On December 11, 2019 Seattle Genetics, Inc. (Nasdaq:SGEN) reported positive pivotal data from the HER2CLIMB trial evaluating tucatinib in patients with HER2-positive metastatic breast cancer (MBC) were presented at the 2019 San Antonio Breast Cancer Symposium (SABCS) and simultaneously published in the New England Journal of Medicine(NEJM) (Press release, Seattle Genetics, DEC 11, 2019, View Source [SID1234552265]). The HER2CLIMB trial compared tucatinib in combination with trastuzumab and capecitabine to trastuzumab and capecitabine alone in patients with unresectable locally advanced or metastatic HER2-positive breast cancer. Patients had previously received trastuzumab, pertuzumab and ado-trastuzumab emtansine (T-DM1). Patients had received a median of four prior lines of therapy overall and three lines in the metastatic setting. Forty-seven percent of the patients enrolled in the trial had brain metastases at the time of enrollment. HER2CLIMB is the first randomized pivotal trial completed to enroll patients with metastatic HER2-positive breast cancer who have untreated or previously treated and progressing brain metastases. Tucatinib is an oral, small molecule tyrosine kinase inhibitor (TKI) that is highly selective for HER2.

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"Following progression on trastuzumab, pertuzumab and T-DM1 in the metastatic HER2-positive breast cancer setting, there is no single standard of care regimen and clinical trial participation is often strongly encouraged. There is a significant unmet medical need for these patients, particularly those who develop brain metastases," said Rashmi Murthy, MD, MBE, Assistant Professor, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. "The addition of tucatinib to the commonly used combination of trastuzumab and capecitabine improved overall survival, reducing the risk of death by 34 percent compared to trastuzumab and capecitabine alone. The results from HER2CLIMB demonstrate tucatinib has the potential to become a new treatment option for patients who have been previously treated with multiple anti-HER2 agents, including patients with and without brain metastases."

"Continued innovation to bring new therapies for the treatment of metastatic HER2-positive breast cancer is urgently needed, and we are encouraged by the impressive clinical activity demonstrated with the addition of tucatinib to trastuzumab and capecitabine in the HER2CLIMB trial," said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics. "Tucatinib demonstrated a statistically significant and clinically meaningful benefit in overall survival, progression-free survival and objective response rate compared to the control arm. We plan to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration and a Marketing Authorization Application (MAA) to the European Medicines Agency by the first quarter of 2020, with the goal of bringing a much-needed new medicine to patients."

Data presented at SABCS and published in NEJM include the primary endpoint of progression-free survival (PFS) as assessed 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 overall survival (OS) as well as progression-free survival (PFS) in patients with brain metastases at baseline.

Pivotal HER2CLIMB Trial Results

Efficacy:

The primary endpoint of PFS showed that the addition of tucatinib was superior to trastuzumab and capecitabine alone, with a 46 percent reduction in the risk of disease progression or death (hazard ratio (HR)=0.54 [95% Confidence Interval (CI): 0.42, 0.71]; p<0.00001).
Estimated PFS at one year was 33 percent (95% CI: 27, 40) in the tucatinib arm, compared to 12 percent (95% CI: 6, 21) in the trastuzumab and capecitabine arm (control arm).
Median PFS was 7.8 months (95% CI: 7.5, 9.6) in the tucatinib arm, compared to 5.6 months (95% CI: 4.2, 7.1) in the control arm.
The addition of tucatinib to trastuzumab and capecitabine prolonged OS, a key secondary endpoint, reducing the risk of death by 34 percent (HR=0.66 [95% CI: 0.50, 0.88]; p=0.0048), compared to the control arm.
Estimated OS at two years was 45 percent (95% CI: 37, 53) in the tucatinib arm, compared to 27 percent (95% CI: 16, 39) in the control arm.
Median OS was 21.9 months (95% CI: 18.3, 31.0) in the tucatinib arm, compared to 17.4 months (95% CI: 13.6, 19.9) in the control arm.
For patients with brain metastases at baseline, a key secondary endpoint, the tucatinib arm also demonstrated superior PFS compared to trastuzumab and capecitabine alone. Findings demonstrated that the tucatinib regimen resulted in a 52 percent reduction in the risk of disease progression or death, compared to the control arm (HR=0.48 [95% CI: 0.34, 0.69]; p<0.00001).
The estimated PFS at one year was 25 percent (95% CI: 17, 34) with the tucatinib regimen, compared to zero percent in the control arm.
Median PFS was 7.6 months (95% CI: 6.2, 9.5) in the tucatinib arm, compared to 5.4 months (95% CI: 4.1, 5.7) in the control arm.
The confirmed objective response rate (ORR) in the patient population with measurable disease at baseline (511/612) was 40.6 percent (95% CI: 35.3, 46.0) in the tucatinib arm, compared with 22.8 percent (95% CI: 16.7, 29.8) for trastuzumab and capecitabine alone (p=0.0008).
Safety:

Tucatinib in combination with trastuzumab and capecitabine was generally well tolerated. The most common adverse events occurring in more than 20 percent of patients in the tucatinib arm vs. the control arm included: diarrhea (80.9 vs. 53.3 percent), palmar-plantar erythrodysaesthesia syndrome (PPE) (63.4 vs. 52.8 percent), nausea (58.4 vs. 43.7 percent), fatigue (45.0 vs. 43.1 percent) and vomiting (35.9 vs. 25.4 percent), which were primarily low grade.
Discontinuation of tucatinib and placebo due to adverse events was 5.7 percent in the tucatinib arm and 3.0 percent in the control arm.
Greater than or equal to Grade 3 diarrhea was seen in 12.9 percent of the patients in the tucatinib arm vs. 8.6 percent in the control arm. Antidiarrheal prophylaxis was not required per protocol. Antidiarrheals were used in less than half of all cycles where diarrhea was reported. In both treatment arms, when used, the duration of antidiarrheal treatment was short (median of 3 days/cycle).
Greater than or equal to Grade 3 aspartate aminotransferase (AST) was seen in 4.5 percent of the patients in the tucatinib arm vs. 0.5 percent in the control arm, and alanine aminotransferase (ALT) elevation in 5.4 percent vs. 0.5 percent, respectively. Discontinuations due to liver transaminase elevations were infrequent in both arms (ALT: 1.0 vs. 0.5 percent; AST: 0.7 vs. 0.5 percent).
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 aggressive spread of cancer cells. An estimated 271,270 new cases of invasive breast cancer will be diagnosed in the U.S. in 2019.1 Between 15 and 20 percent of breast cancer cases worldwide are HER2-positive.2 Historically, HER2-positive breast cancer tends to be more aggressive and more likely to recur than HER2-negative breast cancer.2, 3, 4 In patients with metastatic breast cancer, the most common site of first metastasis is in bone, followed by lung, brain, and liver.5, 6 Up to 50 percent of metastatic HER2-positive breast cancer patients develop brain metastases over time.2, 7 Despite recent treatment advances, there is still a significant need for new therapies that can impact metastatic disease, especially brain metastases. There are currently no approved therapies demonstrating progression-free survival or overall survival benefit for the treatment of patients with HER2-positive metastatic breast cancer after progression on T-DM1.8, 9, 10

About HER2CLIMB

HER2CLIMB is a multinational randomized (2:1), double-blind, placebo-controlled, active comparator, pivotal clinical trial comparing tucatinib 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 overall survival, PFS per BICR in patients with brain metastases at baseline and confirmed objective response rate. Safety data were evaluated throughout the study.

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 targeted 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, colorectal and gastric cancers. HER2 mediates cell growth, differentiation and survival. Tucatinib has been granted orphan drug designation by the FDA for the treatment of breast cancer patients with brain metastases.

In addition to HER2CLIMB, tucatinib is being evaluated in a randomized, double-blind, placebo-controlled, multi-center phase 3 trial of tucatinib in combination with T-DM1 compared to T-DM1 alone, in patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including those with brain metastases, who have had prior treatment with a taxane and trastuzumab. The primary endpoint is progression-free survival per RECIST criteria. Secondary endpoints include overall survival, objective response rate and duration of response. The trial is being conducted in North America and is expected to enroll approximately 460 patients. More information about the phase 3 trial, including enrolling centers, is available at www.clinicaltrials.gov.

Tucatinib is also being evaluated in a multi-center, open-label, single-arm phase 2 clinical trial known as MOUNTAINEER, which is evaluating tucatinib in combination with trastuzumab in patients with HER2-positive, RAS wildtype metastatic or unresectable colorectal cancer. The primary endpoint of the trial is objective response rate by RECIST criteria. Progression-free survival, duration of response, overall survival and safety and tolerability of the combination regimen are secondary objectives. Results for 26 patients were evaluated in an analysis and presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2019 Congress. Enrollment is ongoing. More information about the MOUNTAINEER trial, including enrolling centers, is available at www.clinicaltrials.gov.