Encorafenib-based therapy is life-prolonging in patients with BRAFV600E mutant metastatic colorectal cancer

Results of the phase III BEACON CRC study demonstrate that encorafenib-cetuximab with or without binimetinib significantly prolongs the survival of previously treated patients with metastatic BRAF^V600E-mutated metastatic colorectal cancer, compared to irinotecan-based chemotherapy in combination with cetuximab. In addition to this, both experimental regimens led to a significant reduction in the risk of disease progression and significantly increased the proportion of patients with a response to therapy compared to the control arm. A descriptive comparison between the triplet and the doublet regimen suggests that the addition of binimetinib to the doublet invokes an improved efficacy at the cost of some additional, manageable toxicity.

Background

BRAF mutations are estimated to occur in approximately 8-15% of patients with metastatic colorectal cancer (mCRC) and were found to be associated with a dismal prognosis. The V600E mutation is the most common BRAF mutation and the risk of mortality in CRC patients harboring a BRAF^V600E mutation is more than two times higher than for those with wild-type BRAF. The initial standard chemotherapy for BRAF^V600E-mutated CRC results in poor outcomes, and attempts to intensify therapy were not very successful. The situation for patients failing first-line chemotherapy looks dire, as subsequent lines of treatment only have a minimal effect resulting in rapid disease progression and a short survival prospect.

Although BRAF^V600E is a driver mutation found in multiple tumor types, and BRAF inhibitors have demonstrated substantial clinical activity in BRAF ^V600E-mutated melanoma and non-small-cell lung cancer, BRAF inhibitors alone only had limited activity in BRAF^V600E-mutated CRC. Several (pre)clinical studies have shown that BRAF inhibitors have increased antitumor activity in BRAF^V600E-mutated CRC when they are combined with an anti-EGFR monoclonal antibody. In addition, clinical studies in BRAF-mutated melanoma have established that dual inhibition of both BRAF and MEK is more effective than BRAF inhibition alone. In this light, the phase III BEACON CRC trial evaluated whether treatment with a combination of the BRAF inhibitor encorafenib plus cetuximab with or without the MEK inhibitor binimetinib would result in a longer overall survival (OS) than what is obtained with what is considered as standard therapy in patients with BRAF^V600E-mutated mCRC with disease progression after one or two previous lines of therapy.

Study design

BEACON CRC is the first and only phase III trial designed to test a BRAF/MEK combination targeted therapy in BRAF^V600E-mutant mCRC. Thirty patients were treated with encorafenib (300 mg daily), binimetinib (45 mg twice daily) and cetuximab (per label) in the safety lead-in phase of the trial. The acceptable safety profile of the triplet therapy in this phase supported the initiation of the randomised portion of the trial in which 665 patients were randomised (1:1:1) to receive either encorafenib + binimetinib + cetuximab (triplet), encorafenib + cetuximab (doublet) or irinotecan-based therapy and cetuximab (control). The primary endpoint of the trial consisted of OS with the triplet therapy compared to chemotherapy + cetuximab. Secondary endpoints of the trial also addressed the efficacy of the doublet therapy compared with the control arm, and of the triplet compared to the doublet regimen. Other study objectives included progression-free survival (PFS), duration of response, safety and tolerability.

Results

About one third of patients in the trial had a primary tumor in the left colon and in about half of the patients 3 or more organs were involved. Approximately 60% of patients had liver metastases at the start of therapy. Two thirds of patients received the study drug in second line, the rest in third or later lines. At the time of the presented analysis, treatment was ongoing in 35% of the patients randomized to the doublet or triplet therapy as compared to 17% in the control arm.

As previously presented during the 2019 World Congress on Gastrointestinal Cancer, the triplet combination was associated with a median OS of 9.0 months as compared to 5.4 months in the control arm (HR [95% CI]: 0.52 [0.39-0.70]; p<0.001). In addition to this, the triplet also demonstrated a significantly improved ORR of 26% as compared to 2% for the control arm (p<0.001). Also patients who were treated with the doublet had a significantly longer OS (median OS: 8.4 vs 5.4 months; HR [95% CI]: 0.60 [0.45-0.79]; p=0.0003) and a higher ORR rate (20% vs 2%, p<0.001) than patients in the control arm. Also with respect to PFS both the triplet and doublet combination outperformed the control arm with a median PFS of 4.3 and 4.2 months, respectively, as compared to 1.5 months in the control arm (HR [95% CI]: 0.38 [0.29-0.49] and 0.40 [0.31-0.52], respectively; p<0.001 for both).

The BEACON CRC study was not powered to compare the two experimental arms directly and such a comparison was further limited by the interim nature of the presented analysis. Nevertheless, results of the descriptive survival analysis comparing the triplet regimen to the doublet favored the triplet arm. In an OS analysis for the first 331 patients who were randomised (median follow-up 12.5 months), the median OS was 9.5 months with the triplet regimen as compared to 8.3 months with the doublet (HR [95% CI]: 0.74 [0.53-1.04]). In the same dataset including the first 331 randomized patients the ORR was 26% with the triplet, 20% with the doublet, and 2% in the control arm. Not surprisingly, the response rates were higher when the experimental regimens were used earlier in the disease course. In fact, in the subgroup of patients who received only one prior line of therapy, the ORR with the triplet reached 34%, while this was only 14% in patients who received more than 1 line of therapy (22% and 16%, respectively, for the doublet).

Both the triplet and the doublet regimen showed no unexpected toxicities. Grade 3 or higher adverse events (AEs) were seen in 58%, 50% and 61% of patients treated with the triplet, the doublet and the control, respectively. The 11% treatment discontinuation rate in the control arm was higher than what was seen with the experimental regimens (7% with triplet, 8% with doublet). The most common grade 3 or higher AEs seen in patients treated with the triplet were diarrhea (10% vs. 2% in the doublet arm and 10% in the control arm), abdominal pain (6% vs 2% in the doublet arm and 5% in the control arm) and nausea (5% vs <1% in the doublet arm and 1% in the control arm).

Conclusions

In the BEACON CRC study, the encorafenib-cetuximab combination with or without binimetinib significantly prolonged the survival of previously treated patients with BRAF^V600E-mutated mCRC, compared to irinotecan-based chemotherapy in combination with cetuximab. With respect to the comparison between the triplet and the doublet regimen, the presented data (descriptive only) suggest that the addition of binimetinib to the doublet invokes improved efficacy at the cost of some additional, manageable toxicity.

As such, the BEACON CRC study possibly provides a new standard of care in patients with previously treated BRAF^V600E-mutant mCRC. More research is needed to further elucidate the relative benefit of the two regimens.

Reference

Tabernero J, Grothey A, Van Cutsem E, et al. 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). Presented at ESMO 2019; Abstract LBA32.