Antitumor efficacy of dual blockade with encorafenib plus cetuximab in combination with chemotherapy in human BRAFV600E mutant colorectal cancer

by Selleckchem | May 22 2023

Purpose: Encorafenib plus cetuximab is an effective therapeutic option in chemorefractory BRAFV600E mCRC. However, there is a need to improve the efficacy of this molecular targeted therapy and evaluate regimens suitable for untreated BRAFV600E mCRC patients.

Experimental design: We performed a series of in vivo studies using BRAFV600EmCRC tumor xenografts. Mice were randomized to receive: 5-fluoruracil, irinotecan or oxaliplatin regimens (FOLFIRI or FOLFOX), encorafenib plus cetuximab (E+C) or the combination. Treatments included long term treatment until progression, with de-escalation strategies replicating maintenance treatments. Transcriptomic changes after progression on cytotoxic chemotherapy or targeted therapy were assessed.

Results: Antitumor activity of either FOLFIRI or E+C was better in first-line as compared to second-line, with partial cross-resistance seen between cytotoxic regimen and targeted therapy with average 62% loss of efficacy for FOLFIRI after E+C and 45% loss of efficacy of E+C after FOLFIRI (p<0.001 for both). FOLFIRI treated models had upregulation of EMT and MAPK pathway activation, where E+C treated models had suppressed MAPK signaling. In contrast, with chemotherapy with E+C, EMT and MAPK signaling remained suppressed. FOLFOX or FOLFIRI, each in combination with E+C, were the most active first-line treatments as compared to E+C or to chemotherapy alone. Further, FOLFOX in combination with E+C as first-line induction therapy, followed by E+C +/- 5-FU as maintenance therapy, was the most effective strategy for long term disease control.

Conclusions: These results support the combination of cytotoxic chemotherapy and molecular targeted therapy as a promising therapeutic approach in the first-line treatment of BRAFV600E mCRC.

Comments：

The study aimed to evaluate the efficacy of different treatment regimens in BRAFV600E mCRC, including cytotoxic chemotherapy and molecular targeted therapy. In vivo studies using BRAFV600EmCRC tumor xenografts were conducted, and mice were randomized to receive different treatment regimens, including FOLFIRI, FOLFOX, encorafenib plus cetuximab (E+C), or a combination of these therapies. Long-term treatment until progression was administered, with de-escalation strategies replicating maintenance treatments. The study assessed transcriptomic changes after progression on cytotoxic chemotherapy or targeted therapy.

The results showed that the antitumor activity of FOLFIRI or E+C was better in first-line treatment than in second-line treatment, with partial cross-resistance observed between the cytotoxic regimen and targeted therapy. FOLFIRI-treated models exhibited upregulation of EMT and MAPK pathway activation, while E+C-treated models had suppressed MAPK signaling. In contrast, with chemotherapy with E+C, EMT and MAPK signaling remained suppressed. FOLFOX or FOLFIRI, each in combination with E+C, were the most active first-line treatments as compared to E+C or to chemotherapy alone. Furthermore, FOLFOX in combination with E+C as first-line induction therapy, followed by E+C +/- 5-FU as maintenance therapy, was the most effective strategy for long-term disease control.

Overall, the study suggests that a combination of cytotoxic chemotherapy and molecular targeted therapy is a promising therapeutic approach in the first-line treatment of BRAFV600E mCRC. The study findings have implications for the development of new treatment strategies for this patient population.