ERK Inhibition Does Not Enhance BEACON Regimen Efficacy in Untreated BRAF V600E–Mutated CRC

Although the combination of the ERK inhibitor ERAS-007 and encorafenib (Braftovi) plus cetuximab (Erbitux) did not yield positive outcomes for patients with BRAF inhibitor–naïve BRAF V600E–mutated metastatic colorectal cancer (mCRC), research efforts to develop novel therapies for patients in this disease subset remain strong, according to Aparna Parikh, MD.

In 2021, the FDA expanded its approval of the combination of cetuximab and encorafenib for the treatment of previously treated adult patients with mCRC harboring a BRAF V600E mutation, based on data from the phase 3 BEACON CRC trial (NCT02928224).¹ The phase 1/2 HERKULES-3 trial (NCT05039177) assessed the addition of ERAS-007 to the BEACON regimen in patients with BRAF V600E–mutated mCRC. Among patients naive to prior encorafenib plus cetuximab (n = 20), the confirmed overall response rate (cORR) 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%).²

“Although we had hoped to move the needle for responses and durations of response, not only was the response rate [with the HERKULES-3 regimen] comparable [with that of other regimens], but the time on treatment and the duration of treatment were limited, as well,” Parikh said in an interview with OncLive^® during the 2024 ASCO Annual Meeting.

In the interview, Parikh discussed previous findings with the HERKULES-3 trial regimen that contributed to the rationale for the trial, key findings from the study, and what the future of the BRAF-mutated mCRC treatment paradigm may look like.

Parikh is an associate professor of medicine at Harvard Medical School, as well as an assistant in Medicine, Hematology, and Oncology at Massachusetts General Hospital in Boston, Massachusetts, where she is also an attending oncologist in the Tucker Gosnell Center for Gastrointestinal Cancers and the Henri and Belinda Termeer Center for Targeted Therapies.

OncLive: What unmet needs exist for patients with BRAF V600E–mutated CRC?

Parikh: BRAF V600E–mutated CRC represents a subgroup of patients, approximately 10% to 15% of patients with stage IV CRC. This biomarker is important because patients who harbor this alteration have a poor prognosis. Until recently, there have not been good, targeted therapies available for these patients.

We now have a targeted therapy in our armamentarium, the BEACON regimen, which is the combination of encorafenib and cetuximab in the second line for patients who harbor this alteration. The challenge with the BEACON regimen is that although it was fantastic that we were able to improve outcomes for this patient group, the progression-free survival, overall survival, and response rates are still limited [with this regimen], and when patients respond, the durability of the responses is short. [These patients still have] a tremendous unmet need.

What is the mechanism of action of ERAS-007?

ERAS-007 is an oral inhibitor of ERK. ERK is in the MAPK pathway. Multi-nodal blockade of the MAPK pathway is important. ERK is downstream of [the targets of] encorafenib and cetuximab. The idea is that if you can prevent downstream activation of the pathway in parallel with the upstream activation, you may be able to get better efficacy. That was the hypothesis for combining ERAS-007 with encorafenib and cetuximab.

What preclinical data have been seen with ERAS-007?

Preclinically, a lot of great data [showed] that ERK inhibition, [which occurs] downstream of BRAF inhibition and EGFR inhibition, as monotherapy and particularly as combination therapy, [has promise with regarding] to inhibiting tumor growth.

What patient population was enrolled in HERKULES-3?

HERKULES-3 evaluated several different populations. It only [enrolled patients with CRC and] BRAF V600E [mutations. This trial included cohorts of patients who had either received] prior BRAF-directed therapy or were naive to BRAF-directed therapy. The presentation [given at the 2024 ASCO Annual Meeting included] patients who had not had prior BRAF-directed therapy [in the form of the] BEACON regimen.

What were the key safety and efficacy findings from this trial?

The combination of ERK inhibition with ERAS-007 plus encorafenib and cetuximab was well tolerated. The unfortunate finding we saw was that the response rate [with the ERAS-007 regimen] was not much better than [that obtained with] historical controls and was comparable with what we would expect with the BEACON regimen alone. Unfortunately, the take-home message from this study was that we did not meet the bar to go forward with this combination. [This outcome] highlights the challenges with targeting BRAF and the need for newer approaches to try to move the needle for this patient population that otherwise doesn’t have a lot of options.

What are some of the next steps for developing targeted therapies for patients with BRAF-mutated CRC?

[An area] where we await a lot of data and where there’s a lot of interest is in combining targeted therapies, such as BRAF-targeted therapies, with immunotherapies. Ongoing clinical trials [are evaluating whether we can] add a checkpoint inhibitor [to approved regimens] and prolong the duration of benefit [of those regimens]. Signaling through [the MAPK] pathway has a lot of immune-mediated mechanisms. Those immune-mediated mechanisms may be potentially aided by the addition of a checkpoint inhibitor.

What presentations were you most excited to see at ASCO this year?

For CRC, there were a couple [presentations] we were looking forward to seeing. There were data, not with a therapy but with the approach of liver transplantation, for patients with colorectal liver metastases. [TRANSMET (NCT02597348) was] a small study with 94 patients but it showed that if you do liver transplants for the right patients, you may be able to markedly prolong how long they live compared with [those who receive] chemotherapy alone. We also saw updated data from the phase 3 CodeBreaK 300 study [NCT05198934], which investigated sotorasib [Lumakras], an EGFR inhibitor, [in patients with KRAS G12C–mutated mCRC]. We also saw more updates with immunotherapy, particularly in microsatellite instability–high patients with rectal cancer.

Disclosures: Dr Parikh reports consulting or advisory roles with Abbvie, AstraZeneca, Bayer, Checkmate Pharmaceuticals, CVS, Delcath Systems, Foundation Medicine, Guardant Health, Illumina, KAHR Medical, Pfizer, PMV Pharma (Immediate family), SAGA Diagnostics, Scarce, Seagen, Sirtex Medical, Taiho Oncology, Takeda, UpToDate, Value Analytics Labs, and Xilio Therapeutics; research funding from Array BioPharma (Inst), Bristol-Myers Squibb (Inst), Daiichi Sankyo (Inst), Erasca, Inc, Genentech (Inst), Guardant Health (Inst), Lilly (Inst), Mirati Therapeutics (Inst), Novartis Pharmaceuticals UK Ltd. (Inst), PMV Pharma, PureTech (Inst), and Syndax; receiving travel, accommodations, and expenses from Karkinos Healthcare; and other relationships with C2i genomics, CADEX Genomics, Parithera, and Xact Robotics.

References

1. FDA expands Lilly’s ERBITUX (cetuximab) label with combination of BRAFTOVI (encorafenib) for the treatment of BRAF V600E mutation-positive metastatic colorectal cancer (CRC) after prior therapy. News release. Eli Lilly and Company. September 29, 2021. Accessed June 19, 2024. https://investor.lilly.com/news-releases/news-release-details/fda-expands-lillys-erbituxr-cetuximab-label-combination
2. Parikh AR, Chorean G, Atreya CE, et al. Updated results from ERAS-007 plus encorafenib and cetuximab (EC) in patients (pts) with EC-naïve metastatic BRAF V600E colorectal cancer (CRC) in the phase 1b/2 HERKULES-3 study. J Clin Oncol. 2024;42(suppl 16):3517. doi:10.1200/JCO.2024.42.16_suppl.3517