A Phase III, Open-label, Sponsor-blind, Randomized Study of Dato-DXd With or Without Osimertinib Versus Platinum-based Doublet Chemotherapy for Participants With EGFR-mutated Locally Advanced or Metastatic Non-small Cell Lung Cancer Whose Disease Has Progressed on Prior Osimertinib Treatment (TROPION-Lung15)

This study will assess the effect of Dato-DXd in combination with osimertinib or Dato-DXd monotherapy versus platinum-based doublet chemotherapy in terms of progression-free survival (PFS).

Start Date12 Aug 2024

Sponsor / Collaborator

AstraZeneca PLC

[+1]

CTR20241813 / RecruitingPhase 3

一项在表皮生长因子受体（EGFR）突变阳性的局部晚期或转移性非小细胞肺癌参与者中评价奥希替尼联合或不联合Datopotamab Deruxtecan（Dato-DXd）作为一线治疗的III期、开放性、随机研究（TROPION-Lung14）

[Translation] A phase III, open-label, randomized study evaluating osimertinib with or without datopotamab deruxtecan (Dato-DXd) as first-line treatment in participants with epidermal growth factor receptor (EGFR) mutation-positive locally advanced or metastatic non-small cell lung cancer (TROPION-Lung14)

安全性导入期主要目的：评估奥希替尼联合Dato-DXd在所有接受给药的安全性导入期参与者中的安全性和耐受性。随机化期主要目的：通过评估BICR评估的PFS证明奥希替尼联合Dato-DXd与奥希替尼相比在所有随机化参与者中的优效性。次要目的：通过评估OS证明奥希替尼联合Dato-DXd与奥希替尼相比在所有随机化参与者中的优效性；通过评价CNS PFS证明奥希替尼联合Dato-DXd与奥希替尼相比在基线时存在CNS转移的参与者中对CNS转移的疗效；通过评价研究者评估的PFS证明奥希替尼联合Dato-DXd与奥希替尼相比在所有随机化参与者中的疗效；通过评估ORR证明奥希替尼联合Dato-DXd与奥希替尼相比在所有基线时存在可测量病灶的随机化参与者中的疗效；通过评估DoR证明奥希替尼联合Dato-DXd与奥希替尼相比在所有基线时存在可测量病灶的随机化参与者中的疗效；证明奥希替尼联合Dato-DXd与奥希替尼相比预防CNS转移的疗效；通过评估PFS2证明奥希替尼联合Dato-DXd与奥希替尼相比在所有随机化参与者中的疗效。

[Translation]

The main purpose of the safety run-in period is to evaluate the safety and tolerability of osimertinib combined with Dato-DXd in all participants who received the safety run-in period. The main purpose of the randomization period is to demonstrate the superiority of osimertinib combined with Dato-DXd compared with osimertinib in all randomized participants by evaluating PFS assessed by BICR. Secondary objectives: To demonstrate the superiority of osimertinib combined with Dato-DXd compared with osimertinib in all randomized participants by evaluating OS; to demonstrate the efficacy of osimertinib combined with Dato-DXd compared with osimertinib in participants with CNS metastases at baseline by evaluating CNS PFS; to demonstrate the efficacy of osimertinib combined with Dato-DXd compared with osimertinib in all randomized participants by evaluating investigator-assessed PFS; to demonstrate the efficacy of osimertinib combined with Dato-DXd compared with osimertinib in all randomized participants with measurable lesions at baseline by evaluating ORR; to demonstrate the efficacy of osimertinib combined with Dato-DXd compared with osimertinib in all randomized participants with measurable lesions at baseline by evaluating DoR; to demonstrate the efficacy of osimertinib combined with Dato-DXd compared with osimertinib in the prevention of CNS metastases compared with osimertinib; to demonstrate the efficacy of osimertinib combined with Dato-DXd compared with osimertinib in all randomized participants by evaluating PFS2.

Start Date29 Apr 2024

Sponsor / Collaborator

AstraZeneca Investment (China) Co. Ltd.

[+2]

NCT06350097 / RecruitingPhase 3

A Phase III, Open-label, Randomised Study of Osimertinib With or Without Datopotamab Deruxtecan (Dato-DXd), as First-line Treatment in Participants With Epidermal Growth Factor Receptor (EGFR) Mutation-positive, Locally Advanced or Metastatic Non-small Cell Lung Cancer

The purpose of this study is to evaluate efficacy and safety of osimertinib (tablet) in combination with Datopotamab Deruxtecan (i.v. infusion) compared with osimertinib (tablet) monotherapy as a first-line therapy in participants with locally advanced or metastatic EGFRm (Ex19del and/or L858R) NSCLC.
Study details include:
1. The study duration will be event-driven, with an estimated duration of approximately 9 years.
2. Participants may receive study treatment until disease progression, unacceptable toxicity, or other specific discontinuation criteria are met.
3. The visit frequency will be every 3 weeks during the treatment period.
Note: Participants on osimertinib treatment (osimertinib only arm or who have discontinued Datopotamab Deruxtecan while are still receiving osimertinib) are required to attend visits to perform assessments every 6 weeks from Cycle 7 until Cycle 17 and then visits every 12 weeks until disease progression, IP discontinuation or primary PFS DCO. Participants who are receiving osimertinib + Datopotamab Deruxtecan are still required to attend visit to perform assessment every 3 weeks (q3w) per SoA.

Start Date29 Apr 2024

Sponsor / Collaborator

AstraZeneca PLC

[+1]

100 Clinical Results associated with Datopotamab Deruxtecan

100 Translational Medicine associated with Datopotamab Deruxtecan

100 Patents (Medical) associated with Datopotamab Deruxtecan

Literatures (Medical) associated with Datopotamab Deruxtecan

31 Dec 2024·mAbs

Antibodies to watch in 2024

Article

Author: Reichert, Janice M ; Crescioli, Silvia ; Kaplon, Hélène ; Wang, Lin ; Visweswaraiah, Jyothsna ; Chenoweth, Alicia

The 'Antibodies to Watch' article series provides an annual summary of commercially sponsored monoclonal antibody therapeutics currently in late-stage clinical development, regulatory review, and those recently granted a first approval in any country. In this installment, we discuss key details for 16 antibody therapeutics granted a first approval in 2023, as of November 17 (lecanemab (Leqembi), rozanolixizumab (RYSTIGGO), pozelimab (VEOPOZ), mirikizumab (Omvoh), talquetamab (Talvey), elranatamab (Elrexfio), epcoritamab (EPKINLY), glofitamab (COLUMVI), retifanlimab (Zynyz), concizumab (Alhemo), lebrikizumab (EBGLYSS), tafolecimab (SINTBILO), narlumosbart (Jinlitai), zuberitamab (Enrexib), adebrelimab (Arelili), and divozilimab (Ivlizi)). We briefly review 26 product candidates for which marketing applications are under consideration in at least one country or region, and 23 investigational antibody therapeutics that are forecast to enter regulatory review by the end of 2024 based on company disclosures. These nearly 50 product candidates include numerous innovative bispecific antibodies, such as odronextamab, ivonescimab, linvoseltamab, zenocutuzumab, and erfonrilimab, and antibody-drug conjugates, such as trastuzumab botidotin, patritumab deruxtecan, datopotamab deruxtecan, and MRG002, as well as a mixture of two immunocytokines (bifikafusp alfa and onfekafusp alfa). We also discuss clinical phase transition and overall approval success rates for antibody therapeutics, which are crucial to the biopharmaceutical industry because these rates inform decisions about resource allocation. Our analyses indicate that these molecules have approval success rates in the range of 14-32%, with higher rates associated with antibodies developed for non-cancer indications. Overall, our data suggest that antibody therapeutic development efforts by the biopharmaceutical industry are robust and increasingly successful.

31 Dec 2023·mAbs

Antibodies to watch in 2023

Article

Author: Crescioli, Silvia ; Kaplon, Hélène ; Visweswaraiah, Jyothsna ; Reichert, Janice M. ; Chenoweth, Alicia

In this 14th installment of the annual Antibodies to Watch article series, we discuss key events in commercial monoclonal antibody therapeutics development that occurred in 2022 and forecast events that might occur in 2023. As of mid-November, 12 antibody therapeutics had been granted first approvals in either the United States or European Union (tebentafusp (Kimmtrak), faricimab (Vabysmo), sutimlimab (Enjaymo), relatlimab (Opdualag), tixagevimab/cilgavimab (Evusheld), mosunetuzumab (Lunsumio), teclistamab (TECVAYLI), spesolimab (SPEVIGO), tremelimumab (Imjudo; combo with durvalumab), nirsevimab (Beyfortus), mirvetuximab soravtansine (ELAHERE™), and teplizumab (TZIELD)), including 4 bispecific antibodies and 1 ADC. Based on FDA action dates, several additional product candidates could be approved by the end of 2022. An additional seven were first approved in China or Japan in 2022, including two bispecific antibodies (cadonilimab and ozoralizumab). Globally, at least 24 investigational antibody therapeutics are undergoing review by regulatory agencies as of mid-November 2022. Our data show that, with antibodies for COVID-19 excluded, the late-stage commercial clinical pipeline grew by ~20% in the past year to include nearly 140 investigational antibody therapeutics that were designed using a wide variety of formats and engineering techniques. Of those in late-stage development, marketing application submissions for at least 23 may occur by the end of 2023, of which 5 are bispecific (odronextamab, erfonrilimab, linvoseltamab, zanidatamab, and talquetamab) and 2 are ADCs (datopotamab deruxtecan, and tusamitamab ravtansine).

01 Nov 2023·Journal of clinical pharmacology

Use of Real-World Evidence in a Virtual Bridging Analysis for a Human Epidermal Growth Factor Receptor 2-Targeted Antibody-Drug Conjugate in Gastric Cancer.

Article

Author: Abutarif, Malaz ; Lu, Zheng ; Wada, Russ ; Belli, Andrew J ; Singh, Jasmeet ; Salas, Maribel ; Kawaguchi, Yoshinori ; Garimella, Tushar

This study bridged pharmacokinetic, efficacy, and safety clinical trial data from Japan to a Western population using real-world evidence (RWE) to investigate the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in the treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer. Using population pharmacokinetic and exposure-response (efficacy/safety) models, exposure-efficacy data from 117 patients and exposure-safety data from 158 patients in Japan who received T-DXd 6.4 mg/kg as second-line or later treatment were bridged to RWE including covariate information from 25 Western patients with HER2-positive gastric cancer who received second-line or later T-DXd treatment. Pharmacokinetic simulations indicated that intact T-DXd and released drug (DXd) steady-state exposures were comparable between Western patients and patients from Japan; the Western/Japan ratio of exposure medians ranged from 0.82 (T-DXd steady-state minimum concentration) to 1.18 (DXd steady-state maximum concentration). Exposure-efficacy simulations estimated a confirmed objective response rate of 28.6% (90% confidence interval, 20.8-38.4) in real-world Western patients versus 40.1% (90% confidence interval, 33.5-47.0) in patients from Japan, possibly because of checkpoint inhibitor use in 4% versus 30% of patients, respectively. Western patients had a higher estimated rate of serious adverse events than patients from Japan (42.2% vs 34.6%); however, the rate of interstitial lung disease was lower (less than 10%) in Western patients. Overall, T-DXd was predicted to have meaningful clinical activity and a manageable safety profile in Western patients with HER2-positive gastric cancer. Using RWE, bridging analysis supported US approval of T-DXd 6.4 mg/kg in advanced gastric cancer before a clinical trial was completed in Western patients.

177

News (Medical) associated with Datopotamab Deruxtecan

27 Jun 2024

·pipelinereview.com

Patritumab Deruxtecan BLA Submission Receives Complete Response Letter from FDA Due to Inspection Findings at Third-Party Manufacturer

BASKING RIDGE, NJ & RAHWAY, NJ, USA I June 26, 2024 I The U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) for the Biologics License Application (BLA) seeking accelerated approval of Daiichi Sankyo (TSE: 4568) and Merck’s (known as MSD outside of the United States and Canada) (NYSE: MRK) patritumab deruxtecan (HER3-DXd) for the treatment of adult patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) previously treated with two or more systemic therapies. The CRL results from findings pertaining to an inspection of a third-party manufacturing facility. The CRL did not identify any issues with the efficacy or safety data submitted. Patritumab deruxtecan is a specifically engineered potential first-in-class HER3 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed by Daiichi Sankyo and Merck. “We will work closely with the FDA and the third-party manufacturer to address the feedback as quickly as possible in order to bring the first HER3 directed medicine to patients with previously-treated EGFR-mutated non-small cell lung cancer,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “We remain confident in the ability to develop this medicine to its full potential.” “Patients with previously treated EGFR-mutated non-small cell lung cancer often experience recurrence and have limited treatment options,” said Marjorie Green, MD, Senior Vice President and Head of Oncology, Global Clinical Development, Merck Research Laboratories. “We are committed to working with Daiichi Sankyo and the FDA to prioritize bringing patritumab deruxtecan to these patients in need.” The BLA is based on the primary results from the HERTHENA-Lung01 pivotal phase 2 trial that were presented at the IASLC 2023 World Conference on Lung Cancer (#WCLC23) and simultaneously published in the Journal of Clinical Oncology . In HERTHENA-Lung01, patritumab deruxtecan was studied in 225 patients with EGFR-mutated locally advanced or metastatic NSCLC following disease progression with an EGFR TKI and platinum-based chemotherapy, which demonstrated an objective response rate (ORR) of 29.8% (95% CI: 23.9-36.2), including one complete response and 66 partial responses. The median duration of response (DoR) was 6.4 months (95% CI: 4.9-7.8). The safety profile of patritumab deruxtecan observed in HERTHENA-Lung01 was consistent with previous phase 1 clinical trials in NSCLC with a treatment discontinuation rate of 7.1% due to treatment-emergent adverse events (TEAEs). Grade 3 or higher TEAEs occurred in 64.9% of patients. The most common (≥5%) grade 3 or higher TEAEs were thrombocytopenia (21%), neutropenia (19%), anemia (14%), leukopenia (10%), fatigue (6%), hypokalemia (5%) and asthenia (5%). Twelve patients (5.3%) had confirmed treatment-related interstitial lung disease (ILD) as determined by an independent adjudication committee. One grade 5 ILD event was observed. About HERTHENA-Lung01 HERTHENA-Lung01 is a global, multicenter, open-label, two-arm phase 2 trial evaluating the safety and efficacy of patritumab deruxtecan in patients with EGFR-mutated locally advanced or metastatic NSCLC following disease progression with an EGFR TKI and platinum-based chemotherapy. Patients were randomized 1:1 to receive 5.6 mg/kg (n=225) or an uptitration regimen (n=50). The uptitration arm was discontinued as the dose of 5.6 mg/kg of patritumab deruxtecan was selected following a risk-benefit analysis conducted from the phase 1 trial assessing the doses in a similar patient population. The primary endpoint of HERTHENA-Lung01 was ORR as assessed by blinded independent central review (BICR). Secondary endpoints included DoR, progression-free survival, disease control rate, and time to response – all assessed by both BICR and investigator assessment – as well as investigator-assessed ORR, overall survival, safety and tolerability. HERTHENA-Lung01 enrolled patients in Asia, Europe, North America and Oceania. For more information about the trial, visit ClinicalTrials.gov . About EGFR-Mutated Non-Small Cell Lung Cancer Approximately 226,000 lung cancer cases were diagnosed in the U.S. in 2022. 1 Lung cancer is the third most common cancer and the leading cause of cancer-related deaths in the U.S. 1 NSCLC accounts for approximately 81% of all lung cancers in the U.S., with 52% having distant spread at diagnosis. 2,3 EGFR mutations occur in approximately one in five patients with NSCLC in Western populations. 4 About HER3 HER3 is a member of the EGFR family of receptor tyrosine kinases. 5 It is estimated that about 83% of primary NSCLC tumors and 90% of advanced EGFR-mutated tumors express HER3 after prior EGFR TKI treatment. 6,7 HER3 is associated with poor treatment outcomes, including shorter relapse-free survival and significantly reduced survival. 8,9 There is currently no HER3 directed therapy approved for the treatment of any cancer. About Patritumab Deruxtecan Patritumab deruxtecan (HER3-DXd) is an investigational HER3 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, patritumab deruxtecan is composed of a fully human anti-HER3 IgG1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. Patritumab deruxtecan was granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration in December 2021 for the treatment of patients with EGFR-mutated locally advanced or metastatic NSCLC with disease progression on or after treatment with a third-generation TKI and platinum-based therapies. Patritumab deruxtecan is currently being evaluated as both a monotherapy and in combination with other therapies in a global development program, which includes HERTHENA-Lung02 , a phase 3 trial evaluating the efficacy and safety of patritumab deruxtecan versus platinum-based chemotherapy in patients with EGFR-mutated locally advanced or metastatic NSCLC following disease progression on or after treatment with a third-generation EGFR TKI; HERTHENA-Lung01 , a phase 2 trial in metastatic or locally advanced NSCLC with an activating EGFR mutation previously treated with at least one EGFR TKI and one platinum-based chemotherapy-containing regimen; HERTHENA-PanTumor01 , a phase 2 trial in locally advanced or metastatic solid tumors, including melanoma, gastric and head and neck cancer, among other types of cancer, previously treated with at least one prior systemic therapy; a phase 1 trial in combination with osimertinib in EGFR-mutated locally advanced or metastatic NSCLC; and a phase 1 trial in previously treated patients with advanced NSCLC. A phase 1/2 trial in HER3 expressing metastatic breast cancer also has been completed. About the Daiichi Sankyo and Merck Collaboration Daiichi Sankyo and Merck entered into a global collaboration in October 2023 to jointly develop and commercialize patritumab deruxtecan (HER3-DXd), ifinatamab deruxtecan (I-DXd) and raludotatug deruxtecan (R-DXd), except in Japan where Daiichi Sankyo will maintain exclusive rights. Daiichi Sankyo will be solely responsible for manufacturing and supply. About the DXd ADC Portfolio of Daiichi Sankyo The DXd ADC portfolio of Daiichi Sankyo currently consists of six ADCs in clinical development across multiple types of cancer. ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with Merck. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology to target and deliver a cytotoxic payload inside cancer cells that express a specific cell surface antigen, each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan and DS-3939 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established. About Daiichi Sankyo Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical needs. For more information, please visit www.daiichisankyo.com . Merck’s Focus on Cancer Every day, we follow the science as we work to discover innovations that can help patients, no matter what stage of cancer they have. As a leading oncology company, we are pursuing research where scientific opportunity and medical need converge, underpinned by our diverse pipeline of more than 25 novel mechanisms. With one of the largest clinical development programs across more than 30 tumor types, we strive to advance breakthrough science that will shape the future of oncology. By addressing barriers to clinical trial participation, screening and treatment, we work with urgency to reduce disparities and help ensure patients have access to high-quality cancer care. Our unwavering commitment is what will bring us closer to our goal of bringing life to more patients with cancer. For more information, visit https://www.merck.com/research/oncology/ . About Merck At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter) , Facebook , Instagram , YouTube and LinkedIn . References: 1 World Health Organization. International Agency for Research on Cancer. U.S. Cancer Fact Sheet. Accessed June 2024. 2 American Society of Clinical Oncology. Lung Cancer – Non-Small Cell: Statistics . Accessed June 2024. 3 SEER. Adenocarcinoma of the Lung and Bronchus Stage Distribution of SEER Incidence Cases . 2012-2021. Accessed June 2024. 4 Tan AC, et al. J Clin Oncol . 2022;40(6):611-625. 5 Mishra R, et al. Onco Rev . 2018; 12(355):45-62. 6 Scharpenseel H, et al. Scientific Reports . 2019; 9:7406. 7 Yonesaka K, et al. Clin Cancer Res . 2022; 15:28(2):390-403. 8 Gandullo-Sánchez L et al. J Exp Clin Cancer Res . 2022; 41:310. 9 Yu H.A., et al. Annals of Oncology . 2024; 35(5): P437-447. SOURCE: Daiichi Sankyo

Clinical ResultPhase 1ASCOPhase 2Breakthrough Therapy

25 Jun 2024

·pipelinereview.com

EZHARMIA® Approved in Japan as First Dual EZH1 and EZH2 Inhibitor Therapy for Patients with Peripheral T-Cell Lymphoma

TOKYO, Japan I June 24, 2024 I Daiichi Sankyo’s (TSE: 4568) EZHARMIA® (valemetostat tosilate) has been approved in Japan for the treatment of adult patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). EZHARMIA is now the first dual inhibitor of EZH1 and EZH2 to be approved for PTCL after receiving SAKIGAKE designation for this indication. PTCL is a group of rare and often aggressive blood cancers, which represent about 10 to 15% of all non-Hodgkin lymphomas (NHL).1 PTCL is more common in Asia, including in Japan, compared to other parts of the world.2 A majority of patients with PTCL experience disease progression following initial treatment with a multi-drug chemotherapy-based regimen and median overall survival following relapse is approximately 5.8 months.1 The approval of EZHARMIA by the Japan Ministry of Health, Labour and Welfare (MHLW) is based on results of the VALENTINE-PTCL01 phase 2 trial, which were presented at the 2023 American Society of Hematology (ASH) Annual Meeting. In VALENTINE-PTCL01, an objective response rate (ORR) of 43.7% (n=52, 95% CI: 34.6-53.1) was observed for EZHARMIA in 119 efficacy evaluable patients with relapsed or refractory PTCL as assessed by CT-based blinded independent central review (BICR). Seventeen complete responses (CRs) and 35 partial responses (PRs) were observed. Responses were seen across a variety of PTCL subtypes including angioimmunoblastic T-cell lymphoma (AITL), PTCL not otherwise specified (PTCL-NOS) and other PTCL subtypes. “This second indication for EZHARMIA in Japan is an important advance for the treatment of relapsed or refractory peripheral T-cell lymphoma, as new and effective treatment options are needed to improve patient outcomes,” said Toshinori Agatsuma, PhD, Executive Officer, Head of R&D Division in Japan, Daiichi Sankyo. “EZHARMIA exemplifies the innovative research being conducted by Daiichi Sankyo aimed at creating new medicines with potential to change the standard of care for patients with cancer.” The safety profile of EZHARMIA in VALENTINE-PTCL01 was consistent with previous clinical trials. Treatment-related adverse events occurred in 106 of 133 patients (79.7%) with the most common including platelet count decrease (44.4%), anemia (27.1%), dysgeusia (24.8%) and neutrophil count decrease (21.1%). About VALENTINE-PTCL01 Trial VALENTINE-PTCL01 is a global, open-label, single-arm, two-cohort phase 2 study evaluating the efficacy and safety of EZHARMIA in patients with relapsed or refractory PTCL and adult T-cell leukemia/lymphoma (ATLL) who received at least one systemic therapy and were ineligible for hematopoietic stem cell transplant at the time of screening. One cohort enrolled patients with PTCL and a second cohort enrolled patients with ATLL. The primary endpoint of VALENTINE-PTCL01 is ORR assessed by CT-based BICR. Secondary endpoints include duration of response, CR, PR, duration of CR and progression-free survival – all assessed by both BICR and investigator assessment – as well as ORR assessed by investigator, overall survival, safety and pharmacokinetics. Exploratory endpoints include PET-CT-based BICR and biomarker mutational status. Responses were evaluated based on Lugano 2014 response criteria. VALENTINE-PTCL01 enrolled 133 patients at multiple sites in Asia, Europe, North America and Oceania. For more information about this study, visit ClinicalTrials.gov. About Peripheral T-Cell Lymphoma PTCL is a group of rare and often aggressive blood cancers, which represent 10 to 15% of all NHLs.1 Approximately 553,000 new cases of NHL were diagnosed worldwide in 2022.3 There are at least 29 recognized subtypes of PTCL, which occur with significant geographic variation.4 PTCL is more common in Asia, including in Japan, compared to other parts of the world.2 Prognosis of PTCL is generally poor, with a five-year overall survival rate of 32% in AITL and PTCL-NOS, and 7% or lower in certain subtypes.5 A majority of patients with PTCL experience disease progression following initial treatment with a multi-drug chemotherapy-based regimen and median overall survival following relapse is approximately 5.8 months.1 Development of more effective medicines for PTCL continues to be an unmet clinical need, particularly in the relapsed or refractory setting.1 About EZH1 and EZH2 The EZH1 (enhancer of zeste homolog 1) and EZH2 (enhancer of zeste homolog 2) enzymes help regulate the expression of genes involved in maintaining healthy hematopoietic stem cells (immature blood cells).6 Both enzymes are recurrently mutated or overexpressed in hematologic malignancies, including T-cell lymphomas, and research shows they contribute to the silencing of tumor suppressor genes and drive oncogenic growth. 7,8 About EZHARMIA EZHARMIA (valemetostat tosilate) is first-in-class dual inhibitor of EZH1 and EZH2 that was discovered by Daiichi Sankyo. EZHARMIA is approved in Japan for the treatment of patients with relapsed or refractory PTCL and for the treatment of patients with relapsed or refractory ATLL. It is an investigational medicine in all countries outside of Japan. About EZHARMIA Clinical Development Program A global clinical development program is underway for EZHARMIA in hematologic and solid cancers. In addition to VALENTINE-PTCL01, EZHARMIA is being evaluated in the VALYM phase 2 trial in patients with relapsed or refractory B-cell lymphomas, which is being conducted under a strategic research collaboration with the LYSA-LYSARC-CALYM group in Europe, and a phase 1b study in combination with DXd antibody drug conjugates ENHERTU® (trastuzumab deruxtecan) and datopotamab deruxtecan (Dato-DXd) in patients with solid cancers. About Daiichi Sankyo Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical need. For more information, please visit www.daiichisankyo.com . References 1 Bellei et al. haematologica. Vol. 103 No. 7 (2018): July 2018 2 Vose JM et al. J Clin Oncol. 2008;26:4124-4130 3 Global Cancer Observatory. Cancer Fact Sheet. February 2024 4 Liang X et al. Medicine 2021; 2021 Apr 2;100(13): e25194. 5 Vose JM et al. J Clin Oncol. 2008;26:4124-4130 6 Honma D et al. Cancer Sci. 2017 Oct; 108(10): 2069–2078 7 Nakagawa M and Kitabayashi I. Cancer Sci. 2018;109:2342–2348 8 Yamagishi et al. Cell Reports. 2019; 29, 2321–2337

Phase 2Clinical ResultDrug ApprovalASHPhase 1

24 Jun 2024

·www.biospace.com

5 FDA Decisions to Watch in the Second Half of 2024

Pictured: FDA headquarters with money and pill bottles/Taylor Tieden for BioSpace There has been no shortage of landmark approvals from the FDA this year. From the first tumor-infiltrating lymphocytes therapy to the first gene therapy for a rare pediatric disease to the first targeted therapy for MASH, 2024 has already seen its fair share. Along with being the first TIL therapy, Amtagvi is also the first one-time cell therapy for a solid tumor. Meanwhile, Orchard’s Lenmeldy offers a glimmer of hope to children with metachromatic leukodystrophy, a fatal genetic metabolic disease, and Rezdiffra is Madrigal’s first approved product. While the first half of the year belonged to cell and gene therapy, the second half is dominated by FDA decisions for other modalities in cancer and diseases of the brain. Here are five target action dates to watch for in the second half of 2024: Eli Lilly’s Donanemab Indication: Alzheimer’s disease PDUFA: Unknown Eli Lilly is one step closer to the long-anticipated decision on its Alzheimer’s therapy, donanemab, after an advisory committee voted unanimously in favor of the anti-amyloid antibody. In June, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee deemed donanemab to be an effective treatment for Alzheimer’s patients with mild cognitive impairment and mild dementia and said the benefits outweighed the risks. Donanemab has not had the smoothest regulatory path. The FDA refused accelerated approval for the candidate in January 2023, taking issue with a Phase II trial design that allowed patients to end treatment when amyloid plaques had been cleared past a certain pre-defined level. This meant that fewer than 100 patients were on donanemab for 12 continuous months, something the regulator requested in its Complete Response Letter. Lilly submitted for traditional approval of donanemab in the second quarter of 2023. In the Phase III TRAILBLAZER-ALZ 2 study, study participants with low-medium levels of tau saw their cognitive decline decrease by around 35% on two different clinical rating scales compared to placebo. Across all amyloid-positive early symptomatic participants, these numbers were 22% and 29%, respectively. If approved, donanemab will be a direct competitor of Biogen and Eisai’s Leqembi, which received the FDA’s full nod in July 2023. Adaptimmune’s afami-cel Indication: Advanced synovial sarcoma PDUFA: Aug. 4 Riding the momentum in the cell and gene therapy space, Adaptimmune is anticipating approval of its T cell therapy afami-cel on or before August 4. If approved, afami-cel would be the first engineered T cell therapy for solid tumors and “the first effective treatment option for synovial sarcoma in more than a decade,” according to Adaptimmune. Synovial sarcoma, which makes up 5% to 10% of soft tissue sarcomas, typically affects individuals under 30, with a five-year survival rate of 20% for metastatic cases. In the SPEARHEAD-1 trial, nearly 40% of patients experienced clinical responses, with a median response duration of around 12 months. Median overall survival was approximately 17 months, contrasting with historical data of less than 12 months for those who received two or more prior lines of therapy; 70% of responders to afami-cel were alive two years after treatment. If successful, afami-cel would be the first product in Adaptimmune’s sarcoma franchise. Lykos Therapeutics’ MDMA Indication: Post-traumatic stress disorder PDUFA: Aug. 11 One of the most-watched FDA decisions this summer, an approval for Lykos Therapeutics’ MDMA-assisted post-traumatic stress disorder (PTSD) therapy would be paradigm-changing. However, on June 4, an FDA advisory committee—the first held for a potential new PTSD treatment this century—voted overwhelmingly against such an approval. In a 10-1 tally, the FDA’s Psychopharmacologic Drugs Advisory Committee said the candidate’s potential benefits do not outweigh its risk, even with a strict risk evaluation and mitigation strategy. Seven out of nine external advisors voted that Lykos had not provided sufficient proof of MDMA’s efficacy in PTSD. A key issue highlighted in FDA briefing documents was that of “functional unblinding,” where “the vast majority” of trial participants were able to accurately guess their treatment assignment. Lykos is backing its New Drug Application with two pivotal Phase III studies, MAPP1 and MAPP2, in which the MDMA-assisted regimen “demonstrated clinically meaningful improvements in PTSD symptoms,” according to the company’s briefing documents. If ultimately approved, Lykos’s therapy would be the first psychedelic drug for a neuropsychiatric disease in the U.S. Bristol Myers Squibb’s KarXT Indication: Schizophrenia PDUFA: Sept. 26 By September 26, the FDA will render a decision on another highly anticipated neuropsychiatric treatment: Bristol Myers Squibb’s KarXT (xanomeline-trospium). BMS came into possession of KarXT following its December 2023 acquisition of Karuna Therapeutics. If approved, KarXT, an investigational muscarinic antipsychotic treatment, would represent the first new drug class for schizophrenia in “several decades,” according to a Karuna press release announcing acceptance of the NDA. Unlike existing schizophrenia treatments, KarXT does not directly block dopamine receptors. Instead, it works through the dual activation of the M1 and M4 muscarinic acetylcholine receptors in the central nervous system, a mechanism believed to improve positive, negative and cognitive symptoms in patients with schizophrenia. Combined data from three completed registrational and placebo-controlled trials show “statistically significant and clinically meaningful improvements,” Karuna reported in November. In April, BMS revealed interim data from a fourth study showing the drug can elicit significant and sustained symptom improvement in patients with schizophrenia. More than 75% of KarXT-treated patients saw at least a 30% improvement in symptoms at 52 weeks of follow-up, according to data presented at the Annual Congress of the Schizophrenia International Research Society 2024 conference. Daiichi Sankyo and AstraZeneca’s Dato-DXd Indication: Non-small cell lung cancer PDUFA: Dec. 20 Daiichi Sankyo and AstraZeneca are looking to add Dato-DXd (datopotamab deruxtecan) to a limited club—antibody drug conjugates (ADCs) approved to treat non-small cell lung cancer (NSCLC). The partners are specifically seeking approval for Dato-DXd to treat adults with locally advanced or metastatic nonsquamous NSCLC who have previously received systemic therapy. AstraZeneca and Daiichi Sankyo are backing the Biologics License Application with data from the Phase III Tropion-Lung01 study, in which Dato-DXd reduced the risk of disease progression or death by 25% compared to chemotherapy. Median progression-free survival was 4.4 months, and the overall response rate was confirmed in 26.4% of patients. In terms of overall survival, high-level results “numerically favored” DatoDXd in the overall trial population, but were not statistically significant, the companies reported in May. Clinically significant improvement was demonstrated in a prespecified subgroup of patients. “We’re very optimistic about this, and we think that [Dato-DXd] can be an important drug for non-squamous non-small cell lung cancer patients,” Mark Rutstein, SVP and head of global oncology clinical development at Daiichi Sankyo, told BioSpace in May. If approved, Dato-DXd could be the first TROP2-directed ADC for lung cancer. Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.

Phase 3Clinical ResultDrug ApprovalCell TherapyPhase 2

100 Deals associated with Datopotamab Deruxtecan

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Indication	Highest Phase	Country/Location	Organization	Date
Hormone receptor positive HER2 negative breast cancer	NDA/BLA	EU	Daiichi Sankyo Co., Ltd.	04 Mar 2024
Locally Advanced Lung Non-Squamous Non-Small Cell Carcinoma	NDA/BLA	US	Daiichi Sankyo, Inc.	19 Feb 2024
Locally Advanced Lung Non-Squamous Non-Small Cell Carcinoma	NDA/BLA	US	AstraZeneca PLC	19 Feb 2024
Metastatic Non-Squamous Non-Small Cell Lung Carcinoma	NDA/BLA	US	AstraZeneca PLC	19 Feb 2024
Metastatic Non-Squamous Non-Small Cell Lung Carcinoma	NDA/BLA	US	Daiichi Sankyo, Inc.	19 Feb 2024
EGFR positive non-small cell lung cancer	Phase 3	CN	Daiichi Sankyo, Inc.	29 Apr 2024
EGFR positive non-small cell lung cancer	Phase 3	AU	Daiichi Sankyo, Inc.	29 Apr 2024
EGFR positive non-small cell lung cancer	Phase 3	KR	Daiichi Sankyo, Inc.	29 Apr 2024
EGFR positive non-small cell lung cancer	Phase 3	TW	Daiichi Sankyo, Inc.	29 Apr 2024
EGFR-mutated non-small Cell Lung Cancer	Phase 3	CN	AstraZeneca PLC	29 Apr 2024

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04656652 (TROPION-Lung01, Company_Website) Manual	Phase 3	Non-squamous non-small cell lung cancer	-	datopotamab deruxtecan (nonsquamous NSCLC)	fcuzfhzkus(hnhzizcilv) = In the prespecified subgroup of patients with nonsquamous NSCLC, datopotamab deruxtecan showed a clinically meaningful improvement in OS compared to docetaxel, the current standard-of-care chemotherapy. sdslnieutx (klmnqwwnzk )	Positive	27 May 2024
				docetaxel (nonsquamous NSCLC)
NCT05104866 (TROPION-Breast01, ASCO2024)	Phase 3	Hormone receptor positive HER2 negative breast cancer HR+ \| HER2-negative	-	Datopotamab deruxtecan (Dato-DXd)	qfsfwtfomd(poizaofjlc) = cdujmyrzex lxtfundrep (vhgjwzuyfr, 0.85 [0.68 - 1.07]) View more	Positive	24 May 2024
				Chemotherapy (eribulin/vinorelbine/capecitabine/gemcitabine)	qfsfwtfomd(poizaofjlc) = zsfjkpzawx lxtfundrep (vhgjwzuyfr, 0.85 [0.68 - 1.07]) View more
NCT04526691 (TROPION-Lung02, ASCO2024)	Phase 1	Advanced Lung Non-Small Cell Carcinoma First line PD-L1 expression	96	Dato-DXd plus pembrolizumab	nymkxcqvdr(acsyslvkgf) = Gr ≥3 TEAEs were seen in 57% and 76% of pts; serious TEAEs in 38% and 44%. jgpfqdokya (bctptltknr ) View more	Positive	24 May 2024
				Dato-DXd plus pembrolizumab plus platinum chemotherapy
NCT04484142 (TROPION-Lung05, ASCO2024)	Phase 2	-	137	Dato-DXd 6 mg/kg IV Q3W	spjfcxxytx(qibgfzsffz) = wecbgogbwr isngnxfkep (rqyripgoti, 22 - 69) View more	Positive	24 May 2024
NCT03401385 \| NCT05489211 \| NCT04656652 \| NCT05374512 \| NCT05104866 (TROPION-Lung01, -Lung05, -Breast01, -PanTumor01, -PanTumor03, ASCO2024)	Not Applicable	Lung Diseases, Interstitial	927	Dato-DXd 6 mg/kg monotherapy in NSCLC or BC	pzvwlnkxyj(ivivhnnfgd) = Overall adjudicated drug-related ILD incidence was 5% (43 pts; 28 grade [Gr] 1-2, 15 Gr 3-5); this was largely driven by the NSCLC pt subgroup dpsubiaabo (ibochwqdvb ) View more	Negative	24 May 2024
				Dato-DXd monotherapy in other solid tumor types
NCT05460273 (TROPION-PanTumor02, ASCO2024)	Phase 1/2	metastatic non-small cell lung cancer actionable genomic alterations \| sensitizing EGFR mutations	40	Dato-DXd 6 mg/kg IV Q3W	frosahvsdo(uyskpsmlvr) = epdnfejety mxllnqdcpc (nhbifrupai ) View more	Positive	24 May 2024
NCT06244485 (ASCO2024)	Phase 1	Solid tumor SLFN11 \| HER2-positive	70	Valemetostat + T-DXd	xhtbubhsfq(ozoqxqursm) = eidecgxsbs ujegwdzxdu (qfkvebhcjp )	-	24 May 2024
				Valemetostat + Dato-DXd	xhtbubhsfq(ozoqxqursm) = ktggilhfum ujegwdzxdu (qfkvebhcjp )
NCT05866432 (TUXEDO-2, ESMO_BC2024) Manual	Phase 2	Metastatic Triple-Negative Breast Carcinoma First line	5	datopotamab deruxtecan	murxalhfpk(pprakdxrhv) = gookwgnmum lvnqymnsqs (wfgsosojgh )	Positive	15 May 2024
NCT03401385 (TROPION-PanTumor01, Pubmed)	Phase 1	Triple Negative Breast Cancer TROP2	85	Datopotamab Deruxtecan	uuzfqlrsly(dedrkxusuc) = observed in 100% and 41.5% of patients with HR+/HER2- BC and 100% and 52.3% of patients with TNBC acmjkvazzc (ujskcsmmap ) View more	Positive	23 Apr 2024
				Datopotamab Deruxtecan
NCT04484142 (CTgov)	Phase 2	metastatic non-small cell lung cancer	137	Dato DXd	sutnevnlyx(owjzkjsdix) = bhvhnmaepn bqswparoxf (vzikcsqcox, vqkalaqscu - cwfupflvsp) View more	-	03 Apr 2024

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