Background: TROP2 is an intracellular calcium signaling transducer overexpressed in NSCLC, portending poor survival. DS-1062 is a TROP2-targeting ADC with a novel topoisomerase 1 inhibitor (exatecan derivative, DXd) and promising preclinical antitumor activity. Updated results inclusive of 24 additional dose escalation pts and 32 dose expansion pts from an ongoing phase 1 study of DS-1062 in advanced/metastatic NSCLC are reported (NCT03401385/J101). Methods: Pts aged ≥18 (US) or ≥20 (Japan) with unresectable NSCLC refractory to/relapsed from standard treatment with measurable disease (RECIST v1.1) and available tumor for retrospective TROP2 evaluation were eligible. Primary objectives include maximum tolerated dose (MTD) identification, safety, and tolerability and secondary objectives include efficacy, pharmacokinetics, and incidence of anti-drug antibodies against DS-1062. Pts were eligible regardless of TROP2 level. Results: As of November 16, 2019, 95 pts were treated with ≥1 dose of DS-1062. 63 pts were treated during escalation at 0.27 (n = 4), 0.5 (n = 5), 1.0 (n = 7), 2.0 (n = 6), 4.0 (n = 6), 6.0 (n = 19), 8.0 (n = 8), and 10.0 (n = 8) mg/kg and 32 pts were treated in expansion at the MTD of DS-1062, 8 mg/kg. 59 pts (62%) discontinued (25 [42%] due to progressive disease per RECIST v1.1). Pts were exposed to a median of 3 treatment cycles (range, 1-19). In 88 response-evaluable pts, 22 had partial response (1 PR/6 pts at 2.0 mg/kg, 2 PR/6 pts at 4.0 mg/kg, 5 PR/18 pts at 6.0 mg/kg, 13 PR/34 pts at 8.0 mg/kg, and 1 PR/8 pts at 10.0 mg/kg; 14 PRs were confirmed and 8 PRs are awaiting confirmation). Treatment emergent adverse events (TEAEs) regardless of causality were reported in 91 of 95 pts (96%; 44 pts [46%] experienced ≥grade 3, 30 pts [32%] had serious events). Treatment-related TEAES were reported in 76 of 95 pts (80%; 17 pts [18%] experienced ≥grade 3, 8 pts [8%]) had serious events). Potential interstitial lung disease (ILD) occurred in 8 pts (8%; 2 at 6.0 mg/kg and 6 at 8.0 mg/kg); 6/8 with potential ILDs adjudicated as treatment-related (1 at 6.0 mg/kg [grade 2] and 5 at 8.0 mg/kg [1 grade 1, 2 grade 2, 1 grade 3, and 1 grade 5]). 14 escalation pts and 22 expansion pts remain on trial. Updated trial details/results will be presented. Conclusions: In this first-in-human study of DS-1062, treatment was well tolerated up to 8 mg/kg, and a dose effect on antitumor activity was observed over 2.0-10.0 mg/kg in heavily pretreated pts with prior progression on standard treatment. Clinical trial information: NCT03401385.