I-DXd Shows Promise in Treating Extensive-Stage SCLC

The antibody-drug conjugate (ADC) Ifinatamab deruxtecan (I-DXd) demonstrated notable antitumor activity in patients with previously treated extensive-stage small cell lung cancer (ES-SCLC), according to data from the primary analysis of the phase 2 IDeate-Lung01 study (NCT05280470) presented during the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer.¹

In all patients who received the agent at that dose (n = 137), the confirmed objective response rate (ORR) was 48.2% (95% CI, 39.6%-56.9%), which comprised a complete response (CR) rate of 2.2% and a partial response (PR) rate of 46.0%. The disease control rate (DCR) was 87.6% (95% CI, 80.9%-92.6%). Responses proved to be rapid and durable, with a median time to response (TTR) of 1.4 months (range, 1.0-8.1) and a median duration of response (DOR) of 5.3 months (95% CI, 4.0-6.5).

The median progression-free survival (PFS) was 4.9 months (95% CI, 4.2-5.5); the 3-, 6-, and 9-month PFS rates were 68.0% (95% CI, 59.4%-75.2%), 35.3% (95% CI, 27.3%-43.4%), and 19.3% (95% CI, 12.9%-26.5%), respectively. The median overall survival (OS) was 10.3 months (95% CI, 9.1-13.3); the 3-, 6-, and 9-month OS rates were 89.1% (95% CI, 82.5%-93.2%), 77.4% (95% CI, 69.4%-83.5%), and 59.1% (95% CI, 50.4%-66.8%), respectively.

In those who received the agent as second-line treatment (n = 32), the ORR was 56.3% (95% CI, 37.7%-73.6%), which was made up entirely of PRs. The DCR in this group was 96.9% (95% CI, 83.8%-99.9%). The median TTR was 1.4 months (range, 1.2-4.0) and the median DOR was 7.2 months (95% CI, 3.6-not evaluable). The median PFS was 5.6 months (95% CI, 3.9-8.1) and the median OS was 12.0 months (95% CI, 7.3-19.1). In those who received the agent in the third line or later (n = 105), the ORR was 45.7% (95% CI, 36.0%-55.7%), which includes CR and PR rates of 2.9% and 42.9%, respectively. The DCR was 84.8% (95% CI, 76.4%-91.0%).

“I-DXd 12 mg/kg demonstrated remarkable efficacy in patients with previously treated ES-SCLC, particularly given the inclusion of populations often excluded from clinical trials,” Myung-Ju Ahn, MD, of Samsung Medical Center, Sungkyunkwan University School of Medicine, in Seoul, South Korea, said in a presentation of the data. “Clinically meaningful benefit was observed regardless of platinum sensitivity or line of therapy, [and] meaningful intracranial efficacy was [also] observed.”

What Is the Design of the IDeate-Lung01 Study?

The multicenter, randomized, open-label, phase 2 study enrolled patients with histologically or cytologically documented ES-SCLC who were at least aged 18 years, had an ECOG performance status of 0 or 1, and had received at least 1 prior line of platinum-based chemotherapy but no more than 3 lines. Patients must have experienced radiologically documented disease progression on or following their most recent prior systemic treatment; they also needed to have at least 1 measurable lesion by RECIST v1.1 criteria. Those with asymptomatic brain metastases were permitted.

For part 1 of the study, the dose optimization portion of the research, patients were randomized 1:1 to receive I-DXd, a B7-H3–directed antibody-drug conjugate designed to strengthen selective tumor-cell death and reduce systemic exposure, \at 8 mg/kg every 3 weeks (n = 46; arm 1) or at 12 mg/kg every 3 weeks (n = 42). For part 2, the extension portion, the agent, which is made up of a humanized anti–B7-H3 IgG1 monoclonal antibody, a tetrapeptide-based cleavable linker that covalently bonds antibody and payload, and a TOPO I inhibitor payload, was further evaluated at the 12-mg/kg dose (n = 95). Stratification factors included prior anti–PD-(L)1 treatment (yes vs no) or second-line chemotherapy-free interval (CTFI) less than 90 days vs second-line CTFI of 90 days or longer vs third or fourth line.

The primary end point was ORR by blinded independent central review (BICR), and secondary end points included DOR, PFS, DCR, and TTR by BICR and investigator assessment. Other end points included OS, ORR by investigator assessment, safety, pharmacokinetics, and immunogenicity. Exploratory analysis focused on intracranial ORR by BICR.

Of the 183 patients who received I-DXd, 42 received the agent at 12 mg/kg in part 1 and 95 in part 2. Of the 137 total patients, 10.2% were still receiving treatment at the time of data cutoff, which was March 3, 2025. Of the 123 patients who discontinued, 95 did so because of disease or clinical progression, 15 did so because of treatment-emergent adverse effects, 10 died, and 3 patients withdrew consent. The median follow-up was 12.8 months (95% CI, 12.2-13.1), and the median treatment duration was 4.8 months (range, 0.7-22.7).

The median patient age was 63 years (range, 34-79); most were male (65.7%), about half were Asian (48.9%), and from Asia (48.2%). Most patients had an ECOG performance status of 1 (77.4%) and had ES-SCLC at diagnosis (81.0%). Moreover, 38.0% of patients had brain metastases at baseline, and 40.1% had baseline liver metastases. Regarding CTFI, 13.1% had an interval of up to 30 days, 29.2% had an interval of longer than 30 days but under 90 days, and 52.6% had an interval of 90 days or longer. Moreover, 23.4%, 54.7%, and 21.9% of patients had received 1, 2, or 3 prior lines of systemic therapy, respectively. Prior therapies included TOPO I inhibitor (32.1%), lurbinectedin (Zepzelca; 21.2%), amrubicin (8.8%), DLL3-targeting T-cell engager (8.0%), and anti–PD-L1 (81.0%).

What was the safety profile of I-DXD in ES-SCLC?

The median treatment duration was 4.8 months (range, 0.7-22.7), and the median number of cycles received was 7.0 (range, 1.0-32.0). Any grade treatment-related adverse effects (TRAEs) occurred in 89.8% of patients, 36.5% of which were grade 3 or higher. TRAEs were linked with dose delays or reductions for 25.5% and 15.3% of patients, respectively. They led to treatment discontinuation for 9.5% of patients and proved fatal for 4.4% of patients.

The most common TRAEs experienced by at least 10% of patients who received I-DXd at 12 mg/kg on the trial were nausea (any grade, 43.1%; grade ≥3, 2.2%), neutropenia (34.3%; 13.9%), anemia (34.3%; 10.2%), decreased appetite (32.8%; 1.5%), leukopenia (23.4%; 3.6%), lymphopenia (19.7%; 12.4%), thrombocytopenia (19.0%; 5.8%), asthenia (19.0%; 1.5%), fatigue (16.1%; 2.2%), diarrhea (15.3%; 1.5%), constipation (12.4%; 0%), and vomiting (11.7%; 0.7%).

Adjudicated treatment-related interstitial lung disease (ILD) or pneumonitis was observed in 12.4% of patients; the cases were grade 1 or 2 (8.0%), grade 3 (2.9%), and grade 5 (1.5%). No ILD events were pending adjudication at the time of data cutoff.

What’s Next for I-DXd?

The phase 3 IDeate-Lung02 trial (NCT06203210) is comparing the safety and efficacy of I-DXD given at 12 mg/kg with physician’s choice of treatment in the form of topotecan, amrubicin, or lurbinectedin, in patients with relapsed SCLC with only 1 previous systemic treatment, which must have included platinum-based chemotherapy.²

REFERENCES:

1. Ahn M-J, Johnson ML, Paz-Ares L, et al. Ifinatamab deruxtecan (I-DXd) in extensive-stage small cell lung cancer: primary analysis of the phase 2 IDeate-Lung 01 study. Presented at: IASLC World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract OA06.03.

2. A study of ifinatamab deruxtecan versus treatment of physician’s choice in subjects with relapsed small cell lung cancer (IDeate-Lung02). Clinical Trials.gov. Updated August 7, 2025. Accessed September 7, 2025. https://clinicaltrials.gov/study/NCT06203210