Ifinatamab Deruxtecan Receives Breakthrough Therapy Designation from FDA for Pretreated Extensive-Stage Small Cell Lung Cancer
The oncology research landscape took a significant step forward this week with the announcement that ifinatamab deruxtecan (I-DXd), an investigational antibody-drug conjugate (ADC), has been granted Breakthrough Therapy Designation (BTD) by the U.S. Food and Drug Administration (FDA). The designation applies to the treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) whose disease has progressed after receiving platinum-based chemotherapy.
This regulatory milestone underscores not only the urgency for new therapeutic options in this highly aggressive cancer, but also the growing confidence in ADCs as a transformative modality in oncology. The designation represents the first Breakthrough Therapy Designation for ifinatamab deruxtecan, and importantly, it also marks the first designation achieved since the start of the strategic collaboration between Daiichi Sankyo and Merck (known as MSD outside the United States and Canada).
Understanding the Breakthrough Therapy Designation
The FDA’s Breakthrough Therapy Designation program was established in 2012 as part of the Food and Drug Administration Safety and Innovation Act (FDASIA). Its purpose is to accelerate the development and review of drugs that are intended to treat serious or life-threatening conditions, particularly in cases where existing therapeutic options are insufficient.
To qualify, an investigational medicine must provide preliminary clinical evidence indicating that it may demonstrate a substantial improvement over available therapies on clinically meaningful endpoints. Benefits of the designation include more intensive guidance from the FDA, priority interactions with regulatory officials, and the potential for rolling review of a Biologics License Application (BLA) or New Drug Application (NDA).
In the case of ifinatamab deruxtecan, the FDA’s decision was based on results from the IDeate-Lung01 phase 2 trial, with supporting evidence from the IDeate-PanTumor01 phase 1/2 trial. The recognition signals that regulators see promising signals of efficacy and safety that could alter the treatment paradigm for SCLC.
The Urgent Need for New Therapies in Small Cell Lung Cancer
Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer that accounts for approximately 10–15% of all lung cancer cases worldwide. It is strongly associated with tobacco smoking, tends to progress rapidly, and is often diagnosed at advanced stages.
- Extensive-stage disease (ES-SCLC) represents the majority of cases at diagnosis, where the cancer has already spread beyond one lung and nearby lymph nodes.
- First-line treatment typically involves platinum-based chemotherapy (commonly carboplatin or cisplatin, combined with etoposide) and increasingly includes the addition of immune checkpoint inhibitors such as atezolizumab or durvalumab.
- Unfortunately, despite initial responses to therapy, most patients relapse within months, and outcomes after progression remain exceptionally poor.
The five-year survival rate for patients with extensive-stage SCLC is less than 3%, and the median survival after relapse on platinum-based therapy is often measured in single-digit months. Currently available second-line options, such as topotecan or lurbinectedin, offer limited benefit.
In this context, the FDA’s recognition of ifinatamab deruxtecan reflects both the desperate unmet medical need and the encouraging early clinical results that suggest the drug may achieve superior outcomes compared to existing therapies.
What Is Ifinatamab Deruxtecan (I-DXd)?
Ifinatamab deruxtecan is a specifically engineered antibody-drug conjugate designed to target B7-H3, a protein expressed broadly in many solid tumors, including small cell lung cancer, but with limited expression in normal tissues. This makes B7-H3 an attractive therapeutic target.
The structure of I-DXd is composed of three components:
- The antibody – designed to recognize and bind specifically to B7-H3 on the surface of tumor cells.
- The linker – a stable but cleavable connection that attaches the antibody to the cytotoxic payload, ensuring controlled delivery.
- The payload – a potent topoisomerase I inhibitor (a derivative of Daiichi Sankyo’s DXd technology), which is released inside the cancer cell upon internalization, leading to DNA damage and cell death.
This targeted approach aims to maximize the killing of cancer cells while minimizing exposure to healthy cells, thereby improving the therapeutic window compared to conventional chemotherapy. If successful, ifinatamab deruxtecan could become the first B7-H3 directed ADC to reach patients.
Clinical Evidence Supporting the Designation
IDeate-Lung01 Trial
The pivotal evidence supporting the FDA’s decision came from the IDeate-Lung01 phase 2 trial. This trial is a global, multicenter, randomized, open-label study evaluating the safety and efficacy of ifinatamab deruxtecan in patients with extensive-stage SCLC previously treated with at least one line of platinum-based chemotherapy and up to a maximum of three prior therapies.
Key features of the study include:
- Design: Two-part trial.
- Part 1 (dose optimization): Patients were randomized to receive 8 mg/kg or 12 mg/kg intravenously every three weeks.
- Part 2 (dose expansion): Patients received the selected 12 mg/kg dose every three weeks.
- Primary Endpoint: Objective response rate (ORR), as assessed by blinded independent central review (BICR) according to RECIST v1.1 criteria.
- Secondary Endpoints: Duration of response (DoR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), time to response, safety, and pharmacokinetics.
- Exploratory Endpoint: Intracranial ORR, reflecting the trial’s attention to brain metastases, a common complication in SCLC.
The trial enrolled 187 patients across Asia, Europe, and North America. Importantly, patients with asymptomatic brain metastases were eligible, reflecting real-world clinical scenarios and broadening the relevance of results.
The primary analysis of IDeate-Lung01 will be presented in a late-breaking oral session at the IASLC 2025 World Conference on Lung Cancer (#WCLC25). This upcoming presentation is expected to provide deeper insights into the drug’s efficacy profile, including response durability and impact on survival outcomes.
IDeate-PanTumor01 Trial
Supporting evidence came from the IDeate-PanTumor01 phase 1/2 trial, a first-in-human study that explored ifinatamab deruxtecan across multiple tumor types. While smaller in scale, the study provided early safety data and proof-of-concept signals that reinforced the therapeutic potential of the ADC in SCLC and other malignancies.
Voices from the Development Partners
The announcement was accompanied by statements from leadership at Daiichi Sankyo and Merck, emphasizing both the unmet medical need and the strategic importance of the collaboration.
- Dr. Ken Takeshita, Global Head of R&D at Daiichi Sankyo, highlighted the urgent demand for innovation in this cancer subtype:
“This Breakthrough Therapy Designation granted by the FDA to ifinatamab deruxtecan highlights the urgent need for new treatment options for patients with pretreated extensive-stage small cell lung cancer. We are committed to advancing this medicine with the goal of bringing the first B7-H3 directed antibody drug conjugate to patients in order to transform the outcomes of those facing this aggressive disease.” - Dr. Eliav Barr, Senior Vice President, Head of Global Clinical Development and Chief Medical Officer, Merck Research Laboratories, underscored the potential impact on patient care:
“Patients living with extensive-stage small cell lung cancer often have limited therapeutic options following disease progression after standard of care treatments. This Breakthrough Therapy Designation reinforces our confidence in the promise of ifinatamab deruxtecan to play an important role in the treatment of extensive-stage small cell lung cancer, and we are looking forward to sharing data at the upcoming IASLC 2025 World Conference on Lung Cancer that show the potential of this novel option.”
The Broader Context: ADCs in Oncology
The designation of ifinatamab deruxtecan is also emblematic of a broader trend in oncology drug development: the rising prominence of ADCs.
- Over the past decade, ADCs have moved from niche experimentation to becoming a mainstream class of cancer therapeutics.
- Their appeal lies in their ability to marry the precision of targeted therapy with the potency of chemotherapy.
- Several ADCs are already approved across multiple cancer types, including trastuzumab deruxtecan (HER2-directed), enfortumab vedotin (Nectin-4-directed), and sacituzumab govitecan (Trop-2-directed).
Ifinatamab deruxtecan’s B7-H3 target distinguishes it from existing ADCs and could expand the reach of this modality into a broader spectrum of solid tumors, given B7-H3’s expression profile.
The granting of Breakthrough Therapy Designation does not guarantee approval, but it does significantly enhance the probability that ifinatamab deruxtecan could reach patients more quickly if ongoing trials continue to yield positive results.
Key upcoming milestones include:
- Presentation of primary analysis results from IDeate-Lung01 at WCLC 2025.
- Potential initiation of a registrational phase 3 trial if phase 2 results are sufficiently compelling.
- Ongoing monitoring of safety, particularly in relation to ADC-related toxicities, such as interstitial lung disease (ILD), hematologic adverse events, and gastrointestinal effects.
For patients with relapsed ES-SCLC, where options are sparse and prognosis grim, the promise of a novel, targeted therapeutic with durable efficacy could represent one of the most meaningful advancements in years.
The FDA’s decision to grant Breakthrough Therapy Designation to ifinatamab deruxtecan represents an important moment in the evolution of both small cell lung cancer treatment and the field of antibody-drug conjugates. Backed by data from the IDeate-Lung01 and IDeate-PanTumor01 trials, the designation highlights the potential of B7-H3 as a novel therapeutic target and reinforces the significance of the Daiichi Sankyo–Merck partnership.
For patients, it offers renewed hope in a setting where progress has long been elusive. For the oncology community, it signals another step forward in redefining what is possible for patients facing one of the most difficult-to-treat cancers.
If forthcoming data at WCLC 2025 confirm the promise of ifinatamab deruxtecan, the therapy could soon become a cornerstone of care in pretreated extensive-stage SCLC, potentially rewriting the clinical standard for this aggressive disease.
About IDeate-PanTumor01
IDeate-PanTumor01 is a global, multicenter, first-in-human, open-label phase 1/2 trial evaluating the safety and efficacy of ifinatamab deruxtecan in patients with advanced/unresectable or metastatic solid tumors that are refractory or intolerable to standard treatment or for whom no standard treatment exists.
The phase 1 part of the trial (dose escalation) is assessing the safety and tolerability of increasing doses of ifinatamab deruxtecan to determine the maximum tolerated dose and recommended dose for expansion (RDE). The phase 2 part of the trial (dose expansion) is evaluating the safety and efficacy of ifinatamab deruxtecan at the RDE of 12 mg/kg in patients with squamous non-small cell lung cancer, metastatic castration-resistance prostate cancer or esophageal squamous cell carcinoma.
The dose escalation part of the trial is evaluating dose-limiting toxicity and safety. The dose expansion part of the trial is evaluating overall response rate, duration of response, disease control rate, progression-free survival, overall survival and safety. Pharmacokinetic endpoints, exploratory biomarker and immunogenicity endpoints will also be assessed.
IDeate-PanTumor01 enrolled approximately 250 patients in Asia and North America. For more information about the trial, visit ClinicalTrials.gov.
About Small Cell Lung Cancer
More than 2.48 million lung cancer cases were diagnosed globally in 2022.1 Small cell lung cancer (SCLC) is the second most common type of lung cancer, accounting for approximately 15% of cases.2 SCLC is aggressive and progresses rapidly to the distant metastatic stage, which has a low five-year survival rate 3,4 While conventional standard of care treatments for patients with advanced SCLC may help improve outcomes, there is a need for additional subsequent treatment approaches.5,6,7,8
About B7-H3
B7-H3 is a transmembrane protein that belongs to the B7 family of proteins, which bind to the CD28 family of receptors that includes PD-1.9,10 B7-H3 is overexpressed in a wide range of cancer types, including SCLC, and its overexpression has been shown to correlate with poor prognosis, making B7-H3 a promising therapeutic target.11,12,13,14 There are currently no B7-H3 directed medicines approved for the treatment of any cancer.
About Ifinatamab Deruxtecan
Ifinatamab deruxtecan (I-DXd) is an investigational potential first-in-class B7-H3 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, ifinatamab deruxtecan is comprised of a humanized anti-B7-H3 IgG1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.
Ifinatamab deruxtecan has been granted orphan drug designation by the U.S. FDA, European Commission, Japan Ministry of Health, Labour and Welfare and Taiwan Food and Drug Administration for the treatment of SCLC.
About the Ifinatamab Deruxtecan Clinical Development Program
A comprehensive global clinical development program is underway evaluating the efficacy and safety of ifinatamab deruxtecan monotherapy and in combination with other anticancer medicines across multiple cancers.
About the Daiichi Sankyo and Merck Collaboration
Daiichi Sankyo and Merck (known as MSD outside of the United States and Canada) 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. In August 2024, the global co-development and co-commercialization agreement was expanded to include gocatamig (MK-6070/DS3280), which the companies will jointly develop and commercialize worldwide, except in Japan where Merck & Co., Inc., Rahway, N.J., USA will maintain exclusive rights. Merck & Co., Inc., Rahway, N.J., USA will be solely responsible for manufacturing and supply for gocatamig.
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, N.J., 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.
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 www.merck.com/research/oncology.
