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
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. 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 can enhance selective tumor cell death and reduce systemic exposure of the payload, Dr. Johnson explained.
Melissa L. Johnson, MD
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.
Key Findings
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, you see that 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, you see that 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 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 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 (NCT05280470) of patients with second- or third-line extensive stage SCLC is currently ongoing.
Expert Point of View
Helena Linardou, MD, PhD, Director of the 4th Department of Oncology and Comprehensive Clinical Trials Center, Metropolitan Hospital, Athens, Greece, was invited to discuss the subgroup analysis of SCLC in the DS7300-A-J101 trial. She first noted that the antibody-drug conjugate targets already studied in this disease—DLL3, CD56, and TROP-2—have shown limited efficacy and toxicity concerns.
“But today we saw the preliminary results of a subgroup analysis with ifinatamab deruxtecan (I-DXd), which is an antibody-drug conjugate against another new and interesting target, B7-H3, which is overexpressed in SCLC and several other solid tumors. Although there are small numbers and preliminary data, we saw objective response rates in more than one in two patients, and more importantly, durability,” Dr. Linardou said.
“I remind you that this was a heavily pretreated, refractory SCLC population, so 5.6 months of median progression-free survival and median overall survival of more than a year is, I think, more than promising,” she commented. “I think for refractory SCLC—an area of unmet medical need—we have a potent new molecule.”
DISCLOSURE: Dr. Johnson reported no conflicts of interest. Dr. Linardou 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.
