FDA Grants I-DXd Breakthrough Therapy Designation in Treatment of ES-SCLC

The FDA granted breakthrough therapy designation to ifinatamab deruxtecan (I-DXd; Daiichi Sankyo, Merck) for the treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC).¹ The action is based on findings from the phase 2 IDeate-Lung01 (NCT05280470)² and the phase 1/2 IDeate-PanTumor-01 (NCT04145622)³ clinical trials.¹

I-DXd is an investigational potential first-in-class B7-H3–directed antibody-drug conjugate (ADC) that comprises a humanized anti–B7-H3 immunoglobulin G1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads via tetrapeptide-based cleavable linkers. B7-H3 is overexpressed in a wide range of cancer types—including SCLC—and its overexpression is correlated with poor prognosis. For this reason, B7-H3 is a promising therapeutic target; however, there are currently no B7-H3-directed medicines approved for treating any cancer.¹

“This breakthrough therapy designation granted by the FDA to I-DXd highlights the urgent need for new treatment options for patients with pretreated ES-SCLC,” Ken Takeshita, MD, global head of research and development at Daiichi Sankyo, said in a news release. “We are committed to advancing this medicine with the goal of bringing the first B7-H3-directed ADC to patients in order to transform the outcomes of those facing this aggressive disease.”¹

IDeate-Lung01 is a global, multicenter, randomized, open-label, 2-part phase 2 trial evaluating the safety and efficacy of I-DXd in patients with ES-SCLC who were previously treated with at least 1 prior line of platinum-based chemotherapy and a maximum of 3 prior lines of therapy. A total of 187 patients were randomly assigned to receive 8 or 12 mg/kg of intravenous (IV) I-DXd once every 3 weeks (dose optimization), and then all patients received 12 mg/kg of IV I-DXd once every 3 weeks (dose expansion).

IDeate-Lung01’s primary end points were objective response rate as assessed by blinded independent central review; secondary end points included duration of response, progression-free survival (PFS), disease control rate (DCR), time to response, overall survival (OS), pharmacokinetics, and safety.^1,2 Of note, I-DXd demonstrated clinically meaningful responses in patients, according to results from an interim analysis.⁴

Further, IDeate-PanTumor01 is a global, multicenter, first-in-human, open-label phase 1/2 trial evaluating the safety and efficacy of I-DXd in 250 patients with advanced, unresectable or metastatic solid tumors—such as SCLC, endometrial cancer, melanoma, and others—that are refractory or intolerable to standard treatment or for whom no standard treatment exists. The phase 1 part of the trial is assessing the safety and tolerability of increasing doses of I-DXd to determine the maximum tolerated and recommended dose for expansion (RDE; dose escalation), whereas the phase 2 part is evaluating the safety and efficacy of the RDE of I-DXd (12 mg/kg) in patients with squamous non–small cell lung cancer, metastatic castration-resistant prostate cancer, or esophageal squamous cell carcinoma.^1,3

The dose escalation phase of the trial is evaluating dose-limiting toxicity and safety, whereas the dose expansion phase is evaluating overall response rate, DOR, DCR, PFS, OS, and safety. Pharmacokinetic end points, exploratory biomarkers, and immunogenicity end points are also being assessed, according to the investigators.^1,3

“Patients living with ES-SCLC often have limited therapeutic options following disease progression after standard of care treatments,” Eliav Barr, MD, senior vice president, head of global clinical development, and chief medical officer of Merck Research Laboratories, said in the news release. “This breakthrough therapy designation reinforces our confidence in the promise of I-DXd to play an important role in the treatment of ES-SCLC, and we are looking forward to sharing data at the upcoming [International Association for the Study of Lung Cancer] 2025 World Conference on Lung Cancer that show the potential of this novel option.”¹

REFERENCES

1. Merck. Ifinatamab Deruxtecan Granted Breakthrough Therapy Designation by U.S. FDA for Patients with Pretreated Extensive-Stage Small Cell Lung Cancer. News release. August 18, 2025. Accessed August 26, 2025. https://www.merck.com/news/ifinatamab-deruxtecan-granted-breakthrough-therapy-designation-by-u-s-fda-for-patients-with-pretreated-extensive-stage-small-cell-lung-cancer/

2. Ifinatamab Deruxtecan (I-DXd) in Subjects With Pretreated Extensive-Stage Small Cell Lung Cancer (ES-SCLC) (IDeate-Lung01). ClinicalTrials.gov identifier: NCT05280470. Updated May 14, 2025. Accessed August 26, 2025. https://clinicaltrials.gov/study/NCT05280470

3. Study of Ifinatamab Deruxtecan (DS-7300a, I-DXd) in Participants With Advanced Solid Malignant Tumors. ClinicalTrials.gov identifier: NCT04145622. Updated December 19, 2024. Accessed August 26, 2025. https://clinicaltrials.gov/study/NCT04145622

4. McGovern G, May M. Lurbinectedin and Tarlatamab: Emerging Second-Line Therapies in the SCLC Space. Pharmacy Times. March 25, 2025. Accessed August 26, 2025. https://www.pharmacytimes.com/view/lurbinectedin-and-tarlatamab-emerging-second-line-therapies-in-the-sclc-space