– Trial Designed to Support an Accelerated Approval Application in the U.S. –
BOTHELL, Wash.–(BUSINESS WIRE)– Seagen Inc. (Nasdaq: SGEN) today announced it completed patient enrollment in the phase 2 open-label MOUNTAINEER clinical trial, evaluating TUKYSA® (tucatinib) in combination with trastuzumab (Herceptin®) and as a single agent in patients with HER2-positive (HER2+) metastatic colorectal cancer (mCRC) following previous treatment with first- and second-line standard-of-care therapies.
“Completing enrollment in the MOUNTAINEER trial is an important step toward potentially bringing this therapy to patients with HER2-positive metastatic colorectal cancer,” said Roger D. Dansey, M.D., Chief Medical Officer, Seagen. “We previously expanded the size of this trial, with the intention of supporting registration under accelerated approval regulations in the United States. We look forward to receiving the trial results to potentially address a significant unmet medical need for patients.”
Early results from the MOUNTAINEER trial were presented at the European Society for Medical Oncology (ESMO) 2019 Congress and showed encouraging anti-tumor activity with a well-tolerated safety profile.1
TUKYSA is an oral, small molecule tyrosine kinase inhibitor that is highly selective for HER2. HER2 amplification or overexpression occurs in approximately three-to-five percent of all patients with mCRC.2,3
MOUNTAINEER is a U.S. and European multi-center, open label, phase 2 clinical trial of TUKYSA in combination with trastuzumab and as a single agent in 117 patients with previously treated HER2-positive metastatic or unresectable colorectal cancer. The primary endpoint of the trial is objective response rate by RECIST (Response Evaluation Criteria in Solid Tumors) v1.1 criteria. Duration of response, progression-free survival, overall survival and safety and tolerability of the combination regimen are secondary objectives.
About Colorectal Cancer
Colorectal cancer is the second leading cause of cancer death in the United States (U.S.).4 In 2021, it is estimated there will be 149,500 new cases and 52,980 deaths in the U.S.4 Approximately 22 percent of U.S. patients with colorectal cancer are diagnosed at the advanced stage. 4 According to the U.S. Centers for Disease Control and Prevention, the most effective way to reduce the risk of colorectal cancer is routine screening beginning at age 50. In colorectal cancer, human epidermal growth factor receptor 2 (HER2) is overexpressed in three-to-five percent of patients.2,3 There are currently no therapies approved that specifically target HER2 in colorectal cancer.
About TUKYSA (tucatinib)
TUKYSA 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 in combination with trastuzumab and capecitabine was approved by the U.S. Food and Drug Administration (FDA) in April 2020 for 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 February 2021, the European Medicines Agency (EMA) and U.K. Medicines and Healthcare products Regulatory Agency (MHRA) each approved TUKYSA in combination with trastuzumab and capecitabine for the treatment of adult patients with HER2-positive locally advanced or metastatic breast cancer who have received at least two prior anti-HER2 treatment regimens. TUKYSA is also approved in Canada, Switzerland, Singapore and Australia.
In September 2020, Seagen granted Merck, known as MSD outside the U.S. and Canada, exclusive rights to commercialize TUKYSA in Asia, the Middle East and Latin America and other regions outside of the U.S., Canada and Europe.
U.S. Important Safety Information
Warnings and Precautions
Diarrhea – TUKYSA can cause severe diarrhea including dehydration, hypotension, acute kidney injury, and death. In HER2CLIMB, 81% of patients who received TUKYSA experienced diarrhea, including 12% with Grade 3 diarrhea and 0.5% with Grade 4 diarrhea. Both patients who developed Grade 4 diarrhea subsequently died, with diarrhea as a contributor to death. The median time to onset of the first episode of diarrhea was 12 days and the median time to resolution was 8 days. Diarrhea led to dose reductions of TUKYSA in 6% of patients and discontinuation of TUKYSA in 1% of patients. Prophylactic use of antidiarrheal treatment was not required on HER2CLIMB.
If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Based on the severity of the diarrhea, interrupt dose, then dose reduce or permanently discontinue TUKYSA.
Hepatotoxicity – TUKYSA can cause severe hepatotoxicity. In HER2CLIMB, 8% of patients who received TUKYSA had an ALT increase >5 × ULN, 6% had an AST increase >5 × ULN, and 1.5% had a bilirubin increase >3 × ULN (Grade ≥3). Hepatotoxicity led to dose reduction of TUKYSA in 8% of patients and discontinuation of TUKYSA in 1.5% of patients.
Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every 3 weeks during treatment, and as clinically indicated. Based on the severity of hepatotoxicity, interrupt dose, then dose reduce or permanently discontinue TUKYSA.
- Embryo-Fetal Toxicity – TUKYSA can cause fetal harm. Advise pregnant women and females of reproductive potential risk to a fetus. Advise females of reproductive potential, and male patients with female partners of reproductive potential, to use effective contraception during TUKYSA treatment and for at least 1 week after the last dose.
Serious adverse reactions occurred in 26% of patients who received TUKYSA. Serious adverse reactions in ≥2% of patients who received TUKYSA were diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). Fatal adverse reactions occurred in 2% of patients who received TUKYSA including sudden death, sepsis, dehydration, and cardiogenic shock.
Adverse reactions led to treatment discontinuation in 6% of patients who received TUKYSA; those occurring in ≥1% of patients were hepatotoxicity (1.5%) and diarrhea (1%). Adverse reactions led to dose reduction in 21% of patients who received TUKYSA; those occurring in ≥2% of patients were hepatotoxicity (8%) and diarrhea (6%).
The most common adverse reactions in patients who received TUKYSA (≥20%) were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.
In HER2CLIMB, Grade ≥3 laboratory abnormalities reported in ≥5% of patients who received TUKYSA were: decreased phosphate, increased ALT, decreased potassium, and increased AST. The mean increase in serum creatinine was 32% within the first 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.
- Strong CYP3A or Moderate CYP2C8 Inducers: Concomitant use may decrease TUKYSA activity. Avoid concomitant use of TUKYSA.
- Strong or Moderate CYP2C8 Inhibitors: Concomitant use of TUKYSA with a strong CYP2C8 inhibitor may increase the risk of TUKYSA toxicity; avoid concomitant use. Increase monitoring for TUKYSA toxicity with moderate CYP2C8 inhibitors.
- CYP3A Substrates: Concomitant use may increase the toxicity associated with a CYP3A substrate. Avoid concomitant use of TUKYSA where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP3A substrate dosage.
- P-gp Substrates: Concomitant use may increase the toxicity associated with a P-gp substrate. Consider reducing the dosage of P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicity.
Use in Specific Populations
- Lactation: Advise women not to breastfeed while taking TUKYSA and for at least 1 week after the last dose.
- Renal Impairment: Use of TUKYSA in combination with capecitabine and trastuzumab is not recommended in patients with severe renal impairment (CLcr < 30 mL/min), because capecitabine is contraindicated in patients with severe renal impairment.
- Hepatic Impairment: Reduce the dose of TUKYSA for patients with severe (Child-Pugh C) hepatic impairment.
For more information, please see the full Prescribing Information for TUKYSA here.
Seagen is a global biotechnology company that discovers, develops and commercializes transformative cancer medicines to make a meaningful difference in people’s lives. Seagen is headquartered in the Seattle, Washington area, and has locations in California, Canada, Switzerland and the European Union. For more information on the company’s marketed products and robust pipeline, visit www.seagen.com and follow @SeagenGlobal on Twitter.
Seagen Forward-Looking Statements
Certain of the statements made in this press release are forward-looking, such as those, among others, relating to the therapeutic potential of TUKYSA, its possible efficacy, safety and therapeutic uses, the referenced Phase 2 clinical trial and the potential for data from such trial to support registration under accelerated approval regulations in the United States. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include the failure of TUKYSA to show sufficient activity in the clinical setting referenced above; adverse events and safety signals; adverse regulatory actions; delays or setbacks in the conduct of or obtaining data from clinical trials, the submission of regulatory applications and the regulatory review process for a variety of reasons, including the inherent difficulty and uncertainty of pharmaceutical product development; possible required modifications to clinical trials; the inability to provide information and institute safety mitigation measures as may be required by the FDA or other regulatory authorities from time to time; failure to properly conduct or manage clinical trials; and failure of clinical results to support continued development or regulatory approvals. More information about the risks and uncertainties faced by Seagen is contained under the caption “Risk Factors” included in the company’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2021 filed with the Securities and Exchange Commission. Seagen disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.
- Annals of Oncology (2019) 30 (suppl_5): v198-v252. 10.1093/annonc/mdz246.
- Takegawa N and Yonesaka K (2017). HER2 as an emerging oncotarget for colorectal cancer treatment after failure of anti-epidermal growth factor receptor therapy. Clin Colorectal Cancer 16: 247-51.
- Valtorta E., et al. Assessment of a HER2 scoring system for colorectal cancer: results from a validation study. Mod Pathol 28: 1481-91 2015.
- SEER Cancer Stat Facts: Colorectal Cancer. National Cancer Institute. Bethesda, MD. https://seer.cancer.gov/statfacts/html/colorect.html. Accessed July 26, 2021.
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