Ifinatamab Deruxtecan Development Continues in Phase 3 Study After Robust Results in Pretreated ES-SCLC

The B7-H3–directed antibody-drug conjugate ifinatamab deruxtecan (I-DXd) showed promising activity with a tolerable safety profile for the treatment of patients with extensive-stage small cell lung cancer (ES-SCLC), according to findings from the phase 2 IDeate-Lung01 trial (NCT05280470), which were reviewed during an OncLive® Scientific Interchange and Workshop on evolving approaches in SCLC.1,2

“We now have molecules expressed in SCLC that let us be a part of [ADC] therapy,” stated Neal E. Ready, MD, PhD, who served as the discussion moderator during the workshop. “I-DXd is a humanized, cleavable ADC with a topoisomerase 1 [payload].” Ready is a professor of medicine, head and neck oncologist, and medical oncologist at Duke Health, Durham, North Carolina.

What are the latest data with I-DXd?

I-DXd is being examined for the treatment of patients with ES-SCLC in IDeate-Lung01.2 The multicenter, randomized, open-label study enrolled adult patients with histologically or cytologically documented disease who 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.

During the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer, investigators presented data from the primary analysis of IDeate-Lung01. Patients who received I-DXd at the 12 mg/kg dose level (n = 137) achieved a confirmed overall response rate (ORR) of 48.2% (95% CI, 39.6%-56.9%), including a complete response (CR) rate of 2.2%. The disease control rate (DCR) was 87.6% (95% CI, 80.9%-92.6%).1,2

The median progression-free survival (PFS) in the 12 mg/kg group 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 respective 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%).

In terms of safety, the most common any-grade treatment-related adverse effects (TRAEs) experienced by at least 10% of patients in the 12 mg/kg group included nausea (43.1%) neutropenia (34.3%) anemia (34.3%), decreased appetite (32.8%), leukopenia (23.4%), lymphopenia (19.7%), thrombocytopenia (19.0%), asthenia (19.0%), fatigue (16.1%), diarrhea (15.3%), constipation (12.4%), and vomiting (11.7%). Overall, 89.8% of patients treated at this dose level experienced a TRAE; 36.5% of these were grade 3 or higher. TRAEs associated with dose delay (25.5%), reduction (15.3%), and discontinuation (9.5%) were all reported. Six patients experienced TRAEs associated with death.

In light of the positive data from IDeate-Lung01, I-DXd is being compared with treatment of physician’s choice for the second-line treatment of patients with ES-SCLC in the phase 3 IDeate-Lung02 trial (NCT06203210).3 Additionally, the agent is being evaluated in combination with atezolizumab (Tecentriq) with or without carboplatin for the frontline treatment of patients with ES-SCLC in the phase 1/2 IDeate-Lung03 trial (NCT06362252).4

What other ADCs are showing promise in ES-SCLC?

During the workshop, the participants reviewed other notable ADCs being developed for the management of patients with ES-SCLC. During the 2025 ASCO Annual Meeting, investigators presented primary results from the phase 3 IMforte trial (NCT05091567) of frontline maintenance therapy with lurbinectedin (Zepzelca) plus atezolizumab in patients with ES-SCLC.5

Findings from IMforte revealed that patients who received the doublet (n = 242) achieved a median PFS of 5.4 months (95% CI, 4.2-5.8) compared with 2.1 months (95% CI, 1.6-2.7) among those who received atezolizumab monotherapy (n = 241; HR, 0.54; 95% CI, 0.43-0.67; 2-sided P < .0001). The 6- and 12-month PFS rates in the investigational arm were 41.2% and 20.5%, respectively; in the control arm, these respective rates were 18.7% and 12.0%.

The median OS in the investigational and control arms was 13.2 months (95% CI, 11.9-16.4) vs 10.6 months (95% CI, 9.5-12.2), respectively (HR, 0.73; 95% CI, 0.57-0.95; 2-sided P = .0174). The 12-month OS rates were 56.3% vs 44.1%, respectively.

Another ADC, tarlatamab-dlle (Imdelltra), earned accelerated approval from the FDA in May 2024 for the treatment of patients with ES-SCLC who experienced disease progression on or after platinum-based chemotherapy.6 The approval was supported by data from the phase 2 DeLLphi-301 trial (NCT05060016).

Findings from DeLLphi-301 showed that the ORR per RECIST 1.1 criteria among patients who received the agent (n = 99) was 40% (95% CI, 31%-51%) and the median duration of response was 9.7 months (range 2.7, 20.7+). The CR rate was 3% and the DCR was 70% (95% CI, 60.0%-78.8%).1

The median PFS was 4.3 months (95% CI, 2.9-5.6). The median OS was 15.2 months (95% CI, 10.8-not estimable).

References

1. Evolving approaches in SCLC: practical strategies &
   future directions. An OncLive Scientific Interchange and Workshop. OncLive. September 22, 2025. Accessed November 12, 2025.
2. 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. J Thor Oncol. 2025; 20 (suppl 1): S22-S23. doi: 10.1016/j.jtho.2025.09.048
3. Owonikoko TK, Byers L, Cheng Y, et al. IDeate-Lung02: a phase 3 study of second-line ifinatamab deruxtecan in patients with relapsed small cell lung cancer. Future Oncol. 2025;21(25):3275-3282. doi:10.1080/14796694.2025.2565995
4. A study of I-DXd in combination with atezolizumab with or without carboplatin as first-line induction or maintenance in subjects with extensive stage-small cell lung cancer (IDeate-Lung03). Clinicaltrials.gov. Updated October 10, 2025. Accessed November 11, 2025. https://clinicaltrials.gov/study/NCT06362252
5. Lurbinectedin (lurbi) + atezolizumab (atezo) as first-line (1L) maintenance treatment (tx) in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC): primary results of the phase 3 IMforte trial. J Clin Oncol. 2025;43(suppl 16):8006. doi:10.1200/JCO.2025.43.16_suppl.8006
6. FDA grants accelerated approval to tarlatamab-dlle for extensive stage small cell lung cancer. FDA. May 16, 2024. Accessed November 12, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tarlatamab-dlle-extensive-stage-small-cell-lung-cancer