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]

NCT06508216 / RecruitingPhase 1/2IIT

A Phase Ib/II, Open-label, Modular, Dose-finding and Dose-expansion Study to Explore Safety, Tolerability, Pharmacokinetics, and Anti-tumor Activity of Novel Therapeutics in Patients With Early Relapsed Metastatic Triple-negative Breast Cancer

Choice Of the Most Active Strategies for Short term recurring Triple Negative Breast Cancer:
A phase Ib/II, open-label, modular, dose-finding and dose-expansion study to explore safety, tolerability, pharmacokinetics, and anti-tumor activity of novel therapeutics in patients with early relapsed metastatic triple-negative breast cancer

Start Date05 Jul 2024

Sponsor / Collaborator

Gustave Roussy, Cancer Campus, Grand Paris

[+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]

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: Kaplon, Hélène ; Crescioli, Silvia ; 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.

178

News (Medical) associated with Datopotamab Deruxtecan

05 Jul 2024

·pipelinereview.com

Tagrisso with the addition of chemotherapy approved in the EU as new 1st-line treatment for patients with EGFR-mutated advanced lung cancer

Approval based on FLAURA2 results which showed Tagrisso plus chemotherapy extended median progression-free survival by nearly 9 months vs. standard of care LONDON, UK I July 05, 2024 I AstraZeneca’s Tagrisso (osimertinib) with the addition of pemetrexed and platinum-based chemotherapy has been approved in the European Union (EU) for the 1st-line treatment of adult patients with advanced epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) whose tumours have exon 19 deletions or exon 21 (L858R) mutations. The approval by the European Commission follows the positive opinion of the Committee for Medicinal Products for Human Use and is based on results from the FLAURA2 Phase III trial published in The New England Journal of Medicine . In the trial, Tagrisso with the addition of chemotherapy reduced the risk of disease progression or death by 38% by investigator assessment compared to Tagrisso monotherapy, which is the 1st-line global standard of care (hazard ratio [HR] 0.62; 95% confidence interval [CI] 0.49-0.79; p<0.0001). Median progression-free survival (PFS) was 25.5 months for patients treated with Tagrisso plus chemotherapy, an 8.8-month improvement versus Tagrisso monotherapy (16.7 months). PFS results from blinded independent central review (BICR) were consistent with the results by investigator assessment, showing 29.4 months median PFS with Tagrisso plus chemotherapy, a 9.5-month improvement over Tagrisso monotherapy (19.9 months) (HR 0.62; 95% CI 0.48-0.80; nominal p=0.0002). Results from a prespecified exploratory analysis of patients in the FLAURA2 trial with brain metastases at baseline showed Tagrisso plus chemotherapy reduced the risk of central nervous system (CNS) disease progression or death by 42% compared to Tagrisso monotherapy (HR 0.58; 95% CI 0.33-1.01) as assessed by BICR. With two years of follow up, 74% of patients treated with Tagrisso plus chemotherapy had not experienced CNS disease progression or death versus 54% of patients treated with Tagrisso monotherapy. While the overall survival (OS) results remained immature at the second interim analysis (41% maturity), a trend towards an OS benefit was observed with Tagrisso plus chemotherapy versus Tagrisso alone (HR 0.75; 95% CI 0.57-0.97), as presented at the 2024 European Lung Cancer Congress. The trial continues to assess OS as a key secondary endpoint. David Planchard, MD, PhD, Thoracic Oncologist at Gustave Roussy Institute of Oncology and principal investigator for the trial, said: “Today’s news marks a significant advance for patients with EGFR-mutated lung cancer in Europe, providing a new 1st-line treatment option with osimertinib now in combination with chemotherapy. The FLAURA2 results build on the established efficacy of osimertinib monotherapy, showing a meaningful nine-month improvement in progression-free survival and offering physicians the option to tailor treatment to a patient’s specific needs.” Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: “This approval reinforces Tagrisso as the backbone therapy in EGFR-mutated lung cancer either as monotherapy or in combination with chemotherapy. This is especially important for those with more aggressive disease, including patients whose cancer has spread to the brain and those with L858R mutations.” The safety profile of Tagrisso plus chemotherapy was consistent with the established profiles of the individual medicines. Adverse event (AE) rates were higher in the Tagrisso plus chemotherapy arm, driven by well-characterised chemotherapy-related AEs. Discontinuation rates of Tagrisso due to AEs were 11% for Tagrisso plus chemotherapy and 6% for monotherapy. Tagrisso is approved as monotherapy in more than 110 countries including in the US, EU, China and Japan. Approved indications include for 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC, locally advanced or metastatic EGFR T790M mutation-positive NSCLC, and adjuvant treatment of early-stage EGFRm NSCLC. Tagrisso with the addition of chemotherapy is also approved in the US, China, Japan and several other countries for the 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC. Tagrisso is also currently under review with global regulatory authorities for patients with unresectable, Stage III EGFRm NSCLC based on the LAURA Phase III trial. Notes Lung cancer Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths. 5 Lung cancer is broadly split into NSCLC and small cell lung cancer. 3 Each year there are an estimated 2.4 million people diagnosed with lung cancer globally, with 80-85% of patients diagnosed with NSCLC, the most common form of lung cancer. 3,5-6 In Europe, more than 450,000 people are diagnosed with lung cancer each year. 1 Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC. 7-9 Additionally, the majority of patients with NSCLC are diagnosed with advanced disease. 4 Patients with EGFRm NSCLC are particularly sensitive to treatment with an EGFR-tyrosine kinase inhibitor (EGFR-TKI) which blocks the cell-signalling pathways that drive the growth of tumour cells. 10 FLAURA2 FLAURA2 is a randomised, open-label, multi-centre, global Phase III trial in the 1st-line treatment of patients with locally advanced (Stage IIIB-IIIC) or metastatic (Stage IV) EGFRm NSCLC. Patients were treated with Tagrisso 80mg once-daily oral tablets with the addition of chemotherapy (pemetrexed (500mg/m2) plus cisplatin (75mg/m2) or carboplatin (AUC5)) every three weeks for four cycles, followed by Tagrisso with pemetrexed maintenance every three weeks. The trial enrolled 557 patients in more than 150 centres across more than 20 countries, including in the US, Europe, South America and Asia. The primary endpoint is PFS. The trial is ongoing and will continue to assess the secondary endpoint of OS. Tagrisso Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI with proven clinical activity in NSCLC, including against CNS metastases. Tagrisso (40mg and 80mg once-daily oral tablets) has been used to treat nearly 800,000 patients across its indications worldwide and AstraZeneca continues to explore Tagrisso as a treatment for patients across multiple stages of EGFRm NSCLC. There is an extensive body of evidence supporting the use of Tagrisso in EGFRm NSCLC. Tagrisso is the only targeted therapy to improve patient outcomes in early-stage disease in the ADAURA Phase III trial , locally advanced stages in the LAURA Phase III trial and late-stage disease in the FLAURA Phase III trial and FLAURA2 Phase III trial . As part of AstraZeneca’s ongoing commitment to treating patients as early as possible in lung cancer, Tagrisso is also being investigated in the neoadjuvant setting in the NeoADAURA Phase III trial with results expected later this year and in the early-stage adjuvant resectable setting in the ADAURA2 Phase III trial. The Company is also researching ways to address tumour mechanisms of resistance through the SAVANNAH and ORCHARD Phase II trials, and the SAFFRON Phase III trial, which test Tagrisso plus savolitinib, an oral, potent and highly selective MET TKI, as well as other potential new medicines. AstraZeneca in lung cancer AstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in the resistant and advanced settings. By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most. The Company’s comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations, including Tagrisso and Iressa (gefitinib); Imfinzi (durvalumab) and Imjudo (tremelimumab); Enhertu (trastuzumab deruxtecan) and datopotamab deruxtecan in collaboration with Daiichi Sankyo; Orpathys (savolitinib) in collaboration with HUTCHMED; as well as a pipeline of potential new medicines and combinations across diverse mechanisms of action. AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer, including and beyond treatment. AstraZeneca in oncology AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients. The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience. AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death. AstraZeneca AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca’s innovative medicines are sold in more than 125 countries and used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on social media @AstraZeneca . Contacts For details on how to contact the Investor Relations Team, please click here . For Media contacts, click here . References SOURCE: AstraZeneca

Phase 3Clinical ResultDrug ApprovalPhase 2

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

100 Deals associated with Datopotamab Deruxtecan

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KEGG	Wiki	ATC	Drug Bank
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R&D Status

10 top R&D records.

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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	Daiichi Sankyo Co., Ltd.	29 Apr 2024

Clinical Result

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Evaluation

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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)	llsniiaobh(eiubbltwto) = 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. xdlxqxyhsk (cyboinihhw )	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)	srbxmlouyl(jsrnvdsmpt) = lhnzgvoiwl oxveixzxlx (vhfljrseym, 0.85 [0.68 - 1.07]) View more	Positive	24 May 2024
				Chemotherapy (eribulin/vinorelbine/capecitabine/gemcitabine)	srbxmlouyl(jsrnvdsmpt) = jttssaiuli oxveixzxlx (vhfljrseym, 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	sqifivatkr(csyuakkyap) = Gr ≥3 TEAEs were seen in 57% and 76% of pts; serious TEAEs in 38% and 44%. ucmmiksghp (mxgffsgojw ) 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	xdscxctcka(cqzphcnkuq) = awebdvxpef qjkvgznbir (cubpajslzj, 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	piywwriqcc(fxpcusdxoq) = 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 wtaxebpbqp (pmwbubbxhp ) 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	qsiqxszhkv(slqllllvzj) = kespzssrpv lbiqccgdon (xuxnonsbno ) View more	Positive	24 May 2024
NCT05866432 (TUXEDO-2, ESMO_BC2024) Manual	Phase 2	Metastatic Triple-Negative Breast Carcinoma First line	5	datopotamab deruxtecan	uycovuaomb(yvgcqouyre) = bcxxjzvjhc trsxrkuqzt (ynradutbor )	Positive	15 May 2024
NCT03401385 (TROPION-PanTumor01, Pubmed)	Phase 1	Triple Negative Breast Cancer TROP2	85	Datopotamab Deruxtecan	bccogxlgmn(gmbfeknyue) = observed in 100% and 41.5% of patients with HR+/HER2- BC and 100% and 52.3% of patients with TNBC gxwrckarbh (jtdwemhssg ) View more	Positive	23 Apr 2024
				Datopotamab Deruxtecan
NCT04484142 (TROPION-Lung05, CTgov)	Phase 2	metastatic non-small cell lung cancer	137	Dato DXd	aaevvadhhn(uwabvlcxxm) = jjrkbgavrq drihtitkgl (pksvitocav, pnsgufrbvq - bdkhamhqqb) View more	-	03 Apr 2024
NCT03401385 (TROPION-PanTumor01, ASCO_GU2024) Manual	Phase 1	Transitional Cell Carcinoma	18	Datopotamab deruxtecan	ebaaaotzxp(zkkdfpmhom) = epanmlogch qzcyrnqcbm (zeyozhgtml ) View more	Positive	25 Jan 2024

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