Clinically-meaningful responses with I-DXd in patients with extensive-stage small cell lung cancer

At the interim analysis of the phase II Ideate-Lung01 study, the B7-H3-directed antibody-drug conjugate (ADC) ifinatamab deruxtecan (I-DXd) demonstrated a clinically meaningful response in pre-treated patients with extensive-stage small cell lung cancer (ES-SCLC).

ES-SCLC is aggressive and typically metastasises, complicating treatment. B7 homolog 3 (B7-H3 [CD276]), belonging to the B7 family of immune checkpoint proteins, is highly expressed in SCLC and associated with poor prognosis. Ifinatamab deruxtecan (I-DXd), a B7-H3-directed antibody-drug conjugate, showed durable efficacy at ≥6.4 mg/kg in 21 patients with ES-SCLC in the Phase I/II IDeate-PT01 trial. At WCLC 2024, the interim analysis of results of the dose-optimization part of the ongoing IDeate-Lung01, a phase II trial investigating the potential of I-DXd in patients with ES-SCLC, were presented.

 Study design

IDeate-Lung01 enrolled patients aged 18 years or older with histologically- or cytologically-documented ES-SCLC who had underwent at least one prior line of platinum-based chemotherapy and a maximum of three lines of systemic therapy. Other eligibility criteria include radiologically-documented progressive disease (PD), an ECOG PS of 0-1 and at least one measurable lesion per RECIST 1.1. Patients with previously treated or untreated asymptomatic brain metastases were eligible. Patients were randomised 1:1 to receive either 8mg/kg (n=46) or 12mg/kg (n=42) of I-DXd Q3W. The primary endpoint is overall response rate (ORR) by BICR with key secondary endpoints including duration of response by BICR, progression-free survival (PFS) by BIRC, and overall survival (OS).

Results

At a median follow-up of 14.6 months (8mg/kg) and 15.3 months (12mg/kg), treatment was discontinued in 80 patients due to PD (8mg/kg: n=35; 12mg/kg; n=28), treatment-emergent adverse events (TEAE) (n=3, n=6, respectively), death (n=2 per arm), or withdrawal of consent (n=2 per arm), leaving 4 patients continuing treatment per arm. The median duration of treatment was 3.5 months for the 8mg/kg arm, and 4.7 months for the 12mg/kg arm. Treatment with I-DXd yielded promising anti-tumour activity, with patients receiving 12mg/kg experiencing a higher ORR than those in the 8mg/kg arm (confirmed ORR: 54.8% vs. 26.1%). One patient in the 8mg/kg arm achieved a complete response. A rapid time to response of 1.4 months was seen for both arms, with a median duration of response of 7.9 months vs. 4.2 months (8mg/kg vs. 12mg/kg, respectively). The PFS and OS data were similar between the study arms, although numerically favouring the 12mg/kg dose (PFS: 5.5 months vs. 4.2 months; OS: 11.8 months vs. 9.4 months). In a subgroup analysis of patients with brain target lesions at baseline (n=16), an intracranial response of 66.7% was seen in the 8mg/kg arm (n=6) compared to 50% in the 12mg/kg arm (n=10). In terms of safety, 43.5% and 50% of patients experienced a grade ≥3 TEAE in the 8mg/kg and 12mg/kg arms, respectively. Furthermore, 6.5% of patients in the 8mg/kg arm and 16.7% in the 12mg/kg arm experienced a TEAE associated with discontinuation. The most common TEAE’s were nausea, decreased appetite, and anaemia.

Conclusion

The safety profile of I-DXd was manageable and promising efficacy was seen in patients with heavily pretreated ES-SCLC. I-DXd showed intracranial and systemic activity in a small subset of patients with brain target lesions at baseline. Based on the interim results of this study, the 12mg/kg dose has been selected as the recommended phase III dose for clinical development, including in an ongoing phase III study in patients with relapsed SCLC following one prior line of therapy (IDeate-Lung02).

Reference

Rudin C, et al. Ifinatamab Deruxtecan (I-DXd) in extensive-stage small cell lung cancer (ES-SCLC): Interim analysis of Ideate-lung01 Presented at WCLC 2024; Abstract 2700.