A Treatment for HER2-Positive Colorectal Cancer Receives FDA Approval for the First Time

HER2-positive cancer means that cells have an excess of a protein called HER2, which is involved in growth and proliferation, causing rapid tumour growth. Many new targeted drugs have now been developed specifically for HER2-positive cancers. Until recently, HER2 positivity and anti-HER2 drugs were associated only with breast cancer, but they have become important in other cancers, particularly stomach, lung and colon cancer.

A combination of HER2-targeted drugs familiar from breast cancer, trastuzumab plus tucatinib, is now available for colorectal (colon and rectal) cancer.

On 19 January 2023, the FDA (US Food and Drug Administration) granted accelerated approval for advanced HER2-positive colorectal cancer without a RAS mutation previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, to “trastuzumab in combination with tucatinib (Tukysa, Seagen Inc.)”.

Human epidermal growth factor receptor 2 (HER2) positivity is present in approximately 3% to 5% of metastatic (stage 4) colorectal cancers.

We know that people with HER2-positive metastatic colorectal cancer progressing on previous treatments have an unfavourable prognosis. FDA approval of an HER2-targeted, chemotherapy-free combination regimen for colorectal cancer is very good news for these patients. With this approval, testing for HER2 in tumours of patients with advanced colorectal cancer will become routine practice.

Tucatinib had previously received approval in April 2020 from the FDA for use with trastuzumab and capecitabine to treat advanced HER2-positive breast cancer.

FDA Approval Based on the MOUNTAINEER Study

Efficacy of this anti-HER2 drug combination was evaluated in 84 patients in MOUNTAINEER, an open-label, multicentre study.

Patients were required to have HER2-positive, RAS wild-type, unresectable or metastatic colorectal cancer and previous treatment with fluoropyrimidine, oxaliplatin and irinotecan plus an anti-vascular endothelial growth factor (VEGF) monoclonal antibody (mAb).

Patients whose tumours were deficient in mismatch repair (dMMR) proteins or had high microsatellite instability (MSI-H) must also have received immunotherapy. Patients previously treated with anti-HER2-targeted therapy were excluded.

The main efficacy measures were overall response rate and duration of response. In this patient group receiving trastuzumab plus tucatinib:

• Overall response rate was 38% (95% CI: 28, 49), and
• Median response duration was 12.4 months (95% CI: 8.5, 20.5).

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The most common (≥20%) adverse effects were diarrhoea, fatigue, rash, nausea, abdominal pain, infusion-related reactions and fever. The most common laboratory abnormalities (≥20%) were increased creatinine, increased glucose, increased ALT, decreased haemoglobin, increased AST, increased bilirubin, increased alkaline phosphatase, decreased lymphocytes, decreased albumin, decreased leukocytes and decreased sodium.

The recommended tucatinib dose is 300 mg taken orally twice daily in combination with trastuzumab until disease progression or unacceptable adverse effects.