Ifinatamab Deruxtecan Earns FDA Breakthrough Therapy Designation for Extensive-Stage Small Cell Lung Cancer

Ifinatamab deruxtecan (I-DXd), a potential first-in-class B7-H3–directed DXd antibody-drug conjugate (ADC), received breakthrough therapy designation by the FDA for the treatment of patients with extensive-stage small cell lung cancer (ES-SCLC) who have disease progression on or after platinum-based chemotherapy.1

The breakthrough therapy designation was based on data from the phase 2 IDeate-Lung01 trial (NCT05280470), along with support from the phase 1/2 Ideate-PanTumor01 trial (NCT04145622). Of note, data from the primary analysis of the Ideate-Lung01 trial will be presented at the 2025 IASLC World Conference on Lung Cancer.

“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 R&D at Daiichi Sankyo, the codeveloper of I-DXd, stated 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.”

IDeate-Lung01 Study Design

The global, multicenter, open-label, randomized, 2-part phase 2 study is evaluating the efficacy and safety of I-DXd for the treatment of patients with ES-SCLC who previously received at least 1 line of platinum-based chemotherapy and a maximum of 3 prior lines of therapy.

Patients at least 18 years of age with at least 1 unirradiated lesion per RECIST 1.1 criteria, who are amenable to core biopsy, and have histologically or cytologically confirmed ES-SCLC, were allowed on the study.2 Those with asymptomatic, untreated, or previously treated brain metastases are allowed on the study. Furthermore, patients were required to have received prior therapy with at least 1 platinum-based line as systemic therapy for ES-SCLC and a minimum of 2 previous lines of systemic therapy, with documentation of radiological disease progression on or after the most recent systemic therapy. An ECOG performance status (PS) of 0 or 1 was also required.

Patients were randomly assigned to receive either I-DXd at a dosing level of 8 mg/kg or 12 mg/kg once every 3 weeks.

The primary end point of the study is objective response rate (ORR) by blinded independent central review. Secondary end points include treatment-emergent adverse effects, progression-free survival, duration of response, overall survival, time to response, investigator-assessed ORR, disease control rate, and pharmacokinetics.

IDeate-PanTumor01 Study Design

The global, multicenter, first-in-human, open-label phase 1/2 study is evaluating the safety and efficacy of I-DXd for the treatment of patients with advanced/unresectable or metastatic solid tumors that are refractory or intolerable to standard treatments, or for patients who do not have standard treatments for their disease.1 Patients are required to have an ECOG PS of 0 or 1; at least 1 measurable lesion per RECIST 1.1 criteria; adequate cardiac, hematopoietic, renal, and hepatic function; and an adequate treatment washout period before the start of study treatment.3

Patients allowed on the trial have pathologically documented advanced/unresectable or metastatic head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, squamous and adenocarcinoma non–small cell lung cancer, SCLC, bladder cancer, sarcoma, endometrial cancer, melanoma, castration-resistant prostate cancer, and breast cancer that is refractory or intolerable with standard treatment, or for which no standard treatment is available.

In the dose-escalation portion of the trial, patients with advanced solid tumors are receiving I-DXd every 3 weeks as monotherapy. Notably, enrollment for this phase has been closed. Patients with advanced solid tumors in the dose-expansion portion, which is currently enrolling, are receiving I-DXd every 3 weeks at the recommended dose.

The primary end points are evaluating the incidence of dose-limiting toxicities, safety, and preliminary efficacy. Secondary end points include the pharmacokinetics of I-DXd and the incidence of anti-drug antibodies.

“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 at Merck Research Laboratories, added in the news release.1 “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 [2025] IASLC World Conference on Lung Cancer that show the potential of this novel option.”

References

1. Ifinatamab deruxtecan granted breakthrough therapy designation by U.S. FDA for patients with pretreated extensive-stage small cell lung cancer. News release. Merck. August 18, 2025. Accessed August 18, 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. Updated May 14, 2025. Accessed August 18, 2025. https://clinicaltrials.gov/study/NCT05280470
3. Study of ifinatamab deruxtecan (DS-7300a, I-DXd) in participants with advanced solid malignant tumors. ClinicalTrials.gov. Updated December 19, 2024. Accessed August 18, 2025. https://clinicaltrials.gov/study/NCT04145622