20 January 2023 - - The US Food and Drug Administration has granted accelerated approval to Tukysa (tucatinib) in combination with trastuzumab for adult patients with RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, US-based Seagen Inc. (NASDAQ: SGEN) said.

Tukysa is approved under the FDA's Accelerated Approval Program based on tumor response rate and durability of response from the phase 2 MOUNTAINEER clinical trial.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

This is the first FDA-approved treatment in HER2-positive metastatic colorectal cancer. The FDA previously granted Breakthrough Therapy Designation and Priority Review for TUKYSA in this setting.

Results from the MOUNTAINEER trial showed a 38% overall response rate (95% Confidence Interval [CI]:28, 49) per blinded independent central review in the patients who received TUKYSA in combination with trastuzumab (N=84 with a median age of 55.0 years [range:24 to 77]).

Complete responses were observed in 3.6% of patients, and partial responses were observed in 35% of patients. The median duration of response per BICR was 12.4 months (95% CI: 8.5, 20.5).

At study entry, 64% and 70% of these patients had liver or lung metastases, respectively.

The Prescribing Information for Tukysa includes warnings and precautions for diarrhea, hepatotoxicity and embryo-fetal toxicity, some of which may be severe or fatal.

In MOUNTAINEER, serious adverse reactions occurred in 22% of patients; the most common (in ≥2% of patients) were intestinal obstruction, urinary tract infection, pneumonia, abdominal pain and rectal perforation (2.3% each).

The most common adverse reactions in patients treated with Tukysa and trastuzumab were diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions and pyrexia.

Adverse reactions leading to permanent discontinuation of Tukysa occurred in 6% of patients; the most common (in ≥2% of patients) was increased alanine aminotransferase.

The FDA's Accelerated Approval Program allows for approval of a medicine based on a surrogate endpoint that is reasonably likely to predict clinical benefit if the medicine fills an unmet medical need for a serious condition.

A global, randomized phase 3 clinical trial (MOUNTAINEER-03) is ongoing and will compare Tukysa in combination with trastuzumab and mFOLFOX6 with standard of care, which is intended to serve as a confirmatory trial and potentially support future global regulatory submissions.

Merck, known as MSD outside of the US and Canada, is commercializing Tukysa in regions outside of the US, Canada and Europe and plans to discuss results from the MOUNTAINEER trial with certain health authorities as it continues to accelerate the filing of Tukysa in its territories.

In the US, approximately 153,000 people will be diagnosed with colorectal cancer in 2023, and the rate of the disease is increasing in younger adults.

Approximately 22% of US patients with colorectal cancer are diagnosed at the advanced stage.

Human epidermal growth factor receptor 2 is overexpressed in 3-5% of patients with metastatic colorectal cancer and approximately 10% of patients with RAS wild-type metastatic colorectal cancer.

In 2023, colorectal cancer is anticipated to lead to about 52,550 deaths in the US, where it is the third-leading cause of cancer-related deaths.

MOUNTAINEER is a US and European open-label, multicenter phase 2 clinical trial of TUKYSA in combination with trastuzumab that evaluated 84 patients with HER2-positive, RAS wild-type, unresectable or metastatic colorectal cancer following previous standard-of-care therapies.

Patients evaluated in MOUNTAINEER had not received prior anti-HER2 therapy. Patients received TUKYSA (300 mg) twice per day orally in combination with trastuzumab intravenously (8 mg/kg loading dose, then 6 mg/kg every three weeks thereafter) until disease progression or unacceptable toxicity.

The major efficacy outcome measures were overall response rate and duration of response as assessed by blinded independent central review according to RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1.

Tukysa (tucatinib) tablets (50 | 150 mg tablets) is an oral medicine that is a tyrosine kinase inhibitor of the HER2 protein. In vitro (in lab studies), Tukysa inhibited phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell growth (proliferation), and showed anti-tumor activity in HER2-expressing tumor cells.

In vivo (in living organisms), Tukysa inhibited the growth of HER2-expressing tumors. The combination of Tukysa and the anti-HER2 antibody trastuzumab showed increased anti-tumor activity in vitro and in vivo compared to either medicine alone.

Tukysa was approved by the US FDA in April 2020 in combination with trastuzumab and capecitabine for treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.

In January 2023, Tukysa received accelerated approval by the US FDA in combination with trastuzumab for adult patients with RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy.

US-based Merck (NYSE: MRK), known as MSD outside the US and Canada, has exclusive rights to commercialize Tukysa in Asia, the Middle East and Latin America and other regions outside of the US, Canada and Europe.