BOTHELL, Wash.--(BUSINESS WIRE)--Seattle Genetics, Inc. today announced positive results from exploratory analyses of intracranial efficacy, including survival, in patients with HER2-positive metastatic breast cancer (MBC) who had stable or active brain metastases in the HER2CLIMB pivotal trial of TUKYSA (tucatinib). HER2CLIMB compared TUKYSA in combination with trastuzumab and capecitabine to trastuzumab and capecitabine alone in patients with unresectable, locally advanced or metastatic HER2-positive breast cancer with or without brain metastases. Of the patients enrolled in the trial, 48 percent had a presence or history of brain metastases. Results demonstrated that the addition of TUKYSA to trastuzumab and capecitabine in patients with brain metastases delayed progression in the brain, doubled the intracranial response rate (tumor shrinkage in the brain) and reduced the overall risk of death by nearly half. The data were consistent across patients who had either stable or active brain metastases. Results were presented in an oral presentation in the virtual scientific program of the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in the Journal of Clinical Oncology.

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. Primary results from HER2CLIMB were first presented at the San Antonio Breast Cancer Symposium in December 2019 and published in the New England Journal of Medicine.

It is immensely gratifying to see for the first time, results for patients with stable or active brain metastases who are not typically included in clinical trials, especially when you consider that nearly half of patients with HER2-positive metastatic breast cancer experience disease progression to the brain, said Nancy U. Lin, M.D., director of the Metastatic Breast Cancer Program in the Susan F. Smith Center for Womens Cancers at Dana-Farber in Boston, MA. These additional analyses provide further evidence that TUKYSA improves survival and delays cancer progression in the brain for patients with HER2-positive metastatic breast cancer who have brain metastases.

These additional analyses, together with the primary analysis of HER2CLIMB, show TUKYSA is active for patients with and without disease that has spread to the brain, said Roger Dansey, M.D., Chief Medical Officer of Seattle Genetics. We continue to be encouraged by the remarkable clinical activity of TUKYSA in combination with trastuzumab and capecitabine and look forward to evaluating its potential in additional treatment settings and tumor types through our ongoing clinical program.

The new data that further examine TUKYSAs effect in the brain include exploratory analyses for central nervous system progression-free survival (CNS-PFS), overall survival (OS), intracranial objective response rate (ORR-IC) and duration of response in HER2-positive metastatic breast cancer patients whose disease had spread to the brain.

The exploratory analyses demonstrated that patients with brain metastases who received the TUKYSA combination versus trastuzumab and capecitabine alone had:

Endpoint

TUKYSA Arm (TUKYSA + trastuzumab + capecitabine)

Control Arm (Placebo + trastuzumab + capecitabine)

OS Benefit in All Patients with Brain Metastases

N=198

N=93

Risk Reduction

42% (Hazard Ratio [HR]=0.58 [95% Confidence Interval (CI): 0.40, 0.85]; p=0.005)

One-Year OS

70.1% (95% CI: 62.1, 76.7)

46.7% (95% CI: 33.9, 58.4)

Median OS

18.1 months (95% CI: 15.5, not estimable)

12 months (95% CI: 11.2, 15.2)

CNS-PFS Benefit in All Patients with Brain Metastases

N=198

N=93

Risk Reduction

68% (HR=0.32 [95% CI: 0.22, 0.48]; p<0.0001)

One-year CNS-PFS

40.2% (95% CI: 29.5, 50.6)

0%

Median CNS-PFS

9.9 months (95% CI: 8.0, 13.9)

4.2 months (95% CI: 3.6, 5.7)

Intracranial Objective Response Rate (ORR-IC) in Patients with Active Brain Metastases and Measurable Intracranial Lesions at Baseline

N=55

N=20

Complete Response (CR)

3 (5.5%)

1 (5.0%)

Partial Response (PR)

23 (41.8%)

3 (15.0%)

Stable Disease

24 (43.6%)

16 (80.0%)

Progressive Disease

2 (3.6%)

0

Not Available

3 (5.5%)

0

ORR-IC (CR+PR)

26 (47%) (95% CI: 34, 61)

4 (20%) (95% CI: 6, 44)

Duration of Response-IC

6.8 months (95% CI: 5.5, 16.4)

3 months (95% CI: 3.0, 10.3)

About HER2CLIMB

HER2CLIMB is a multinational randomized (2:1), double-blind, placebo-controlled, active comparator, pivotal clinical trial comparing TUKYSA in combination with trastuzumab and capecitabine compared with trastuzumab and capecitabine alone in patients with locally advanced unresectable or metastatic HER2-positive breast cancer who were previously treated with trastuzumab, pertuzumab and T-DM1. The primary endpoint of the trial was PFS per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as determined by blinded independent central review (BICR) in the first 480 patients enrolled in the trial. HER2CLIMB enrolled a total of 612 patients to support the analyses of key secondary endpoints, including OS, PFS per BICR in patients with brain metastases at baseline and confirmed ORR.1

Results of Primary Analysis of HER2CLIMB

Control Arm (Placebo + trastuzumab + capecitabine)

PFS by BICR in the first 480 patients

46% reduction in risk of progression or death (HR=0.54 [95% CI: 0.42, 0.71]; p<0.00001; N=480)

OS

34% reduction in risk of death (HR=0.66 [95% CI: 0.50, 0.87]; p=0.0048; N=612)

PFS* by BICR in patients with brain metastases

52% reduction in risk of progression or death (HR=0.48 [95% CI: 0.34, 0.69]; p<.0.00001; N=291)

One-Year PFS

25% (95% CI: 17, 34)

0%

Median PFS

7.6 months (95% CI: 6.2, 9.5)

5.4 months (95% CI: 4.1, 5.7)

*standard RECIST, includes brain and body

In HER2CLIMB, serious adverse reactions occurred in 26 percent of patients who received TUKYSA. Serious adverse reactions occurring in 2 percent or more of patients who received TUKYSA were diarrhea (4%), vomiting (2.5%), nausea, abdominal pain, and seizure (2% each). The most common adverse reactions occurring in 20 percent or more of patients who received TUKYSA were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash. Adverse reactions leading to treatment discontinuation occurred in 6 percent of patients who received TUKYSA; adverse reactions leading to treatment discontinuation of TUKYSA (in 1 percent or more of patients) were hepatotoxicity (1.5%) and diarrhea (1%).1

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. An estimated 279,100 new cases of breast cancer will be diagnosed in the U.S. in 2020.2 Between 15 and 20 percent of breast cancer cases are HER2-positive.3 Historically, HER2-positive breast cancer tends to be more aggressive and more likely to recur than HER2-negative breast cancer.3,4,5 Up to 50 percent of metastatic HER2-positive breast cancer patients develop brain metastases over time. 6,7,8

About TUKYSA (tucatinib)

TUKYSA is an oral, small molecule tyrosine kinase inhibitor (TKI) of HER2, a protein that contributes to cancer cell growth.1,9 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.1

Important Safety Information

Warnings and Precautions

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.

Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every 3 weeks during treatment, and as clinically indicated. Based on the severity of hepatoxicity, interrupt dose, then dose reduce or permanently discontinue TUKYSA.

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

Use in Specific Populations

For more information, please see the full Prescribing Information for TUKYSA here.

About Seattle Genetics

Seattle Genetics, Inc. is a global biotechnology company that discovers, develops and commercializes transformative medicines targeting cancer to make a meaningful difference in peoples lives. The company is headquartered in the Seattle, Washington area, and has offices in California, Switzerland and the European Union. For more information on our robust pipeline, visit http://www.seattlegenetics.com and follow @SeattleGenetics on Twitter.

Forward Looking Statements

Certain statements made in this press release are forward looking, such as those, among others, relating to the therapeutic potential of TUKYSA including its efficacy, safety and therapeutic uses, including its use in combination with trastuzumab and capecitabine to treat patients with HER2-positive metastatic breast cancer with brain metastases who have received one or more previous anti-HER2 therapies, and its potential use in additional treatment settings and tumor types. 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; the possibility that adverse events or safety signals may occur; that utilization and adoption of TUKYSA by prescribing physicians may be limited due to impacts related to the COVID-19 pandemic, availability and extent of reimbursement or other factors; and that adverse regulatory actions may occur. More information about the risks and uncertainties faced by Seattle Genetics is contained under the caption Risk Factors included in the companys Quarterly Report on Form 10-Q for the quarter ended March 31, 2020 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.

1 TUKYSA [package insert]. Bothell, WA: Seattle Genetics, Inc.2 Cancer Facts & Figures 2020. American Cancer Society website. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf. Accessed May 28, 2020.3 Loibli 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. http://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-her2-status.html. Accessed May 28, 2020.6 Freedman RA, Gelman RS, Anders CK, et al. TBCRC 022: a phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. J Clin Oncol. 2019;37:1081-1089.7 Olson EM, Najita JS, Sohl J, et al. Clinical outcomes and treatment practice patterns of patients with HER2-positive metastatic breast cancer in the post-trastuzumab era. Breast. 2013;22:525-531.8 Bendell JC, Domchek SM, Burstein HJ, et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer. 2003;97:2972-2977.9 Anita Kulukian, Patrice Lee, Janelle Taylor, et al. Preclinical Activity of HER2-Selective Tyrosine Kinase Inhibitor Tucatinib as a Single Agent or in Combination with Trastuzumab or Docetaxel in Solid Tumor Models. Mol Cancer Ther 2020;19:976-987.

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Seattle Genetics Announces Positive Results from Exploratory Analyses of HER2CLIMB for TUKYSA (tucatinib) in Brain Metastases Patients With...