518MO TROPION-Lung05: Datopotamab deruxtecan (Dato-DXd) in previously treated non-small cell lung cancer (NSCLC) with actionable genomic alterations (AGAs)

Once targeted therapies and platinum-based chemotherapy (PBC) become ineffective in patients (pts) with advanced/metastatic (a/m) NSCLC with AGAs, few treatments with limited benefit are available. Dato-DXd is an antibody-drug conjugate composed of a TROP2 directed monoclonal antibody covalently linked to a highly potent cytotoxic payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. We report primary results from the global, open-label, phase 2 TROPION-Lung05 trial (NCT04484142) evaluating Dato-DXd in pts with a/m NSCLC with AGAs progressing on or after ≥1 AGA-specific therapy and PBC. Dato-DXd 6 mg/kg was given every 21 days to pts with a/m NSCLC, ECOG status 0 or 1, and ≥1 documented AGA in EGFR, ALK, ROS1, NTRK, BRAF, MET exon 14 skipping, or RET. The primary endpoint was confirmed objective response rate (cORR) by blinded independent central review (BICR). Secondary endpoints included duration of response (DOR) and disease control rate (DCR) by BICR, and safety. A total of 137 pts received ≥1 dose and had a median age of 61.0 y; 71.5% had ≥3 prior lines of therapy for a/m NSCLC; 56.9% had EGFR mutations. As of 14 Dec 2022, 85.4% discontinued therapy, 63.5% had disease progression, and 49.6% died. Median pt duration on study was 15.2 months (mo); cORR was 35.8%, DCR, 78.8%, and median DOR, 7.0 mo; similar response was seen in pts with EGFR mutations (Table). The most common grade ≥3 TEAEs were stomatitis (9.5%), anemia (5.8%), and increased amylase (5.8%).Table: 518MOPrimary results (N=137)EfficacyacORR, n (%) (95% CI)49 (35.8) (27.8-44.4)Complete response4 (2.9)Partial response45 (32.8)cORR in pts with EGFR mutation (n=78)34 (43.6)DCR, n (%)108 (78.8)Median DOR in confirmed responders, mo7.0Safety, n (%)Grade ≥3 TEAEs65 (47.4)Serious TEAEs34 (24.8)TEAEs associated with:Dose reduction30 (21.9)Drug discontinuation13 (9.5)Death2 (1.5)bAdjudicated drug-related ILDGrade 1/24 (2.9)Grade ≥31 (0.7)cILD, interstitial lung disease.aBy BICR. bTwo cases associated with disease progression, unrelated to study drug by investigator. cOne grade 3 reported event, with death due to disease progression by investigator and adjudicated grade 5 ILD. Open table in a new tab ILD, interstitial lung disease.aBy BICR. bTwo cases associated with disease progression, unrelated to study drug by investigator. cOne grade 3 reported event, with death due to disease progression by investigator and adjudicated grade 5 ILD. Dato-DXd showed encouraging antitumor activity, with a clinically meaningful and durable response, in heavily pretreated pts with NSCLC with AGAs. The safety profile was manageable and consistent with prior safety observed with Dato-DXd. These data support inclusion of pts with AGAs in the TROPION-Lung01 study (NCT04656652).