On April 16, 2018 Exicure, Inc., the pioneer in gene regulatory and immunotherapeutic drugs utilizing three-dimensional, spherical nucleic acid (SNA) constructs, reported that it will present preclinical data in a poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2018 Annual Meeting in Chicago, Illinois from April 14-18, 2018 (Press release, Exicure, APR 16, 2018, View Source;p=RssLanding&cat=news&id=2342684 [SID1234525342]). The poster titled "TLR9 agonist SNA-induced innate and adaptive immune responses in tumor microenvironment enhance checkpoint inhibitor antitumor activity in mouse tumor models" supports the ongoing clinical development of the company’s proprietary SNA technology and highlights its potential impact in the tumor microenvironment in potentiating antitumor effects of anti-PD-1.

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The data presented in the poster, in combination with many other preclinical studies, provided the basis for advancing Exicure’s drug candidate, AST-008, into its Phase 1 clinical trial. We began subject dosing in our Phase 1 clinical trial for AST-008 in the fourth quarter of 2017 and expect this trial to be completed in mid-2018.

AST-008 utilizes Exicure’s proprietary spherical nucleic acid (SNA) technology designed in this case to agonize toll-like receptor 9, or TLR9, for application in immuno-oncology. Exicure has observed that administration of AST-008 as a monotherapy can have anti-tumor activity in colon cancer, breast cancer, lymphoma and melanoma mouse models. The company has also observed that, in preclinical studies in a variety of tumor models, AST-008 applied in combination with certain checkpoint inhibitors exhibited anti-tumor responses and survival rates that were greater than those demonstrated by checkpoint inhibitors alone.

Details on the poster presentation are as follows:

Title: TLR9 agonist SNA-induced innate and adaptive immune responses in tumor micro-environment enhance checkpoint inhibitor antitumor activity in mouse tumor models
Abstract No: 3758
Session Title: Immunomodulatory Agents and Interventions 1
Date/Time: April 17, 2018; 8:00 AM – 12:00 PM CT
Location: McCormick Place South, Exhibit Hall A, Poster Section 32

Full abstracts are available on the AACR (Free AACR Whitepaper) conference website at View Source

On April 16, 2018 A proprietary,precision cancer therapy platform from SRI International has reported that identified new molecular targets for the treatment and prevention of an aggressive and difficult-to-treat type of breast cancer (Press release, SRI International, APR 16, 2018, View Source [SID1234525359]). Subarna Sinha, Ph.D., bioinformatics program leader at SRI, presented new data describing the platform and the validated target today during a minisymposium at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting.

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Identification of new molecular targets for drug therapy is an area of active investigation and continued need in oncology. The Mining Synthetic Lethals (MiSL) platform offered by SRI may accelerate the discovery of new targeted oncology drugs by integrating a computational approach that mines patterns from primary tumor data with pre-clinical validation of potential targets.

The MiSL platform works by "looking" for synthetic lethal (SL) partners among primary tumor data and then validating them in vivo. Synthetic lethality offers a new approach to finding targeted therapies for previously "undruggable" tumor mutations. In SL interactions, a diseased cell with a mutation is dependent on a second gene for cell survival. Inhibiting activity of the second gene in these cells leads to cell death.

"If you can inhibit the SL partner, you can very exquisitely kill cancer cells," said Dr. Sinha. "MiSL overcomes the limitations of cell line screening methods such as shRNA and CRISPR, and has previously demonstrated ability to identify valid SL partners in multiple tumor types, including acute myeloid leukemia and kidney cancer. Today we presented the first data demonstrating the platform’s ability to identify new targets in triple-negative breast cancer."
BRCA1 is mutated in 15 to 20 percent of triple negative breast cancer (TNBC). SRI researchers used MiSL to identify and predict 22 SL partners of the BRCA1 mutation in TNBC, including XRCC6. To test the prediction that XRCC6 is an SL partner of BRCA1 in TNBC, SRI researchers examined the effect of inhibiting XRCC6 in a BRCA1-mutated TNBC cell line. The researchers found that this XRCC6 "knockdown" significantly increased cell death (37.3 percent) and reduced viability (50 percent reduction, p < 0.0001) as compared to controls. SRI researchers are testing the remaining SL partners identified by MiSL in an effort to expand the set of available molecular targets that may become the focus of new drug discovery projects.

"This platform opens the door for discovering new options to treat BRCA1-mutated breast cancers and could lead to new chemo-prevention strategies for individuals carrying germline BRCA1 mutations," added Dr. Sinha.

On April 16, 2018 X4 Pharmaceuticals, a clinical stage biotechnology company developing novel CXCR4 inhibitor drugs to improve immune cell trafficking to treat cancer and rare diseases, reported data from a presentation at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, X4 Pharmaceuticals, APR 16, 2018, View Source [SID1234525412]) The data, generated from serial tumor biopsies and blood draws taken from melanoma patients, demonstrated dramatic infiltration and activation of cytotoxic CD8+ T cells and increased inflammatory status in the tumor microenvironment (TME) following once-daily oral administration of X4P-001-IO. X4P-001-IO is an investigational CXCR4 allosteric antagonist. Findings highlight single agent X4P-001-IO has the ability to help restore immunity within the TME and has the potential to enhance the anti-tumor activity of agents such as checkpoint inhibitors.

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Results from the tumor biopsies taken from melanoma patients before and after receiving single agent X4P-001-IO treatment for 3 weeks, were analyzed and presented. Single agent X4P-001-IO showed evidence of enhanced immune cell infiltration and activation in the tumor microenvironment, including:

Increases in proliferating CD8+ cells, indicative of cytotoxic T cell activation,
Increases in Granzyme B, a marker of immune-mediated cell killing,
Decreases in distance between CD8+ T cells and the nearest tumor cells, indicative of increased CD8+ T cell infiltration,
Increases in antigen presentation/processing gene expression, suggesting enhanced antigen priming and activation, and
Increases in the Tumor Inflammation Signature (TIS), indicative of increased inflammation status in the TME.
After single agent X4P-001-IO treatment, patients received X4P-001-IO in combination with Keytruda (pembrolizumab) for an additional 6 weeks. Continued signs of positive immune cell changes in the tumor microenvironment were seen. The combination of X4P-001-IO alone and in combination with Keytruda was well tolerated.

"These results demonstrate that CXCR4 inhibition substantially alters the tumor microenvironment in a way that is consistent with the emerging understanding of tumor immunity and inflammatory response," said Robert Andtbacka, MD, CM, a surgeon and investigator with the Huntsman Cancer Institute of the University of Utah, Associate Professor in the Division of Surgical Oncology at the University of Utah School of Medicine, and Principle Investigator of the X4P-001-IO study in melanoma.

In a separate poster presentation, preclinical findings showed that CXCR4 inhibition increases CD8+ T cells in the tumor microenvironment and has potent anti-tumor activity in the syngenic B16-OVA murine melanoma model. The anti-tumor activities were associated with the increase in immunostimulatory CD8+/Perforin+ cells and the reduction of immunosuppressive myeloid derived suppressor cells (MDSCs) and Treg populations in the tumor microenvironment.

"Results from these posters demonstrate the unique mechanism of X4P-001-IO, as it impacts critical aspects of immune cell trafficking, infiltration and activation – playing a positive role in tumor immunity," said Sudha Parasuraman, MD, X4’s Chief Medical Officer. "These data, together with X4P-001-IO’s favorable safety and tolerability profile, support the potential for X4P-001-IO to improve outcomes for patients with tumors that are less responsive to checkpoint inhibitors."

The posters were presented in the Immune Response to Therapy Session at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, taking place April 14-18, 2018 in Chicago, IL.

About X4P-001-IO in Cancer

X4P-001-IO is an investigational selective, oral, small molecule inhibitor of CXCR4 (C-X-C receptor type 4) that regulates the tumor microenvironment thereby enhancing endogenous anti-tumor responses. CXCR4 is a chemokine receptor that modulates immune function and angiogenesis through the trafficking of key immune cells such as T- cells, dendritic cells, and myeloid derived suppressor cells. CXCR4 signaling is disrupted in a broad range of cancers, facilitating tumor growth by allowing cancer cells to evade immune detection and creating a pro-tumor microenvironment. X4P-001-IO is being investigated in three separate clinical studies in solid tumors.

On April 15, 2018 AstraZeneca and Merck & Co., Inc., Kenilworth, N.J., US (Merck: known as MSD outside the US and Canada) reported that presented data from the Phase III OlympiAD trial showing the final overall survival (OS) results for Lynparza (olaparib) in metastatic breast cancer at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Chicago, US, 14-18 April 2018 (Press release, AstraZeneca, APR 15, 2018, View Source [SID1234525367]).

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The trial compared Lynparza with chemotherapy (physician’s choice of capecitabine, eribulin or vinorelbine) for patients with germline BRCA-mutated (gBRCAm) HER2-negative metastatic breast cancer and met its primary endpoint of progression-free survival (PFS).

Results at AACR (Free AACR Whitepaper) include updated findings from the secondary endpoint of overall survival (OS). While the trial was not powered to demonstrate a statistically-significant difference, the median OS was 19.3 months in patients treated with Lynparza and 17.1 months for patients treated with chemotherapy (HR 0.90; 95% CI 0.66-1.23; p=0.513). At the final OS data cut-off (64% maturity), nearly 13% of patients remained on Lynparza and no patients remained on chemotherapy.

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: "OlympiAD is the first Phase III trial to demonstrate disease control with a PARP inhibitor in BRCA-mutated HER2-negative metastatic breast cancer. While the trial was not powered to show overall survival compared to chemotherapy, the results are another encouraging marker in the use of Lynparza for this patient population."
Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "For patients and physicians, these results are meaningful in that they support the progression-free survival endpoint – which showed that patients treated with Lynparza gained seven months chemotherapy-free time – and reinforce the importance of identifying BRCA status to optimise metastatic breast cancer management."
When analysing the predefined subgroups, the results were consistent with the overall analysis, which did not show a statistically-significant difference between arms. The greatest difference was seen in patients who had not received chemotherapy in the metastatic setting with a median difference in OS of 7.9 months with Lynparza (HR 0.51; 95% CI 0.29-0.90; nominal p=0.02; median 22.6 vs 14.7 months).

The safety profile of Lynparza remained consistent with the primary analysis, indicating no relevant cumulative toxicity with extended exposure. Serious adverse events (Grade >3) were reported in 38% of patients who received Lynparza vs 49.5% of patients in the chemotherapy arm.

These results build on previously reported findings, which demonstrated Lynparza significantly improved PFS (HR 0.58; 95% CI 0.43-0.80; p=0.0009 median 7.0 vs 4.2 months) and showed benefit beyond initial disease progression, prolonging time to second progression or death (PFS2) by 3.9 months (HR 0.57; 95% CI 0.40-0.83; p=0.003 median 13.2 months vs 9.3 months). Previously reported findings also showed Lynparza doubled objective response rates (52% [95% CI 44-60] vs 23% [95% CI 13-35]) and improved quality-of-life scores. The data from the OlympiAD trial can be found in the 10 August 2017 issue of the New England Journal of Medicine.
In January 2018, Lynparza was approved by the US FDA for the treatment of metastatic breast cancer, based on the OlympiAD data. A Type II variation application was recently validated by the European Medicines Agency for Lynparza in gBRCAm HER2-negative metastatic breast cancer.

A Phase III trial (n=1800), OlympiA, is evaluating Lynparza as an adjuvant treatment in patients with gBRCA HER2-negative breast cancer, with results expected in 2020. The trial is powered to assess potential benefit in OS.
Lynparza is approved in around 60 countries for advanced ovarian cancer and has treated more than 20,000 patients globally. It has the broadest clinical development programme of any PARP inhibitor and AstraZeneca and MSD are working together to bring Lynparza to more patients across multiple cancers.
NOTES TO EDITORS
About OlympiAD
OlympiAD is a global, randomised, open-label, multi-centre Phase III trial of 302 patients, assessing the efficacy and safety of Lynparza tablets (300 mg twice daily) compared to chemotherapy (physician’s choice of capecitabine, eribulin or vinorelbine). 205 patients were randomised to receive Lynparza and 97 patients were randomised to receive chemotherapy.
Patients in the OlympiAD trial had germline BRCA-mutated, HER2-negative (hormone receptor-positive or triple negative) breast cancer and received Lynparza for treatment in the metastatic setting. Prior to enrolment, 71% of patients had received no more than two previous chemotherapy treatments for metastasised breast cancer and 28% of patients had received prior platinum-based chemotherapy. Also enrolled were patients with HR+ breast cancer who had received at least one endocrine therapy (adjuvant therapy or therapy for metastatic disease) and had disease progression during therapy, unless they had disease for which the endocrine therapy was considered inappropriate.

The primary endpoint was PFS. Secondary endpoints included OS, time to second progression or death, objective response rate, health-related quality of life and safety and tolerability.
About Metastatic Breast Cancer

PRs, ERs and HER2 receptors may be expressed on breast cancer cells. A patient’s breast cancer will test either negative or positive for these three receptors. If a tumour tests positive for PR and/or ER, it is considered hormone-receptor positive. If a tumour tests negative for all three receptors, it is considered triple negative. These receptors indicate which hormones or other proteins may be promoting growth of the cancer.
Metastatic Breast Cancer (MBC) is the most advanced stage of breast cancer (Stage IV), and occurs when cancer cells have spread beyond the initial tumour site to other parts of the body, outside of the breast and nearby lymph nodes.

Despite the increase in treatment options during the past three decades, there is currently no cure for patients diagnosed with MBC and only 26.9% of patients survive for five years after diagnosis. Thus, the primary aim of treatment is to slow progression of the disease for as long as possible, improving, or at least maintaining, a patient’s quality of life.

Breast cancer is the most common cancer in women, with an estimated 1.67 million new cases diagnosed worldwide in 2012 alone – one in four of all cancer cases. Approximately 30% of women who are diagnosed with early breast cancer will go on to develop advanced disease.

About BRCA Mutations
BRCA1 and BRCA2 are human genes that produce proteins responsible for repairing damaged DNA and play an important role maintaining the genetic stability of cells. When either of these genes is mutated, or altered, such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly and cells become unstable. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.

About Lynparza
Lynparza was the first in class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Specifically, in vitro studies have shown that Lynparza-induced cytotoxicity may involve inhibition of PARP-enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.
Lynparza, which has the broadest clinical development programme of any PARP inhibitor, is being investigated in a range of DDR-deficient tumour types, and is the foundation of AstraZeneca’s industry-leading portfolio of compounds targeting DDR mechanisms in cancer cells.
About the AstraZeneca and MSD Strategic Oncology Collaboration
In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the United States and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world’s first PARP inhibitor and potential new medicine selumetinib, a MEK inhibitor, for multiple cancer types. The collaboration is based on increasing evidence that PARP and MEK inhibitors can be combined with PD-L1/PD-1 inhibitors for a range of tumour types. Working together, the companies will develop Lynparza and selumetinib in combination with other potential new medicines and as a monotherapy. Independently, the companies will develop Lynparza and selumetinib in combination with their respective PD-L1 and PD-1 medicines.
About AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020 and a broad pipeline of small molecules and biologics in development, we are committed to advance Oncology as one of AstraZeneca’s Four Growth Platforms focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy as illustrated by our investment in Acerta Pharma in haematology.
By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DDR and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

On April 15, 2018 Blueprint Medicines Corporation (NASDAQ:BPMC), a leader in discovering and developing targeted kinase medicines for patients with genomically defined diseases, reported the online publication of preclinical and clinical proof-of-concept data for BLU-667 in Cancer Discovery, an American Association for Cancer Research (AACR) (Free AACR Whitepaper) journal (Press release, Blueprint Medicines, APR 15, 2018, View Source;p=RssLanding&cat=news&id=2342579 [SID1234525368]). Designed and developed by Blueprint Medicines, BLU-667 is a potent and highly selective inhibitor targeting oncogenic RET fusions and mutations, which are key drivers across multiple cancers, including subsets of patients with non-small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC).

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The manuscript reports detailed preclinical data characterizing the potency and selectivity of BLU-667 against oncogenic RET variants and resistant mutants and anti-tumor activity in multiple solid tumor models. In addition, four patient vignettes from the ongoing Phase 1 ARROW clinical trial describe clinical responses in patients with RET-KIF5B-altered NSCLC and medullary thyroid cancer (MTC) harboring multiple RET mutations, including patients who had progressed on prior multi-kinase therapy
.
"The publication of our work in Cancer Discovery highlights BLU-667’s compelling preclinical profile and preliminary clinical activity in patients with RET-altered cancers and further demonstrates the power of Blueprint Medicines’ scientific platform," said Erica Evans, Ph.D., Senior Director of Biology at Blueprint Medicines and the senior author of the paper. "The published data show BLU-667 has the potential to deliver anti-tumor activity and meaningful clinical responses, regardless of tumor type, RET alteration or prior therapy. Coupled with the initial results from the ongoing Phase 1 ARROW clinical trial that will be presented today at the AACR (Free AACR Whitepaper) Annual Meeting, these data support the rapid development of BLU-667 in patients with RET-altered cancers."

RET has long been recognized as an oncogene that drives multiple cancers. However, there are currently no approved selective RET inhibitors, and RET-targeted treatment is limited to non-selective multi-kinase therapies that can have significant off-target toxicities and limited efficacy. BLU-667 was specifically designed by Blueprint Medicines to target oncogenic RET fusions and mutations, including predicted resistance mutations, with the goal of providing durable clinical responses to patients with RET-altered cancers.
Key highlights included:

In vitro studies show BLU-667 has 10- to 10,000-fold increased potency against oncogenic RET variants and resistant mutants over approved multi-kinase inhibitors. In addition, BLU-667 has 20-fold increased potency against RET-KIF5B fusions, the most common RET alteration in patients with NSCLC, compared to the investigational multi-kinase inhibitor RXDX-105.

Additional in vitro studies show BLU-667 is 88-fold more selective for RET over VEGFR-2, which when inhibited can result in dose-limiting toxicities. Overall, BLU-667 is 100-fold more selective for RET over 96 percent of 371 kinases tested.

In vivo studies show BLU-667 potently inhibits the growth of NSCLC, MTC and colorectal tumors in RET-driven disease models, including models harboring multi-kinase inhibitor-resistant mutants.
Four patient vignettes from the ongoing Phase 1 ARROW clinical trial show that BLU-667 significantly inhibits RET signaling and induces durable clinical responses in patients with RET-altered NSCLC and MTC without notable off-target toxicity, providing clinical validation for selective RET targeting.
The paper, titled "Precision targeted therapy with BLU-667 for RET-driven cancers," was published online in Cancer Discovery on April 15, 2018.
About BLU-667

BLU-667 is an orally available, potent and highly selective inhibitor designed to target RET fusions, mutations and predicted resistance mutations. Blueprint Medicines is developing BLU-667, an investigational medicine, for the treatment of patients with RET-altered NSCLC, MTC and other solid tumors. BLU-667 was discovered by Blueprint Medicine’s research team leveraging its proprietary compound library, and Blueprint Medicines retains worldwide development and commercialization rights for BLU-667.
About RET-Altered NSCLC, MTC and Other Solid Tumors
RET activating fusions and mutations are a key disease driver in multiple cancers, including NSCLC and MTC. RET fusions are implicated in approximately 1-2% of patients with NSCLC, while RET mutations are implicated in approximately 60% of patients with MTC and 10% of papillary thyroid cancer. In addition, genomic analyses published by scientists at Blueprint Medicines have identified RET fusions at low frequencies in colon and breast cancer. Currently, there are no approved therapies that selectively target RET-driven cancers, though there are several approved multi-kinase inhibitors with RET activity being evaluated in clinical trials. Thus far, clinical activity attributable to RET inhibition has been uncertain for these inhibitors, likely due to insufficient inhibition of RET and off-target toxicities.