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
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"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.

On April 14,2018 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that it will present data from across its broad cancer immunotherapy development programme, including approved and investigational medicines, during the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting from 14 April to 18 April in Chicago, IL, United States (Press release, Hoffmann-La Roche, APR 14, 2018, View Source [SID1234525313]). More than 42 abstracts have been accepted, including five "late breakers" and seven oral presentations.

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"Through our extensive research in the areas of tumour characterisation we are developing therapies that help the immune system to mount a deep and long lasting anti-cancer response," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "A personalised combination approach of cancer immunotherapies like TECENTRIQ with various chemotherapies, targeted medicines and other immunotherapies is central to our goal of providing transformative outcomes for people living with cancer."

Key highlights from the Roche cancer immunotherapy portfolio include an updated analysis from the Phase III IMpower150 study of TECENTRIQ and Avastin plus paclitaxel and carboplatin chemotherapy in people with advanced non-squamous non-small cell lung cancer (NSCLC). The study demonstrated significantly improved progression free survival (PFS) across all PD-L1 subgroups (ITT-WT, hazard ratio [HR]=0.61; p<0.0001%; CI: 0.51-0.72), including in people whose tumours are considered PD-L1-negative regardless of the PD-L1 IHC assay used, compared to Avastin plus paclitaxel and carboplatin chemotherapy. A clinically meaningful progression free survival (PFS) advantage was also seen in people with sensitising EGFR mutations, ALK genomic rearrangements, and in people with liver metastases. Importantly, IMpower150 recently met it’s co-primary endpoint of overall survival (OS) and showed that the combination of TECENTRIQ and Avastin plus paclitaxel and carboplatin chemotherapy helped people with advanced lung cancer live longer compared to Avastin plus carboplatin and paclitaxel as an initial treatment for people with advanced NSCLC. These data will be presented at an upcoming oncology meeting in 2018.

There is a scientific rationale for combining TECENTRIQ and abraxane which suggests that the mechanisms of action of each of the medicines may be complementary in the treatment of mTNBC, as they each target different steps in the cancer immunity cycle.

Results from this single arm cohort (N=33) of the Phase 1b study of TECENTRIQ plus nab-paclitaxel chemotherapy in people with metastatic triple negative breast cancer (mTNBC) show encouraging efficacy signals, and the safety of TECENTRIQ plus nab-paclitaxel in this combination is, so far, consistent with the safety profiles of the individual medicines, and no new safety signals were identified with the combination.
A trend toward higher response rates and longer PFS and OS was seen for patients treated in the 1L setting compared to later lines. The ongoing randomised Phase III trial, IMpassion130, is investigating the same regimen as the Phase 1b study, with topline data expected later in 2018.

A retrospective analysis of the biology underlying primary immune escape and responsiveness to TECENTRIQ in tumour samples of people from the phase II IMvigor210 study for people with metastatic urothelial cancer showed that response to TECENTRIQ was highly associated with tumour mutational burden (TMB) and pre-existing T cell immunity. Additionally, another signalling protein known as transforming growth factor-beta (TGF-β) appears to be a negative indicator of response to TECENTRIQ, especially in the immune-excluded tumour phenotype that is common in mUC. Integration of these three independent biological features provides a foundation for understanding outcomes for people living with mUC.
Overview of key Cancer Immunotherapy data AACR (Free AACR Whitepaper) 2018

About TECENTRIQ (atezolizumab)
TECENTRIQ is a monoclonal antibody designed to bind with a protein called PD-L1 expressed on tumour cells and tumour-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, TECENTRIQ may enable the activation of T cells. TECENTRIQ has the potential to be used as a foundational combination partner with cancer immunotherapies, targeted medicines and various chemotherapies across a broad range of cancers.

TECENTRIQ is already approved in the European Union, United States and more than 50 countries for people with previously treated metastatic NSCLC and for people with locally advanced or metastatic urothelial cancer (mUC) who are not eligible for cisplatin chemotherapy, or who have had disease progression during or following platinum-containing therapy.

About the TECENTRIQ (atezolizumab) and Avastin (bevacizumab) combination
There is a strong scientific rationale to support combining TECENTRIQ and Avastin. The TECENTRIQ and Avastin regimen may enhance the potential of the immune system to combat a broad range of cancers, including first-line advanced NSCLC. Avastin, in addition to its established anti-angiogenic effects, may further enhance TECENTRIQ’s ability to restore anti-cancer immunity, by inhibiting VEGF-related immunosuppression, promoting T-cell tumour infiltration and enabling priming and activation of T-cell responses against tumour antigens.
About Roche in cancer immunotherapy
For more than 50 years, Roche has been developing medicines with the goal to redefine treatment in oncology. Today, we’re investing more than ever in our effort to bring innovative treatment options that help a person’s own immune system fight cancer.

By applying our seminal research in immune tumour profiling within the framework of the Roche-devised cancer immunity cycle, we are accelerating and expanding the transformative benefits with TECENTRIQ to a greater number of people living with cancer. Our cancer immunotherapy development programme takes a comprehensive approach in pursuing the goal of restoring cancer immunity to improve outcomes for patients.
To learn more about the Roche approach to cancer immunotherapy please follow this link: View Source

On April 13,2018 MabSpace Biosciences reported that the first subject has been dosed in a Phase 1 clinical study of MSB2311 , for the treatment of advanced solid tumors (Press release, Mabspace, APR 13, 2018, View Source [SID1234525306]). MSB2311 is a 2nd Generation PD-L1 antibody with a unique pH-dependent antigen binding property that enables intra-tumor recycling and potentiates tumor penetration. It is the first clinical asset generated by MabSpace’s proprietary Immune Tolerance Breaking Technology (IMTB) platform.

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Yuntao Wan, vice president and head of clinical development operations at MabSpace, said, "With seamless execution we moved quickly from IND clearance by FDA to first patient dosed in less than 2 months, by Dr. Papadopoulos and his team at the START clinic of San Antonio, Texas. We’d also like to thank Dr. Adjei from Mayo Clinic, for his expert input into the trial design from the very beginning. He will lead a group of prominent Mayo investigators to join the study soon. Of course, we couldn’t have achieved such a speedy and quality start without the strong support from our CRO partners Syneos Healthcare and Q2 Solutions."

This study, MSB2311-CSP-001, is a first-in-human, open-label, Phase 1 dose-escalation study of MSB2311, a humanized anti-PD-L1 monoclonal antibody in patients with advanced solid tumors. More information can be found at www.clinicaltrials.gov (NCT03463473). A separate China Phase 1 study with several disease expansion cohorts to evaluate preliminary efficacy is at the final stage of regulatory review, and is expected to be initiated soon upon CFDA approval.

"We are excited to start the testing of MSB2311 in cancer patients and can’t wait to see how well the superior pre-clinical efficacy of MSB2311 will translate in clinical setting," said Xueming Qian, Founder and CEO, MabSpace Biosciences

On April !3, 2018 AstraZeneca reported that presented new post-progression outcomes data from an exploratory analysis of the global Phase III FLAURA trial, which assessed the efficacy and safety of Tagrisso (osimertinib) as 1st-line therapy in patients with locally advanced or metastatic epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) (Press release, AstraZeneca, APR 13, 2018, View Source [SID1234525369]). The presentation at the European Lung Cancer Conference (ELCC) in Geneva during the "Best of ELCC" session showed that the progression-free survival (PFS) benefit of 1st-line Tagrisso over the EGFR tyrosine kinase inhibitors (TKIs), erlotinib or gefitinib, was sustained throughout post-progression outcomes [Abstract #128O].

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Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: "The new analysis from the FLAURA trial shows that 1st-line treatment with Tagrisso has a sustained effect beyond subsequent therapy by almost halving the risk of a second progression or death. These findings build on the clinically-meaningful PFS benefit of Tagrisso and reinforce its potential as a new standard of care.
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At the time of data cut-off, fewer patients on 1st-line Tagrisso had discontinued treatment compared to patients on the EGFR-TKI comparator arm (49% vs. 77%) and 29% received a subsequent treatment compared to 46% on the comparator arm. Median time to first subsequent therapy or death was 23.5 months (95% confidence interval [CI] 22.0, NC) for those treated with 1st-line Tagrisso vs. 13.8 months (95% CI 12.3, 15.7) for patients on erlotinib or gefitinib (hazard ratio [HR] 0.51, 95% CI 0.40, 0.64, p<0.0001).

Patients treated with 1st-line Tagrisso experienced a longer time before discontinuation of EGFR-TKI therapy (median 23.0 months (95% CI 19.5, NC), compared to a median of 16.0 months (95% CI 14.8, 18.6) for comparator arm patients, which included patients who had crossed over to Tagrisso in the 2nd line. 1st-line Tagrisso patients had almost half the risk of second progression or death (PFS2) compared to the comparator arm (HR 0.58, 95% CI 0.44, 0.78, p<0.001).

Dr. David Planchard, Associate Professor of Medicine, Thoracic Tumour Board, Gustave Roussy, France, said: "Post-progression outcomes are increasingly recognised as important measures of efficacy for 1st-line cancer therapies, and the consistency in risk reduction across these endpoints in FLAURA provides confidence in the data from the interim overall survival analysis."

Safety data for 1st-line Tagrisso in FLAURA were in line with those observed in prior clinical trials. It was well tolerated, with fewer Grade 3 or higher adverse events (AEs) than with standard EGFR-TKIs (34% vs. 45%). In patients treated, the most common adverse reactions were rash (58% [1.1% Grade ≥3] for Tagrisso vs. 78% [6.9% Grade ≥3] for the comparator arm), diarrhoea (58% [2.2% Grade ≥3] for Tagrisso vs. 57% [2.5% Grade ≥3] for the comparator arm) and dry skin (36% [<1% Grade ≥3] for Tagrisso vs. 36% [1.1% Grade ≥3] for the comparator arm).

NOTES TO EDITORS
About NSCLC
Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths, more than breast, prostate and colorectal cancers combined. Approximately 10-15% of patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC. These patients are particularly sensitive to treatment with EGFR-TKIs, which block the cell-signalling pathways that drive the growth of tumour cells. Tumours almost always develop resistance to EGFR-TKI treatment, however, leading to disease progression. Approximately half of patients develop resistance to approved EGFR-TKIs such as gefitinib, erlotinib and afatinib due to the EGFR T790M resistance mutation. There is also a need for medicines with improved CNS efficacy, since approximately 25% of patients with EGFRm NSCLC have brain metastases at diagnosis, increasing to approximately 40% within two years of diagnosis.

About Tagrisso
Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI designed to inhibit both EGFR-sensitising and EGFR T790M-resistance mutations, with improved clinical activity against CNS metastases. Tagrisso 40mg and 80mg once-daily oral tablets have been approved in more than 75 countries, including the US, EU, Japan and China for patients with EGFR T790M mutation-positive advanced NSCLC. Tagrisso is also being investigated in the adjuvant setting and in combination with other treatments.

About the FLAURA trial
The FLAURA trial assessed the efficacy and safety of 1st-line Tagrisso 80mg once daily vs. standard-of-care EGFR-TKIs (either erlotinib [150mg orally, once daily] or gefitinib [250mg orally, once daily]) in previously-untreated patients with locally-advanced or metastatic EGFRm NSCLC. The trial was double-blinded and randomised, with 556 patients across 29 countries.

About AstraZeneca in Lung Cancer
AstraZeneca is committed to developing medicines to help every patient with lung cancer. We have three approved medicines and a growing pipeline that targets genetic changes in tumour cells and boosts the power of the immune response against cancer. Our unrelenting pursuit of science aims to deliver more breakthrough therapies with the goal of extending and improving the lives of patients across all stages of disease and lines of therapy.
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 a key growth platform for AstraZeneca 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, DNA Damage Response 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 13, 2018 Novocure (NASDAQ: NVCR) reported that new data on Tumor Treating Fields will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2018, which will be held April 14 through April 18, in Chicago (Press release, NovoCure, APR 13, 2018, View Source [SID1234525307]). Tumor Treating Fields is a cancer therapy that uses electric fields tuned to specific frequencies to disrupt cell division, inhibiting tumor growth and causing affected cancer cells to die.

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A total of 35 presentations on the application of Tumor Treating Fields in seven cancer types will be presented. Of the 35 presentations, 18 are externally led research. Highlights include data demonstrating the utility of Tumor Treating Fields in various applications and include the following:

A phase 2 pilot study is assessing the safety of Tumor Treating Fields when administered concomitant to radiation therapy in newly diagnosed glioblastoma patients. The interim results found that newly diagnosed GBM patients who received Tumor Treating Fields at the same time of radiation therapy reported similar proportions of Tumor Treating Fields-related skin toxicity as reported by patients in a phase 3 pivotal study of newly diagnosed GBM patients who received Tumor Treating Fields plus temozolomide four weeks or more after radiation therapy (40 percent versus 52 percent). No other toxicities related to Tumor Treating Fields were reported.

A retrospective safety analysis of Novocure’s EF-14 phase 3 pivotal trial found that the combination of Tumor Treating Fields and the chemotherapy lomustine was a feasible combination in glioblastoma patients who had a recurrence.

Novocure has conducted four phase 2 pilot trials of Tumor Treating Fields in solid tumors located outside of the brain: non small-cell lung cancer, mesothelioma, pancreatic cancer and ovarian cancer. A meta-analysis of 176 patients from these trials found that Tumor Treating Fields applied to the lungs, abdomen and upper pelvis did not result in treatment-related pulmonary, cardiac, hematological or gastrointestinal toxicities. The only common adverse event related to Tumor Treating Fields was skin irritation beneath the device transducer arrays.

"In our preclinical studies to date, Tumor Treating Fields has shown promise in multiple solid tumor types, and we believe it may provide additive or synergistic benefits when combined with certain other anti-cancer agents, which may lead to greater efficacy without significantly increasing the side effects," said Dr. Eilon Kirson, Novocure’s Chief Science Officer and Head of Research and Development. "We must first determine the safety of Tumor Treating Fields in any new application before we can explore potential efficacy. These data support the mild side effect profile of Tumor Treating Fields that we have seen to date."