Only about 3% to 5% of patients with metastatic colorectal cancer have tumors that are positive for human epidermal growth factor receptor 2 (HER2), and until recently there was no treatment approved by the US Food and Drug Administration (FDA) for this subset of patients.
That all changed, in January of 2023. At that time, the FDA granted accelerated approval to tucatinib (Tukysa) in combination with trastuzumab for RAS wild-type HER2-positive unresectable or metastatic colorectal cancer that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.
The combination was the first FDA-approved treatment for this patient population.
The only other FDA-approved therapy for metastatic HER2-positive CRC is the antibody-drug conjugate trastuzumab deruxtecan (Enhertu). That drug received accelerated approval from the FDA for metastatic HER2-positive CRC for which no other suitable therapeutic option exists, on April 5, 2024. This FDA action represented an expansion of the drug’s earlier approvals for treating several cancer types, including certain patients with unresectable or metastatic HER2-positive breast cancer and adults with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who had received a prior trastuzumab-based regimen.
Drug Combo’s Use With Capecitabine in Breast Cancer
Tucatinib is a potent oral tyrosine kinase inhibitor (TKI) that has been shown to be highly selective for HER2. Prior to approval of the colorectal cancer indication, tucatinib had received FDA approval (in April 2020) in combination with trastuzumab and capecitabine for the treatment of patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who had received one or more prior anti-HER2-based regimens in the metastatic setting.
In these patients the combination was associated with significant improvements in both progression-free survival (PFS) and overall survival compared with trastuzumab and capecitabine.
Approval for the colorectal cancer indication was based on results of the phase 2 MOUNTAINEER trial, which were published in The Lancet Oncology.
Real-World Setting
Clinical experience with the combination in a real-world setting is still limited due to the relatively uncommon RAS wild-type HER2-positive CRC subtype, so most of what’s known about the efficacy and safety of tucatinib plus trastuzumab comes from clinical trials. But oncologists interviewed for this article emphasized that the tucatinib-trastuzumab combination nonetheless represents a major breakthrough.
“The population of RAS wild-type HER2-positive is small in colorectal cancer, but the benefit of this treatment is really remarkable. With this combination therapy there was a 38% response rate, and there was a very respectable duration of response. So the population is small, but the benefit of the treatment is by no means small,” said Afsaneh Barzi, MD, PhD, a medical oncologist specializing in gastrointestinal cancers at City of Hope in Duarte, California.
Another medical oncologist interviewed for this piece, who treats patients with HER2-positive metastatic CRC, said that the performance of tucatinib in the real-world setting is in keeping with the efficacy seen in clinical trials.
“There is a group of patients who have a very good response to HER2 [targeted] therapy. Often these are patients who have higher degrees of HER2 amplification, and they do not have concomitant other mutations that activate the pathway, such as RAS mutations,” said Kanwal PS Raghav, MD, MBBS, from the University of Texas MD Anderson Cancer Center in Houston.