Ifinatamab deruxtecan

At the forefront of cancer treatment, scientists are continually exploring new targets and therapeutic strategies to address this global health challenge. B7-H3 (CD276), a type I transmembrane glycoprotein, has garnered significant attention due to its overexpression in a wide range of human cancers. Initially believed to function as a T-cell costimulatory molecule, B7-H3 has since been found to possess complex immunomodulatory properties, capable of both promoting and suppressing immune responses. As research has progressed, B7-H3 has been shown to play important roles not only in immune regulation but also in non-immune biological processes such as bone development and tumor progression. This multifunctionality positions B7-H3 as a highly promising novel target in oncology, spurring the development of innovative therapeutic approaches including antibody-drug conjugates (ADCs), CAR-T cell therapies, and bispecific antibodies. B7-H3-Targeting Drug Candidates in Clinical Development as of 2024B7-H3 (CD276), as a member of the B7 superfamily, plays a multifaceted role in both immune regulation and tumor biology. It was originally identified as a T-cell costimulatory molecule due to its ability to promote the proliferation of CD4+ and CD8+ T cells and enhance the secretion of interferon-gamma (IFN-γ). This finding highlighted the molecule’s potential to amplify T-cell-mediated immune responses, contributing to the clearance of pathogens or tumor cells. Researchers observed that when B7-H3 interacts with receptors on the surface of T cells, it can significantly boost their activity, thereby enhancing the body's defense against infection and cancer. Structures, distributions, interactions and biological functions of B7-H3 and putative receptors1The Coinhibitory Role of B7-H3 and Its Effects on the Immune SystemWhile early studies focused on B7-H3’s costimulatory properties, subsequent research revealed its coinhibitory functions, particularly in dampening the activity of T cells and natural killer (NK) cells. Specifically, B7-H3 suppresses T-cell function by reducing the secretion of immune-stimulating cytokines such as interferons and tumor necrosis factor-alpha (TNF-α). It also inhibits NK cell activity, indicating that B7-H3 influences both adaptive and innate immunity. This dual role makes B7-H3 a complex immune regulator, with context-dependent biological effects that vary based on environmental and pathological conditions. Non-Immune Functions: Bone Development and Tumor ProgressionBeyond its role in the immune system, B7-H3 is also involved in non-immune processes such as regulating bone development. In tumor biology, B7-H3 has been implicated in several critical mechanisms including tumor cell proliferation, migration, angiogenesis, and epigenetic modifications. These findings suggest that B7-H3 is not merely an immune checkpoint molecule but also a key player in maintaining physiological balance and driving disease progression. Notably, high levels of B7-H3 expression in malignant tumors are often associated with increased invasiveness and metastatic potential, underscoring its clinical relevance in oncology. Current immune checkpoint receptors and their respective ligands1B7-H3 as a Novel Target in Cancer ImmunotherapyGiven its widespread overexpression in various cancers and its role in facilitating immune evasion, B7-H3 has emerged as a promising target for cancer immunotherapy. Multiple therapeutic strategies are currently under development to target B7-H3, including antibody-drug conjugates (ADCs), CAR-T cell therapies, and bispecific antibodies. These approaches aim to block the immunosuppressive functions of B7-H3 and restore or enhance the immune system's ability to effectively attack tumor cells, offering new hope and treatment options for cancer patients. Interactions of B7-H3 with immune cells1I. Antibody-Drug Conjugates (ADCs) Targeting B7-H3Ifinatamab Deruxtecan (DS-7300, DS-7300a), BGB-C354, and SKB-500 are all antibody-drug conjugates (ADCs) targeting the B7-H3 (CD276) antigen, but they differ in terms of development progress, mechanism of action, and technical characteristics. 1) Ifinatamab Deruxtecan Ifinatamab Deruxtecan (DS-7300, DS-7300a) is an antibody-drug conjugate (ADC) designed to leverage the high specificity of monoclonal antibodies to target antigens expressed on the surface of tumor cells. By selectively binding to B7-H3, Ifinatamab Deruxtecan delivers a cytotoxic payload directly to cancer cells, thereby minimizing damage to healthy tissues. Structure of Ifinatamab DeruxtecanThis ADC consists of a humanized anti-B7-H3 IgG1 monoclonal antibody linked to the topoisomerase I inhibitor DXd. Upon binding to B7-H3 on the cancer cell surface, the entire complex is internalized. Inside the cell, the linker is enzymatically cleaved, releasing DXd. As a potent cytotoxic agent, DXd disrupts DNA structure within cancer cells, inducing apoptosis. This approach enhances treatment precision and helps overcome drug resistance. As of the latest data, Ifinatamab Deruxtecan has entered global Phase III clinical trials—a significant milestone in its development. In the earlier Phase II IDeate-Lung01 study, it demonstrated promising results, particularly in patients with extensive-stage small cell lung cancer (ES-SCLC), achieving an objective response rate (ORR) of 54.8%. The drug has also shown potential in other cancer types. Given the widespread overexpression of B7-H3 across various malignancies, Ifinatamab Deruxtecan may benefit a broad range of cancers beyond a single type, including diseases of the digestive and respiratory systems. Further research may expand its indications, positioning it as a key weapon against refractory tumors. While Ifinatamab Deruxtecan has shown significant efficacy, it is also associated with some risks. Common adverse events include nausea, anemia, and fatigue. To ensure optimal safety and efficacy, researchers are closely monitoring side effects and exploring optimized dosing strategies to reduce patient burden. 2) BGB-C354 BGB-C354 operates through a similar mechanism, using a monoclonal antibody specific for B7-H3 conjugated with a topoisomerase I inhibitor (TOP1). When the ADC binds to B7-H3-expressing tumor cells, the complex is internalized, and the linker is cleaved to release the cytotoxic payload, which damages the DNA of the cancer cell, leading to its death. This enhances treatment specificity while reducing harm to surrounding healthy tissue. Structure of B7-H3 Protein2BGB-C354 is currently undergoing Phase I clinical trials to assess its safety, tolerability, pharmacokinetics, and preliminary antitumor activity. This phase is critical for establishing the optimal dose range and supporting future Phase II and III studies. Notably, BGB-C354 has shown potential applications in patients with advanced solid tumors, including lung and gastric cancers. Compared to Daiichi Sankyo’s DS-7300, BGB-C354 has a higher drug-to-antibody ratio (DAR) of 8, versus 4 for DS-7300. A higher DAR means each antibody molecule carries more cytotoxic payload, which could enhance tumor-killing efficacy. However, this also requires careful design to balance potency with tolerability and avoid unacceptable toxicity. 3) SKB-500 SKB-500 is designed to deliver a cytotoxic drug directly into cancer cells, minimizing harm to healthy tissues. It uses a high-affinity humanized monoclonal antibody to recognize and bind B7-H3 on tumor cells. The other end of the antibody is linked to a potent cytotoxic agent. Upon successful binding, the entire complex is internalized, and the cytotoxic payload is released inside the cell to destroy key structures such as DNA or microtubules, leading to cancer cell death. This strategy improves treatment precision and helps combat drug resistance. SKB-500 is currently in Phase I/II clinical trials to evaluate its safety, tolerability, and preliminary efficacy. These early studies are essential for determining optimal dosing and laying the foundation for broader clinical development. Researchers are also exploring its use across a range of advanced solid tumors, including but not limited to lung cancer and gastric cancer. Because B7-H3 is widely expressed in many human cancers, SKB-500 has broad therapeutic potential. In addition to lung and gastric cancers, it may also prove effective in treating other advanced solid tumors such as breast and prostate cancers. As more clinical data emerges, SKB-500 may offer a new treatment option for patients who do not respond well to conventional therapies. II. CAR T Therapies Targeting B7-H31) B7H3 IL-7Ra CAR T Cell Therapy B7H3 IL-7Ra CAR T cell therapy is an innovative autologous CAR T cell approach specifically designed to target B7-H3 (CD276). By reprogramming a patient’s T cells into "smart bombs" that specifically attack B7-H3–positive cancer cells, this therapy offers a more precise and effective treatment option. The core mechanism involves genetically engineering T cells to express a chimeric antigen receptor (CAR) on their surface that can recognize and bind to B7-H3 on tumor cells. To enhance the persistence and anti-tumor activity of these engineered T cells, an IL-7Ra signaling domain is incorporated into the CAR construct. This modification helps counteract immunosuppressive effects within the tumor microenvironment and promotes prolonged in vivo survival and function of the T cells. As a result, B7H3 IL-7Ra CAR T cells not only kill tumor cells directly but also help recruit other immune cells to support the anti-cancer response. A diagram of the interaction of B7-H3 with immune cells2This therapy is currently in Phase I clinical trials, marking its transition from preclinical research to human testing. The primary goals of this phase are to evaluate safety, tolerability, and to gather preliminary efficacy data. While early results have not yet been published, the therapy has shown potential in small patient populations, especially in cases of relapsed solid tumors and diffuse intrinsic pontine glioma (DIPG), which typically respond poorly to conventional therapies. DIPG is located deep within the brain and is difficult to surgically remove, making standard radiation and chemotherapy largely ineffective. B7H3 IL-7Ra CAR T therapy may offer new hope for such patients. Given the widespread expression of B7-H3 across multiple cancer types, this technology could potentially be expanded to treat a broader range of malignancies. Despite its promise, CAR T therapy carries inherent risks and challenges. Common adverse events include cytokine release syndrome (CRS) and neurotoxicity. Therefore, close patient monitoring and prompt adjustments to the treatment plan are critical during early-phase trials. Researchers are also working to optimize CAR constructs and manufacturing processes to further enhance safety and efficacy. 2) GD2/B7H3 CAR T Cell Therapy GD2/B7H3 CAR T cell therapy is a novel immunotherapy that targets two antigens—disialoganglioside (GD2) and B7-H3 (CD276)—to enhance tumor cell recognition and killing. Both antigens are highly expressed in various cancers, particularly in pediatric neuroblastoma. This dual-targeting strategy improves the specificity of CAR T therapy and may help overcome resistance and relapse often seen with single-antigen targeting. A schematic of CAR T targeting tumors3In this design, CAR T cells are engineered to recognize and bind both GD2 and B7H3, enabling more effective detection and destruction of cancer cells. Notably, researchers have implemented a SynNotch system, which acts as a logic gate: CAR T cells are first primed by GD2 recognition, and only upon encountering sufficient B7-H3 in the tumor microenvironment is their CAR function activated. This gatekeeping mechanism enhances treatment precision, reduces potential off-target effects, and improves T cell persistence and activity in vivo. According to recent data, GD2/B7H3 CAR T therapy has demonstrated significant efficacy in preclinical models. For example, in a mouse model of metastatic neuroblastoma, this dual-target CAR T cell therapy not only effectively controlled tumor growth but also showed favorable metabolic adaptation and reduced T cell exhaustion. These findings lay a solid foundation for future clinical trials and support continued development. Although initially focused on neuroblastoma, GD2/B7H3 CAR T therapy may be applicable to a wide range of solid tumors due to the broad expression of both GD2 and B7-H3. This approach may be especially beneficial for patients who have not responded well to traditional therapies or who have developed drug resistance. As more clinical data become available, the therapy could be expanded to include adult patients and a wider range of cancers. 3) TX-103 TX-103 is another autologous CAR T cell therapy. It involves engineering a patient’s T cells to express a chimeric antigen receptor that specifically recognizes the B7-H3 molecule. Once re-infused into the patient, these engineered T cells can precisely locate and attack B7-H3–expressing tumor cells. This approach enhances treatment specificity and may reduce damage to healthy tissue, thereby minimizing side effects. Because B7-H3 is expressed in many cancer types, TX-103 has a wide range of potential applications—from brain tumors to other advanced solid tumors. TX-103 is currently undergoing Phase I clinical trials, primarily to assess its safety and feasibility in patients with relapsed malignant gliomas and other B7-H3–positive solid tumors. In addition to monitoring the incidence and severity of adverse events, researchers aim to determine the maximum tolerated dose and establish appropriate dosing regimens for subsequent Phase II studies. Secondary endpoints include evaluating treatment response rates, monitoring cytokine level fluctuations, and analyzing changes in immune cell phenotypes. These data are essential for understanding TX-103's mechanism of action and long-term efficacy. III. Bispecific T Cell Engagers Targeting B7-H3CC-3 is a bispecific antibody (bsAb) developed by the German Cancer Consortium (DKTK), engineered with dual specificity for CD276 (B7-H3) and CD3. It is being developed to treat patients with metastatic colorectal cancer (CRC) who have failed at least three prior lines of therapy. What sets CC-3 apart is its dual-targeting mechanism—simultaneously binding to CD276 on tumor cells and tumor-associated vasculature—enabling a two-pronged attack on both cancer cells and their blood supply. By engaging CD3, CC-3 directs T cells to target and destroy CD276-expressing tumor cells and enhances immune cell infiltration into the tumor microenvironment. Targeting B7-H3 include chimeric antigen receptor (CAR) T-cells, anti-B7-H3 bispecific antibodies4CC-3 exerts its antitumor effect through a bispecific antibody design. One arm binds specifically to CD3 on T cells, activating them even in the absence of conventional T cell receptor (TCR)-mediated antigen recognition. Once activated, T cells release cytotoxic molecules such as perforin and granzyme to kill target cells. The other arm of CC-3 binds to CD276 on the surface of tumor cells, guiding T cells to CD276-positive cells and mediating their destruction. In addition to direct tumor cell targeting, CC-3 interacts with tumor vasculature in CRC, helping to disrupt the tumor’s blood supply and "starve" it, while also facilitating immune cell access to the tumor. CC-3 was specifically engineered to minimize off-target effects by promoting T cell activation primarily within the tumor microenvironment rather than systemically, thereby reducing the risk of adverse effects. To enhance in vivo stability, CC-3 incorporates YTE modifications—engineered mutations that extend the antibody’s half-life in human serum. This prolongs drug activity, simplifies dosing regimens, and improves patient convenience and compliance. The first-in-human clinical trial for CC-3 includes two phases: an initial dose-escalation phase to determine the maximum tolerated dose (MTD), followed by a dose-expansion phase aimed at identifying the recommended Phase II dose. These studies will also evaluate CC-3’s pharmacokinetics, including its half-life and immunogenicity, and assess immune responses induced by the therapy. Given the differences between animal models and humans—particularly in pharmacokinetics and immunogenicity—conducting these evaluations in humans is critical. As a novel treatment strategy, CC-3 holds promise for patients with metastatic CRC who are unresponsive to or have relapsed after standard therapies. More importantly, since CD276 is expressed on both tumor cells and vasculature, the application of CC-3 could extend beyond CRC to other types of solid tumors. Thus, CC-3 not only offers a potential breakthrough for treatment-resistant cancers but also opens new avenues for broadening B7-H3–targeted therapies. ConclusionIn summary, B7-H3 has emerged as a compelling target in cancer therapy due to its high expression across various malignancies. Initially identified as a co-stimulatory molecule, B7-H3 was later found to have co-inhibitory functions and roles in non-immune biological processes, underscoring its complex, multifaceted nature. Innovative therapies targeting B7-H3—including antibody-drug conjugates (ADCs) like Ifinatamab Deruxtecan, BGB-C354, and SKB-500, as well as CAR T cell therapies like B7H3 IL-7Ra CAR T and GD2/B7H3 CAR T cells—have shown promising anticancer potential. These therapies precisely target tumor cells and enhance immune responses, offering new hope for patients with treatment-resistant cancers. Despite ongoing challenges such as managing side effects and optimizing efficacy, advances in research and technology continue to position B7-H3 as a key component of future precision medicine, heralding a new era in cancer treatment. Meanwhile, bispecific antibodies like CC-3 further expand the therapeutic landscape, signaling a shift toward more precise and effective immunotherapies in oncology. How to obtain the latest development progress of all targets? In the Synapse database, you can stay updated on the latest research and development advances of all targets. This service is accessible anytime and anywhere, with updates available daily or weekly. Use the "Set Alert" function to stay informed. Click on the image below to embark on a brand new journey of drug discovery! Refrence  1.Zhao B, Li H, Xia Y, Wang Y, Wang Y, Shi Y, Xing H, Qu T, Wang Y, Ma W. Immune checkpoint of B7-H3 in cancer: from immunology to clinical immunotherapy. J Hematol Oncol. 2022 Oct 25;15(1):153. doi: 10.1186/s13045-022-01364-7. PMID: 36284349; PMCID: PMC9597993.2.Getu AA, Tigabu A, Zhou M, Lu J, Fodstad Ø, Tan M. New frontiers in immune checkpoint B7-H3 (CD276) research and drug development. Mol Cancer. 2023 Mar 2;22(1):43. doi: 10.1186/s12943-023-01751-9. PMID: 36859240; PMCID: PMC9979440.3.Lin YJ, Mashouf LA, Lim M. CAR T Cell Therapy in Primary Brain Tumors: Current Investigations and the Future. Front Immunol. 2022 Feb 21;13:817296. doi: 10.3389/fimmu.2022.817296. PMID: 35265074; PMCID: PMC8899093.4.Koumprentziotis IA, Theocharopoulos C, Foteinou D, Angeli E, Anastasopoulou A, Gogas H, Ziogas DC. New Emerging Targets in Cancer Immunotherapy: The Role of B7-H3. Vaccines (Basel). 2024 Jan 5;12(1):54. doi: 10.3390/vaccines12010054. PMID: 38250867; PMCID: PMC10820813.

TOKYO, Japan & BASKING RIDGE, NJ, USA I June 09, 2025 I The first patient has been dosed in the DESTINY-Endometrial01 phase 3 trial evaluating ENHERTU ® (trastuzumab deruxtecan) in combination with rilvegostomig or pembrolizumab versus platinum-based chemotherapy (carboplatin and paclitaxel) in combination with pembrolizumab as a first-line therapy in patients with HER2 expressing (IHC 3+/ 2+), mismatch repair proficient (pMMR) primary advanced or recurrent endometrial cancer. DESTINY-Endometrial01 will be conducted in collaboration with The GOG Foundation, Inc. (GOG-F) and the European Network of Gynecological Oncological Trial (ENGOT). ENHERTU is a specifically engineered HER2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca (LSE/STO/Nasdaq: AZN). Endometrial cancer that is recurrent or diagnosed in advanced stages has a median overall survival of up to 30 months. 1 While there have been recent treatment advances, there is still a need to further improve outcomes for patients. HER2 expression (IHC 3+/2+) is associated with aggressive disease and is present in 18% to 56% of endometrial cancers. 2,3,4,5,6 There currently are no HER2 directed medicines approved in the first-line endometrial cancer setting. “Following the positive results in the endometrial cancer cohort of DESTINY-PanTumor02, which contributed to a tumor agnostic approval for previously treated patients with HER2 positive metastatic tumors in several regions, we are initiating this first phase 3 trial of ENHERTU in the first-line setting of advanced endometrial cancer,” said Mark Rutstein, MD, Head, Therapeutic Area Oncology Development, Daiichi Sankyo. “The DESTINY-Endometrial01 trial will help us better understand the role of ENHERTU in combination with immunotherapy as a potential treatment strategy to help improve outcomes compared to the current standard of care in this specific gynecological cancer setting.” About DESTINY-Endometrial01 DESTINY-Endometrial01 is a global, multicenter, randomized, open-label phase 3 trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) in combination with rilvegostomig or pembrolizumab versus platinum-based chemotherapy (carboplatin and paclitaxel) in combination with pembrolizumab as a first-line therapy in patients with HER2 expressing (IHC 3+/2+), pMMR, primary advanced (stage III/IV) or first recurrent endometrial cancer of any histologic subtype except sarcoma. Patients will be randomized in a 1:1:1 ratio to receive either ENHERTU in combination with rilvegostomig, ENHERTU in combination with pembrolizumab or platinum-based chemotherapy in combination with pembrolizumab. The primary endpoint is progression-free survival (PFS) as assessed by blinded independent central review (BICR). The key secondary endpoint is overall survival. Additional secondary endpoints include PFS as assessed by investigator, objective response rate, duration of response and safety. DESTINY-Endometrial01 will enroll approximately 600 patients across multiple sites in Asia, Europe, North America, Oceania and South America. For more information about the trial, visit ClinicalTrials.gov . Rilvegostomig is AstraZeneca’s PD-1/TIGIT bispecific antibody. The TIGIT component of rilvegostomig is derived from the clinical-stage anti-TIGIT antibody, COM902, developed by Compugen Ltd. (Nasdaq/TASE: CGEN). Pembrolizumab (KEYTRUDA ® ) is Merck’s (known as MSD outside of the US and Canada) anti-PD-1 therapy. About Endometrial Cancer Endometrial cancer is the second most common gynecologic cancer and the sixth most common cancer among women worldwide. 7 Approximately 420,000 endometrial cancer cases were diagnosed in 2022, with more than 97,000 deaths globally. 8 Incidence and mortality rates of endometrial cancer are expected to increase by approximately 61% and 87% respectively by 2050. 9 Patients with advanced or recurrent endometrial cancer have a poor prognosis, with a median overall survival of up to 30 months. 1 Endometrial cancer comprises several molecular subtypes. 10 Approximately 20% to 30% of all endometrial cancers exhibit high microsatellite instability (MSI) due to a defective mismatch repair system and are classified as MSI-high or MMR deficient (dMMR). 10 The remaining 70% to 80% of cases are considered mismatch repair proficient (pMMR) tumors. 10 HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors. 11 HER2 expression (IHC 3+/ 2+) is present in 18% to 56% of endometrial cancers and is associated with markers of aggressive disease. 2,3,4,5,6 HER2 expression is observed almost exclusively in pMMR tumors. 2 Standard of care first-line treatment of advanced or recurrent endometrial cancer has long included carboplatin plus paclitaxel. 12 The treatment paradigm has recently evolved to incorporate an immune checkpoint inhibitor with carboplatin and paclitaxel, particularly for patients with dMMR endometrial cancer; however, the benefit of this treatment regimen in pMMR endometrial cancer is less pronounced. 13,14,15,16 There currently are no HER2 directed medicines approved in the first-line endometrial cancer setting. About ENHERTU ENHERTU (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the U.S. only) is a HER2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, ENHERTU is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca’s ADC scientific platform. ENHERTU consists of a HER2 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. ENHERTU (5.4 mg/kg) is approved in more than 80 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2 positive (immunohistochemistry [IHC] 3+ or in-situ hybridization (ISH)+) breast cancer who have received a prior anti-HER2-based regimen, either in the metastatic setting or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within six months of completing therapy based on the results from the DESTINY-Breast03 trial. ENHERTU (5.4 mg/kg) is approved in more than 80 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2 low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial. ENHERTU (5.4 mg/kg) is approved in more than 30 countries for the treatment of adult patients with unresectable or metastatic hormone receptor (HR) positive, HER2 low (IHC 1+ or IHC 2+/ISH-) or HER2 ultralow (IHC 0 with membrane staining) breast cancer, as determined by a locally or regionally approved test, that has progressed on one or more endocrine therapies in the metastatic setting based on the results from the DESTINY-Breast06 trial. ENHERTU (5.4 mg/kg) is approved in more than 60 countries worldwide for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 ( ERBB2 ) mutations, as detected by a locally or regionally approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 and/or DESTINY-Lung05 trials. Continued approval in China and the U.S. for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. ENHERTU (6.4 mg/kg) is approved in more than 70 countries worldwide for the treatment of adult patients with locally advanced or metastatic HER2 positive (IHC 3+ or IHC 2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 , DESTINY-Gastric02 and/or DESTINY-Gastric06 trials. Continued approval in China for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. ENHERTU (5.4 mg/kg) is approved in Brazil, Israel, Russia, Saudi Arabia, Switzerland, Taiwan, U.K. and the U.S. for the treatment of adult patients with unresectable or metastatic HER2 positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options based on efficacy results from the DESTINY-PanTumor02 , DESTINY-Lung01 and DESTINY-CRC02 trials. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. About the ENHERTU Clinical Development Program A comprehensive global clinical development program is underway evaluating the efficacy and safety of ENHERTU as a monotherapy or in combination or sequentially with other anti-cancer therapies across multiple HER2 targetable cancers. About the Daiichi Sankyo and AstraZeneca Collaboration Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU in March 2019 and DATROWAY ® in July 2020 , except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of ENHERTU and DATROWAY. About the ADC Portfolio of Daiichi Sankyo The Daiichi Sankyo ADC portfolio consists of seven ADCs in clinical development crafted from two distinct ADC technology platforms discovered in-house by Daiichi Sankyo. The ADC platform furthest in clinical development is Daiichi Sankyo’s DXd ADC Technology where 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. The DXd ADC portfolio currently consists of ENHERTU, a HER2 directed ADC, and DATROWAY, a TROP2 directed ADC, which 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 & Co., Inc, Rahway, NJ, USA. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo. The second Daiichi Sankyo ADC platform consists of a monoclonal antibody attached to a modified pyrrolobenzodiazepine (PBD) payload. DS-9606, a CLDN6 directed PBD ADC, is the first of several planned ADCs in clinical development utilizing this platform. Ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, DS-3939 and DS-9606 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established. Please see accompanying full Prescribing Information , including Boxed WARNINGS, and Medication Guide . 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 Coleman RL, et al. JHEOR .2023;10(2):82-90. 2 Vermij L, et al. Cancers (Basel) . 2020;13(1):44. 3 Buza N. Arch Pathol Lab Med . 2021;145(6):687–691. 4 Uzunparmaek B, et al. Ann Oncol . 2023;34(11):1035-1046. 5 Semiz SH, et al. Turkish Journal of Pathology .2023;39(1):055-063 6 Halle MK, et al. Br J Cancer . 2017;118(3):378-387. 7 GLOBOCAN. International agency for research on cancer (IARC): Age-Standardized Rate (World) per 100 000, Incidence and Mortality, Females, all ages in 2022 . Accessed June 2025. 8 GLOBOCAN. Uterine Cancer Fact Sheet . Accessed June 2025. 9 World Health Organization. Cancer Tomorrow: Corpus Uteri. Accessed June 2025. 10 Corr B, et al. BMJ Med . 2022;1:e000152. 11 Omar N, et al. Pathogenesis . 2015 2(3):1-9. 12 Miller DS, et al. J Clin Oncol . 2020;38:3841–3850. 13 Mirza MR, et al. N Engl J Med . 2023:8;388:2145–2158. 14 Eskander RN, et al. N Engl J Med . 2023;388:2159–2170. 15 Westin SN, et al. J Clin Oncol . 2024;42:283–299. 16 Colombo N, et al. Lancet Oncol . 2024;25:1135–1146. SOURCE: Daiichi Sankyo