Seattle Genetics Announces Publication of Results from Two Tucatinib Phase 1b Clinical Trials in HER2-Positive Metastatic Breast Cancer

Results of Combination "Triplet" of Tucatinib with Trastuzumab and Capecitabine Published in The Lancet Oncology

Results of Tucatinib in Combination with Ado-trastuzumab Emtansine Published in JAMA Oncology

Seattle Genetics, Inc. SGEN today announced that results of a phase 1b clinical trial of tucatinib in combination with standard of care agents for the treatment of patients with advanced HER2-positive (HER2+) metastatic breast cancer were recently published in the journal The Lancet Oncology. Results demonstrated that tucatinib in combination with trastuzumab (Herceptin^®) and capecitabine (Xeloda^®) was generally well-tolerated and had encouraging clinical activity in heavily pre-treated patients with advanced HER2+ breast cancer, including those with brain metastases (ONT-380-005/triplet study). A separate phase 1b clinical trial of tucatinib in combination with ado-trastuzumab emtansine (T-DM1, Kadcyla^®) was published in JAMA Oncology. Results showed an acceptable safety profile and preliminary antitumor activity among heavily pretreated patients with HER2+ metastatic breast cancer, with and without brain metastases (ONT-380-004). Tucatinib is an oral, small molecule tyrosine kinase inhibitor that is highly selective for HER2.

"There remains a need for a well-tolerated, oral targeted therapy to treat patients with HER2+ metastatic breast cancer whose disease progresses on conventional anti-HER2 treatments, particularly for those whose cancer has metastasized to the brain, which occurs in up to 50 percent of these patients," said Rashmi Murthy, M.D., MBE, Assistant Professor, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. "In the ONT-380-005 triplet study, durable responses were seen in heavily pretreated patients with metastatic HER2+ breast cancer, including those with brain metastases, after treatment with tucatinib. Importantly, in the trial, tucatinib treatment was associated with few clinically significant side effects, such as diarrhea or skin rash, commonly seen with other tyrosine kinase inhibitors targeting this disease, which may allow for prolonged use and as a result potentially improve outcomes for patients."

"The results of the combination tucatinib with trastuzumab and capecitabine triplet study support the development of this regimen in the ongoing pivotal HER2CLIMB trial to provide a meaningful advancement in the use of targeted therapies to treat this disease," said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics. "In addition, based on the results of the combination of tucatinib with T-DM1, we are evaluating development opportunities for this combination in earlier lines of HER2+ metastatic breast cancer."

The manuscript entitled "Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomized, open-label, phase 1b study" was published in the July print edition of The Lancet Oncology.

The phase 1b triplet study was an open-label dose-escalation and expansion cohort study of tucatinib in combination with capecitabine and/or trastuzumab in patients with HER2+ metastatic breast cancer, including those with or without brain metastases. The objective of the study was to assess the safety, tolerability, pharmacokinetics and antitumor activity, and to determine the recommended phase 2 dose of tucatinib in combination with these agents. Once a recommended phase 2 dose of 300 mg BID was established in the triplet combination, an expansion cohort using that regimen was opened. The trial enrolled 60 patients with HER2+ metastatic breast cancer who had previously received a median of three HER2-targeted agents, such as trastuzumab, pertuzumab (Perjeta^®), lapatinib (Tykerb^®) or T-DM1.

Data from patients treated with the triplet combination at 300 mg BID (n=27) included:

• Median progression-free survival (PFS) was 7.8 months.
• Objective response rate (ORR) was 61 percent (n=14/23) with a median duration of response of 11.0 months.
• Median PFS for patients with brain metastases (n=11) was 6.7 months.
• ORR was 42 percent (n=5/12) in patients with measurable brain metastases that had received the 300mg BID tucatinib dose in any combination.
• The triplet combination was well-tolerated and the majority of adverse events were grade 1, with most patients being able to continue on the full dose of tucatinib. Grade 3 diarrhea was infrequent without a requirement for prophylactic anti-diarrheal medicine.

An ongoing randomized, double-blind, placebo-controlled pivotal trial called HER2CLIMB is comparing tucatinib vs. placebo, each in combination with capecitabine and trastuzumab in patients with pretreated, unresectable, locally advanced or metastatic HER2+ breast cancer, including patients with or without brain metastases.

"The combination of tucatinib and T-DM1 in the phase 1b clinical trial was tolerable and appeared to show antitumor activity among heavily pretreated patients with HER2+ metastatic breast cancer with and without brain metastases," said Virginia Borges, M.D., Deputy Head of the Division of Medical Oncology and the Robert F. & Patricia Young Endowed Chair in Young Women's Breast Cancer Research at the University of Colorado School of Medicine. "Based on these data, tucatinib may have the potential to be a new therapeutic option for these patients and warrants further investigation."

The manuscript entitled "Tucatinib combined with ado-trastuzumab emtansine in advanced HER2-positive metastatic breast cancer: A phase 1b open-label clinical trial" was published in the July print edition of JAMA Oncology.

This phase 1b, open-label dose escalation and expansion cohort study of tucatinib in combination with T-DM1 enrolled 57 patients with HER2+ breast cancer. The objective of the study was to assess the safety, tolerability, pharmacokinetics and antitumor activity, and to determine the recommended phase 2 dose of tucatinib in combination with T-DM1. Participants in the study previously received a median of two prior HER2-directed therapies.

Data from the phase 1b study of tucatinib and T-DM1 (n=57) included:

• Median PFS was 8.2 months.
• ORR was 47 percent (n=34/50).
• The combination of tucatinib and T-DM1 was well-tolerated and the majority of adverse events were grade 1.

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 U.S. Food and Drug Administration ("FDA") for the treatment of breast cancer patients with brain metastases.

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. The American Cancer Society estimates 268,670 new cases of invasive breast cancer will be diagnosed in the U.S. in 2018. Approximately 15 to 20 percent of breast cancers are HER2-positive.³ 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.^4,5 Over the past two decades, the approvals of four targeted treatments (trastuzumab, pertuzumab, lapatinib and T-DM1) have led to improved time to progression and survival rates of patients with 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 continued enrollment of patients in HER2CLIMB, 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 the 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 March 31, 2018 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.

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. ASCO Cancer.Net, Treatment of Metastatic HER2-Positive Breast Cancer. Accessed July 2018.

4. 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.

5. Ramakrishna N., et al., Journal of Clinical Oncology 32, no. 19 (July 2014) 2100-2108.

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