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Could Amgen’s Xgeva boost immunotherapy in breast cancer?

On December 14, 2020 Amgen reported that osteoporosis drug denosumab is approved as Xgeva for the prevention and treatment of some bone metastases in cancer (Press release, Amgen, DEC 14, 2020, View Source [SID1234572972]). But could the drug’s mechanism of action help breast cancer patients respond to immunotherapy drugs that typically don’t work well in those tumors?

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That was the premise behind a new study led by the Bellvitge Institute for Biomedical Research (IDIBELL) in Spain and partially funded by Amgen. The researchers studied cells from mouse models and from premenopausal patients with luminal breast cancer to determine whether Xgeva’s inhibition of a signaling pathway called RANK might make the tumor cells more sensitive to immunotherapy.

They discovered that the RANK protein is involved in the communication between cancer cells and immune cells. Inhibiting RANK in the breast tumor cells improved responses to drugs that block the immune checkpoints CTLA-4 and PD-L1, they reported in the journal Nature Communications.

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RELATED: Manipulating proteins to make ‘cold’ tumors responsive to immunotherapies

The researchers started by showing in mice that inhibiting the RANK protein boosts the recruitment of immune cells to breast tumors. Inhibiting RANK and PD-L1 together cancer reduced tumor growth in half the tumors studied, while blocking PD-L1 alone had no effect. Their research suggested that cancer cells use RANK as "a possible escape route" from immunotherapy, according to a statement.

They went on to study cells from patients that participated in a clinical trial of Xgeva in premenopausal women with early-stage breast cancer. During the trial, patients received two doses of Xgeva before surgery. The study, which enrolled 27 participants, was ended in 2018 because of a recruitment shortfall, but the Spanish researchers were able to analyze tumor samples from 24 of the patients to back up their mouse findings.

They found that while the short course of Xgeva did inhibit the RANK protein, it did not shrink tumors or enhance survival. But, in most of the tumor samples, they found a significant increase in immune cells.

Some immune checkpoint inhibitors, such as Merck’s PD-1 blocker Keytruda, are approved for use in breast cancer, but improving their efficacy in tough-to-treat tumors is a major focus of research. Several academic teams are investigating the roles of different tumor-promoting proteins in suppressing responses to immunotherapy. Earlier this year, for example, a University of Cincinnati team showed it could improve PD-1 and CTLA-4 inhibition by blocking a protein called FIP200.

The IDIBELL-led team noted that during the clinical trial of pre-surgery administration of Xgeva, researchers identified biomarkers that might help clinicians select patients most likely to respond to a combination of RANK inhibition and immunotherapy.

"This strategy could turn immunologically cold breast cancers into [tumors] sensitive to the immune system activity," said co-author Eva Gonzalez-Suarez of the Spanish National Cancer Research Center in the statement.

Junshi’s PD-1 Meets Survival Endpoint as First-Line NSCLC Treatment

On December 14, 2020 Shanghai Junshi Bio reported its lead anti-PD-1 drug met the primary endpoint in an interim analysis as a first-line treatment in patients with non-small cell lung cancer (NSCLC) (Press release, Shanghai Junshi Bioscience, DEC 14, 2020, View Source [SID1234572964]). Toripalimab (JS001), which was administered in combination with chemotherapy in a China trial among patients with advanced disease, showed improvement in progression-free survival, though specific results were not disclosed. In 2018, toripalimab was first approved in China as a second-line treatment for unresectable or metastatic melanoma.

AXIM® Biotechnologies to Present at the 13th Annual LD Micro Main Event Investor Conference on Monday, December 14

On December 14, 2020 AXIM Biotechnologies, Inc. (OTCQB: AXIM) ("AXIM Biotech," "AXIM" or "the Company"), an international healthcare solutions company targeting oncological and COVID-19 research, reported that the Company’s CEO John W. Huemoeller II will be presenting at the 13th Annual LD Micro Main Event investor conference on Monday, December 14, 2020, at 11:00 a.m. PST/2:00 p.m. EST (Press release, AXIM Biotechnologies, DEC 14, 2020, View Source;utm_medium=rss&utm_campaign=axim-biotechnologies-to-present-at-the-13th-annual-ld-micro-main-event-investor-conference-on-monday-december-14 [SID1234572924]).

During the 10-minute presentation, Huemoeller will discuss AXIM’s COVID-focused research and testing tools, including an update on progress around the Company’s Emergency Use Authorization (EUA) application on its rapid point-of-care COVID-19 neutralizing antibody test. Directly following his presentation, Huemoeller will take questions from a panel of investors and analysts.

AXIM Biotech CEO John W. Huemoeller II commented: "As we move close to having the first COVID-19 vaccines available in the U.S., our rapid COVID-19 neutralizing antibody test can serve as an easy, quick and relatively inexpensive way for researchers to determine the efficacy of their vaccines. I look forward to presenting on this topic and the other highlights of AXIM’s COVID-focused research during the LD Micro Main Event investor conference."

To register for the conference, visit ve.mysequire.com/. The LD Micro Main Event investor conference will take place on December 14th and 15th, exclusively on the Sequire Virtual Events platform.

Entry into a Material Definitive Agreement

On December 14, 2020, Allogene Therapeutics, Inc. (the "Company") and Overland Pharmaceuticals (CY) Inc. ("Overland")reported that Allogene Overland Biopharm (CY) Limited (the "JV Company") for the development, manufacturing and commercialization of certain of the Company’s allogeneic chimeric antigen receptor ("CAR") T cell therapies for patients in China, Taiwan, South Korea and Singapore (the "Territory") pursuant to a Share Purchase Agreement and a Shareholders’ Agreement (Filing, 8-K, Allogene, DEC 14, 2020, View Source [SID1234572867]). In connection with the formation of the joint venture, the Company also entered into a License Agreement with the JV Company.

Pursuant to the Share Purchase Agreement, the Company acquired Seed Preferred shares in the JV Company representing 49% of the JV Company’s outstanding stock as partial consideration for the License Agreement, and Overland acquired Seed Preferred shares representing 51% of the JV Company’s outstanding stock for $117 million in upfront and certain quarterly cash payments. The JV Company shall use $77 million of such cash for operating capital and $40 million of such cash as upfront cash payment to the Company under the License Agreement described below. The Share Purchase Agreement includes customary representations and warranties on behalf of the Company, Overland and the JV Company.

Under the terms of the Shareholders’ Agreement, the board of directors of the JV Company will be comprised of five directors, with two directors designated by the Company, two directors designated by Overland and one director serving as the chief executive officer of the JV Company. The Shareholders’ Agreement provides each of the Company and Overland certain shareholder-level consent rights, certain director-level consent rights, registration rights, information rights, and pre-emptive rights for future equity issuances. The Shareholders’ Agreement shall terminate upon the consent of the parties, provided that its provisions with respect to director designation rights, shareholder-level consent rights, director-level consent rights, information rights, and pre-emptive rights shall terminate upon a qualified IPO or sale of the JV Company or its assets.

Pursuant to the License Agreement, the Company will grant the JV Company an exclusive license to develop, manufacture and commercialize specific Company product candidates targeting BCMA, CD70, FLT3, and DLL3 (the "Licensed Products") in the Territory. The Company retains exclusive rights to, among other things, develop, manufacture and commercialize the Licensed Products outside the Territory.

The Company will receive an upfront cash payment of $40 million described above as well as up to $40 million in total development milestones. In addition, the Company will receive tiered low to mid single-digit royalties on net sales in the Territory, subject to reductions in specified circumstances.

Under the License Agreement, each party has granted the other party specified intellectual property licenses to enable the other party to perform its obligations and exercise its rights under the License Agreement, including license grants to enable each party to conduct development, manufacturing and commercialization activities pursuant to the terms of the License Agreement. The Company plans to supply the JV Company with ALLO-647, which is intended to be used as part of the lymphodepletion regimen for certain CAR T cell product candidates in the Territory, pursuant to a supply agreement and for agreed upon consideration.

The License Agreement will remain in effect on a Licensed Product-by-Licensed Product and jurisdiction-by-jurisdiction basis, unless terminated earlier, until the expiration of the royalty term with respect to such Licensed Product in such jurisdiction. Each party has the right to terminate the License Agreement for the other party’s material breach of its obligations under the License Agreement, subject to cure rights. Additionally, the JV Company may terminate the License Agreement in its sole discretion and in its entirety after a certain time period with sufficient prior written notice. The Company may also terminate the licenses of specified patent rights upon notice if the JV Company challenges the enforceability or validity of any patent rights belonging to the Company that are licensed to the JV Company. Either party to the License Agreement may terminate the License Agreement if the other party declares bankruptcy. Upon termination, any license granted by the Company to the JV Company will terminate.

The License Agreement includes customary representations and warranties on behalf of the Company and the JV Company as are customarily found in transactions of this nature, including representations and operative provisions as to the licensed intellectual property, regulatory matters and compliance with applicable laws. The License Agreement also provides for certain mutual indemnities for breaches of representations, warranties and covenants.

The foregoing description of the material terms of the License Agreement, the Share Purchase Agreement and the Shareholders’ Agreement is qualified in its entirety by reference to the complete text of such agreements, which the Company intends to file with the Securities and Exchange Commission as exhibits to the Company’s Annual Report on Form 10-K for the fiscal year ending December 31, 2020.

TROPION-Lung01 Head-to-Head Phase 3 Trial Initiated to Evaluate Datopotamab Deruxtecan Versus Docetaxel in Previously Treated Patients with Advanced or Metastatic NSCLC Without Actionable Genomic Alterations

On December 14, 2020 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) and AstraZeneca reported the initiation of TROPION-Lung01, a global pivotal phase 3 head-to-head study of datopotamab deruxtecan (Dato-DXd; DS-1062), a TROP2 directed antibody drug conjugate (ADC), versus docetaxel in patients with advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations who have previously received platinum-based chemotherapy and immunotherapy (Press release, Daiichi Sankyo, DEC 14, 2020, View Source [SID1234572856]).

Patients with advanced or metastatic NSCLC without actionable genomic alterations (such as EGFR, ALK, ROS1, NTRK, BRAF, RET, or MET exon 14 skipping) have demonstrated an unmet need after currently approved front-line and second-line therapies are exhausted. Current treatment guidelines recommend varying combinations of platinum-based chemotherapy and/or immune checkpoint inhibitors in the front-line and second-line settings based on lung cancer subtype, immune biomarker status and other factors.1 For patients whose cancer progresses after initial treatment containing a platinum-based chemotherapy and a checkpoint inhibitor, therapeutic options are limited.1

TROP2 expression has been associated with poor overall and disease-free survival in several types of solid tumors. TROP2 expression has been observed in the majority of adenocarcinoma and squamous cell carcinoma NSCLC.2,3,4 There are no TROP2 directed therapies or ADCs currently approved for the treatment of NSCLC.

"We recognize the need to continue to improve treatment for patients with NSCLC who are not eligible for currently approved targeted therapies, particularly those who progress following initial treatment with an immunotherapy and platinum-based chemotherapy," said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. "This head-to-head trial will determine whether targeting TROP2 with datopotamab deruxtecan will improve survival as compared to the standard therapy used in this setting."

"TROP2 is highly expressed in NSCLC and other cancers, making it a promising target for therapeutic development," said José Baselga, MD, PhD, Executive Vice President, Oncology R&D, AstraZeneca. "This trial will provide an opportunity to evaluate a targeted approach with datopotamab deruxtecan, a potent ADC specifically designed to enhance selective tumor cell death, while reducing systemic exposure to chemotherapy."

TROPION-Lung01 was initiated following the encouraging clinical activity of datopotamab deruxtecan in patients with heavily pre-treated advanced NSCLC observed in the ongoing TROPION-PanTumor01 phase 1 trial, which completed enrollment of patients with lung cancer in October of 2020. Preliminary data from TROPION-PanTumor01 was recently presented at the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Scientific Program (#ASCO20) and updated data will be presented at an upcoming medical meeting.

About TROPION-Lung01

This global, multicenter, randomized, open-label phase 3 trial will evaluate the efficacy and safety of datopotamab deruxtecan (6.0 mg/kg) versus docetaxel (75 mg/m2) in patients with advanced or metastatic NSCLC without actionable genomic alterations and with progression on or after platinum-based chemotherapy and anti-PD-1/anti-PD-L1 immunotherapy received either in combination or sequentially.

Approximately 590 patients will be randomized into two arms in a 1:1 ratio to receive either datopotamab deruxtecan or docetaxel. Randomization will be stratified by histology (squamous versus nonsquamous), most immediate prior therapy and geographic region.

The primary trial endpoints are progression-free survival and overall survival. Secondary endpoints include overall response rate, duration of response, time to response, disease control rate and patient reported outcomes. Safety endpoints include treatment emergent adverse events and other safety parameters. Pharmacokinetic and immunogenicity endpoints will also be evaluated.

The study will enroll patients at sites in North America, South America, Europe and Asia. For more information visit ClinicalTrials.gov.

About Non-Small Cell Lung Cancer (NSCLC)

Lung cancer is the most common cancer and the leading cause of cancer mortality worldwide; there were an estimated 2.1 million new cases of lung cancer in 2018 and 1.8 million deaths.5 NSCLC accounts for 80 to 85 percent of all lung cancers.6

For patients with advanced NSCLC that do not carry actionable genomic alterations (i.e., for which no targeted therapies are approved), treatment has traditionally been limited to platinum chemotherapy.7 The introduction of immune checkpoint inhibitors in the past two decades has offered improved survival rates over traditional chemotherapy regimens, creating new options and shifting treatment to a more personalized approach for subsets of patients with NSCLC. Over the past five years, immunotherapies have become part of the treatment paradigm.7

About TROP2

TROP2 (trophoblast cell-surface antigen 2) is a transmembrane glycoprotein that is overexpressed in many cancers.8 TROP2 expression has been associated with poor overall and disease-free survival in several types of solid tumors. TROP2 expression has been observed in up to 64% of adenocarcinoma and up to 75% of squamous cell carcinoma NSCLC.2,3,4 There are no TROP2 directed therapies or ADCs currently approved for the treatment of NSCLC.

About Datopotamab Deruxtecan (Dato-DXd; DS-1062)

Datopotamab deruxtecan (Dato-DXd; DS-1062) is one of three lead DXd antibody drug conjugates (ADCs) in the oncology pipeline of Daiichi Sankyo.

ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, datopotamab deruxtecan is comprised of a humanized anti-TROP2 IgG13 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a tetrapeptide-based cleavable linker with a drug-to-antibody ratio (DAR) of four.

TROPION is the broad and comprehensive clinical development program to evaluate the efficacy and safety of datopotamab deruxtecan across multiple TROP2 cancers as both a monotherapy and in combination with other anticancer treatments. In addition to TROPION-Lung01, datopotamab deruxtecan is currently being evaluated in a number of clinical trials, including TROPION-Lung05, a phase 2 study in patients with advanced or metastatic non-small cell lung cancer (NSCLC) with actionable genomic alterations previously treated with a kinase inhibitor and platinum chemotherapy and TROPION-PanTumor01, a phase 1 study in patients with advanced solid tumors that have progressed on standard treatments or for whom no standard treatment is available, which has completed enrollment of patients into a unresectable advanced NSCLC cohort and is currently enrolling patients into a triple negative breast cancer (TNBC) cohort.

Datopotamab deruxtecan is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.

About the Collaboration between Daiichi Sankyo and AstraZeneca

Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize trastuzumab deruxtecan (a HER2 directed ADC) in March 2019, and datopotamab deruxtecan (a TROP2 directed ADC) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for manufacturing and supply of trastuzumab deruxtecan and datopotamab deruxtecan.

About Daiichi Sankyo Cancer Enterprise

The mission of Daiichi Sankyo Cancer Enterprise is to leverage our world-class, innovative science and push beyond traditional thinking to create meaningful treatments for patients with cancer. We are dedicated to transforming science into value for patients, and this sense of obligation informs everything we do. Anchored by our DXd antibody drug conjugate (ADC) technology, our powerful research engines include biologics, medicinal chemistry, modality and other research laboratories in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in Berkeley, CA. For more information, please visit: www.DSCancerEnterprise.com.