Tucatinib Plus Trastuzumab Receives FDA Approval for RAS Wild-Type, HER2-Positive Colorectal Cancer

John Strickler, MD, Duke University, Durham, North Carolina, discusses the US Food and Drug Administration’s (FDA) accelerated approval of tucatinib in combination with trastuzumab for RAS wild-type, HER2-positive colorectal cancer.

This approval was based on results from the phase 2, open-label, multi-center MOUNTAINEER trial. There were 84 patients with HER2-positive, RAS wild-type, unresectable or metastatic colorectal cancer, and prior treatment with fluoropyrimidine, oxaliplatin, irinotecan, and an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, who received 300 mg oral tucatinib twice daily with trastuzumab. In this study, the overall response rate was 38% and the median duration of response was 12.4 months.

On January 19, 2023, the FDA granted accelerated approval to tucatinib in combination with trastuzumab was granted accelerated approval in this patient population.

Transcript:

Hi, I'm John Strickler, Associate Professor at Duke University.

What is tucatinib and how does tucatinib works to treat patients with RAS wild-type, HER2-positive colorectal cancer?

Tucatinib is an oral, highly selective anti-HER2 therapy. It's given in combination with trastuzumab in patients with metastatic colorectal cancer. And this chemotherapy-free regimen has found to be highly active with a response rate approaching 40% with generally good tolerability.

What data led to this accelerated approval?

MOUNTAINEER was a multi-site, international, non-randomized Phase II trial. All patients were HER2 positive by local testing. So, that allowed either next generation sequencing, IHC, or FISH testing. So, local testing qualified the patients, and we enrolled in total of 84 patients received the combination of tucatinib and trastuzumab. And in this study, the primary endpoint was confirmed objective response rate.

Where does the tucatinib-trastuzumab combination fit into the current treatment paradigm?

The MOUNTAINEER study was designed for patients who had received prior 5FU, oxaliplatin, irinotecan, and an anti-VEGF monoclonal antibody. It did not require prior anti-EGFR therapies. So, in patients who have received those prior therapies, the tucatinib/trastuzumab combination has shown significant activity, and that's the patient population for which that combination is approved.

What is the safety profile of this combination?

In general, the tucatinib/trastuzumab combination is very well tolerated. The most common treatment related side effect is diarrhea, but that rarely leads to either dose reductions or treatment discontinuation. The most serious, very rare side effects would be signs of liver inflammation or hepatotoxicity, which occurs in maybe 2% to 3% of patients. In general, most patients tolerate this treatment quite well, and it is manageable in the vast majority of patients.

Will be an immediate, real-world impact with this approval?

I do think there will be an immediate real-world impact with this approval. We've known for some time that anti-HER2 therapies are highly active in patients with HER2 positive metastatic colorectal cancer. And we've had small non-randomized studies that have led to various anti-HER2 regimens being listed in our national guidelines. With the FDA approval, it greatly facilitates access to this regimen off of a clinical trial as part of our standard practice. And what it does is it paves the way for HER2 pathway for patients who have HER2 positive metastatic colorectal cancer, much in the same way that we have pathways for other alterations that are common in colorectal cancer. So, it allows us to treat these patients in a much more of a precise manner, really designed to attack the key alteration driving that cancer. It allows patients to get therapies that are what we call more precise or personalized to that patient's underlying tumor drivers.

What are the next steps for the tucatinib/trastuzumab combination?

This is an exciting time for patients with HER2 positive disease. We plan to explore the tucatinib trastuzumab combination in the frontline in combination with chemotherapy. That's the so-called MOUNTAINEER-03 trial. And that study is ongoing nationally and internationally. Our next step is to bring this regimen up into the frontline to help even more patients with this disease.

Source:

FDA grants accelerated approval to tucatinib with trastuzumab for colorectal cancer. Press Release. United States Food and Drug Administration. January 19, 2023. Accessed January 19, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tucatinib-trastuzumab-colorectal-cancer