Seattle Genetics Announces Initiation of Phase 3 Clinical Trial of Tucatinib in Combination with Ado-trastuzumab Emtansine (T-DM1, Kadcyla®) for Patients with Advanced or Metastatic HER2-Positive Breast Cancer

Seattle Genetics, Inc. (Nasdaq:SGEN) today announced dosing of the first patient in HER2CLIMB-02, a randomized phase 3 clinical trial evaluating investigational agent tucatinib versus placebo, in combination with standard-of-care ado-trastuzumab emtansine (T-DM1, Kadcyla^®), for patients with locally advanced or metastatic HER2-positive (HER2+) breast cancer. This trial is intended to support registration in the U.S. Tucatinib is an oral, small molecule tyrosine kinase inhibitor that is highly selective for HER2.

“We are building a comprehensive strategy for tucatinib in combination with other medicines across a range of HER2-positive cancers,” said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics. “We are pleased to advance this tucatinib clinical trial with the vision of improving combination outcomes for patients with HER2-positive metastatic breast cancer who receive T-DM1. This trial has the potential to support tucatinib use in earlier lines of therapy.”

HER2CLIMB-02 is a multi-center, randomized, double-blind, placebo-controlled phase 3 trial designed to evaluate tucatinib versus placebo, in combination with T-DM1, in patients with unresectable locally-advanced or metastatic HER2+ breast cancer, including those with brain metastases, who have had prior treatment with a taxane and trastuzumab in any setting. The primary endpoint is progression-free survival per Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints include overall survival, objective response rate and duration of response. The trial is expected to enroll approximately 460 patients. More information about this phase 3 trial, including enrolling centers, is available at www.clinicaltrials.gov.

HER2CLIMB-02 is based on the results from a completed phase 1b study. The manuscript entitled “Tucatinib combined with ado-trastuzumab emtansine in advanced ERBB2/HER2-positive metastatic breast cancer: The results of a phase 1b trial” evaluating tucatinib with the current standard of care HER2-targeted antibody-drug conjugate, T-DM1, in previously treated metastatic HER2-positive breast cancer was published in the July 2018 print edition of JAMA Oncology.

About Tucatinib

Tucatinib is an investigational, orally bioavailable, potent tyrosine kinase inhibitor that is highly selective for HER2 without significant inhibition of EGFR. Inhibition of EGFR has been associated with significant toxicities, including skin rash and diarrhea. Tucatinib has shown activity as a single agent and in combination with both chemotherapy and other HER2 directed agents such as trastuzumab.^1,2 Studies of tucatinib in these combinations have shown activity both systemically and in brain metastases. HER2 is a growth factor receptor that is overexpressed in multiple cancers, including breast, ovarian and gastric cancers. HER2 mediates cell growth, differentiation and survival. Tumors that overexpress HER2 are more aggressive and historically have been associated with poor overall survival compared with HER2-negative cancers. Tucatinib has been granted orphan drug designation by the FDA for the treatment of breast cancer patients with brain metastases.

Tucatinib is being evaluated in an ongoing randomized, double-blind, placebo-controlled pivotal trial called HER2CLIMB comparing tucatinib vs. placebo, in combination with capecitabine and trastuzumab in patients with pretreated, unresectable, locally advanced or metastatic HER2-positive breast cancer, including patients with or without brain metastases. In addition, tucatinib is being evaluated in other solid tumor clinical trials, including colorectal cancer.

About HER2-Positive Metastatic 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 aggressive spread of cancer cells. BreastCancer.org estimates 271,270 new cases of invasive breast cancer will be diagnosed in the U.S. in 2019.³ Approximately 25 percent of breast cancers are HER2-positive.⁴ Historically, HER2 disease has been associated with shorter survival times as well as a higher risk of recurrence and CNS disease (brain metastases). Approximately 30 to 50 percent of HER2-positive breast cancer patients develop brain metastases over time.^5,6 Over the past two decades, the approvals of four targeted treatments (trastuzumab, pertuzumab, lapatinib and T-DM1) have led to improved progression-free survival and survival rates of patients with metastatic HER2-positive breast cancer. Despite these advances, there is still a significant need for new therapies that can impact metastatic disease, including brain metastases, and be tolerated for longer periods of time.

About Seattle Genetics

Seattle Genetics, Inc. is an emerging multi-product, global biotechnology company that develops and commercializes transformative therapies targeting cancer to make a meaningful difference in people’s lives. ADCETRIS^® (brentuximab vedotin) utilizes the company’s industry-leading antibody-drug conjugate (ADC) technology and is currently approved for the treatment of multiple CD30-expressing lymphomas. Beyond ADCETRIS, the company has established a pipeline of novel targeted therapies at various stages of clinical testing, including three in ongoing pivotal trials for solid tumors. Enfortumab vedotin for metastatic urothelial cancer and tisotumab vedotin for metastatic cervical cancer utilize our proprietary ADC technology. Tucatinib, a small molecule tyrosine kinase inhibitor, is in a pivotal trial for HER2-positive metastatic breast cancer. In addition, we are leveraging our expertise in empowered antibodies to build a portfolio of proprietary immuno-oncology agents in clinical trials targeting hematologic malignancies and solid tumors. The company is headquartered in Bothell, Washington, and has a European office in Switzerland. For more information on our robust pipeline, visit www.seattlegenetics.com and follow @SeattleGenetics on Twitter.

Forward Looking Statements

Certain of the statements made in this press release are forward looking, such as those, among others, relating to therapeutic potential of tucatinib, its possible safety, efficacy, and therapeutic uses and anticipated development activities including the enrollment of patients in the company’s phase 3 clinical trial evaluating tucatinib in combination with ado-trastuzumab emtansine for patients with locally advanced or metastatic HER2+ breast cancer, development of tucatinib for breast and other cancers, future clinical trials and intended regulatory actions. 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 difficulty and uncertainty of pharmaceutical product development, including the inability to show sufficient activity in clinical trials, the risk of adverse events or safety signals, and the possibility of adverse regulatory actions as tucatinib advances in clinical trials even after promising results in earlier clinical trials. More information about the risks and uncertainties faced by Seattle Genetics is contained under the caption “Risk Factors” included in the company’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2019 filed with the Securities and Exchange Commission. Seattle Genetics 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. Moulder, S. et al., Phase 1 Trial of ONT-380, a HER2 Inhibitor, in Patients with HER2+ Advanced Solid Tumors, with an Expansion Cohort in HER2+ Metastatic Breast Cancer. Clin Cancer Res, May 2017.
2. Hamilton, E. et al., Efficacy of a Phase 1b Trial of Tucatinib (ONT-380), an Oral HER2-Specific Inhibitor, in Combination with Capecitabine and Trastuzumab in HER2+ Metastatic Breast Cancer, Including Patients with Brain Metastases. Presented at the San Antonio Breast Cancer Symposium (SABCS) Annual Meeting 2016, San Antonio, TX, December 9, 2016 (Poster P4-21-01).
3. BreastCancer.org, U.S. Breast Cancer Statistics. Accessed August 2019.
4. BreastCancer.org, HER2 Status. Accessed August 2019.
5. Metro, et al., Clinical outcome of patients with brain metastases from HER2-positive breast cancer treated with lapatinib and capecitabine. Annals of Oncology, vol. 212, no. 3, pp. 625-630, 2011.
6. Ramakrishna N., et al., Journal of Clinical Oncology 32, no. 19 (July 2014) 2100-2108.

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