Episode 10: MOUNTAINEER-02 introducing TUC with Tras as a new standard for HER2+ RAS WT mCRC patients

Prof Eric Van Cutsem from University Hospitals Leuven and Prof Marc Van den Eynde from Cliniques Universitaires Saint Luc are discussing the findings of the MOUNTAINEER-02 trial.

Depending on the molecular profile of the tumour different treatment options for metastatic colorectal cancer (mCRC) emerge. The MOUNTAINEER-02 trial presents results of combining tucatinib (TUC) with trastuzumab (Tras) in a subgroup of HER2+, RAS WT mCRC patients. HER2 positivity is primarily observed in RAS WT tumours, more prevalent in left-sided than right-sided tumours. TUC, a TKI, targets RAS WT, HER2+ patients identified through criteria similar to gastric cancer, i.e., IHC 3+/2+ followed by a positive FISH test.

An initial US study randomized HER2+ chemorefractory patients to TUC with or without Tras. While TUC monotherapy showed minimal activity, the combination with Tras was highly effective, leading to FDA approval for this refractory HER2+ RAS WT mCRC subgroup. Around 40% of patients showed a durable ORR with manageable GI toxicity, setting a new standard for HER2+ patients.

A new study is underway, in first-line HER2+ RAS WT patients comparing standard chemotherapy to chemotherapy plus TUC with Tras, aiming to explore treatment advancement. There’s speculation about HER2+ patients’ resistance to EGFR antibody treatment, yet unproven, warranting investigation in the first line.

The results of the MOUNTAINEER-02 study are impressive, regarding the response rate reached in refractory patients. The DESTINY-CRC02 study introduced trastuzumab deruxtecan (T-DXd), showing a similar response rate of about 40%, including RAS-mutated patients. Experts discuss the future of HER2 inhibition, recognizing that both agents are active but operate through distinct mechanisms: TUC with Tras is a TKI combined with a monoclonal antibody, while T-Dxd is an antibody conjugated to a cytotoxic agent.

RAS mutated, HER2+ patients represent a rare subgroup, potentially a distinguishing factor for the treatment approach. T-DXd presents a different toxicity profile, including interstitial lung disease in up to 10% of patients, necessitating further study in larger cohorts to compare the impact of toxicity of TUC with Tras treatment versus T-DXd. A sequential treatment approach is also considered; especially considering earlier HER2 inhibition still yielding responses to T-DXd.

Further research is essential, but both agents hold promise in colorectal cancer treatment.