DB-1310, a HER3-targeted ADC, in pts with advanced solid tumors: Preliminary results from the phase 1/2a trial.

3000 Background: DB-1310 is a novel ADC comprised of a humanized anti-HER3 IgG1 monoclonal antibody, cleavable peptide linker, and DNA topoisomerase I inhibitor. Here, we report the preliminary results of the FIH trial. Methods: This global, multi-center, open-label Ph 1/2a trial includes dose escalation and expansion. Pts with advanced solid tumors who had failed standard therapy were enrolled. In Ph1, DB-1310 was planned to be administered at doses from 1.5 mg/kg to 6.5 mg/kg, Q3W, iv, using a 3+3 design, with additional pts enrolled to determine the RP2D. Ph 2a will include approximately 30-40 pts per cohort to optimize the RP2D and assess efficacy. Results: As of Jan 17, 2025, 123 pts were enrolled and treated with DB-1310 monotherapy in Ph1 (ECOG PS 1, 80.5%; White, 39.0%, Asian, 52.8%; NSCLC, 65.0%, EGFRm NSCLC, 37.4%; brain metastasis, 17.1%), median prior lines of systemic therapy was 3 (range, 1-11). Of the 42 efficacy-evaluable pts with EGFRm NSCLC, 92.9% had previously received 3 rd generation EGFR TKI, 92.9% had received platinum-based chemotherapy. The unconfirmed ORR was 25.5% (95% CI, 17.63, 34.65) across all tumor types and 35.7% (95% CI, 21.55, 51.97) in EGFRm NSCLC. Median PFS was 5.4 months overall and 7.0 months for EGFRm NSCLC. 38 (30.9%) pts experienced ≥ G3 TRAEs, while 7 (5.7%) had drug-related SAEs. TRAEs led to dose reduction in 14 (11.4%) pts and discontinuation in 5 (4.1%) pts. No TRAE leading to death was reported. Most common TRAE ( > 20%, any grade/≥G3) were nausea (36.6%/0.8%), anemia (35.8%/4.1%), neutrophil count decreased (34.1%/17.9%), platelet count decreased (31.7%/9.8%), white blood cell count decreased (29.3%/8.9%), decreased appetite (23.6%/0.8%), and vomiting (21.1%/0%). Interstitial lung disease occurred in 7 pts (5.7%, 6 G1 and 1 G2). PK exposure was increased through dose escalation, with low systemic payload exposure and no accumulation of DB-1310 upon repeated administration. Conclusions: DB-1310 showed a manageable safety profile and encouraging antitumor activity in pts with heavily pretreated advanced solid tumors, particularly EGFRm NSCLC. Clinical trial information: NCT05785741 . Tumor response by dose (efficacy-evaluable). Dose (mg/kg) 1.5 3 4.5 5.0 5.5 6 Total All tumors, n 3 10 25 53 16 3 110 uORR, n (%) (95% CI) 0 (0)(0.00, 70.76) 1(10.0)(0.25, 44.50) 8 (32.0)(14.95, 53.50) 13 (24.5) (13.76, 38.28) 6 (37.5) (15.20, 64.57) 0 (0)(0.00, 70.76) 28 (25.5) (17.63, 34.65) DCR, n (%) (95% CI) 3 (100.0)(29.24, 100.00) 8 (80.0)(44.39, 97.48) 23 (92.0)(73.97, 99.02) 42 (79.2) (65.89, 89.16) 11 (68.8) (41.34, 88.98) 2 (66.7) (9.43, 99.16) 89 (80.9) (72.31, 87.78%) EGFRm NSCLC, n 0 7 9 16 8 2 42 uORR, n (%) (95% CI) - 1 (14.3)(0.36, 57.87) 4 (44.4) (13.70, 78.80) 5 (31.3) (11.02, 58.66) 5 (62.5) (24.49, 91.48) 0 (0)(0.00, 84.19) 15 (35.7) (21.55, 51.97) DCR, n (%) (95% CI) - 6 (85.7) (42.13, 99.64) 9 (100.0) (66.37, 100.00) 14 (87.5) (61.65, 98.45) 7 (87.5) (47.35, 99.68) 2 (100.0)(15.81, 100.00) 38 (90.5) (77.38, 97.34)