Triplet combination of encorafenib, binimetinib and cetuximab safe and effective in patients with BRAFV600E-mutant metastatic colorectal cancer

As patients with BRAF^V600E-mutant metastatic colorectal cancer (mCRC) face a poor prognosis, new effective therapies are urgently needed. In this respect, the ANCHOR CRC study assessed the combination of a BRAF-, MEK-, and EGFR-inhibitor (encorafenib, binimetinib and cetuximab, respectively). Despite the fact that the study was conducted in a population with a high median age and an advanced disease stage at diagnosis, the triplet was found to be associated with a high objective response rate (ORR, 50%), with almost all patients having a decrease in tumour size. The progression-free survival (PFS) in ANCHOR CRC was similar to what can be achieved with chemotherapy in the first-line treatment of BRAF-mutant metastatic CRC and the triplet combination was well tolerated and manageable with no unexpected toxicities.

Background

BRAF^V600E mutations occur in about10-15% of patients with metastatic colorectal cancer (mCRC) and confer a poor prognosis. Recent studies with chemotherapy-based regimens have shown poor outcomes with an expected median overall survival (OS) with first-line irinotecan-based chemotherapy with/without cetuximab of only 10 to 14 months. With this treatment, the median PFS rarely exceeds 6 months with an ORR of 15 to 19%. Unfortunately, monotherapy with BRAF-inhibitors proved to be fairly ineffective in these patients due to the feedback activation of EGFR in BRAF-mutant CRC, leading to continued cell proliferation. This feedback mechanism may be overcome by targeting multiple nodes in the MAPK pathway.

The ANCHOR CRC study is a phase II study in first-line BRAF^V600E mCRC and has a 2-stage design. Enrolled patients could not have received prior treatment with any BRAF-inhibitor, MEK-inhibitor or anti-EGFR inhibitor and must have an ECOG performance status of 0 or 1. Stage 1 of the study included 40 patients with a confirmed BRAF-mutation who all received encorafenib, binimetinib and cetuximab. Stage 2 of the study will enrol additional patients only if at least twelve responses were observed in stage 1. All patients received treatment until disease progression, unacceptable toxicity or consent withdrawal and continued follow-up for survival every three months.

Results

The median age of study participants in stage 1 of the study was 67 years with 61% being at least 65 years old. The median time since the initial diagnosis was 63 days and most patients (78%) had at least two metastatic organs. Metastatic site locations were characteristic for BRAF-mutant tumours and mostly involved the peritoneum (51% of patients) and lymph nodes (51% of patients). After a median of 4.9 months on treatment, 50% of patients had a confirmed objective response (all partial responses) with an additional 35% of patients experiencing disease stabilization. As such, the study results met the futility criteria of stage 1 and enrolment for stage 2 of the study was initiated. Virtually all patients, including those with progressive disease, experienced some form of tumour shrinkage upon treatment with the triplet regimen. Nine patients (22%) were still on treatment at the cut-off date of February 6^th, 2020. After a median follow-up of 4.6 months, the investigator assessed median PFS was 4.9 months, which is in line with what was observed with chemotherapy in the first line treatment of BRAF-mutant mCRC patients.

In total, 68% of patients experienced a grade ≥3 adverse event (AE) and 49% had a serious AE of grade ≥3.  AEs led to dose interruptions or dose reductions in 68% of patients and to treatment discontinuation of at least one study drug in 20% of patients. Three patients (7%) died because of an adverse event. The most frequent grade ≥3 AEs were diarrhoea, anaemia and acute kidney injury, which is in line with what was seen with this triple combination in the BEACON study.

Conclusions

The ANCHOR CRC study is the first prospective study using a BRAF-inhibitor based therapy in the first line treatment of BRAF^V600E-mutant mCRC. The study was conducted in a population with a high median age and an advanced stage at diagnosis, making this population notably different to that observed in retrospective analyses of prior studies. Despite these dismal characteristics, a high ORR (50%) was observed, with almost all patients experiencing a decrease in their tumour size. The median PFS of five months is similar to that observed with chemotherapy in first line BRAF-mutant metastatic CRC. Finally, the triplet combination was well tolerated and manageable with no unexpected toxicities. Additional patients are now allowed to enrol for Stage 2 of the study.

Reference

Grothey A, Tabernero J, Taïeb J, et al. ANCHOR CRC: a single-arm,phase 2 study of encorafenib, binimetinib plus cetuximab in previously untreated BRAFV600E–mutant metastatic colorectal cancer. Presented at ESMO World GI 2020; Abstract LBA-5.