The antibody-drug conjugate ifinatamab deruxtecan has demonstrated “robust and durable efficacy” in patients with heavily pretreated small cell lung cancer, according to a subset analysis of the DS7300-A-J101 trial presented at the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer (WCLC) by Melissa L. Johnson, MD, Director of Lung Cancer Research at Sarah Cannon Research Institute, Nashville.¹

Melissa L. Johnson, MD

B7 homolog 3 (B7-H3), a transmembrane immunoregulatory protein, is overexpressed in several tumor types, including small cell lung cancer (SCLC), where about two-thirds of patients have moderate-to-high expression of B7-H3, which has been associated with disease progression and lower survival rates. Ifinatamab deruxtecan (I-DXd) is a novel B7-H3–directed antibody-drug conjugate that leverages the clinically validated deruxtecan technology. The compound has a plasma-stable linker and potent topoisomerase I inhibitor payload that may enhance selective tumor cell death and reduce systemic exposure of the payload, Dr. Johnson explained.

She and her colleagues conducted the phase I/II DS7300-A-J101 trial of I-DXd in 205 heavily pretreated patients with advanced solid tumors. At the WCLC, Dr. Johnson presented outcomes for the SCLC subgroup from part 1 of the trial. The analysis included 22 patients with SCLC unselected for B7-H3 expression who were treated with I-DXd at doses ranging from 4.8 to 16.0 mg/kg. The efficacy analysis, at a median follow-up of 11.7 months, included 21 patients who received ≥ 6.4 mg/kg.

The 22 patients had received a median of two prior lines of therapy, mostly platinum-based chemotherapy, and immunotherapy. Confirmed responses were achieved by 52.4% of patients, including complete responses in 4.8%. The median progression-free survival was 5.8 months and median overall survival was 12.2 months. Two patients remain on treatment, Dr. Johnson reported.

“On the waterfall plot, all but one patient showed some element of disease response. Median time to response was 1.2 months, and median duration of response was 5.9 months. On the spider plot, these responses were durable,” she said.

All 17 patients who were evaluable for B7-H3 expression analysis showed moderate-to-high expression. “We saw no trend of a correlation of B7-H3 combined membrane/cytosol H-score with best overall response, progression-free survival, or overall survival. More work needs to be done to understand the association between efficacy markers and B7-H3 expression. The correlative relationship between B7-H3 level and clinical efficacy will be further evaluated in future I-DXd studies,” she said.

I-DXd was reported to be tolerable, with manageable toxicity. Grade ≥ 3 treatment-related adverse events were observed in 36.4% of patients, and one death was associated with treatment. Five patients discontinued treatment due to treatment-emergent adverse events, including one each with interstitial lung disease, pneumonia, cardiac failure, embolism, and COVID-19 pneumonia. “Nausea was the most common treatment-emergent adverse event…. It’s worth pointing out that prophylactic premedication for nausea and vomiting was not allowed during cycle 1, but antiemetic prophylaxis is now required for all I-DXd studies,” she said.

A phase II study (ClinicalTrials.gov identifier NCT05280470) of patients with second- or third-line extensive-stage SCLC is currently ongoing. 

DISCLOSURE: Dr. Johnson reported no conflicts of interest.

REFERENCE

1. Johnson M, Awad M, Koyama T, et al: Ifinatamab deruxtecan (I-DXd; DS-7300) in patients with refractory SCLC: A subgroup analysis of a phase 1/2 study. 2023 World Conference on Lung Cancer. Abstract OA05.05. Presented September 10, 2023.