First-line (1L) datopotamab deruxtecan (Dato-DXd) + rilvegostomig in advanced or metastatic non-small cell lung cancer (a/mNSCLC): Results from TROPION-Lung04 (cohort 5).

Abstract

8521 Background: 1L anti–PD-(L)1 antibodies ± chemotherapy are standard of care for patients (pts) with a/mNSCLC without actionable genomic alterations (AGAs). However, not all pts experience response to treatment. Dato-DXd, a TROP2-directed antibody-drug conjugate, has shown efficacy in pts with a/mNSCLC alone or combined with PD-(L)1 inhibitors. Rilvegostomig, a bispecific antibody targeting PD-1 and TIGIT, has also shown preliminary efficacy in pts with a/mNSCLC. Consequently, the combination of Dato-DXd and rilvegostomig may have the potential to enhance responses. Methods: TROPION-Lung04 (NCT04612751) is a phase 1b, open-label, dose-escalation and expansion study enrolling pts with a/mNSCLC without AGAs. In cohort 5 (C5; C5a, PD-L1 tumor proportion score [TPS] ≥50% and C5b, PD-L1 TPS <50%) treatment-naïve pts received Dato-DXd (6 mg/kg) + rilvegostomig IV Q3W. Pts were treated until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included objective response rate (ORR), duration of response (DoR) and progression-free survival (PFS) per investigator (RECIST v1.1). Results: At data cut-off (DCO; 24 Oct, 2024), 40 pts had received Dato-DXd + rilvegostomig (C5a, n=20; C5b, n=20); 29 (72.5%) had non-squamous histology. Median treatment duration was 5.1 months (range 0.7–18.6); 21 pts discontinued Dato-DXd (adverse events [AEs], n=9; progressive disease [PD], n=9), 20 discontinued rilvegostomig (AEs, n=8; PD, n=9) and 20 (50.0%) pts were still on any study treatment at DCO. All pts (N=40, 100%) had treatment-emergent adverse events (TEAEs); 60.0% (n=24) had grade ≥3 TEAEs and 50.0% (n=20) had serious TEAEs. The most common TEAEs were stomatitis (52.5%; grade 3, 2.5% [n=1]), fatigue (grouped term, 50.0%, all grade 1/2), alopecia (45.0%, all grade 1/2) and nausea (42.5%, all grade 1/2). Ocular surface events occurred in 12 pts (30.0%); grade 4, n=1. Adjudicated drug-related interstitial lung disease/pneumonitis was reported in 5 pts (grade 3, n=2). There were six fatal TEAEs (respiratory failure, general physical health deterioration, death, intestinal perforation, sepsis, cardiac arrest); however, none were related to either study treatment. Confirmed ORR for all pts was 57.5% (95% CI 40.9, 73.0); disease control rate was 95.0% (95% CI 83.1, 99.4). Responses were observed across both squamous (45.5%; 95% CI 16.7, 76.6) and non-squamous histologies (62.1%; 95% CI 42.3, 79.3) and all PD-L1 levels. DoR and PFS were immature at DCO. Conclusions: The safety profile for the combination of Dato-DXd + rilvegostomig was consistent with the expected toxicities of each agent and without new safety findings. Dato-DXd + rilvegostomig had encouraging activity as 1L treatment for pts with a/mNSCLC without AGAs, with responses seen in both histologies and across all PD-L1 levels. Clinical trial information: NCT04612751 .