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BOTHELL, Wash.–(BUSINESS WIRE) January 19, 2023 — Seagen Inc. (Nasdaq: SGEN) today announced that the U.S. Food and Drug Administration (FDA) 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. 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.

“Historically, cephalexin 500mg for urinary tract infection patients with HER2-positive metastatic colorectal cancer who have progressed following frontline therapy have had poor outcomes,” said John Strickler, M.D., associate professor of medicine, Duke University Medical Center, and lead investigator for the MOUNTAINEER trial. “The FDA approval of a chemotherapy-free combination regimen that specifically targets HER2 is great news for these patients.”

“Biomarker testing is bringing new hope to people living with some types of colorectal cancer by opening the door to targeted treatments like Tukysa for those who have RAS wild-type, HER2-positive disease,” said Michael Sapienza, CEO, Colorectal Cancer Alliance. “It is critical that physicians and patients understand the importance of comprehensive biomarker testing at diagnosis because it can inform treatment decisions and help improve outcomes.”

Results from the MOUNTAINEER trial showed a 38% overall response rate (ORR) (95% Confidence Interval [CI]: 28, 49) per blinded independent central review (BICR) 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 (n=3), and partial responses were observed in 35% of patients (n=29). The median duration of response (DOR) 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 (7%), urinary tract infection (3.5%), pneumonia, abdominal pain and rectal perforation (2.3% each). The most common adverse reactions (≥20%) 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 (ALT) (2.3%). Please see additional Important Safety Information below.

“The accelerated approval of Tukysa for RAS wild-type, HER2-positive metastatic colorectal cancer expands Tukysa-based therapy to patients across two distinct types of cancer,” said Marjorie Green, M.D., Senior Vice President and Head of Late-Stage Development, Seagen. “We believe the efficacy and safety profile of the Tukysa and trastuzumab-based regimen further establishes its role as an important backbone of dual HER2 inhibition in the treatment of adult patients with certain HER2-expressing breast and colorectal cancers.”

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 U.S. and Canada, is commercializing Tukysa in regions outside of the U.S., 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.

About Colorectal Cancer

In the U.S., approximately 153,000 people will be diagnosed with colorectal cancer in 2023, and the rate of the disease is increasing in younger adults.¹ Approximately 22% of U.S. patients with colorectal cancer are diagnosed at the advanced stage.² Human epidermal growth factor receptor 2 (HER2) is overexpressed in 3-5% of patients with metastatic colorectal cancer and approximately 10% of patients with RAS wild-type metastatic colorectal cancer.³ In 2023, colorectal cancer is anticipated to lead to about 52,550 deaths in the U.S., where it is the third-leading cause of cancer-related deaths.¹

About MOUNTAINEER

MOUNTAINEER is a U.S. 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 (ORR) and duration of response (DOR) as assessed by blinded independent central review (BICR) according to RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1.

About Tukysa (tucatinib)

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 U.S. FDA in April 2020 in combination with trastuzumab and capecitabine for treatment of adult patients with advanced unresectable or metastatic HER2-positive breastcancer, 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 U.S. 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. Merck, known as MSD outside the U.S. and Canada, has exclusive rights to commercialize TUKYSA in Asia, the Middle East and Latin America and other regions outside of the U.S., Canada and Europe.

Important Safety Information

Warnings and Precautions

Adverse Reactions

In HER2CLIMB, serious adverse reactions occurred in 26% of patients; the most common (in ≥2% of patients) 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; the most common (in ≥1% of patients) were hepatotoxicity (1.5%) and diarrhea (1%). Adverse reactions led to dose reduction in 21% of patients who received TUKYSA; the most common (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, hepatotoxicity, vomiting, stomatitis, decreased appetite, anemia and rash.

In MOUNTAINEER, serious adverse reactions occurred in 22% of patients; the most common (in ≥2% of patients) were intestinal obstruction (7%), urinary tract infection (3.5%), pneumonia, abdominal pain and rectal perforation (2.3% each). Adverse reactions leading to permanent discontinuation of TUKYSA occurred in 6% of patients; the most common (in ≥2% of patients) was increased ALT (2.3%). Adverse reactions leading to dosage interruption occurred in 23% of patients; the most common (in ≥3% of patients) were increased ALT and diarrhea (3.5% each). Adverse reactions leading to dose reduction occurred in 9% of patients; the most common (in ≥2% of patients) were increased ALT and diarrhea (2.3% each). The most common adverse reactions (≥20%) in patients treated with TUKYSA and trastuzumab were diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions and pyrexia. Other adverse reactions (<10%) include epistaxis (7%), weight decreased (7%), oropharyngeal pain (5%), oral dysesthesia (1%) and stomatitis (1%).

Lab Abnormalities

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.

In MOUNTAINEER, Grade ≥3 laboratory abnormalities reported in ≥5% of patients who received TUKYSA were decreased lymphocytes, decreased sodium, increased AST, and increased bilirubin. 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 in 87% of patients with values outside normal lab limits upon treatment completion. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.

Drug Interactions

Use in Specific Populations

About Seagen

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.

Forward-Looking Statements

Certain of the statements made in this press release are forward looking, such as those, among others, relating to the potential for continued FDA approval of TUKYSA in the referenced newly-approved indication; the potential for the ongoing global, randomized phase 3 clinical trial (MOUNTAINEER-03) to serve as a confirmatory trial and potentially support future global regulatory submissions; and the therapeutic potential of TUKYSA, including its possible efficacy, safety and therapeutic uses. 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 possibility that MOUNTAINEER-03 and subsequent clinical trials may fail to establish sufficient efficacy; that adverse events or safety signals may occur; that utilization and adoption of TUKYSA by prescribing physicians may be limited by the availability and extent of reimbursement or other factors; and that adverse regulatory actions may occur. 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 September 30, 2022, and subsequent periodic reports, 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.

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¹ American Cancer Society: Key Statistics for Colorectal Cancer. https://www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.html. Accessed January 2023.
² Wang J., et al. Metastatic patterns and survival outcomes in patients with stage IV colon cancer: A population‐based analysis. Cancer Med. 2020 Jan; 9(1): 361–373.
³ Ahcene Djaballah S, Daniel F, Milani A, Ricagno G, Lonardi S. HER2 in Colorectal Cancer: The Long and Winding Road From Negative Predictive Factor to Positive Actionable Target. Am Soc Clin Oncol Educ Book. 2022;42:1-14. doi:10.1200/EDBK_351354.

Source: Seagen Inc.

Posted: January 2023

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• FDA Approves Tukysa (tucatinib) for People with Advanced Unresectable or Metastatic HER2-Positive Breast Cancer – April 17, 2020
• Seattle Genetics Announces FDA Filing Acceptance for Priority Review of Tucatinib New Drug Application (NDA) for Patients with Locally Advanced or Metastatic HER2-Positive Breast Cancer – February 13, 2020
• Seattle Genetics Announces Submission of Tucatinib New Drug Application to the U.S. FDA for Patients with Locally Advanced or Metastatic HER2-Positive Breast Cancer – December 23, 2019

Tukysa (tucatinib) FDA Approval History

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