Charles M. Rudin, MD, PhD
The antibody-drug conjugate ifinatamab deruxtecan (I-DXd) showed clinically meaningful responses in pretreated patients with extensive-stage small cell lung cancer (SCLC) in an interim analysis of the phase II IDeate-Lung01 study.1 The findings were presented at the International Association for the Study of Lung Cancer (IASLC) 2024 World Conference on Lung Cancer by Charles M. Rudin, MD, PhD, Deputy Director of Memorial Sloan Kettering Cancer Center, Co-Director of the Druckenmiller Center for Lung Cancer Research, and the Sylvia Hassenfield Chair in Lung Cancer Research.
“There has been a real need for additional drugs in the small cell lung cancer space. We think I-DXd is a highly active agent, with a high response rate and an impressive disease control rate,” said Dr. Rudin, who reported these rates as 55% and 90%, respectively, at the optimal dose of 12 mg/kg. “I think I-DXd has a clear potential path forward.”
Background
I-DXd is an antibody-drug conjugate directed against B7 homolog 3 (B7-H3), part of the B7 family that includes immune checkpoint proteins such as PD-L1. High and consistent expression of B7-H3 has been shown across all molecular subtypes of SCLC and has been linked to a poor prognosis.
In the dose-optimization part of IDeate-Lung01, two doses of I-DXd (8 mg/kg and 12 mg/kg intravenously every 3 weeks) were evaluated in patients with extensive-stage SCLC previously treated with one to three prior lines. The primary endpoint was objective response rate by blinded independent central review. Secondary endpoints included duration of response, progression-free survival, overall survival, disease control rate, time to response, and safety. The interim analysis included 88 patients (42% with asymptomatic stable brain metastases) randomly assigned between the two doses. Median follow-up was approximately 15 months.
Key Results
The confirmed response rate was 26.1% with 8 mg/kg, essentially doubling to 54.8% with 12 mg/kg. Responses were rapid with both doses, around 1.4 months. Disease control was achieved by 80.4% with I-DXd at 8 mg/kg and by 90.5% with 12 mg/kg. In an analysis of 16 patients with brain target lesions at baseline, the intracranial response rate was 66.7% with 8 mg/kg and 50.0% with 12 mg/kg, Dr. Rudin reported.
Median progression-free survival and overall survival were similar between the study arms, but they numerically favored the 12-mg/kg dose. For the 8-mg/kg and 12-mg/kg cohorts, respectively, median progression-free survival was 4.2 months and 5.5 months, and median overall survival was 9.4 months and 11.8 months.
In a press briefing, Dr. Rudin commented that the clear difference in efficacy between 8 mg/kg and 12 mg/kg was “somewhat surprising” to him and the Steering Committee, and it left no doubt that the higher dose would be the optimal dose for further study. He also said that although the drug might have benefits in other settings, the goal was to identify its value in extensive-stage SCLC.
No Unexpected Toxicities
“At this point, we have a fair bit of experience with antibody-drug conjugates, particularly with the deruxtecan payload, and I don’t think there were any great surprises” in terms of safety, Dr. Rudin said.
Treatment-related adverse events of all grades were similar between the arms, approximately 96% to 97%, but more grade ≥ 3 toxicities occurred with 12 mg/kg (50.0% vs 43.5%), as did more treatment discontinuations (15.7% vs 6.5%). The most common adverse events were gastrointestinal and hematologic toxicities, “which are not unexpected in the context of a topoisomerase-1 payload,” he noted.
Adjudicated interstitial lung disease/pneumonitis was documented in nine patients, for an incidence of 8.7% with 8 mg/kg and 11.9% with 12 mg/kg. Of these nine cases, one such event was grade 5, and one was grade 3; the others were grade 1 or 2.
The 12-mg/kg dose was selected as the optimal dose for SCLC monotherapy. It will be further studied in the extension part of IDeate-Lung01 and in the phase III IDeate-Lung02 trial.
DISCLOSURE: Dr. Rudin reported financial relationships with AbbVie, Amgen, AstraZeneca, D2G, Daiichi Sankyo, Epizyme, Genentech/Roche, Ipsen, Jazz, Kowa, Lilly, Merck, Syros, Auron, Bridge Medicines, DISCO, Earli, and Harpoon Therapeutics.
REFERENCE
1. Rudin CM, Ahn MJ, Johnson M, et al: Ifinatamab deruxtecan (I-DXd) in extensive-stage small cell lung cancer. 2024 World Conference on Lung Cancer. Abstract OA04.03. Presented September 8, 2024.
