% CI, 1.21-7.12; 95% CI, P = .017). Other factors that had a statistically significant impact on OS were carcinoembryonic antigen levels higher than 10 (HR, 4.03; 95% CI, 1.47-11.04; P = .007) and a high BRAF allele fraction (HR, 4.74; 95% CI, 1.52-14.81; P = .008).

Patients with low BRAF allele fraction experienced similar outcomes with triplet and doublet therapy in terms of OS (HR, 0.90; 95% CI, 0.38-2.14), whereas those with a high BRAF allele fraction had better OS with triplet combinations compared with doublet treatments (HR, 0.17; 95% CI, 0.06-0.53; interaction test = .002).

In terms of PFS, there was no difference in outcomes with doublet or triplet therapy for low BRAF allele fraction patients (HR, 1.12; 95% CI, 0.47-2.68), although those with a high BRAF allele fraction derived greater benefit from triplet therapy compared with doublet therapy (HR, 0.27; 95% CI, 0.11-0.68; interaction test = .005).

“The current study suggests the existence of a subgroup of patients [who] can potentially obtain benefit from more intensive treatment including a MEK inhibitor,” the study authors wrote. “Overall, our results highlight the utility of plasmatic BRAF [allele fraction] using ddPCR, particularly considering the difficulties of obtaining tissue samples in this specific population.”

Reference

Ros J, Matito J, Villacampa G, et al. Plasmatic BRAF-V600E allele fraction as a prognostic factor in metastatic colorectal cancer treated with BRAF combinatorial treatments. Ann Oncol. Published online March 13, 2023. doi:10.1016/j.annonc.2023.02.016