Based on the results of the pivotal HER2CLIMB Trial (NCT02614794) presented at the 42nd San Antonio Breast Cancer Symposium (SABCS) held in San Antonio, Texas, December 10 14, 2019, and data published in the New England Journal of Medicine (NEJM), Seattle Genetics confirmed that the company completed the submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for tucatinib.

Tucatinib is an investigational, oral, small molecule tyrosine kinase inhibitor (TKI). Tyrosine kinases are enzymes that are a part of many cell functions, including cell signaling, growth, and division. But in some cases they may be too active or found at high levels in some types of cancer cells. In that case, blocking them may help keep cancer cells from growing.

Tucatinib is highly selective for HER2.

HER2-positive breast cancerPatients with HER2-positive breast cancer have tumors with high levels human epidermal growth factor receptor 2 (HER2), a protein which promotes the aggressive spread of cancer cells.

According to the American Cancer Society, in the United Stated, an estimated 271,270 new cases of invasive breast cancer were diagnosed in in 2019.[1] In addition, based on the available data, between 15% and 20% of all diagnosed 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] In about 50% of metastatic HER2-positive breast cancer cases, patients develop brain metastases over time. [2][7]

Although there have been many advances in the treatment of metastatic HER2-positive breast cancer, there is still a significant unmet medical 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 following treatment with trastuzumab emtanzine.[8][9][10]

Combination therapyIn their NDA, Seattle Generics requested the FDA to approve tucatinib in combination with capecitabine (Xeloda; Genentech/Roche) and trastuzumab (Herceptin; Genentech/Roche) for treatment of patients with locally advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received at least three prior HER2-directed agents separately or in combination, in the neoadjuvant, adjuvant or metastatic setting.

This setting is the same setting for which the investigational drug was recently granted Breakthrough Therapy designation by the FDA and included patients with brain metastases, who have been treated with trastuzumab, pertuzumab (Perjeta; Genentech/Roche), and trastuzumab emtanzine (Kadcyla; Genentech/Roche).

HER2CLIMB TrialThe HER2CLIMB study is a multinational randomized (2:1), double-blind, placebo-controlled, active comparator, pivotal clinical trial included data from 612 enrolled patients.

The trial results published in the NEJM, presented at the SABCS by Rashmi K. Murthy, M.D., assistant professor of Breast Medical Oncology, demonstrated that tucatinib significantly improved progression free survival (PFS) and overall survival (OS) in patients with advanced HER2-positive breast cancer, with and without brain metastasis.

The trial met its primary endpoint of the study demonstrated that the treatment combination reduced the risk of death by 46% compared with trastuzumab and capecitabine alone. The trial also met its secondary endpoints at interim analysis, demonstrating prolonged OS, reduced the risk of death by 34% and extended PFS by 52% among patients with brain metastasis.

Furthermore, with 41%, the overall response rate was higher in the tucatinib group compared with 23% in the standard of care treatment.

This is a uniquely designed trial in that it allowed patients to enroll if they had untreated, treated stable or previously treated, but progressive brain metastasis, Murthy noted.

Brain metastasizes are common in up to half of patients during the disease course, but there are limited systemic treatment options because most available agents have difficulty crossing the blood brain barrier, she added.

Well toleratedThe study results demonstrated that the triplet combination of tucatinib + capecitabine + trastuzumab was generally well tolerated with no unexpected toxicities. In the tucatinib arm the investigators observed diarrhea, hand-foot syndrome, nausea, fatigue, and vomiting, all mostly low grade, as the reported adverse events. Furthermore, there was a low drug discontinuation rate of 5.7% in the triplet arm compared with 3% in the control arm.

This trial verified that tucatinib is both a safe and effective treatment, Murthy explained during the SABCS.

These results are realy unprecedented for late line therapy in locally advanced, metastatic, breast cancer. This is a major treatment advance for patients who have significant unmet medical need. I believe that tucatinib in combination with trastuzumab and capecitabine could be the new standard of care for patients pretreated with multiple anti-HER2 agents including patients with brain metastasis, Murthy said.

Todays submission marks another important milestone for Seattle Genetics and tucatinib, and a potential advance for patients with either locally advanced or metastatic HER2-positive breast cancer, including those with and without brain metastases, said Roger Dansey, MD, Chief Medical Officer at Seattle Genetics.

We look forward to working with the FDA on the review of this application, he concluded.

Clinical trialsTucatinib, Trastuzumab, and Capecitabine for the Treatment of HER2+ LMD NCT03501979A Study of Tucatinib vs. Placebo in Combination With Ado-trastuzumab Emtansine (T-DM1) for Patients With Advanced or Metastatic HER2+ Breast Cancer NCT03975647A Study of Tucatinib vs. Placebo in Combination With Capecitabine & Trastuzumab in Patients With Advanced HER2+ Breast Cancer (HER2CLIMB) NCT02614794

References[1] American Cancer Society, Cancer Facts and Figures 2018-2019.[2] Loibl S, Gianni L (2017). HER2-positive breast cancer. The Lancet 389(10087): 2415-29.[3] Slamon D, Clark G, Wong S, et al. (1987). Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785): 177-82.American Cancer Society (ACS) (2018). Breast cancer HER2 status. Last accessed: December 20, 2018.[4] Kennecke H, Yerushalmi R, Woods R, et al. (2010). Metastatic Behavior of Breast Cancer Subtypes. Journal of Clinical Oncology 28(20): 3271-7.[5] Berman AT, Thukral AD, Hwang W-T, et al. (2013). Incidence and Patterns of Distant Metastases for Patients With Early-Stage Breast Cancer After Breast Conservation Treatment. Clinical Breast Cancer 13(2): 88-94.[6] Duchnowska R, Loibl S, Jassem J (2018). Tyrosine kinase inhibitors for brain metastases in HER2-positive breast cancer. Cancer Treatment Reviews 67: 71-7.[7] Verma S, Miles D, Gianni L, et al. (2012). Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer. New England Journal of Medicine 367(19): 1783-91.[8] Geyer CE, Forster J, Lindquist D, et al. (2006). Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer. New England Journal of Medicine 355(26): 2733-43.[9] Blackwell KL, Burstein HJ, Storniolo AM, et al. (2012). Overall Survival Benefit With Lapatinib in Combination With Trastuzumab for Patients With Human Epidermal Growth Factor Receptor 2Positive Metastatic Breast Cancer: Final Results From the EGF104900 Study. Journal of Clinical Oncology 30(21): 2585-92.

Excerpt from:
Seattle Genetics Submits New Drug Application to the US FDA for Tucatinib - OncoZine

You've likely heard about direct-to-consumer DNA testing kits. In the past few years, at-home genetic testing has been featured in the lyrics of chart-topping songs, and has helped police solve decades-old cold cases, including identifying the Golden State Killer in California.

Even if you don't find a DNA testing kit under your own Christmas tree, there's a good chance someone you know will.

Whether you're motivated to learn about your health or where your ancestors came from, it is important to understand how these tests work - before you spit in the tube.

While exciting, there are things that these genetic testing kits cannot tell users - and important personal implications that consumers should consider.

My main area of research is around clinical genome sequencing, where we look through all of a person's DNA to help diagnose diseases. With a PhD in genetics, I often get questions from friends and family about which direct-to-consumer genetic test they should buy, or requests to discuss results. Most questions are about two types of products: ancestry and health kits.

The most popular ancestry kit is from AncestryDNA. These kits are aimed at giving users insight into where their ancestors might be from. They can also connect users with family members who have used the service and have opted into having their information shared.

Another option is Living DNA, which has a smaller dataset but provides more precise information on the UK and Ireland.

The most popular health kit is from 23andMe. Depending on the user's preference, results include information on predispositions for diseases such as diabetes and Alzheimer's, as well as on the likelihood of having certain traits such as hair colour and taste.

This company also offers ancestry analysis, as well as ancestry and trait-only kits that don't provide health information. The kit offered by the newer MyHeritage DNA also provides a combined ancestry and health option.

There are other kits out there claiming to evaluate everything from athletic potential to relationship compatibility. But gift-buyers beware: for most of these, in contrast to those above, the evidence is seriously lacking.

A direct-to-consumer DNA testing kit. (Shutterstock)

For all of these tests, customers receive a kit in the mail. The kits contain instructions for collecting a saliva sample, which you mail back to the company for analysis.

During this analysis, these popular tests do not look at the entire genome. Instead, they employ single nucleotide polymorphism (SNP) genotyping. As humans we all share 99.9 per cent of our DNA. SNPs are essentially what is left: all of the points at which we can differ from our neighbour, making us unique. SNP genotyping looks at a subset of these sites to "survey" the user's genome.

These SNPs are then compared to reference datasets of individuals with known conditions or ancestry. Most results are based on the SNPs shared with a given group.

For example, if your results say that you are 42 per cent Southeast Asian, it's because 42 per cent of your SNPs were most likely to have come from a group in the reference dataset labelled "Southeast Asian." The same goes for traits and health conditions.

Direct-to-consumer genetic tests are not a substitute for clinical assessment. The methods used differ dramatically from what is done to diagnose genetic diseases.

In a clinical setting, when suspicion of a genetic condition is high, entire genes are often analyzed. These are genes where we understand how changes in the DNA cause cellular changes that can cause the disease. Furthermore, clinical assessment includes genetic counselling that is often key to understanding results.

In contrast, findings from direct-to-consumer genetic tests are often just statistical links; there is commonly no direct disease-causing effect from the SNPs.

Users may interpret a result as positive, when the risk increase is only minimal, or entirely false. These tests can also give false reassurance because they do not sequence genes in their entirety and can miss potentially harmful variants.

These tests are exciting: they introduce new audiences to genetics and get people thinking about their health. They're also helping to build vast genetic databases from which medical research will be conducted.

But for individual users, there are important caveats to consider. Recent reports have questioned the accuracy of these tests: identical twins can receive different results. Furthermore, a lack of diversity in the reference data has caused particular concern regarding accuracy of results for ethnic minorities.

There are also concerns about the way these tests emphasize racial categories that science considers to be social constructs and biologically meaningless.

A recent paper in the British Medical Journal suggests four helpful questions for users to consider. First, users should ask themselves why they want the test. If it is to answer a medical question, then they should speak with their doctor. Users should also think about how they might feel when they receive results containing information they would rather not know.

Users should also consider issues around security and privacy. It is important to read the fine print of the service you're using, and determine whether you're comfortable sharing personal information, now and in the future.

In Canada, policies around genetics have not always kept up with the science. At present, direct-to-consumer genetic testing is unregulated. And, although Canadians have legislative protections against genetic discrimination, those laws are being challenged in the courts, and could change.

Finally, it may also be worth discussing DNA testing with relatives. We share half of our genome with our immediate family members, and smaller fractions with more distant relatives. Genetic results not only affect us, but our family.

Some users may feel they learn more about themselves. For others, results may bring people closer together - not a bad outcome for the holiday season.

At the end of the day, these genetic testing kits are for entertainment: they should not be used to assess health risk in any meaningful way.

If you have any questions related to your health or a genetic disease, discuss these with your family doctor or a suitable health-care professional.

Michael Mackley, Junior Fellow, MacEachen Institute for Public Policy and Governance; Medical Student, Dalhousie University.

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Read more from the original source:
DNA Tests Make a Fun Gift But Here's What You Need to Know Before You Unwrap - ScienceAlert

BOTHELL, Wash.--(BUSINESS WIRE)--Seattle Genetics, Inc. (Nasdaq:SGEN) today announced it has completed the submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for tucatinib. This NDA requests FDA approval of tucatinib in combination with trastuzumab and capecitabine for treatment of patients with locally advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received at least three prior HER2-directed agents separately or in combination, in the neoadjuvant, adjuvant or metastatic setting. The submission is based on the results of HER2CLIMB, a randomized pivotal trial comparing tucatinib added to trastuzumab and capecitabine versus trastuzumab and capecitabine alone. HER2CLIMB trial results were presented on December 11, 2019 at the 2019 San Antonio Breast Cancer Symposium and published in the New England Journal of Medicine. Tucatinib is an oral, small molecule tyrosine kinase inhibitor (TKI) that is highly selective for HER2.

Tucatinib was recently granted Breakthrough Therapy designation by the FDA in combination with trastuzumab and capecitabine, for treatment of patients with locally advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have been treated with trastuzumab, pertuzumab, and T-DM1. This designation was based on data from the HER2CLIMB trial.

Todays submission marks another important milestone for Seattle Genetics and tucatinib, and a potential advance for patients with either locally advanced or metastatic HER2-positive breast cancer, including those with and without brain metastases, said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics. We look forward to working with the FDA on the review of this application.

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 http://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) 2019 Congress. Enrollment is ongoing. More information about the MOUNTAINEER trial, including enrolling centers, is available at http://www.clinicaltrials.gov.

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. ADCETRIS (brentuximab vedotin) and PADCEV (enfortumab vedotin-ejfv) use the companys industry-leading antibody-drug conjugate (ADC) technology designed to bring a powerful medicine directly to cancer cells. ADCETRIS is approved for the treatment of several types of CD30-expressing lymphomas, and PADCEV is approved to treat adults with metastatic urothelial cancer. In addition, investigational agent tucatinib, a small molecule tyrosine kinase inhibitor, is in late-stage development for HER2-positive metastatic breast cancer, and in clinical development for metastatic colorectal cancer. The company is headquartered in Bothell, Washington, 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 of the statements made in this press release are forward looking, such as those, among others, relating to the potential FDA approval of tucatinib in combination with trastuzumab and capecitabine for treatment of patients with locally advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received at least three prior HER2-directed agents separately or in combination, in the neoadjuvant, adjuvant or metastatic setting; the therapeutic potential of tucatinib, including its possible efficacy, safety and therapeutic uses and anticipated development activities including ongoing and future 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 possibility that the New Drug Application submission based on the HER2CLIMB trial may not be accepted for filing by, or ultimately approved by, the FDA in a timely manner or at all or with the requested label; the difficulty and uncertainty of pharmaceutical product development; the risk of adverse events or safety signals; and the possibility of disappointing results in ongoing or future clinical trials despite earlier promising clinical results. 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 September 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:

View original post here:
Seattle Genetics Announces Submission of Tucatinib New Drug Application to the U.S. FDA for Patients with Locally Advanced or Metastatic HER2-Positive...

BOTHELL, Wash.--(BUSINESS WIRE)--Seattle Genetics, Inc. (Nasdaq:SGEN) today announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to tucatinib, in combination with trastuzumab and capecitabine, for treatment of patients with locally advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have been treated with trastuzumab, pertuzumab, and T-DM1. The positive topline results of the pivotal HER2CLIMB clinical trial were announced in October 2019, and additional data were presented at the 2019 San Antonio Breast Cancer Symposium (SABCS) on December 11, 2019 and were simultaneously published in the New England Journal of Medicine (NEJM). Tucatinib is an oral, small molecule tyrosine kinase inhibitor (TKI) that is highly selective for HER2.

The FDAs Breakthrough Therapy process is intended to expedite the development and review of promising drug candidates intended for serious or life-threatening conditions. Designation is based upon preliminary clinical evidence of the potential for substantial improvement over existing therapies on one or more clinically significant endpoints.

The addition of tucatinib to the commonly used combination of trastuzumab and capecitabine demonstrated superior activity compared to trastuzumab and capecitabine alone in patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including those with and without brain metastases, said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics. The decision by the FDA to grant Breakthrough Therapy designation to tucatinib recognizes the urgent need for new medicines that can impact the lives of those with HER2-positive metastatic breast cancer. We intend to submit a New Drug Application to the FDA and an MAA to the EMA by the first quarter 2020, with the goal of making tucatinib available to patients in this setting as soon as possible.

This Breakthrough Therapy designation was based on data from the pivotal HER2CLIMB clinical trial, which compared tucatinib in combination with trastuzumab and capecitabine to trastuzumab and capecitabine alone in patients with locally advanced unresectable 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 in the metastatic setting. Forty-seven percent of the patients enrolled in the trial had brain metastases at the time of enrollment.

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. 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). The trial met the two key secondary endpoints at interim analysis. The tucatinib arm demonstrated an improvement in overall survival, with a 34 percent reduction in the risk of death (HR=0.66 [95% CI: 0.50, 0.88]; p=0.0048), compared to the control arm. For patients with brain metastases at baseline, the tucatinib arm also demonstrated superior PFS, with 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).

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, palmar-plantar erythrodysaesthesia syndrome (PPE), nausea, fatigue, and vomiting. 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 http://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) 2019 Congress. Enrollment is ongoing. More information about the MOUNTAINEER trial, including enrolling centers, is available at http://www.clinicaltrials.gov.

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 peoples lives. ADCETRIS (brentuximab vedotin) utilizes the companys industry-leading antibody-drug conjugate (ADC) technology and is currently approved for the treatment of multiple CD30-expressing lymphomas. Beyond ADCETRIS, the company has a late-stage pipeline including enfortumab vedotin for metastatic urothelial cancer, currently being reviewed for approval by the FDA, and tisotumab vedotin in clinical trials for metastatic cervical cancer, which utilize our proprietary ADC technology. In addition, tucatinib, a small molecule tyrosine kinase inhibitor, is in late-stage development for HER2-positive metastatic breast cancer and in clinical development for metastatic colorectal cancer. We are also 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 http://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 the therapeutic potential of tucatinib, including its possible efficacy, safety and therapeutic uses; anticipated development activities including ongoing and future clinical trials; and intended regulatory actions, including the plan to submit an NDA to the FDA and a MAA to the EMA by the first quarter of 2020. 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 risk of adverse events or safety signals, the possibility of disappointing results in ongoing or future clinical trials despite earlier promising clinical results, the possibility of delays in the submission of an NDA to the FDA and a MAA to the EMA, the possibility that data from the HER2CLIMB trial may not be sufficient to support approval of tucatinib, the possibility of adverse regulatory action. 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 September 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. American Cancer Society, Cancer Facts and Figures 2018-2019.

2. Loibl S, Gianni L (2017). HER2-positive breast cancer. The Lancet 389(10087): 2415-29.

3. Slamon D, Clark G, Wong S, et al. (1987). Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785): 177-82.

4. American Cancer Society (ACS) (2018). Breast cancer HER2 status. Accessed: December 10, 2018.

5. Kennecke H, Yerushalmi R, Woods R, et al. (2010). Metastatic Behavior of Breast Cancer Subtypes. Journal of Clinical Oncology 28(20): 3271-7.

6. Berman AT, Thukral AD, Hwang W-T, et al. (2013). Incidence and Patterns of Distant Metastases for Patients With Early-Stage Breast Cancer After Breast Conservation Treatment. Clinical Breast Cancer 13(2): 88-94.

7. Duchnowska R, Loibl S, Jassem J (2018). Tyrosine kinase inhibitors for brain metastases in HER2-positive breast cancer. Cancer Treatment Reviews 67: 71-7.

8. Verma S, Miles D, Gianni L, et al. (2012). Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer. New England Journal of Medicine 367(19): 1783-91.

9. Geyer CE, Forster J, Lindquist D, et al. (2006). Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer. New England Journal of Medicine 355(26): 2733-43.

10. Blackwell KL, Burstein HJ, Storniolo AM, et al. (2012). Overall Survival Benefit With Lapatinib in Combination With Trastuzumab for Patients With Human Epidermal Growth Factor Receptor 2Positive Metastatic Breast Cancer: Final Results From the EGF104900 Study. Journal of Clinical Oncology 30(21): 2585-92.

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Seattle Genetics Announces U.S. FDA Grants Breakthrough Therapy Designation for Tucatinib in Locally Advanced or Metastatic HER2-Positive Breast...

When she was in her early 30s, Katy Mathes decided to check her cancer risk. A genetic test showed a mutation on a BRCA gene, which significantly raises a persons lifetime risk of developing hereditary breast or ovarian cancer.

Thirteen people in the family got testedher mother, her sister, cousins and aunts. Eleven had the mutation. Almost all did their testing with Myriad Genetics Inc., which introduced the first BRCA tests in 1996.

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A Genetic Test Led Seven Women in One Family to Have Major Surgery. Then the Odds Changed. - The Wall Street Journal

Here we are at the end of yet another year, a year that definitely went by faster than the year before or for that matter the year before that. And as ever at this time of year tis the season for casting ahead and divining what the future holds, delivering lists of top 10s and predictions of what will be hot and what will not.

In some fields, the resultant list will look very much like something delivered by the toss of a coin, but in the science and research areas it is pretty certain what will land in the top two or three subjects.

Number one has got to be climate and the impact of global warming. There is no other area that can match it for the variety and depth of research activity being applied to a whole range of climate-related subjects. And the hard news stories keep tumbling out of this endeavour, helping to show that global changes are taking place due to the alterations in climate that we as humans have set in motion.

One peer-reviewed study about the increasingly rapid loss of ice mass over Greenland was published less than a fortnight before Christmas. It showed that the biggest block of land ice in the northern hemisphere was melting away much faster than expected, seven times faster the study suggests.

Published in the journal Nature, it said the island lost 33 billion tonnes of ice on average during the last decade of the 20th century but the average annual ice loss for the most recent 10 years now stands at 254 billion tonnes of ice a year.

This is just one story and one research area, but climate-related studies arise in many fields from alteration of ocean currents to changed rainfall patterns and from species loss to poor air quality. It is also a subject area that affects us all given the potential of coastal flooding, crop losses and human migration to name but a few possible future impacts.

The impacts for humanity are also there in research into new ways to alter our genetic blueprints. The key to unlocking the potential to overcome gene-based diseases relates CRISPR CAS9, our current best technology for getting into the genome and then adding, deleting or altering individual genes.

It has the potential to reverse disease states by correcting unwanted mutations. It is being used in labs around the world as scientists seek to fully understand the method and apply it to alter genes. It is a powerful research tool, for example to create a mouse model that imitates a human disease state and then developing and testing drugs that might be used in humans. It also allows the researcher to look for any unwanted downstream effects arising from genetic alterations.

There are so many scientists using the CRISPR tools that news reports and discoveries will certainly follow. Yet most research scientists are concerned about the lack of controls or limits on what kind of genetic experiments that might be conducted on the human genome. Too little is known about unexpected problems if a number of genes are altered to eliminate a genetic disorder.

There is also the issue of genetic alteration of the germline, the genetic material that moves across to the next generation. There is currently an international block on germline alterations but that has not stopped at least one researcher who went ahead and created the worlds first two genetically modified humans. Breakthroughs will be delivered all through 2020 it is probably safe to say.

What might come third in this short list is up for grabs, and what might produce the next big scientific discovery could come from any direction. For that reason this report becomes a wish list relevant to Irish research and scientific endeavour related to our engagement with important international research bodies.

One of the most important decisions in this regard brings us closer to membership of Cern, Europes premier nuclear research body. A Dil committee studied the research and commercial potential arising from membership and called on the Government to join Cern as quickly as possible.

Cerns huge atom smasher confirmed the existence of the Higgs Boson, an international effort that involved many countries. Ireland could become more involved in this kind of research if it were a member. The Government has already taken the leap and announced our membership of the European Southern Observatory.

Our astronomers and physicists can now get access to some of the worlds largest telescopes based in Chile. The ESO is also a mill for discoveries and this membership gives us the potential to become international players in this field. And in more familiar territory, the Government has renewed its commitment to invest 100 million in the European Space Agency between now and 2024, a decision that ensures Ireland can bid for commercial contracts and researchers can participate in ESA activities. Our investment pays for itself given Irish companies can share in contracts.

All of the research areas mentioned here show how important it is to internationalise Irelands involvement in science. By doing this, we give more opportunities to promising young Irish scientists and help build a strong international reputation for research. Certainly that is not too much to ask for this Christmas.

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Another year of climate change, genetics and Irish scientific ambition - The Irish Times

New research led by La Trobe University in Australia has uncovered genetic clues which could explain why some people have more severe side effects from long-term methamphetamine use than others.

The research, published in Molecular Psychiatry found that variations in the gene known as BDNF strongly determine the effects of methamphetamine in the brain. This could potentially explain why some users develop methamphetamine-induced psychosis, which is similar to schizophrenia.

La Trobe neuroscientist Professor Maarten van den Buuse said the research, conducted using animal models, may lead to ways of identifying individuals at particular risk of developing psychosis and could mean a fundamental change in the way the effects of drug-induced psychosis on the brain are treated.

Drug-induced psychosis is generally treated with anti-psychotic medications, but these are not generally effective and are often associated with side effects. If further research is able to provide more details on the role genetics plays in the effects of long-term methamphetamine use, we could begin looking at therapies that would make a real difference for people affected by it."

Professor Maarten van den Buuse, La Trobe neuroscientist

The research looked specifically into the impact of methamphetamine use in adolescence and early adulthood, which is often when long-term users begin taking the drug, Professor van den Buuse said.

The findings are the result of collaboration between academics at La Trobe's School of Psychology and Public Health, and the La Trobe Institute of Molecular Science.

Source:

Journal reference:

Greening, D.W., et al. (2019) Chronic methamphetamine interacts with BDNF Val66Met to remodel psychosis pathways in the mesocorticolimbic proteome. Molecular Psychiatry. doi.org/10.1038/s41380-019-0617-8.

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Genetics plays a role in the effects of long-term methamphetamine use - News-Medical.net

NEW YORK The Jackson Laboratory announced on Wednesday that it has received $2.5 million from the Mark Foundation for Cancer Research to study the influence of host genetics on response to immunotherapy.

The researchers, who are conducting the study in mice, are aiming to generate new insights on which cancer patients will respond positively to immunotherapies, based on their genetic backgrounds. The project, "Dissecting the Genetic Control of Response to Immune Checkpoint Inhibitors in Cancer," has implications for how oncologists prescribe a treatment regimen, the lab noted.

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Jackson Laboratory Receives $2.5M Grant to Study Influence of Host Genetics on Immunotherapy - GenomeWeb

(WZAW) -- Jenna Finley is a board-certified genetic counselor at Invitae, a leading medical genetics company. After counseling patients for years, Jenna knew the power with genetic information, but with no strong family history of disease she wasnt concerned about her risk. She mostly wanted to better understand the experience of her patients.

Her results revealed a genetic change in a gene associated with an increased risk of breast cancer. She went to see her doctor, who referred her to a high-risk breast cancer clinic, where she worked with a team to establish a plan to carefully monitor her health. Now any signs of breast cancer that develop will be caught early.

With her job experience, Jenna knew that the other members of her family should be tested in case they, too, faced an increased health risks based on their shared genes. In fact, her mothers test came back positive for the same cancer-causing genetic change Jenna has. More surprisingly, her father learned that he has a disorder that causes excess iron in the bodys organs, which can be fatal.

Jennas father quickly went to his doctor who found his iron levels were so high that he had to begin treatment immediately to avoid potentially irreversible damage. Had Jenna and her parents not gone through the process of genetic testing, they might have ever known about these health conditions.

Studies show that increased genetic risks are common. In fact, 1 in 6 consumers in the U.S. have a medically actionable disorder and may not know it.

Genetic testing help with a wide range of health questions, whether youre current facing a health issue, planning for a family, currently expecting or interested in preventing disease.

For more information, visit http://www.invitae.com

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One woman's genetic test might have saved her father's lilfe - WSAW

Triplet Therapeutics, a biotechnology startup harnessing human genetics to develop treatments for repeat expansion disorders at their source, officially launched today with $59 million in financing including a $49 million Series A financing led by MPM Capital and Pfizer Ventures U.S. LLC, the venture capital arm of Pfizer Inc.Atlas Venture, which co-founded and seeded Triplet with a $10 million investment, also participated in the Series A alongside Invus, Partners Innovation Fund and Alexandria Venture Investments.

The company will use the Series A funds to progress its first development candidates into IND-enabling studies, as well as to advance natural history studies to inform its clinical development plan and contribute to the scientific understanding of repeat expansion disorders.

The Cambridge, Mass.-based Triplet was founded in 2018 by Nessan Bermingham, Ph.D., a serial biotech entrepreneur and venture partner at Atlas Venture, along with Atlas Venture and Andrew Fraley, Ph.D., to pursue a transformative approach to developing treatments for repeat expansion disorders, a group of more than 40 known genetic diseases associated with expanded DNA nucleotide repeats.Triplet Therapeutics is developing transformational treatments for patients with unmet medical needs by leveraging insights of human genetics to target the underlying cause of repeat expansion disorders, a group of more than 40 known genetic diseases including Huntingtons disease, myotonic dystrophy and spinocerebellar ataxias.

Triplet is developing antisense oligonucleotide (ASO) and small interfering RNA (siRNA) development candidates to precisely knock down key components of the DDR pathway that drive repeat expansion. This approach operates upstream of current approaches in development, targeting the fundamental driver of these diseases. By precisely reducing activity of select DDR targets, Triplets approach is designed to halt onset and progression across a wide range of repeat expansion disorders.

Were excited to launch Triplet today to transform the treatment of repeat expansion disorders, Dr. Bermingham said. This milestone would not have been possible without the contributions of thousands of patients, whose participation in genetic research has enabled us to build a fundamentally new understanding of the cause of these diseases. With this financing we are positioned to rapidly advance our initial development candidates toward the clinic for patients.

More than 40 repeat expansion disorders have been identified, and most of these diseases are severe with limited to no treatment options, said Jean-Franois Formela, M.D., partner at Atlas Venture and Board Chair of Triplet. We have built Triplet to fundamentally transform what has been the treatment strategy for these diseases up to now.

Continued here:
Biotech startup Triplet Therapeutics launches with $59M to harness human genetics to develop treatments for repeat expansion disorders -...