Success of Tucatinib/Trastuzumab in the First Line May ‘Eliminate the Need’ for EGFR Inhibitors in HER2+ Metastatic CRC


An expert from the Mayo Clinic discusses how findings from the ongoing phase 3 MOUNTAINEER trial may enable access to tucatinib, trastuzumab, and chemotherapy in earlier lines of treatment for patients with HER2-positive metastatic colorectal cancer.

The treatment landscape could “change dramatically” if tucatinib (Tukysa) plus trastuzumab (Herceptin) and chemotherapy demonstrate efficacy in the first line in patients with HER2-positive metastatic colorectal cancer (CRC), according to Tanios S. Bekaii-Saab, MD, FACP.

During the 2023 ASCO Gastrointestinal Cancer Symposium, CancerNetwork® spoke with Bekaii-Saab, leader of the Gastrointestinal Cancer Program at the Mayo Clinic Comprehensive Cancer Center, medical director of the Cancer Clinical Research Office, and vice chair/section chief for Medical Oncology, Department of Internal Medicine, at Mayo Clinic, Phoenix, Arizona, about the potential impact of the ongoing phase 3 MOUNTAINEER trial (NCT05253651) should its findings prove to be positive.

Bekaii-Saab and other study investigators are assessing the efficacy of tucatinib plus trastuzumab and modified leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin (mFOLFOX6) in patients with RAS wild-type, HER2-positive CRC. According to Bekaii-Saab, positive findings from the trial could enable a new first-line treatment option for HER2-amplified tumors that have demonstrated resistance to other EGFR inhibitors.

Additionally, Bekaii-Saab explained that fully understanding the role the combination plays in those with lower HER2 expression or resistance to other HER2-targeted agents will be important next steps for creating a strategy.


If MOUNTAINEER-3 is positive, it will certainly ensure that patients with HER2-amplified tumors will get access to tucatinib and trastuzumab in earlier lines of therapy; [it will be] the first line of defense with chemotherapy.

Another interesting twist is that it will also continue to enhance the capacity to move away from EGFR inhibitors in this subgroup of patients. Testing for HER2 early [is commonly done] now, and I advocate for it to be done more widely. HER2-amplified tumors appear to be resistant to EGFR inhibitors. It's interesting because those end up being mostly left-sided tumors and RAS wild type.

If one didn't have the HER2 data, they would typically consider EGFR inhibitors. But for those patients with left-sided tumors, RAS wild-type tumors, if they have that HER2 amplification—similar to BRAF V600E mutations—they don't appear to benefit from the addition of EGFR inhibitors.

The landscape will change dramatically where, for those [with] target tumors, we can afford to give them better options with tucatinib, trastuzumab, and chemotherapy if the study is positive in the first line.

As we test more consistently in patients in the first line, that will essentially eliminate the need for EGFR inhibitors in the first line for this subgroup of patients, which will certainly continue to improve overall outcomes for patients.

What follows though is where do we move next? [Do] we move to the adjuvant setting, perhaps. with rectal cancer, or to the neoadjuvant setting. [We] also [must] understand the role of this combination in patients with lower levels of expression or resistance to HER2-targeted strategies. Understanding overall mechanisms of resistance would be important to develop future strategies to salvage and move more and more patients to a more solid response with these targeted agents. It will open a whole world for us in the 3% to 4% of patients with colon cancer and HER2-amplified tumors.


Bekaii-Saab TS, Cutsem EV, Tabernero J, et al. MOUNTAINEER-03: phase 3 study of tucatinib, trastuzumab, and mFOLFOX6 as first-line treatment in HER2+ metastatic colorectal cancer—trial in progress. J Clin Oncol. 2023;41(suppl 4):TPS261. doi:10.1200/JCO.2023.41.3_suppl.TPS261

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