AstraZeneca has come up short in another lung cancer trial of its immuno-oncology combo, this time in patients who’ve failed on two prior treatments (Press release, AstraZeneca, APR 24, 2018, View Source;utm_medium=rss [SID1234525635]).

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But investors shouldn’t use the outcome to predict the forthcoming results of a closely watched first-line study, analysts say.

Tuesday, the British drugmaker said its PD-L1 med Imfinzi and candidate tremelimumab had failed to improve survival in third-line patients whose tumors didn’t express PD-L1. There was a bright spot, though: A substudy that pitted solo Imfinzi against chemo in PD-L1-positive patients showed a "clinically meaningful" difference for the AZ drug in the risk of death.

The results weren’t terribly surprising to analysts; Bernstein’s Tim Anderson, for one, said in a note to clients that he thought the trial, dubbed Arctic, "was likely to yield mixed results (and it did)."

And the way he sees it, that’s not such a bad thing. Overall, "the field has moved on," he said, calling Arctic "basically the hangover from a now abandoned hypothesis" that PD-L1/CTLA4 pairings such as AZ’s will extend benefits to the PD-L1 negative population.

ODDO BHF’s Pierre Corby wrote in his own note to clients that removing the combination from models would have "minimum impact."

RELATED: AstraZeneca’s Mystic shortfall is an immuno-oncology shake-up for Bristol-Myers and a bolster for Merck and Roche

And while investors may be tempted to take the outcome as a sign that the Imfinzi-tremelimumab combo is destined for failure in first-line, PD-L1-positive patients—the all-important population in the I-O market—they shouldn’t, Anderson said.

"That outcome is certainly not foreshadowed" by the miss in PD-L1 negative patients, he wrote.

If there’s any readthrough to Mystic, AstraZeneca’s first-line trial, it’s that Imfinzi still holds promise as a monotherapy, Anderson figures.

"We continue to believe that Imfinzi is likely is show an OS benefit in 1L PD-L1(+) patients, and obtain a (modest) foothold in the market," he wrote.

RELATED: 2018 is here. Now get ready for ‘market-defining’ I-O readouts

Of course, it’ll still be a while before industry watchers have that data, which is slated to arrive in the second half of the year. And in the meantime, there will be plenty of other key I-O news from companies including Merck and Roche that should keep investors busy.

On April 24, 2018 REVOLUTION Medicines, Inc., a drug discovery and development company focused on frontier cancer targets, reported it has raised $56 million in a Series B financing to support its ongoing R&D programs and general business activities (Press release, Revolution Medicines, APR 24, 2018, View Source [SID1234525652]). The financing was supported by a syndicate of premier life sciences investors led by Nextech Invest, an oncology-focused investment firm, and included participation from Casdin Capital, Schroder Adveq, The Column Group, Third Rock Ventures and additional undisclosed institutional investors.

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In addition, the company announced the expansion of its leadership team with the appointment of Ryan Martins as chief financial officer; Xiaolin Wang, D.Sc., as senior vice president, clinical development; and Hirdesh Uppal, D.V.M., Ph.D., as vice president, development sciences. Thilo Schroeder, Ph.D., partner at Nextech Invest, and Barbara Weber, M.D., chief executive officer of Tango Therapeutics, joined the company’s board of directors.

"We appreciate the strong support shown by our founding and new investors in this significant financing that will fuel the advancement of our exciting SHP2 program and innovative pipeline," said Mark A. Goldsmith, M.D., Ph.D., president and chief executive officer at REVOLUTION Medicines. "The raise of new capital, expansion of our executive team and board with seasoned leaders, and multiple presentations about progress in our SHP2 program at the recent AACR (Free AACR Whitepaper) conference all reflect enormous momentum in our effort to outsmart cancer."

Leadership Team and Board of Directors Appointments

Mr. Martins joins REVOLUTION Medicines from Ultragenyx, where he served as vice president, finance, corporate strategy and investor relations with responsibility for capital raising, investor relations, financial and competitive analysis, strategic planning and business development. Mr. Martins was previously a biotechnology analyst at investment banks including Lehman Brothers, Barclays, Lazard and Jefferies.
Dr. Wang joins the company from Acerta Pharma, where she held a senior leadership position in clinical development and was instrumental in the recent approval of acalabrutinib (Calquence). Dr. Wang previously served in leadership positions in clinical development and biometrics at Genentech and Geron.
Dr. Uppal joins REVOLUTION Medicines from Medivation, where he led translational medicine and diagnostics until the company’s acquisition by Pfizer. Prior to Medivation, Dr. Uppal served in development roles at Roche and Genentech.
Dr. Schroeder is a partner at Nextech Invest. He has served as director or observer on the boards of Blueprint Medicines, IDEAYA Bioscience, and Peloton Therapeutics, and previously conducted research on designed ankyrin repeat proteins (DARPins) as specific protein inhibitors at the University of Zurich.
Dr. Weber is chief executive officer of Tango Therapeutics. Prior to Tango, she led oncology translational medicine at Novartis, oncology discovery and translational medicine at GlaxoSmithKline, the University of Pennsylvania Cancer Center Breast Cancer Program and cancer genomics at the Abramson Cancer Research Institute.
"I am very enthusiastic about the high-quality cancer drug discovery and development work being done by REVOLUTION Medicines and am pleased to support this world-class team to help advance the company’s mission on behalf of patients in need," said Dr. Schroeder.

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Media Contact:
Katie Engleman
W2O Group
910-509-3977
[email protected]

On April 24, 2018 AstraZeneca and MedImmune, reported its global biologics research and development arm, reported high-level results from the Phase III ARCTIC trial in patients with locally-advanced or metastatic non-small cell lung cancer (NSCLC) who have received at least two prior treatments (Press release, AstraZeneca, 24 24, 2018, View Source [SID1234525617]). This randomised, open-label, multi-centre trial assessed the efficacy and safety of the combination of Imfinzi (durvalumab) plus tremelimumab, as well as Imfinzi and tremelimumab monotherapies, versus standard-of-care chemotherapy (SoC) in patients with PDL1-low/negative NSCLC (sub-study B), and Imfinzi monotherapy versus SoC in patients with PDL1-high NSCLC (sub-study A).

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In sub-study B, the combination of Imfinzi plus tremelimumab in patients with PD-L1 low/negative NSCLC did not meet the primary endpoints of a statistically-significant and clinically-meaningful improvement in progression-free survival (PFS) and overall survival (OS) compared to SoC. Activity and safety of monotherapy arms of sub-study B were consistent with prior published data.

Sub-study A was not powered for statistical significance; however, Imfinzi monotherapy showed a clinically-meaningful reduction in the risk of death compared to chemotherapy.

Full data from the ARCTIC trial will be presented at a forthcoming medical meeting.

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer, said: "While we are disappointed that the combination of Imfinzi plus tremelimumab did not result in a statistically-significant survival benefit in this heavily pre-treated patient population, we are encouraged by the activity of Imfinzi monotherapy observed in this trial and look forward to presenting the full data from the ARCTIC trial at an upcoming medical meeting."

AstraZeneca recently received approval from the US FDA for Imfinzi for the treatment of patients with unresectable, Stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.

NOTES TO EDITORS
About ARCTIC

The ARCTIC trial was a randomised, open-label, multi-centre, global Phase III trial containing two sub-studies: sub-study A (1:1 randomisation of patients with PDL1-high tumours to Imfinzi (durvalumab) vs. SoC) and sub-study B (2:3:1:2 randomisation of patients with PDL1-low/negative tumours to Imfinzi monotherapy, Imfinzi plus tremelimumab or tremelimumab vs SoC). Tumour PD-L1 expression was assessed with the Ventana PD-L1 (SP263) assay with PD-L1 high defined as ≥25% of tumour cells with membrane staining.

About Imfinzi

Imfinzi is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

In February 2018, Imfinzi received US FDA approval for the treatment of patients with unresectable, Stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. Imfinzi also received accelerated approval in the US for the treatment of patients with locally-advanced or metastatic urothelial carcinoma, who have disease progression during or following platinum-containing chemotherapy, or whose disease has progressed within 12 months of receiving platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery.

As part of a broad development programme, Imfinzi is also being tested as a monotherapy and in combination with tremelimumab, an anti-CTLA-4 monoclonal antibody and potential new medicine, as a first-line treatment for patients with NSCLC, small cell lung cancer, locally-advanced or metastatic urothelial carcinoma, head and neck cancer and other solid tumours.

About tremelimumab

Tremelimumab is a human monoclonal antibody and potential new medicines that targets the activity of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Tremelimumab blocks the activity of CTLA-4, contributing to T cell activation and boosting the immune response to cancer. Tremelimumab is being tested in an extensive clinical-trial programme in combination with Imfinzi in NSCLC, locally-advanced or metastatic urothelial carcinoma, head and neck cancer, liver cancer and blood cancers.

About AstraZeneca in NSCLC

Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-third of all cancer deaths and more than breast, prostate and colorectal cancers combined.

AstraZeneca has a comprehensive portfolio of approved and potential new medicines in late-stage clinical development for the treatment of NSCLC across all stages of disease and lines of therapy. We aim to address unmet needs of patients with EGFR-mutated tumours as a genetic driver of disease, which occur in 10-15% of NSCLC patients in the US and EU and 30-40% of NSCLC patients in Asia, with our approved medicines Iressa and Tagrisso and ongoing FLAURA and ADAURA trials. Our extensive late-stage immuno-oncology programme focuses on 75-80% of patients with NSCLC without a known genetic mutation. Our portfolio includes Imfinzi, an anti-PDL1 antibody, which is in development as monotherapy (ADJUVANT, PACIFIC, MYSTIC, PEARL and ARCTIC trials) and in combination with tremelimumab (MYSTIC, NEPTUNE, ARCTIC and POSEIDON trials).

About AstraZeneca’s Approach to Immuno-Oncology

Immuno-Oncology (IO) is a therapeutic approach designed to stimulate the body’s immune system to attack tumours. At AstraZeneca and MedImmune, our biologics research and development arm, our IO portfolio is anchored by immunotherapies that have been designed to overcome anti-tumour immune suppression. We believe that IO-based therapies will offer the potential for life-changing cancer treatments for the clear majority of patients.

We are pursuing a comprehensive clinical-trial programme that includes Imfinzi (anti-PD-L1) as monotherapy and in combination with tremelimumab (anti-CTLA-4) in multiple tumour types, stages of disease, and lines of therapy, using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient. In addition, the ability to combine our IO portfolio with small, targeted molecules from across our Oncology pipeline, and with those of our research partners, may provide new treatment options across a broad range of tumours.

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 advancing Oncology as a growth driver 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.

About MedImmune

MedImmune is the global biologics research and development arm of AstraZeneca, a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialisation of small-molecule and biologic prescription medicines. MedImmune is pioneering innovative research and exploring novel pathways across Oncology; Respiratory; Cardiovascular, Renal & Metabolic Diseases; and Infection and Vaccines. The MedImmune headquarters is located in Gaithersburg, MD, one of AstraZeneca’s three global R&D centres, with additional sites in Cambridge, UK, and Mountain View, CA. For more information, please visit www.medimmune.com.

On April 24, 2018 Takeda Pharmaceutical Company Limited ("Takeda") reported the statement made by Shire plc ("Shire") and confirms that it has made a revised proposal to the Board of Shire.

There can be no certainty that any firm offer for the Company will be made nor as to the terms on which any firm offer might be made.

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Other matters

In accordance with Rule 2.6(a) of the Code, Takeda must, by no later than 5.00 p.m. (London time) on 25 April 2018, either announce a firm intention to make an offer, subject to conditions or pre-conditions if relevant, for Shire in accordance with Rule 2.7 of the Code or announce that it does not intend to make an offer for Shire, in which case the announcement will be treated as a statement to which Rule 2.8 of the Code applies. This deadline will only be extended with the consent of the UK Panel on Takeovers and Mergers (the "Panel") in accordance with Rule 2.6(c) of the Code.

In accordance with Rule 26.1 of the Code, a copy of this announcement will be published on the Takeda website (View Source) by no later than 12 noon (London time) on April 25, 2018. The content of the websites referred to in this announcement is not incorporated into and does not form part of this announcement.

On April 24, 2018 Checkmate Pharmaceuticals (Checkmate)  reported that it had initiated treatment with CMP‐001 combined with atezolizumab (TECENTRIQ) in a Phase 1b clinical trial of patients with advanced non‐small cell lung cancer (NSCLC) and disease progression on prior anti‐PD‐1/PD‐L1 therapy (Press release, Checkmate Pharmaceuticals, APR 24, 2018, View Source [SID1234525653]).

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CMP-001 is designed to activate innate immunity to convert "uninflamed" tumors, which generally do not respond to anti-PD-1/L1 therapy, into "inflamed" tumors, which are responsive to PD-1 inhibition. When used in combination with PD-1/PD-L1 inhibitors, CMP-001 has the potential to increase the number of cancer patients who respond to checkpoint inhibitor therapies and to increase the magnitude and duration of the antitumor responses, possibly providing added clinical benefit.

"We are pleased to be advancing the clinical development of CMP-001 into a second tumor type," stated Art Krieg, founder and CEO of Checkmate Pharmaceuticals. "The mechanism of action of CMP-001 should apply across most or all tumor types, and so we expect CMP-001 to reverse PD-1 resistance in NSCLC, just as we reported for PD-1 resistant advanced melanoma last week at the 2018 American Association of Cancer Research Annual Meeting in Chicago," noted Dr. Krieg.

The trial is designed as a multi-center, open label, two-part Phase 1b study of CMP-001 administered in combination with atezolizumab with and without low-level radiation therapy. Part one of the study will evaluate CMP-001 (5 mg dose) administered subcutaneously (SC) weekly for two weeks and then intratumorally (IT) weekly for three weeks, followed by either SC or IT injection every three weeks.

In the second part of the trial, the combination of CMP-001 and atezolizumab therapy will be preceded by low-level radiation therapy to the target lesion. "In our ongoing melanoma trial we learned that patients whose tumors contain more plasmacytoid dendritic cells (pDC) appear to be more likely to respond to CMP-001 in combination with checkpoint inhibitor therapy. Low dose radiation therapy recruits pDC into tumors, and so we expect this triple combination regimen to increase the response rate to our therapy," explained Dr. Krieg. Patients will be monitored for safety and tolerability, as well as clinical response. Correlative studies will also be undertaken to characterize the immune effects of treatment in the blood and tumors.

About CMP-001

CMP-001, is a first-in-class CpG-A Toll-like receptor 9 (TLR9) agonist, that is encapsulated in a virus-like particle (VLP) and is designed to activate the innate immune system via TLR9 and mediate tumor control by the subsequent induction of both innate and adaptive anti-tumor immune responses, thereby converting immunologically "cold" tumors to immunologically "hot" tumors. It is the only CpG-A class TLR9 agonist in clinical trials and differs from other CpG classes in clinical development by having a native DNA backbone that induces the highest levels of type I IFN. Based on analysis of gene expression in human tumors showing that increased IFN gene expression is associated with better response to PD-1 inhibition, it is believed that this mechanism of action may restore, enable or improve responses to anti-PD-1/PD-L1 therapeutics.

CMP-001 is being evaluated in multiple tumor types to assess its safety, activity, alternative routes of administration and combination with other immunotherapies and modalities. For information on CMP-001 trials that are currently recruiting patients, please visit www.clinicaltrials.gov.