On June 4, 2017 Myriad Genetics, Inc. (NASDAQ:MYGN), a leader in molecular diagnostics and personalized medicine, reported that its BRACAnalysis CDx companion diagnostic test successfully identified BRCA-mutated patients with HER2- metastatic breast cancer in the OlympiAD trial (NCT02000622) who responded better to treatment with olaparib than standard chemotherapy (Press release, Myriad Genetics, JUN 4, 2017, View Source [SID1234519454]).

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OlympiAD compared olaparib (300mg twice daily) to physician’s choice of a standard chemotherapy (capecitabine, vinorelbine or eribulin) in the treatment of 302 patients with HER2-negative metastatic breast cancer harboring germline BRCA1/2 mutations as determined by Myriad’s BRACAnalysis CDx companion diagnostic test. The results showed that BRCA-positive patients treated with olaparib had a statistically-significant and clinically-meaningful PFS benefit of compared to the control group.

"In this study, patients with BRCA mutations experienced significantly prolonged PFS when treated with olaparib versus standard of care chemotherapy," said Johnathan Lancaster, M.D., Ph.D., chief medical officer, Myriad Genetic Laboratories. "Based on these findings, all patients with metastatic breast cancer should know their BRCA status as it will be a critical factor in guiding therapy selection for patients with metastatic breast cancer."

It is estimated there are approximately 60,000 patients per year in the United States who are newly diagnosed with or progress to HER2- metastatic breast cancer. Of these patients, two-thirds are not eligible for BRCA testing based upon current testing criteria. If approved by the FDA as a new indication this would potentially triple the number of patients with metastatic breast cancer who are candidates for BRCA testing.

"We believe the results from the OlympiAD study will expand the population who can benefit from the BRACAnalysis CDx test, and the results will help doctors improve care for their patients with metastatic breast cancer," said Lancaster. "This study further supports the use of advanced biomarkers, like BRACAnalysis CDx, to enable precision medicine, which benefits both patients and the healthcare ecosystem."

The collaboration between Myriad and AstraZeneca to develop a novel companion diagnostic test for olaparib began in 2007. OlympiAD is the first Phase 3 trial to demonstrate the clinical utility of the BRACAnalysis CDx test outside of ovarian cancer for which the test was approved by the U.S. Food and Drug Administration (FDA) in Dec. 2014. Based on the robustness of the OlympiaAD results, Myriad plans to submit a supplementary premarket approval (sPMA) application under its existing PMA for BRACAnalysis CDx to include the HER2- metastatic breast cancer indication.

About BRACAnalysis CDx
BRACAnalysis CDx is an in vitro diagnostic device intended for the qualitative detection and classification of variants in the protein coding regions and intron/exon boundaries of the BRCA1 and BRCA2 genes using genomic DNA obtained from whole blood specimens collected in EDTA. Single nucleotide variants and small insertions and deletions (indels) are identified by polymerase chain reaction (PCR) and Sanger sequencing. Large deletions and duplications in BRCA1 and BRCA2 are detected using multiplex PCR. Results of the test are used as an aid in identifying ovarian cancer patients with deleterious or suspected deleterious germline BRCA variants, who are or may become eligible for treatment with Lynparza (olaparib). This assay is for professional use only and is to be performed only at 320 Wakara Way, Salt Lake City, UT 84108.

About Lynparza
Lynparza (olaparib) is an innovative, first-in-class oral poly ADP-ribose polymerase (PARP) inhibitor that may exploit tumour DNA damage response (DDR) pathway deficiencies to preferentially kill cancer cells. Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of compounds targeting DNA damage response (DDR) mechanisms in cancer cells. Lynparza is currently approved by regulatory health authorities in the EU for use as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic) high grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy. It is also approved in the US as monotherapy in patients with deleterious or suspected deleterious germline BRCA-mutated (as detected by an FDA-test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Lynparza is currently being investigated in another separate non-metastatic breast cancer Phase III study called OLYMPIA. This study is still open and recruiting patients internationally.

On June 3, 2017 Bristol-Myers Squibb Company (NYSE:BMY) and QIAGEN (NASDAQ:QGEN; Frankfurt Prime Standard:QIA) reported that they have signed an agreement to explore the use of next-generation sequencing (NGS) technology to develop gene expression profiles (GEPs) as predictive or prognostic tools for use with Bristol-Myers Squibb novel immuno-oncology (I-O) therapies in cancer treatment (Press release, Bristol-Myers Squibb, JUN 3, 2017, View Source [SID1234519383]). This will leverage the combination of Bristol-Myers Squibb’s portfolio of I-O therapies with QIAGEN’s proven track record in developing and commercializing companion and complementary diagnostics as well as QIAGEN’s portfolio of NGS technologies. I-O therapies offer a novel way to treat cancer by using drugs to target the body’s immune system to help fight cancer.

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QIAGEN and Bristol-Myers Squibb intend to develop GEPs for several Bristol-Myers Squibb I-O molecules under the initial agreement. The companies also plan to enter into a further agreement to develop diagnostic products using the jointly developed GEPs and to expand the use of NGS technology with other Bristol-Myers Squibb I-O therapies.

"Greater precision in the treatment of cancer may enable faster decision making to identify which patient populations are most likely to derive benefit from our immuno-oncology agents," said Fouad Namouni, M.D., head of Development, Oncology, Bristol-Myers Squibb. "We believe working with QIAGEN will help develop better diagnostic tools to target the most appropriate immunotherapies across a number of different tumor types."

"We are very pleased to work with Bristol-Myers Squibb to potentially create what could be the first-ever NGS-based companion or complementary diagnostic to provide key insights for personalized decision-making in the rapidly expanding area of immuno-oncology," said Peer M. Schatz, Chief Executive Officer of QIAGEN. "Our teams at QIAGEN are looking forward to working with Bristol-Myers Squibb to leverage the power of NGS technology to potentially improve outcomes for patients."

QIAGEN and Bristol-Myers Squibb have been partnering since 2009. A key milestone in this partnership was the FDA approval of the Therascreen KRAS companion/complementary diagnostic assay in 2012.

Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research

At Bristol-Myers Squibb, patients are at the center of everything we do. Our vision for the future of cancer care is focused on researching and developing transformational Immuno-Oncology (I-O) medicines for hard-to-treat cancers that could potentially improve outcomes for these patients.

We are leading the scientific understanding of I-O through our extensive portfolio of investigational compounds and approved agents. Our differentiated clinical development program is studying broad patient populations across more than 50 types of cancers with 14 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs position us to advance I-O/I-O, I-O/chemotherapy, I-O/targeted therapies and I-O/radiation therapies across multiple tumors and potentially deliver the next wave of therapies with a sense of urgency. We also continue to pioneer research that will help facilitate a deeper understanding of the role of immune biomarkers and how patients’ individual tumor biology can be used as a guide for treatment decisions throughout their journey.

We understand making the promise of I-O a reality for the many patients who may benefit from these therapies requires not only innovation on our part but also close collaboration with leading experts in the field. Our partnerships with academia, government, advocacy and biotech companies support our collective goal of providing new treatment options to advance the standards of clinical practice.

QIAGEN GeneReader NGS System

The GeneReader NGS System provides the first true Sample to Insight NGS workflow for laboratories worldwide – and increasingly also pharmaceutical companies – to take advantage of the power of NGS technology. The system’s integrated bioinformatics for analysis and interpretation of NGS data, as well as a family of gene panels under the GeneRead QIAact brand, enable laboratories to identify gene variations linked to cancers and to deliver actionable molecular insights. The capabilities of this unique system also include high-sensitivity detection in liquid biopsy samples, compatibility with the QIAsymphony automation platform for high-throughput sample processing, and software integration with leading Laboratory Information Management Systems (LIMS). The current version of the GeneReader NGS System is available in the United States for research use only.

On June 3, 2017 Loxo Oncology, Inc. (Nasdaq:LOXO), a biopharmaceutical company innovating the development of highly selective medicines for patients with genetically defined cancers, reported the online publication of a new research brief in Cancer Discovery outlining the preclinical rationale for LOXO-195 and clinical proof-of-concept data from the first two patients treated (Press release, Loxo Oncology, JUN 3, 2017, View Source [SID1234519387]). LOXO-195 was developed to treat patients with TRK fusion cancers who become resistant while receiving another TRK inhibitor, such as Loxo Oncology’s larotrectinib.

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"This publication highlights the potential for LOXO-195 to extend the period of durable disease control for patients with TRK fusion cancers," said Josh Bilenker, M.D., chief executive officer of Loxo Oncology. "We believe that today’s ASCO (Free ASCO Whitepaper) presentation establishes larotrectinib as the clear first choice for patients with TRK fusion cancers. However, over time, patients will require new treatment options, since oncogene-addicted metastatic cancers ultimately evade targeted therapies. We have been relentless in the development of LOXO-195 so that it could be ready in time for the current larotrectinib clinical trial participants and future patients who depend upon us to realize the full potential of TRK inhibition in the management of advanced cancer."

LOXO-195 was designed to address anticipated mechanisms of acquired resistance in cancers exposed to a prior TRK inhibitor, including "solvent front" mutations (e.g. NTRK1 G595R, NTRK3 G623R), which are not well-addressed by existing investigational agents. LOXO-195 will be developed as a sequential treatment, to follow larotrectinib or another TRK inhibitor, to extend the total time of benefit from TRK inhibition.

The Cancer Discovery research brief provides early but encouraging evidence that the sequential use of larotrectinib followed by LOXO-195 could extend the total duration of disease control for patients with TRK fusion cancers. An analogous paradigm has already been established for other oncogene-addicted tumors, such as those driven by androgen and estrogen signaling, EGFR mutations and ABL gene fusions. The brief describes the first two patients with TRK fusion cancers who responded to larotrectinib but later relapsed. An adult with colorectal cancer and a child with infantile fibrosarcoma were biopsied at the time of tumor progression and found to have a solvent front TRK mutation in the existing TRK fusion, which explained the diminished activity of larotrectinib. As no other treatment options exist to address TRK fusion solvent front mutations, Loxo Oncology, in collaboration with the U.S. FDA, enabled these patients to access LOXO-195 through emergency use Investigational New Drug applications (INDs). Both patients responded to LOXO-195, with minimal adverse events reported.

A formal LOXO-195 IND was recently cleared by the U.S. FDA, and a Phase 1/2 trial is opening globally.

About LOXO-195
LOXO-195 is a potent, oral and selective investigational new drug in clinical development for the treatment of patients with cancers that have acquired resistance to initial TRK therapy such as larotrectinib. Growing research suggests that the NTRK genes, which encode for TRKs, can become abnormally fused to other genes, resulting in growth signals that can lead to cancer in many sites of the body. Though drugs such as larotrectinib can induce durable responses in these patients, the cancer may eventually begin to grow again. This phenomenon is called "acquired resistance," in that the cancer has acquired features conferring resistance to the initial therapy that was once effective. Emerging data in the field of TRK inhibition suggest that acquired resistance may emerge due to TRK kinase point mutations, such as those in the solvent front domain, xDFG domain, or gatekeeper region. LOXO-195 was designed to address these new point mutations and induce a new response in the patient’s cancer. Interested patients and physicians can contact the Loxo Oncology Physician and Patient Clinical Trial Hotline at 1-855-NTRK-123 or email [email protected].

About TRK Fusion Cancer
TRK fusions are chromosomal abnormalities that occur when one of the NTRK genes (NTRK1, NTRK2, NTRK3) becomes abnormally connected to another, unrelated gene (e.g. ETV6, LMNA, TPM3). This abnormality results in uncontrolled TRK signaling that can lead to cancer. TRK fusions occur rarely but broadly in various adult and pediatric solid tumors, including appendiceal cancer, breast cancer, cholangiocarcinoma, colorectal cancer, GIST, infantile fibrosarcoma, lung cancer, mammary analogue secretory carcinoma of the salivary gland, melanoma, pancreatic cancer, thyroid cancer, and various sarcomas. TRK fusions can be identified through various diagnostic tests, including targeted next-generation sequencing (NGS), immunohistochemistry (IHC), polymerase chain reaction (PCR), and fluorescent in situ hybridization (FISH). For more information, please visit www.TRKtesting.com.

On June 3, 2017 Pfizer Inc. (NYSE:PFE) reported Phase 2 data showing that its investigational, dual-mechanism poly ADP ribose polymerase (PARP) inhibitor, talazoparib, demonstrated anti-tumor activity in patients with germline (inherited) BRCA1/2-positive (gBRCA+) advanced breast cancer (Press release, Pfizer, JUN 3, 2017, View Source [SID1234519408]). Results from the Phase 2 ABRAZO trial were presented during an oral session at the 53rd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago.

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"Every day, I see the devastating effects of gBRCA+ advanced breast cancer – one of the most common forms of inherited breast cancer," said Nicholas C. Turner, MD, PhD, consultant medical oncologist at the Royal Marsden Hospital in London, United Kingdom. "As we learn more about the genetic drivers of cancer, mechanisms such as PARP inhibition are emerging as a potential therapeutic approach for this patient population."

ABRAZO is an open-label Phase 2, 2-stage, single arm, parallel cohort study that investigated the clinical efficacy and safety of single-agent talazoparib in 83 evaluable, heavily pretreated gBRCA+ advanced breast cancer patients. The primary endpoint was objective response rate (ORR) by independent radiology review.

Cohort 1 consisted of 49 patients who previously responded to platinum-based chemotherapy and subsequently developed disease progression. A 21% ORR (95% CI: 10-35) was observed in this group of patients. Cohort 2 consisted of 35 patients who developed disease progression following at least three lines of non-platinum-based therapy. This group of patients had a 37% ORR (95% CI: 22-55).

The most common adverse events (AEs) observed in at least 20% of patients consisted of anemia (51.8%), thrombocytopenia (32.5%), neutropenia (26.5%), fatigue (44.6%), nausea (42.2%), diarrhea (32.5%), decreased appetite (24.1%), dyspnea (24.1%), alopecia (21.7%), back pain (21.7%) and vomiting (20.5%). Grade 3 or 4 AEs observed in at least 10% of patients were anemia (34.9%), thrombocytopenia (19.3%) and neutropenia (14.5%). Hematological AEs were addressed with dose management. No clinically significant cardiovascular events were observed. Discontinuation rates due to drug-related AEs were low (4%).

"The activity observed in patients with gBRCA+ advanced breast cancer in the ABRAZO trial is highly encouraging. The Phase 3 EMBRACA trial was designed to build upon these results to determine whether talazoparib represents a potential treatment option in this type of breast cancer," said Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development.

Talazoparib is also being assessed in the open-label Phase 3 randomized, parallel, 2-arm EMBRACA trial. EMBRACA is evaluating talazoparib vs. protocol-specific physician’s choice of chemotherapy in patients with advanced and/or metastatic gBRCA+ breast cancer who have received zero to three prior chemotherapy regimens for advanced disease. The EMBRACA trial has completed enrollment and results will be made available at a future date.

About the ABRAZO Trial

Patients enrolled in the multicenter, open-label Phase 2, 2-stage, parallel cohort study received talazoparib once daily for 21 days in repeated 21-day cycles. Patients had triple negative breast cancer, hormone receptor-positive (HR+) breast cancer, or human epidermal growth factor 2 (HER2)-positive breast cancer that was refractory to HER2-targeted therapy. The median number of prior lines of chemotherapy for advanced breast cancer was two in Cohort 1 and four in Cohort 2. Investigators required at least five objective responses per cohort in ≤35 patients to progress from the first stage of the trial to the second stage. Both cohorts met the response criteria for advancement.

About Talazoparib

Talazoparib is an investigational anticancer compound called a PARP (poly ADP ribose polymerase) inhibitor, which is being evaluated in gBRCA+ breast cancer, as well as other cancer types with deficiencies in DNA damage repair (DDR). Preclinical studies suggest that talazoparib has a dual mechanism of action, with the potential to induce tumor cell death by blocking PARP enzyme activity and trapping PARP on the sites of DNA damage. Talazoparib has not been approved by any regulatory authorities for the treatment of any disease.

About Germline BRCA1/2-Positive Breast Cancer

BRCA1 and BRCA2 are human genes that produce proteins involved in DNA repair. When either of these genes is altered or mutated, DNA repair may not progress correctly. This can lead to the development of certain types of cancer – such as breast cancer.1,2,3 BRCA mutations can be hereditary (germline) or occur spontaneously (sporadic).1 BRCA mutations are the most common cause of hereditary breast cancers, and up to 65% of women who inherit a BRCA mutation will develop breast cancer by age 70.1,4 Epidemiologic studies indicate that individuals with gBRCA+ status are diagnosed with breast cancer at a median age of 40-45, which is approximately 20 years younger than the overall breast cancer population.5 Literature indicates that 5-10% of all breast cancer patients have a gBRCA mutation.6

On June 3, 2017 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, reported the presentation of positive results from an ongoing Phase II clinical trial (Translational Breast Cancer Research Consortium TBCRC 022) of Puma’s investigational drug PB272 (neratinib) for the treatment of HER2-positive metastatic breast cancer that has metastasized to the brain (Press release, Puma Biotechnology, JUN 3, 2017, View Source [SID1234519409]). The data were presented today in an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2017 Annual Meeting in Chicago, Illinois.

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The multicenter Phase II clinical trial enrolled patients with HER2-positive metastatic breast cancer who have brain metastases. The trial is being performed by the TBCRC and enrolled three cohorts of patients. Patients in the first cohort (n=40) included those with progressive brain metastases who were administered neratinib monotherapy. Data from this cohort were previously reported at the 2014 ASCO (Free ASCO Whitepaper) Annual Meeting and published in the Journal of Clinical Oncology in 2016. Patients in the second cohort (n=5) represent patients who had brain metastases which were amenable to surgery and who were administered neratinib monotherapy prior to and after surgical resection. The third cohort (target enrollment=60) enrolled two sub-groups of patients (prior lapatinib-treated and no prior lapatinib) with progressive brain metastases who were administered neratinib in combination with the chemotherapy drug capecitabine. The oral presentation reflects only the patients in the third cohort of patients without prior lapatinib exposure (cohort 3A, n=37), who all had progressive brain metastases at the time of enrollment and who received the combination of capecitabine plus neratinib. A full copy of the oral presentation that was presented at the ASCO (Free ASCO Whitepaper) Annual Meeting is available on the Puma Biotechnology website. Results from the second cohort and cohort 3B (prior lapatinib-treated) will be presented at a forthcoming medical meeting.

In cohort 3A, 30% of the patients had received prior craniotomy, 65% of the patients had received prior whole brain radiotherapy (WBRT), and 35% had received prior stereotactic radiosurgery (SRS) to the brain. No patients had received prior treatment with lapatinib.

The primary endpoint of the trial was central nervous system (CNS) Objective Response Rate according to a composite criteria that included volumetric brain MRI measurements, steroid use, neurological signs and symptoms, and RECIST evaluation for non-CNS sites. The secondary endpoint of the trial was CNS response by Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) Criteria. The efficacy results from the trial showed that 49% of patients experienced a CNS Objective Response by the composite criteria. The results also showed that the CNS response rate using the RANO-BM criteria was 24%. The median time to CNS progression was 5.5 months and the median overall survival was 13.5 months, though 49% of patients remain alive and survival data are immature.

The results for cohort 3A showed that the most frequently observed severe adverse event for the 37 patients evaluable for safety was diarrhea. Patients received antidiarrheal prophylaxis consisting of high dose loperamide, given together with the combination of capecitabine plus neratinib for the first cycle of treatment in order to try to reduce the neratinib-related diarrhea. Among the 37 patients evaluable for safety, 32% of the patients had grade 3 diarrhea and 41% had grade 2 diarrhea.

"Neratinib given in combination with capecitabine showed promising activity in patients with heavily pre-treated HER2-positive disease metastatic to the CNS," said Rachel A. Freedman, MD, MPH, Breast Oncology Center, Susan F. Smith Center for Women’s Cancers, Dana-Farber Cancer Institute. "Despite the introduction of several new treatments for patients with HER2-positive metastatic breast cancer, CNS progression events remain a major source of patient morbidity and mortality. Based on the results from TBCRC-022, we look forward to additional trials with neratinib-based regimens for HER2-positive CNS disease."

"We are very pleased with the activity seen in this trial with the combination of neratinib plus capecitabine," said Alan H. Auerbach, CEO and President of Puma Biotechnology. "As a small molecule that can cross the blood brain barrier, neratinib potentially offers patients with HER2-positive metastatic breast cancer that has metastasized to the CNS a novel HER2 targeted treatment option. We look forward to working with TBCRC on future trials of neratinib in patients with HER2-positive disease metastatic to the CNS."