Dr Parikh on Outcomes from the HERKULES-3 Trial in BRAF V600E–Mutant mCRC

Aparna Parikh, MD, associate professor, medicine, Harvard Medical School; assistant in Medicine, Hematology, Oncology, Massachusetts General Hospital; attending oncologist, Tucker Gosnell Center for Gastrointestinal Cancers, the Henri and Belinda Termeer Center for Targeted Therapies, discusses updated results from the phase 1/2 HERKULES-3 trial (NCT05039177) of ERAS-007 plus cetuximab (Erbitux) and encorafenib (Braftovi) in BRAF V600E–mutated metastatic colorectal cancer (mCRC).

The FDA expanded the indication for cetuximab and encorafenib to include previously treated adult patients with mCRC harboring a BRAF V600E mutation in 2021. This regulatory decision was based on data from the phase 3 BEACON CRC trial (NCT02928224). Accordingly, the HERKULES-3 trial was conducted to assess the addition of ERAS-007, an ERK inhibitor, to the BEACON regimen in BRAF V600E–mutated mCRC.

At the 2024 ASCO Annual Meeting, updated safety and efficacy results from the HERKULES-3 trial were presented, Parikh begins. This cohort included patients who had not previously received BRAF-directed therapy in the form of the BEACON regimen, she notes.

Results showed that ERK inhibition with ERAS-007 plus encorafenib and cetuximab was well tolerated, Parikh reports. However, the response rate with this regimen was not significantly better than that of historical controls and was comparable to what would be expected with the BEACON regimen alone, she details. The confirmed overall response rate (cORR) in patients who had not previously received encorafenib plus cetuximab (n = 20) was 15.0% (95% CI, 3.21%-37.89%); in the overall study population (n = 27), which included patients who had received prior treatment with the BEACON regimen, the ORR was 11.1% (95% CI, 2.35%-29.16%).

Ultimately, the combination of ERAS-007 with the BEACON regimen did not meet the efficacy threshhold required to warrant further development, Parikh concludes. The outcomes from HERKULES-3 underscore the challenges associated with targeting BRAFmutations in mCRC and highlights the need for innovative approaches to improve treatment outcomes for this patient population, which currently has limited therapeutic options.