Phase I study of iza-bren (BL-B01D1), an EGFR x HER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with driver genomic alterations (GA) outside of classic EGFR mutations.

3001 Background: iza-bren is a first-in-class ADC comprised of an EGFR x HER3 bispecific antibody conjugated to a novel topo-I inhibitor payload (Ed-04) via a stable tetrapeptide-based cleavable linker. Safety/efficacy data from the phase Ib study are presented, focusing on NSCLC patients (pts) with driver mutations outside of classic TKI-sensitizing EGFR mutations. Methods: Phase Ib part of this study included the expansion cohorts, each defined by a pre-specified GA, including EGFR exon 20 insertions, non-classical EGFR mutations, mutations in HER2, ALK, ROS1, BRAF (V600E and others), KRAS (G12C and others), SMARCA4, MET (Exon 14), RET, and NTRK. Pts with these GA who progressed on standard targeted therapies (if available) and no more than one prior line of chemotherapy were enrolled. iza-bren was given at 2.5 mg/kg D1D8 Q3W. Results: As of Dec 5, 2024, a total of 73 NSCLC pts with listed GA were enrolled. Five pts were still on treatment, but were excluded from the analysis due to insufficient follow-up for the first post-baseline scan (see table below). Among 7 pts with EGFR exon 20 insertions, 85.7% (6 out of 7) achieved cPR. Among 8 pts with KRAS G12C mutations, 3 cPR and 1 PR pending confirmation were observed. Efficacy for subgroups will be presented. The most frequent hematologic TRAEs (all grades) were anemia (87.7%), leukopenia (74.0%), thrombocytopenia (74.0%), and neutropenia (72.6%); the most frequent non-hematologic TRAEs were asthenia (42.5%), nausea (41.1%), stomatitis (37.0%), diarrhea (32.9%), and alopecia (31.5%). Grade 3 and above TRAEs which were predominantly hematologic in nature, were able to be effectively managed with standard supportive measure including dose reductions, as demonstrated by the TRAE leading to discontinuation rate of 2.7%. Only 1 case of G2 ILD was observed. Notably, no iza-bren related death was reported. No new safety signals were observed. Conclusions: In NSCLC pts with these GAs, iza-bren showed promising activity with a manageable safety profile, supporting further evaluation of iza-bren in these populations. Clinical trial information: NCT05194982 . Total (N = 68) EGFR mut exon20ins/non-classical(N=12) HER2 mut(N=13) ALK/ROS1/RET fusion(N=19) KRAS/BRAF/MET mut(N=22) SMARCA4(N=2) Prior lines of therapy, median (range) 1 (1-5) 1 (1-2) 1 (1-3) 3 (1-5) 1 (1-2) 1 (1-1) BOR, n PR 31 9 8 5 9 0 cPR 24 8 7 3 6 0 PR pending confirmation 6 1 1 2 2 0 SD 25 3 5 10 7 0 PD 9 0 0 3 5 1 NE [ 1 ] 3 0 0 1 1 1 ORR, % 45.6 75.0 61.5 26.3 40.9 0 cORR, % 35.3 66.7 53.8 15.8 27.3 0 DCR, % 82.4 100.0 100.0 78.9</