- Long-Term Data for Overall Survival in Patients with Brain Metastases Consistent with Primary Analysis of Pivotal HER2CLIMB Trial -

- Investigator-Sponsored Trial Shows TUKYSA Regimen is First Systemic Therapy to Prospectively Demonstrate Clinical Benefit in HER2-Positive Breast Cancer Patients with Leptomeningeal Metastases, Cancer that has Spread to Membranes Lining the Brain and Spinal Cord -

Seagen, Inc. (Nasdaq:SGEN) today announced upcoming data presentations for TUKYSA^® (tucatinib) at the San Antonio Breast Cancer Symposium (SABCS), taking place December 7-10, 2021. Seven abstracts – including three spotlight posters – highlight the company’s commitment to addressing unmet needs in advanced breast cancer.

“Data to be presented at this year’s SABCS add to the breadth of evidence supporting the use of TUKYSA in patients with HER2-positive metastatic breast cancer, including long term data from the pivotal HER2CLIMB trial, which continues to demonstrate clinical benefit in patients including those with active and stable brain metastases after an additional 15.6 months of follow up,” said Roger Dansey, M.D., Chief Medical Officer at Seagen.

“When a patient has leptomeningeal metastases, it is a difficult-to-treat situation with a very poor prognosis, so I’m very encouraged by results from a trial that showed clinically meaningful activity of the TUKYSA regimen in these patients,” said Rashmi Murthy, M.D., Associate Professor, Department of Breast Medical Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center.

Two abstracts featured in spotlight poster presentations show:

Continued Clinical Benefit in HER2-Positive Metastatic Breast Cancer Patients (MBC) with Active and Stable Brain Metastases

Updated exploratory results from the pivotal HER2CLIMB trial showed that TUKYSA combined with trastuzumab and capecitabine resulted in a robust and durable prolongation of overall survival (OS) that was consistent with results from the primary analysis for HER2-positive metastatic breast cancer patients with brain metastases after an additional 15.6 months of follow-up. The benefit was maintained in patients with active and stable brain metastases. These results will be featured in a spotlight poster (Abstract #PD4-04) presented by Nancy U. Lin, M.D., Director of the Metastatic Breast Cancer Program in the Susan F. Smith Center for Women’s Cancers at Dana-Farber in Boston, MA.

Promising Activity of TUKYSA Regimen in HER2-Positive MBC Patients with Leptomeningeal Metastases

A single-arm, investigator-sponsored phase 2 trial (n=17) of TUKYSA combined with trastuzumab and capecitabine represents the first prospective evidence of a systemic regimen demonstrating clinical benefit for HER2-positive breast cancer patients with leptomeningeal metastases, cancer that has spread to the membranes lining the brain and spinal cord. The findings showed a median OS of nearly one year (11.9 months [95% Confidence Interval: 4.1, NR]). Patients with leptomeningeal disease have a historically poor prognosis with median survival of four to five months.^1,2 The most common treatment for leptomeningeal metastases is radiation therapy. These results will be featured in a spotlight poster (Abstract #PD4-02) presented by Rashmi Murthy, M.D., University of Texas MD Anderson Cancer Center.

Presentations of Company-Sponsored Trials:

Presentations of Investigator-Sponsored TUKYSA Trials:

About HER2-Positive Breast Cancer

Patients with HER2-positive breast cancer have tumors with high levels of a protein called human epidermal growth factor receptor 2 (HER2), which promotes the growth of cancer cells. Up to 50 percent of metastatic HER2-positive breast cancer patients develop brain metastases over time.^3,4,5 In 2020, more than two million new cases of breast cancer were diagnosed worldwide.⁶ Between 15 and 20 percent of breast cancer cases are HER2-positive.⁷

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 is approved in 36 countries. It was approved by the U.S. FDA in April 2020 and by the European Medicines Agency and the U.K. Medicines and Healthcare Products Regulatory Agency in February 2021. 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.

U.S. Indication and Important Safety Information

TUKYSA is indicated 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.

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.

Adverse Reactions

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.

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.

Drug Interactions

• 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.

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.

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, and the referenced clinical trials. 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 inherent difficulty and uncertainty of pharmaceutical product development, the risk of adverse events or safety signals, the inability to show sufficient activity in clinical trials and the possibility of adverse regulatory actions. 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, 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.

References:

1. Abouharb S, et al. Breast Cancer Res Treat. 2014;146:477-486.
2. Morikawa A, et al. Clin Breast Cancer. 2017;17(1):23-28.
3. Loibl S, Gianni L. HER2-positive breast cancer. Lancet. 2017; 389(10087): 2415-29.
4. Slamon D, Clark G, Wong S, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987; 235(4785): 177-82.
5. Breast Cancer HER2 Status. American Cancer Society website. https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-her2-status.html. Accessed November 15, 2021.
6. Breast. Globocan 2021. World Health Organization. 2021. https://www.who.int/news-room/fact-sheets/detail/cancer
7. Breast Cancer HER2 Status. American Cancer Society website. https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-her2-status.html. Accessed November 12, 2021.

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