Ifinatamab Deruxtecan Receives FDA Breakthrough Therapy Designation in SCLC

The US FDA has granted breakthrough therapy designation (BTD) to ifinatamab deruxtecan (I-DXd), a B7-H3–directed DXd antibody-drug conjugate (ADC) for the treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) whose disease has progressed on or after platinum-based chemotherapy.¹

The BTD was granted based on compelling preliminary clinical data from the IDeate-Lung01 phase 2 trial (NCT05280470), with supporting evidence from the IDeate-PanTumor01 phase 1/2 trial (NCT04145622). The preliminary results demonstrate a substantial improvement on a clinically significant end point over currently available medicines. The data from the primary analysis of the IDeate-Lung01 trial is expected to be presented at the upcoming IASLC 2025 World Conference on Lung Cancer (WCLC) in September.

“Patients living with extensive-stage small cell lung cancer often have limited therapeutic options following disease progression after standard of care treatments,” said Eliav Barr, MD, senior vice president, head of global clinical development, and chief medical officer, Merck Research Laboratories, in a press release. “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.”

Addressing a Critical Unmet Need

Extensive-stage small cell lung cancer represents a particularly challenging subset of lung cancer. While conventional standard of care treatments, such as platinum-based chemotherapy, can initially provide a clinical benefit, most patients eventually experience disease progression. This leaves a significant portion of the patient population with a paucity of effective subsequent treatment options. The granting of BTD for I-DXd signals the FDA’s recognition of its potential to fill this critical therapeutic gap and improve outcomes for a patient community facing limited prognosis.

The mechanism of action of ifinatamab deruxtecan targets B7-H3, a protein that is overexpressed in a wide range of cancer types, including SCLC. The overexpression of B7-H3 has been correlated with poor prognosis, making it a promising and novel therapeutic target. Currently, there are no B7-H3–directed medicines approved for the treatment of any cancer, positioning I-DXd as a potential first-in-class agent.

About IDeate-Lung01

The phase 2 IDeate-Lung01 study consists of 2 parts: dose optimization and dose extension.² The study has enrolled 187 patients with ES-SCLC across 58 sites in the US, China, France, Germany, Japan, the Republic of Korea, Spain, and Taiwan. Patients are randomized to receive the ADC I-DXd at 8 mg/kg or 12 mg/kg, and in part 2, all patients will receive I-DXd at 12 mg/kg.

The primary end point is objective response rate (ORR), with secondary end points including incidence of treatment-related adverse events, progression-free survival, duration of response, overall survival, time to response, disease control rate, and pharmacokinetics.

Those with histologically confirmed ES-SCLC with at least 1 measurable lesion that has not been previously irradiated were eligible for enrollment in the study. Further, patients were required to have disease progression on or after their most recent systemic therapy and have received at least 1 prior platinum-based line of therapy for at least 2 cycles. Those who previously discontinued an ADC containing an exatecan derivative, had clinically active brain metastases, had clinically significant corneal disease, had a history of noninfectious interstitial lung disease, or had a history of a malignancy other than SCLC within 3 years of enrollment were not eligible to participate in the study.

Data presented from IDeate-Lung01 from last year’s WCLC revealed that at an interim analysis of the dose-optimization portion of the study, a confirmed ORR of 54.8% (95% CI, 38.7%–70.2%) was observed in patients receiving the 12 mg/kg dose (n = 42), with 23 partial responses (PRs). An ORR of 26.1% (95% CI, 14.3%–41.1%) was reported in the 8 mg/kg cohort (n = 46), with 11 PRs and 1 complete response.³

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://tinyurl.com/4dup6uhp

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. Ifinatamab deruxtecan continues to demonstrate promising objective response rates in patients with extensive-stage small cell lung cancer in IDeate-Lung01 phase 2 trial. News release. Merck. September 7, 2024. Accessed August 18, 2025. https://tinyurl.com/4dtf7tj7