Early data for a novel antibody-drug conjugate (ADC) targeting B7 homolog 3 (B7-H3 or CD276) with a topoisomerase I (TOPO-I) inhibitor payload showed meaningful clinical response against heavily pre-treated extensive-stage small cell lung cancer (ES-SCLC). The phase II IDeate-Lung01 trial of ifinatamab deruxtecan (I-DXd), 8 mg/kg or 12 mg/kg every 3 weeks yielded overall response rates (ORR) of 26% and 55% respectively after a mean follow up of about 15 months.
The data were presented during an oral abstract session at the 2024 World Conference on Lung Cancer.
The target antigen of I-DXd (B7-H3) is absent or expressed at low levels in normal tissue, however, it is commonly expressed across multiple malignancies, said thoracic oncologist Charles M. Rudin, MD, PhD, Deputy Director of Memorial Sloan Kettering Cancer Center, New York. B7-H3 is highly and consistently upregulated across all molecular subtypes of SCLC and is associated with poor prognosis.
At the data cutoff in April 2024, 46 patients had been randomized to I-DXd 8 mg/kg and 42 to the 12 mg/kg dose. Median treatment was 4 months for the 8 mg/kg cohort and 5 months for the 12 mg/kg group, respectively.
All patients had ES-SCLC and exposure to one to four lines of previous therapy. About 76% of patients had prior anti-PD-L1 therapy and 35% received a prior TOPO-I inhibitor, either irinotecan or topotecan. The median patient age was 64; 72% were male, and 42% had brain metastases, including untreated asymptomatic metastases.
While the primary endpoint was ORR, key secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Intracranial ORR was an exploratory analysis.
Patients had good DCR, Dr. Rudin reported, with 80% for 8 mg/kg and 91% for 12 mg/kg.
“These responses, when they occur, occur early and are brisk,” he said. “Most responses occur at the first CT scan, at the 6-week time point. Although some of these responses are transient, there is a patient population that is experiencing durable benefits with prolonged responses now lasting over a year on treatment.”
The median PFS was 4 months for 8 mg/kg and 6 months for 12 mg/kg with OS of 9 months and almost 12 months, respectively.
Importantly, the subset of patients with brain metastases had an ORR of 26% at 8 mg/kg and 61% at 12 kg/mg. Patients with intracranial target lesions also did well with systemic response of 17% for 8 mg/kg and 60% for 12 mg/kg and intracranial response rates of 67% and 50% respectively. Dr. Rudin said the high response rates suggest that this relatively large molecule has activity in the central nervous system.
More than 95% of patients had treatment-emergent adverse events (TEAEs) regardless of dose. Both doses were relatively well tolerated with 7% of TEAEs associated with drug discontinuation for 8 mg/kg and 17% for 12 mg/kg. There were deaths in both arms, largely associated with disease progression and infectious complications, Dr. Rudin said.
As expected, the most common TEAEs were gastrointestinal and hematologic, primarily nausea, decreased appetite, anemia, and decreased neutrophil count. Most were grade 1 or 2, he said.
“I-DXd demonstrates promising efficacy in patients with pretreated extensive-stage small cell lung cancer,” Dr. Rudin said. “The 12 mg/kg dose is the recommended phase III dose, and is featured in the ongoing phase III trial in patients with one prior line of therapy, IDeate-Lung02.”
