Iflinatamab Deruxtecan Elicits Clinical Activity in SCLC

Treatment with the antibody-drug conjugate (ADC) ifinatamab deruxtecan (I-DXd; DS-7300) in heavily pretreated patients with small cell lung cancer (SCLC) led to promising efficacy and a manageable safety profile, according to data from a phase 1/2 study (NCT04145622) presented at the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer.¹

At median follow-up of 11.7 months for the phase 1/2 study (NCT04145622), there was a 52.4% objective response rate (ORR) in patients with SCLC (95% CI, 29.8-74.3), with a median progression-free survival (PFS) of 5.6 months (95% CI, 3.9-8.1). Although I-DXd targets B7 homolog 3 (B7-H3), an analysis showed no correlation between B7-H3 and efficacy parameters in these patients.

“I-DXd, a novel B7-H3–directed DXd-ADC, continues to demonstrate robust and durable efficacy in patients with heavily pretreated SCLC,” investigators stated in their presentation.

B7-H3 is a transmembrane immunoregulatory protein that is overexpressed in cancers, including SCLC, in which 65% of patients have moderate to high expression. This 2-part study investigated I-DXd in patients with advanced solid tumors, including SCLC, using dose-escalation followed by dose-expansion to investigate its safety, tolerability, and antitumor activity.

Investigators presented a subgroup analysis of 22 patients in the dose-escalation portion who had SCLC, 21 of whom received at least 6.4 mg/kg of I-DXd and were evaluable for efficacy. These patients received I-DXd between 3.2 mg/kg and 16.0 mg/kg. They had a median age of 61 (range, 40-84), 14 (63.6%) of them were male, and 15 (68.2%) had an ECOG performance status of 1, with the rest having a performance status of 0. All had received prior platinum-based chemotherapy, with 81.8% having received immunotherapy. Seventeen patients were in the United States and 5 were located in Japan.

Key primary end points for the dose-escalation portion of the trial were dose-limiting toxicities, serious adverse events, treatment-emergent adverse events (TEAEs), and adverse events of special interest. In the dose-expansion portion, ORR, duration of response (DOR), PFS, disease control rate, and overall survival (OS) were evaluated as primary end points. Secondary end points included pharmacokinetics and immunogenicity.

Almost all patients had a reduction in target lesion size in post-baseline scans, with a median time to response of 1.2 months (95% CI, 1.2-1.4). Partial responses were observed in 47.6% and complete responses in 4.8%, confirmed by RECIST v1.1 criteria. The median DOR was 5.9 months (95% CI, 2.8-7.5). At the data cutoff of January 31, 2023, the median OS was 12.2 months (95% CI, 6.4-not applicable).

Patients with SCLC were treated for a median of 3.9 months (range, 0.03-12.5), with a median of 6.5 cycles (range, 1.0-18.0). Two patients remained on treatment after the data cutoff.

The safety profile in the SCLC subgroup was consistent overall with that reported in the overall population. All patients reported at least 1 TEAE, and 8 (36.4%) had a grade 3 or higher TEAE. Five patients (22.7%) had a TEAE associated with discontinuation of I-DXd, whereas 3 each had TEAEs that led to dose delay and dose reduction, respectively. There was 1 TEAE associated with death, which was COVID-19 pneumonia, that was determined to not be treatment-related.

The most common any-grade TEAEs included nausea in 13 (59.1%), fatigue in 11 (50.0%), anemia in 6 (27.3%), vomiting in 6 (27.3%), and decreased appetite in 5 (22.7%). Grade 3 or higher TEAEs included 1 patient with nausea (4.5%), 1 with decreased appetite (4.5%), and 1 with constipation (4.5%). Three patients (13.6%) experienced interstitial lung disease (ILD) or pneumonitis, 2 of which were grade 1 and 1 which was grade 2. The patient with grade 2 ILD received a dose of 8.0 mg/kg, and this was determined to be treatment-related, leading to treatment discontinuation. Patients were not permitted to receive premedication for nausea, vomiting, and infusion-related reaction in cycle 1.

Seventeen patients were retrospectively examined for B7-H3 protein level by immunohistochemistry for correlative analysis. There was no correlation found between B7-H3 combined membrane/cytosol H-score with ORR, PFS, or OS. Patients with above-median H-score had an ORR of 55.6% vs 62.5% for below-median. The median PFS was 5.3 months (1.4- not applicable [NA] in above-median B7-H3 vs 5.8 months (0.7-NA) for those below the median. The median OS was 6.9 months (2.8-NA) in those with above-median B7-HC vs 12.2 months (5.8-NA) in those with below-median B7-H3.

Investigators stated that the correlative relationship between the protein level and efficacy will be evaluated further in future I-DXd studies. These include the IDeate-1 phase 2 trial (NCT05280470) of patients with extensive-stage SCLC which will randomly assign patients to 1 of 2 dose levels (8.0 mg/kg or 12.0 mg/kg) of I-DXd to determine the recommended phase 2 dose.

“These data support further clinical development of I-DXd, including a phase 2 study of patients with extensive stage SCLC following 1-3 prior lines of therapy,” investigators stated in their presentation.

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. Presented at: World Conference on Lung Cancer; September 9-12, 2023; Singapore. Oral abstract OA05.05.