On January 30, 2023 Daiichi Sankyo (TSE: 4568) reported that the first patient has been dosed in the global, randomized TROPION-Lung07 phase 3 trial evaluating datopotamab deruxtecan (Dato-DXd) in combination with pembrolizumab with or without platinum chemotherapy, in patients with previously untreated advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) with PD-L1 expression less than 50% (TPS<50%) and without actionable genomic alterations (Press release, Daiichi Sankyo, JAN 30, 2023, View Source [SID1234626656]).

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Datopotamab deruxtecan is a specifically engineered TROP2 directed DXd antibody drug conjugate (ADC) being jointly developed by Daiichi Sankyo and AstraZeneca (LSE/STO/Nasdaq: AZN).

Among patients with NSCLC, nearly half are diagnosed at an advanced stage and generally have a poor prognosis.1,2,3 While first-line treatment with pembrolizumab or other checkpoint inhibitors, with or without chemotherapy, has improved outcomes in patients with NSCLC without actionable genomic alterations, disease progression still occurs in the majority of patients.4,5

"Metastatic non-squamous non-small cell lung cancer remains a challenge because the majority of patients experience disease progression following their initial treatment, underscoring the need for more effective treatment options in the first-line setting," said Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo. "The TROPION-Lung07 trial will assess the potential of the combination of datopotamab deruxtecan and pembrolizumab with and without chemotherapy, to evaluate whether this combination may be a more effective standard treatment option than the current standard of care for patients in the first-line setting."

"The combination of datopotamab deruxtecan with a checkpoint inhibitor with or without chemotherapy, has shown increased activity and a manageable safety profile in early trials, including TROPION-Lung02," said Cristian Massacesi, MD, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca. "With this initiation, TROPION-Lung07 becomes the third phase 3 trial in our evaluation of these investigational combinations for the first-line treatment of patients with non-small cell lung cancer, across PD-L1 segments and tumor histologies."

TROPION-Lung07 is the third clinical trial collaboration and supply agreement between Daiichi Sankyo and AstraZeneca with a subsidiary of Merck & Co., Inc., Rahway, NJ., USA to evaluate the combination of datopotamab deruxtecan and pembrolizumab. Previous clinical trial collaboration agreements were entered in October 2021 for the TROPION-Lung08 phase 3 trial and May 2020 for the TROPION-Lung02 phase 1b trial.

About TROPION-Lung07
TROPION-Lung07 is a global, randomized, open-label, phase 3 trial assessing the efficacy and safety of datopotamab deruxtecan in combination with pembrolizumab with or without platinum chemotherapy compared with pembrolizumab and platinum chemotherapy in patients with previously untreated, advanced or metastatic non-squamous NSCLC with less than 50% programmed death-ligand (PD-L1) expression (tumor proportion score [TPS] < 50%) and without actionable genomic alterations. Eligible participants in the three-arm study will be randomized in a 1:1:1 ratio to the following intervention arms: Arm A (datopotamab deruxtecan [6 mg/kg] plus pembrolizumab 200 mg IV plus platinum chemotherapy every three weeks), Arm B (datopotamab deruxtecan [6 mg/kg] plus pembrolizumab 200 mg IV every three weeks), and Arm C (pembrolizumab 200 mg IV plus pemetrexed [500 mg/m2] plus platinum chemotherapy every three weeks).

The primary endpoints of TROPION-Lung07 are progression-free survival (PFS) as assessed by blinded independent central review and overall survival. Secondary endpoints include objective response rate, duration of response, time to response, disease control rate as assessed by both investigator and blinded independent central review, PFS as assessed by investigator, PFS2 and safety.

TROPION-Lung07 will enroll approximately 975 patients at sites in North America, South America, Europe, Asia and Oceania. For more information visit ClinicalTrials.gov.

About Non-Small Cell Lung Cancer Without Actionable Genomic Alterations
Lung cancer is the second most common cancer and the leading cause of cancer-related mortality worldwide.1 NSCLC is diagnosed at an advanced stage in nearly 50% of patients and often has a poor prognosis with worsening outcomes after each line of subsequent therapy.6,7,8

While the introduction of targeted therapies and checkpoint inhibitors in recent years have improved outcomes for patients with advanced NSCLC, the majority of tumors do not have known actionable genomic alterations.7,8,9,10 The current standard of care in the first-line treatment of patients with advanced NSCLC without actionable genomic alterations consists of checkpoint inhibitors with or without platinum-based chemotherapy based on PD-L1 expression. While these therapies may improve survival, at least 40% to 60% of patients experience disease progression, underscoring the need for new therapeutic approaches and options.11,12,13,14

TROP2 (trophoblast cell-surface antigen 2) is a transmembrane glycoprotein that is widely expressed in several types of tumors, including NSCLC.15,16,17,18 TROP2 is expressed across all lung cancer subtypes with the highest expression seen in the majority of adenocarcinoma and squamous cell carcinoma (the most common forms of NSCLC).19 No TROP2 directed therapies are currently approved for the treatment of patients with NSCLC.19,20,21

About Datopotamab Deruxtecan (Dato-DXd)
Datopotamab deruxtecan (Dato-DXd) is an investigational TROP2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, datopotamab deruxtecan is one of the three lead ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programs in AstraZeneca’s ADC scientific platform. Datopotamab deruxtecan is comprised of a humanized anti-TROP2 IgG1 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a number of topoisomerase I inhibitor payloads, an exatecan derivative, via tetrapeptide-based cleavable linkers.

A comprehensive development program called TROPION is underway globally with more than 10 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple tumors including NSCLC, triple negative breast cancer and HR positive, HER2 low or negative breast cancer. Trials in combination with other anticancer treatments are also underway.

On January 30, 2023 Qurient Co. Ltd. (KRX: 115180), a clinical-stage biotech company based in Korea, reported that the first patient has been dosed in the Phase 1b/2 clinical study of Q702 in combination with KEYTRUDA (pembrolizumab) (Press release, Qurient Therapeutics, JAN 30, 2023, View Source [SID1234626655]).

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The Q702 Phase 1b/2 study (NCT05438420) is being conducted at seven investigative sites in the U.S. and Korea, and approximately 142 patients with advanced solid tumors are scheduled to be enrolled. The primary objectives of the Phase 1b/2 study are to determine the safety and efficacy of Q702 in combination with KEYTRUDA in study subjects with advanced solid cancers.

"We are pleased to initiate evaluation of Q702 in combination with KEYTRUDA for the treatment of esophageal, gastric, hepatocellular, and cervical cancers, where limited immuno-oncology treatment options are currently available," said Kiyean Nam, Ph.D., CEO of Qurient. "We have previously shown the potential additive benefit of Q702 in combination with anti-PD-1 therapy in preclinical models, and we expect the same clinical benefits of Q702 in combination with KEYTRUDA for patients."

About Q702

Q702 is an orally available novel Axl/Mer/CSF1R inhibitor and is designed to modulate innate immune components leading to T cell activation. Q702 was also shown to increase antigen presentation in the tumor cells demonstrating dual mode of action. A phase 1/2 clinical trial is currently underway in the U.S. (Clinical Trials.gov Identifier: NCT04648254) to evaluate safety and efficacy of Q702 as a monotherapy treatment for solid cancers.

On January 30, 2023 Oricell Therapeutics Co., Ltd (Oricell), an innovative pharmaceutical company committed to the development of clinical-stage oncology cell therapies, reported publication of data from a clinical study evaluating the efficacy of OriCAR-017, an autologous GPRC5D-directed CAR-T cell therapy, in the treatment of relapsed/refractory multiple myeloma (RRMM) in an article entitled "Phase 1 Open-Label Single-Centre Single Arm Study of GPRC5D CAR T Cells(OriCAR-017) in Patients with Relapsed/Refractory Multiple Myeloma (POLARIS)" in The Lancet Haematology (2022 impact factor: 30.153) (Press release, OriCell Therapeutics, JAN 30, 2023, View Source [SID1234626654]).

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The POLARIS study, the first-in-human study of OriCAR-017, explores the safety, tolerability and preliminary anti-tumor efficacy for a single intravenous infusion of OriCAR-017 in patients with RRMM (NCT05016778). As of June 30, 2022, the study had showed exciting clinical results for OriCAR-017 in the treatment of 10 patients with RRMM:

Median follow-up time: 238 days (range: 99-345 days)

Safety: Dose-limiting toxicities (DLTs), serious adverse events (SAEs), neurotoxicity and deaths were not observed. The common treatment-emergent AEs were Grade 3 or 4 hematologic toxicities, including neutropenia, leukopenia, thrombocytopenia and anemia. Cytokine release syndrome (CRS) was observed in all patients (9 patients in G1 and one patient in G2).

Preliminary clinical efficacy: the study revealed an impressive 100% overall response rate, with 60% stringent complete response and 40% very good partial response. All patients (100%) achieved MRD negative (10-5/ml). Additionally, of the 5 patients who relapsed after BCMA CAR T-cell therapy, 2 achieved stringent complete response and 3 achieved very good partial response. At the date cut-off time, the mPFS (median progression-free survival) has not yet been reached; for the 2 patients who had disease progression, one with GPRC5D-positive while the other one with GPRC5D-negative.
"Advances in the treatment of R/RMM, including the introduction of immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies as well as stem cell transplantation, have prolonged survival in R/RMM patients, the disease remains a clinically incurable plasma cell neoplasm," said Prof. He Huang, Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University. "Nevertheless, almost all R/RMM patients eventually experience one or more relapses, with poorer survival outcomes for those with high-risk cytogenetic characteristics or refractory diseases. Data from our study showed that with extraordinary clinical efficacy, OriCAR-017 has been proved to be a novel, safe and effective therapy for patients with R/RMM, especially for those who experienced a relapse after receiving BCMA-targeted therapy. We are looking forward to continuously conducting follow-up clinical studies of OriCAR-017 in concert with Oricell."

"OriCAR-017 has demonstrated 100% ORR and controllable safety in the POLARIS study, providing a solid foundation for Oricell’s subsequent registration of clinical studies," stated Helen Yang, Chairman and CEO of Oricell. "The firm is in the process of submitting an application in the US and China for the registration of clinical studies of OriCAR-017 while advancing the therapy to critical phases of clinical research as soon as possible."

About OriCAR-017

OriCAR-017, one of the key therapies developed by Oricell based on the company’s two proprietary technology platforms OriAb and OriCAR, is a GPRC5D-targeted CAR T-Cell therapy used to treat relapsed/refractory multiple myeloma (RRMM).

In June 2022, Oricell announced data from Phase I POLARIS clinical trial conducted by investigators in China at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting for 2022. As of April 30, 2022, all evaluable data of the study had showed 100% ORR as well as 100% minimal residual disease (MRD) negative rate as measured by flow cytometry (10-5) at day 28 after infusion in all participators, including those who relapsed following the BCMA CAR-T therapy.

In October 2022, OriCAR-017 received Orphan Drug Designation from the U.S. Food and Drug Administration for the treatment of RRMM.

Currently, the company is accelerating the registration of the therapy in both China and the US.

About Multiple Myeloma

Multiple myeloma (MM), one of the most common blood cancers, is a malignant disease of abnormal proliferation of clonal plasma cells. For newly treated MM patients, commonly used first-line treatment drugs include proteasome inhibitors, immunomodulatory drugs and alkylating agents. For most patients, the commonly used first-line treatments can stabilize the patient’s condition for 3-5 years, but a small number of patients show primary drug resistance at initial treatment, and the disease cannot be effectively controlled. Most of the newly treated patients with effective treatment will inevitably enter the relapse and refractory stage after the stable disease period. Therefore, there is still an unmet clinical need for patients with relapsed/refractory multiple myeloma. In the United States, MM accounts for nearly 2% of all new cancer cases and more than 2% of cancer deaths. (For more information, see View Source )

On January 30, 2023 Deka Biosciences ("Deka"), a biotech company focused on developing novel cytokine therapies to treat cancer and inflammatory diseases, reported that the U.S. Food and Drug Administration (FDA) has completed its review of the investigational new drug (IND) application for DK210 (EGFR) and concluded that Deka may proceed with a Phase 1 clinical trial in the United States (Press release, Deka Biosciences, JAN 30, 2023, View Source [SID1234626653]). The Phase 1, first-in-human, multicenter clinical study seeks to characterize the safety, and biomarkers for response of DK210 (EGFR) in patients with advanced solid cancer who are overexpressing epidermal growth factor receptors (EGFR) (NCT05704985).

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"Obtaining FDA clearance for our company’s first program to start clinical trials is a significant achievement," said Dr. John Mumm, CEO and co-founder of Deka. "We are excited to move forward with the clinical development of DK210 (EGFR) and the potential it holds for positively impacting the lives of many cancer patients."

DK210 (EGFR) is the first of several experimental therapeutics developed as part of Deka’s platform of molecules. Each DiakineTM in Deka’s platform consists of two cytokines coupled together onto a single chain variable fragment targeting system that enables the cytokines to accumulate more specifically into specific tissues. The combination of the two cytokines increases potency and reduces toxicity while the targeting system also improves the drug’s efficacy, safety, and manufacturability. Deka has identified genetic markers that are related to responses to each DiakineTM. These markers will be evaluated in early clinical trials with the hope of using them as potential diagnostic tools to match patients with the most effective DiakineTM treatment in later stage trials.

On January 30, 2023 Mickey Mikitani, Co-CEO of Rakuten Medical, Inc. reported a presentation to investors from around the world at the 41st Annual J.P. Morgan Healthcare Conference (JPM2023) on January 10, 2023, in San Francisco, California, U.S (Press release, Rakuten Medical, JAN 30, 2023, View Source;301734064.html [SID1234626652]). The presentation included an overview of Rakuten Medical’s third antibody-dye conjugate,"RM-0256," to potentially reach the clinic, an update on the pipeline as a whole including its second asset "RM-1995" which is already in the clinical stage, an overview of the commercial growth in Japan for the Alluminox treatment using its leading compound "ASP-1929", global expansion of the company leveraging the success in Japan, and key milestones for the next few years.

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RM-0256 – currently being evaluated in pre-clinical studies – is a conjugate of an anti-PD-L1 antibody and IRDye700DX (IR700), a light-activatable dye, that accumulates specifically on PD-L1-expressing cells. PD-L1 is a protein that inhibits the anti-cancer immune response by deactivating killer T cells, by binding to PD-1 which is abundantly expressed on the T cell surface.1 PD-L1 is expressed in many solid tumors such as melanoma, lung, urothelial, gastrointestinal, gynecological, breast, and head and neck, among others, helping these tumors evade the immune system.2 In addition to being present on tumor cells, PD-L1 is also expressed on suppressive immune cells within the tumor microenvironment such as tumor associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs).3 In pre-clinical studies, Alluminox therapy using RM-0256 has been observed to enable the accumulation of RM-0256 on PD-L1-expressing target cells followed by activation of the IR700 by illumination with 690nm non-thermal light, resulting in destruction of the target cells by its photochemical reaction. This reaction may lead to immunogenic cell death (ICD) and activation of an anti-cancer immune response. Furthermore, the anti-PD-L1 antibody itself comprising RM-0256 has been observed to inhibit the PD-L1:PD-1 interaction and may act systemically as an immune checkpoint inhibitor, further enhancing the anticancer immune response after light irradiation.

In Japan, commercial launch of ASP-1929 (brand name in Japan: Akalux) continues to accelerate. 230+ doctors at 100+ institutions have been certified to provide the novel treatment, leading to 200+ treatments being administered in the 2 years since launch. (*ASP-1929 is investigational outside of Japan.) Publications based on real world data in Japan, "Quality-of-Life Evaluation of Patients with Unresectable Locally Advanced or Locally Recurrent Head and Neck Carcinoma Treated with Head and Neck Photoimmunotherapy"4 and "Near-Infrared Photoimmunotherapy for Oropharyngeal Cancer,"5 indicated that the treatment using ASP-1929 achieved good disease control without decreasing the Quality of Life (QOL). (**ASP-1929 is investigational outside of Japan and these quality-of-life assessments are specific to the Japanese population studied.)

Leveraging on the data and knowledge that is being accumulated in Japan, Rakuten Medical is further pursuing global expansion. For India, where it has established a subsidiary in 2022, global phase III trial of ASP-1929 in locoregional recurrent head and neck squamous cell carcinoma (ASP-1929-301 / ClinicalTrials.gov Identifier: NCT03769506) is being prepared for initiation in the country. Subject to positive clinical trial results, ASP-1929 could be approved as early as 2025 in the U.S., Taiwan, India, and other countries. A number of pipeline milestones are expected in the next few years, including the initiation of RM-1995 and RM-0256 clinical trials and the progression of several clinical trials with ASP-1929.

Mickey started his J.P. Morgan presentation with the question "What kind of future would open up if we could kill only targeted cells?" and showcased the potential of Rakuten Medical’s investigational technology by saying "In the decade since I first encountered this therapy, which is completely different from existing treatments, we have been developing the technology at a tremendous pace. Our goal goes beyond establishing a position as a local treatment. Existing therapies have taken over a century to evolve and establish themselves as standards of care – we aim to achieve this same position for our technology on a much shorter timeline."

The slides and audio of Mickey’s presentation at JPM2023 are available for download at the following links.

Slides: View Source
Audio: View Source