Efficacy results of first targeted therapy for HER2+ mCRC

Metastatic colorectal cancer (mCRC) remains a leading cause of cancer-related mortality, and amplification of the HER2 gene is the latest molecular subset to be therapeutically targetable in this disease. HER2 status is unlikely to have a strong prognostic effect in patients with mCRC, although retrospective studies suggest that HER2 amplification is associated with anti-EGFR therapeutic resistance. There are not many patients with metastatic colorectal cancer who overexpress the HER2 protein, representing around 3 to 5%. But this does not stop the search for and development of treatments that can use this overexpression as a target. This is the case with the combination of tucatinib (a kinase inhibitor that induces the death of HER2-boosted cancer cells) and trastuzumab (a monoclonal antibody that binds to the HER2 protein and prevents tumour cells from dividing and growing). The safety and efficacy results from the MOUNTAINEER clinical trial, which assessed this combination. Chemotherapy-refractory patients who express HER2 achieve limited clinical benefit with current therapies. The results obtained now make optimistic and think that the combination of tucatinib and trastuzumab has the potential to become a new therapeutic option.

Tukysa (tucatinib) is an oral medicine that is a tyrosine kinase inhibitor of the HER2 protein, a protein that contributes to cancer cell growth. HER2 is overexpressed in multiple cancers, including colorectal cancers. Tukysa in combination with trastuzumab and capecitabine was approved by the US FDA in April 2020 for adult patients with advanced unresectable or metastatic HER2 positive breast cancer, including patients with brain metastases. With a median follow-up of over 20 months, the study found that the patients who received the combined treatment obtained an objective response rate of 38.1%, with a median response time of 12.4 months. In contrast, the monotherapy treatment produced an objective response rate of just 3.3%. The initial data also served to show how disease-free progression reached 8.2 months in these patients and overall survival exceeded two years, respectively. Diarrhea was predominantly low grade and manageable. In short, the combination of tucatinib and trastuzumab produced an optimum clinical benefit and was also well tolerated, with a safety profile similar to the patients who received the tucatinib monotherapy.

Conclusion- Overall data from MOUNTAINEER support concurrent initiation of dual-HER2 blockade with tucatinib and trastuzumab to achieve optimal clinical benefits. The trial evaluates the efficacy of tucatinib, trastuzumab and mFOLFOX6 compared with SoC in 1L HER2+ mCRC. Based on these results, the US FDA granted TUKYSA Breakthrough Therapy Designation. From being identified as a negative predictive factor to becoming a positive, actionable target, multiple pharma companies have been trying to target HER2+ mCRC patients, and there are now a plethora of HER2-targeted therapies in clinical trials. The approval of Tukysa will open a new personalized treatment approach in mCRC, a leading cause of cancer-related mortality despite great advances in treatment over the years.

Expert Opinion: “This study has shown the benefits of dual-HER2 inhibition with tucatinib and trastuzumab in patients with HER2-positive metastatic colorectal cancer, including many whose cancer had spread to the liver or lungs before joining the trial”.

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