On August 23, 2022 Daiichi Sankyo (TSE: 4568) reported that the European Medicines Agency (EMA) has validated the marketing authorization application (MAA) for quizartinib in combination with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, and as continuation monotherapy following consolidation, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) that is FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) positive (Press release, Daiichi Sankyo, AUG 23, 2022, View Source [SID1234618575]).

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AML is one of the most common forms of leukemia in adults, representing about one-third of all cases.1 In Europe, approximately 18,000 people are diagnosed with AML each year and the five-year survival rate is reported at 17% for adult patients.2,3 Of all newly diagnosed cases of AML, approximately 25% carry the FLT3-ITD gene mutation, which is associated with a particularly unfavorable prognosis including increased risk of relapse and shorter overall survival.4

"There is a need to improve survival for the majority of patients with acute myeloid leukemia, particularly those with the FLT3-ITD subtype, which is aggressive and difficult to treat," said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. "We look forward to working with the EMA to support their review of quizartinib as a potential option for patients with newly diagnosed FLT3-ITD positive acute myeloid leukemia."

Validation confirms that the application is complete and commences the scientific review process by the EMA’s Committee for Medicinal Products for Human Use (CHMP). The application is based on data from the QuANTUM-First phase 3 trial recently presented at the European Hematology Association (EHA) (Free EHA Whitepaper) (#EHA2022) Congress. In QuANTUM-First, quizartinib combined with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, and continued as monotherapy following consolidation, demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) in adult patients with newly diagnosed FLT3-ITD positive AML compared to chemotherapy alone. The safety of quizartinib combined with intensive chemotherapy and as continuation monotherapy in QuANTUM-First was generally manageable and consistent with previous clinical trials. The incidence of Grade ≥3 QT prolongation was low, with uncommon ventricular arrythmia events. Overall, the risk of QT prolongation was manageable with ECG monitoring, quizartinib dose modification and correction/elimination of additional risk factors.

About QuANTUM-First

QuANTUM-First is a randomized, double-blind, placebo-controlled global phase 3 study evaluating quizartinib in combination with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, and as continuation monotherapy following consolidation, in adult patients aged 18-75 with newly diagnosed FLT3-ITD positive AML. Patients were randomized 1:1 into two treatment groups to receive quizartinib or placebo combined with anthracycline- and cytarabine-based regimens. Eligible patients, including those who underwent hematopoietic stem cell transplant (HSCT), continued with quizartinib or placebo for up to 36 cycles.

The primary study endpoint was OS. Secondary endpoints include event-free survival (EFS), post-induction rates of complete remission (CR) and composite complete remission (CRc), and the percentage of patients who achieve CR or CRc with FLT3-ITD minimal residual disease negativity. Safety and pharmacokinetics, along with exploratory efficacy and biomarker endpoints, also were evaluated. QuANTUM-First enrolled 539 patients at 193 study sites across Asia, Europe, North America, Oceania and South America. For more information, visit Clinicaltrialsregister.eu or ClinicalTrials.gov.

About Acute Myeloid Leukemia (AML)

More than 474,500 new cases of leukemia were reported globally in 2020 with more than 311,500 deaths.5 AML is one of the most common types of leukemia in adults, representing about one-third of all cases, and the average age of diagnosis is 68 years old.1 In Europe, approximately 18,000 people are diagnosed with AML each year and the five-year survival rate is reported at 17% for adult patients.2,3 The conventional treatment for newly diagnosed AML is intensive induction and consolidation chemotherapy with HSCT for eligible patients.6,3

About FLT3-ITD

FLT3 (FMS-like tyrosine kinase 3) is a tyrosine kinase receptor protein normally expressed by hematopoietic stem cells that plays an important role in cell development, promoting cell survival, growth and differentiation through various signaling pathways.4 Mutations of the FLT3 gene, which occur in approximately 30% of AML patients, can drive oncogenic signaling.4 FLT3-ITD (internal tandem duplication) is the most common type of FLT3 mutation in AML, occurring in about 25% of all newly diagnosed patients, and is associated with increased risk of relapse and shorter overall survival.4

About Quizartinib

Quizartinib is an oral, selective type II FLT3 inhibitor currently in clinical development for treatment of FLT3-ITD positive AML. In addition to QuANTUM-First, the quizartinib development program includes a phase 1/2 trial in pediatric and young adult patients with relapsed/refractory FLT3-ITD positive AML in Europe and North America. Several phase 1/2 combination studies with quizartinib are also underway at The University of Texas MD Anderson Cancer Center as part of a strategic research collaboration focused on accelerating development of Daiichi Sankyo pipeline therapies for AML.

Quizartinib, which is currently not approved in Europe, has been granted Orphan Drug Designation for the treatment of AML in Europe, Japan and the U.S. Quizartinib has received Fast Track Designation from the U.S. Food and Drug Administration for the treatment of adult patients with newly diagnosed AML that is FLT3-ITD positive, in combination with standard cytarabine and anthracycline induction and cytarabine consolidation chemotherapy. Quizartinib is currently approved for use in Japan for the treatment of adult patients with relapsed/refractory FLT3-ITD AML, as detected by an approved test. Quizartinib is an investigational medicine in all countries outside of Japan.

On August 23, 2022 GeneCentric Therapeutics, a company making precision medicine more precise through RNA-based diagnostics, reported its new publication in Cancer Research Communications that compares the immunogenomic response profiles to anti-PD-(L)1 or IL-2 therapy and the development of a novel response classifier to IL-2 treatment1 (Press release, GeneCentric Therapeutics, AUG 23, 2022, View Source [SID1234618560]). Cancer Research Communications is an open access peer-reviewed journal published by the American Association for Cancer Research (AACR) (Free AACR Whitepaper). The study was conducted as a collaboration between Atrium Health Levine Cancer Institute, Sanofi, and GeneCentric and evaluated real-world data from patients diagnosed with renal cell carcinoma (RCC) who were treated with immune-oncology agents. Results suggest that common and distinct immune-related response markers for IL-2 and anti-PD-(L)1 therapy may help guide their use, either alone or in combination.

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"It is exciting to share the initial findings from this important collaboration where we attempted to identify the immunogenomic differences between IL-2 and anti-PD-1 responders in renal cell carcinoma," said Dr. Asim Amin, medical oncologist, Atrium Health Levine Cancer Institute, and study co-principal investigator. "Using RNA expression analysis, we were able to identify key characteristics that are unique to each treatment modality, as well as those that are shared between the two. With this work we were able to develop a novel IL-2 response signature that may have prognostic potential."

A primary focus of the study was to obtain a deeper understanding of the tumor microenvironment similarities and/or differences that may lead to IL-2 or anti-PD-(L)1 therapy response. Retrospective tumor samples and corresponding clinical response data were collected from patients with a primary diagnosis of RCC who were treated with high-dose IL-2 (HD-IL-2; aldesleukin) and compared to existing data from a similar cohort of RCC patients treated with the anti-PD-1 nivolumab2. Tumor samples from HD-IL-2 treated patients underwent RNA sequencing (RNAseq) prior to immunogenomic analysis. As a result, a novel RNA-based IL-2 treatment response signature was discovered that could ultimately assist in further developing diagnostics for next-generation IL-2 agents, several of which are in clinical development.

About Renal Cell Carcinoma
Renal cell carcinoma (RCC) is the most common type of kidney and renal pelvis cancer in adults. In the United States, it is estimated that there will be approximately 79,000 new cases of kidney and renal pelvis cancer in 2022 and almost 14,000 deaths. Kidney and renal pelvis cancer, which includes RCC, is considered the 8th most common type of cancer. Standard treatment options for RCC are surgery, radiation, chemotherapy, targeted therapy or immunotherapy.

On August 23, 2022 NorthStar Medical Radioisotopes, LLC, a global innovator in the development, production and commercialization of radiopharmaceuticals used for therapeutic applications and medical imaging, reported the signing of a long-term supply agreement for the therapeutic radioisotope actinium-225 (Ac-225) with Aktis Oncology, Inc (Press release, NorthStar Medical Radiostopes, AUG 23, 2022, View Source [SID1234618576]). Under terms of the agreement, NorthStar will be a major supplier of high purity non-carrier-added (n.c.a.) Ac-225 to Aktis. Aktis will use NorthStar’s Ac-225 to advance development of its proprietary tumor-targeting agents intended to deliver transformative efficacy for patients with solid tumors.

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Ac-225 is a high energy alpha-emitting radioisotope of increasing interest for clinical studies investigating the use of targeted radiopharmaceutical therapy, which combines select molecules with therapeutic radioisotopes to directly target and deliver therapeutic doses of radiation to destroy cancer cells in patients with serious disease. Ac-225 carries sufficient radiation to cause cell death in a localized area of targeted cells, while its half-life limits unwanted radioactivity in patients. Clinical research and commercial use of Ac-225 have been constrained by chronic short supply due to limitations of current production technology. NorthStar is positioned to be the first commercial-scale producer of Ac-225 for advancing clinical research and commercial radiopharmaceutical therapy products. The Company will use its electron accelerator technology to produce n.c.a. Ac-225 that is free of long-lived radioactive contaminants and byproducts associated with other production methods. Such contaminants pose regulatory and waste management challenges for pharmaceutical companies, hospitals, and health systems.

"We are very pleased to enter this Ac-225 supply agreement with Aktis Oncology, and we look forward to working with them in their efforts to provide targeted alpha radiopharmaceuticals to treat patients with cancer," Stephen Merrick, Chief Executive Officer of NorthStar Medical Radioisotopes. "NorthStar is poised to be the first commercial-scale producer of Ac-225, utilizing our n.c.a. Ac-225 production technology that is environmentally preferable and non-uranium based, utilizing state-of-the-art electron beam accelerator production that provides increased capacity and scheduling flexibility. Construction of our dedicated Actinium-225 Production facility is well underway, with initial production of radiochemical grade Ac-225 planned for late 2023. We expect to submit a Drug Master File to the FDA in 2024, which, upon acceptance, will allow NorthStar to provide cGMP grade Ac-225."

"Aktis Oncology is harnessing the power of targeted alpha radiotherapy to treat a broad range of cancers, including breast, lung, colorectal, bladder, and liver cancers," said Matthew Roden, PhD, Aktis Oncology President and Chief Executive Officer. "Aktis is pleased have NorthStar as an experienced and reliable partner in innovative, accelerator-based radioisotope production technology as our programs advance towards the clinic. We look forward to working with NorthStar to supply Ac-225 to deliver highly transformative treatments for patients with cancer."

On August 23, 2022 Mabwell (stock code: 688062.SH), an innovative biopharmaceutical company with the layout of the whole industry chain, reported that the IND application for the self-developed 6MW3511 injection has been formally approved by the Center for Drug Evaluation (CDE) of China National Medical Products Administration for clinical trial in advanced solid tumor (Press release, Mabwell Biotech, AUG 23, 2022, View Source [SID1234618983]).

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6MW3511 is a bifunctional group drug protein independently constructed by Mabwell using humanized anti-PD-L1 nanobodies to link to TGF-β RII mutants. The mutant design facilitates the maintenance of whole-molecule stability and reduces degradation of the natural TGF-β group during the manufacture process and in vivo. By blocking PD-1/PD-L1 and TGF-β/TGF-β-R dual pathways simultaneously, and with the excellent local tumor penetrability resulting from the concise structure, 6MW3511 is expected to further address the difficult problem of immunosuppression in the tumor microenvironment. The results of preclinical studies showed that 6MW3511 injection had good in vivo anti-tumor efficacy and good tolerability in animals.

On August 23, 2022 Erasca, Inc. (Nasdaq: ERAS), a clinical-stage precision oncology company singularly focused on discovering, developing, and commercializing therapies for patients with RAS/MAPK pathway-driven cancers, and The University of Texas MD Anderson Cancer Center (MD Anderson), reported a strategic research and development collaboration to evaluate multiple agents from Erasca’s pipeline targeting the RAS/MAPK pathway as either single-agent or combination therapies (Press release, Erasca, AUG 23, 2022, View Source [SID1234639376]).

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The initial focus of the alliance will be Erasca’s potentially best-in-class ERK1/2 inhibitor ERAS-007 and its potentially best-in-class SHP2 inhibitor ERAS-601, which together comprise Erasca’s first MAPKlamp combination. ERAS-007 is being investigated in multiple ongoing trials, including in non-small cell lung cancer (NSCLC) as part of the HERKULES-2 master protocol and in gastrointestinal (GI) malignancies as part of the HERKULES-3 master protocol. ERAS-601 is being investigated in multiple ongoing trials, including the FLAGSHP-1 trial in triple wildtype (KRAS/NRAS/BRAF wildtype) colorectal cancer (CRC) and human papillomavirus (HPV)-negative advanced head and neck squamous cell carcinoma (HNSCC) and the HERKULES-2 NSCLC master protocol.

"Our strategic collaboration with MD Anderson broadens the evaluation of ERAS-007 and ERAS-601 and explores additional therapeutic opportunities across our pipeline," said Jonathan E. Lim, M.D., Erasca’s chairman, CEO, and co-founder. "The RAS/MAPK pathway is one of cancer’s most frequently altered pathways, affecting more than 5 million new patients with cancer annually worldwide. We have designed our pipeline to comprehensively shut down this highly oncogenic pathway at multiple critical nodes, and we’re excited to work with MD Anderson to potentially address major unmet needs in the treatment of cancer."

The alliance will build on Erasca’s existing collaborations with MD Anderson investigators Scott Kopetz, M.D., Ph.D., professor of Gastrointestinal Medical Oncology, and David S. Hong, M.D., professor of Investigational Cancer Therapeutics. Kopetz is an investigator in HERKULES-3, which is evaluating ERAS-007 plus encorafenib and cetuximab in BRAF V600E-mutant metastatic CRC and ERAS-007 plus palbociclib in KRAS-mutant/NRAS-mutant CRC and KRAS-mutant pancreatic cancer. Hong is an investigator in FLAGSHP-1, which is evaluating ERAS-601 as monotherapy and in combination with cetuximab in triple wildtype CRC and HPV-negative advanced HNSCC.

"Durability and treatment resistance continue to present challenges in the treatment of lung cancers and GI malignancies, particularly stemming from reactivation of the RAS/MAPK pathway. Erasca’s pipeline of agents that target key nodes, including previously undruggable genetic drivers, has the potential to improve durability and minimize resistance," Kopetz said. "We look forward to collaborating with Erasca to further maximize the potential of promising treatment combinations across its pipeline."

The new strategic collaboration will enhance Erasca’s and MD Anderson’s evaluation of ERAS-007 and ERAS-601 in combination with investigational and standard-of-care agents, including with Erasca’s proprietary pipeline programs, such as the KRAS G12D inhibitor ERAS-4. Under the terms of the five-year agreement, collaborative preclinical and clinical studies will be conducted in NSCLC, GI malignancies and additional mutually agreed-upon indications.

About ERAS-007
ERAS-007 is a potential best-in-class oral ERK1/2 inhibitor being investigated alone or in combination with different inhibitors targeting upstream nodes of the MAPK pathway as part of Erasca’s MAPKlamp strategy. The extracellular signal-regulated kinases (ERK), ERK1 and ERK2, belong to a family of serine-threonine kinases that regulate cellular signaling and comprise the terminal node of the RAS/MAPK pathway. The broad therapeutic potential of ERAS-007 is being investigated initially across a series of HERKULES clinical trials that span multiple tumor types and include both monotherapy and combinations with approved and investigational agents, such as RTK, SHP2, RAS, RAF, and/or cell cycle inhibitors. HERKULES-1 is a Phase 1b/2 clinical trial for ERAS-007 as a single agent and in combination with the SHP2 inhibitor ERAS-601 (together, Erasca’s first MAPKlamp combination) in advanced solid tumors. HERKULES-2 is a Phase 1b/2 clinical trial for ERAS-007 in combination with various agents in patients with NSCLC. HERKULES-3 is a Phase 1b/2 clinical trial for ERAS-007 in combination with various agents in patients with GI cancers.

About ERAS-601
ERAS-601 is a potential best-in-class oral, selective SHP2 inhibitor being investigated alone or in combination. SHP2 acts as a convergent node for receptor tyrosine kinase (RTK) signaling, relaying growth and survival signals from RTKs to intracellular signaling pathways. ERAS-601 is being investigated across a series of clinical trials that span multiple tumor types and include both monotherapy and combinations with approved and investigational agents. FLAGSHP-1 is a Phase 1/1b dose escalation trial evaluating ERAS-601 as a monotherapy in advanced solid tumors and in combination in triple wildtype CRC and HPV-negative advanced HNSCC. HERKULES-2 is a Phase 1b/2 master protocol clinical trial that includes evaluation of ERAS-601 in combination with various agents in patients with NSCLC.