Canafenib/encofenib combination approved in China in BRAF V600E+ metastatic colorectal cancer

Encorafenib plus cetuximab has received marketing authorization in China for the treatment of previously treated adult patients with metastatic colorectal cancer (CRC) harboring the BRAF V600E mutation.

Supporting data for China approval comes fromBEACON CRC A phase 3 trial (NCT02928224), in which researchers evaluated encofenib in combination with cetuximab and binimetinib, Therapeutic efficacy of dual encofenib/cetuximab therapy and the investigators' choice of cetuximab plus irinotecan or cetuximab plus leucovorin, fluorouracil, and irinotecan (FOLFIRI). Additionally, the approval is based on results from the Chinese Phase 2 NAUTICARC-trial (NCT05004350), which evaluated encofenib/cetuximab versus irinotecan/cetuximab or FOLFIRI/cetuximab in a similar patient population in China.

This approval marks a major advance and is critical for patients in China suffering fromBRAF V600E mutated [metastatic] CRC, where the prognosis is particularly unfavorable. So far, Chinese authorities have not approved treatments specifically for this population, leaving an unmet medical need. From now on, the combination treatment of encofenib and cetuximab will change the treatment mode of Chinese patients, providing the possibility to slow down the progression of the disease and increase the life expectancy of patients.

The data showed that the median overall survival (OS) for encofenib/cetuximab was 8.4 months (95% CI, 7.5-11.0), compared with 5.4 months (95% CI, 4.8-6.6) for the control treatment. The risk of death was significantly lower in the dual-drug group compared with the control group (HR, 0.60; 95% CI, 0.45-0.79; P<0.001). 2 The objective response rate (ORR) in each treatment group was 20% (95% CI, 13%-29%) and 2% (95% CI, 0%-7%) respectively; experimental dual treatment significantly improved response (P<0.001).

Adverse events (AEs) of any grade occurred in 98% of the dual-drug group and 97% of the control group, with grade 3 or higher toxicities affecting 50% and 61% of patients, respectively. The most common adverse events of any grade in each group included nausea (34% vs. 41%), diarrhea (33% vs. 48%), and fatigue (30% vs. 27%).

In both arms of the trial, patients with metastatic BRAF V600E-mutant CRC received encofenib 300 mg daily and cetuximab 400 mg/m2 as an initial dose, followed by 250 mg/m2 weekly. The primary endpoints of the trial were OS and ORR in the triplet group versus the control group. Secondary endpoints included OS in both arms and control arms.

According to the study results, median progression-free survival (PFS) for patients who received encofenib/cetuximab was 4.2 months (95% CI, 3.0-7.3) in the dual arm compared with 2.5 months (95% CI, 1.3-4.3) in the control arm (stratified HR, 0.37; 95% CI, 0.20-0.68; P=0.0004). Additionally, the median OS in each group was 11.6 months (95% CI, 8.1-14.7) compared with 8.2 months (95.CI, 5.2-12.1) in the control group (stratified heart rate, 0.55; 95% CI, 0.31-0.99). In each arm, the ORR was 24.6% (95% CI, 14.8%-36.9%) and 6.3% (95% CI, 0.8%-20.8%), respectively, and the median duration of response was 8.2 months (95% CI-2.8-not evaluable [NE]) and 4.2 months (95% CI, NE-NE), respectively.

All patients in the dual-drug group and control group experienced a treatment-emergent adverse event (TEAE) of any grade, with 47.7% and 51.9% of patients in each group experiencing grade 3 or higher TEAEs. The most common TEAEs in each group included anemia (30.8% vs. 37.0%), vomiting (26.2% vs. 33.3%), and rash (24.6% vs. 29.6%).

In both arms of the NAUTICARCC trial, patients who had received 1 or 2 prior treatment regimens for metastatic BRAF V600E mutant CRC received encofenib 300 mg orally daily, cetuximab 400 mg/m intravenously, and then 250 mg/m intravenously weekly. The trial's primary endpoint was PFS, according to blinded independent central review. Secondary endpoints include investigator-assessed PFS, ORR, OS, and safety.

Reference materials:https://www.cancernetwork.com/view/encorafenib-combo-earns-chinese-approval-in-braf-v600e-metastatic-crc