This the background for the primary analysis of MOUNTAINEER which is a phase II study of tucatinib and trastuzumab for HER2 positive metastatic colorectal cancer. HER2 amplification or overexpression occurs in about 3% of all patients with metastatic colorectal cancer but in patients with RAS and BRAF wildtype disease that rate is higher – upwards of 10%. We’ve seen from prior studies that patients with HER2 positive metastatic colorectal cancer who progress on early lines of chemotherapy receive limited benefit from current standard of care treatments. On the other hand, there have been already signals of activity suggesting that HER2 is an actionable target and anti-HER2 therapies are active for this cancer. 

So the MOUNTAINEER trial took a drug called tucatinib which is a highly selective tyrosine kinase inhibitor, it’s highly selective for HER2, it has minimal inhibitory effects on other receptors like EGFR. This drug, tucatinib, is combined with trastuzumab which is also frequently utilised for patients with HER2 positive advanced cancer. The MOUNTAINEER trial evaluated the efficacy and safety of this investigational combination of tucatinib and trastuzumab in patients with HER2 positive and RAS wildtype metastatic colorectal cancer.

MOUNTAINEER was a global open label phase II trial. Key eligibility included patients with metastatic colorectal cancer with progression or intolerance to a fluoropyrimidine, oxaliplatin, irinotecan and an anti-VEGF monoclonal antibody. Prior exposure to an anti-EGFR antibody was not required. All patients had HER2 positive disease by local testing and that could have been either immunohistochemistry, FISH or NGS testing, and all patients had RAS wildtype disease. 

This study was initially established as an investigator sponsored trial at eight US sites and all patients in this initial experience were treated with the tucatinib and trastuzumab combination. Based on very favourable results seen in this initial cohort, which we call cohort A, the study was then expanded. After completion of cohort A patients were randomised to either the combination of trastuzumab tucatinib in cohort B or tucatinib alone. The primary endpoint for this study was objective response rate for patients receiving the tucatinib trastuzumab combination.

What did you find?

The results of the study for the primary endpoint found a response rate of 38% by blinded independent central review. Additionally, we found an unexpectedly high progression free survival of 8.2 months with median overall survival exceeding two years. We also noted that there was a long duration of response with the median duration of response exceeding 12 months. We also found that the study combination of tucatinib and trastuzumab was very well tolerated. So the majority of adverse events, treatment related adverse events, were grade 1 or grade 2, that was typically either diarrhoea, fatigue or nausea. There were no treatment related deaths. 

MOUNTAINEER is so far the largest prospective trial to date for patients with HER2 positive metastatic colorectal cancer. Based on the response rate and the duration of response we observed, together with the progression free survival, we feel that this combination has clinically meaningful anti-tumour activity. Based on these results, this combination has the potential to become a new standard of care in patients with HER2 positive, RAS wildtype metastatic colorectal cancer. 

These results also provide a rationale to bring this combination of tucatinib and trastuzumab into earlier lines of therapy. So there is currently ongoing the MOUNTAINEER-03 trial which is a global open-label randomised phase III study looking at tucatinib and trastuzumab in combination with FOLFOX versus standard of care FOLFOX-based therapy with the primary endpoint being progression free survival. So this study provides rationale to further support that type of study as well.