Reduction in circulating tumor DNA (ctDNA) in relation to radiographic response and tumor PD-L1 expression in a phase 1 study of PDL1V (PF-08046054) in patients with non-small cell lung cancer (NSCLC).

Abstract

8609 Background: PDL1V (PF-08046054) is a novel, first-in-class, PD-L1–directed vedotin antibody-drug conjugate that consists of MMAE connected to an anti–PD-L1 antibody. Prior results from the phase 1 study (NCT05208762) showed promising antitumor activity and manageable safety in patients (pts) with refractory (2L+) NSCLC. We present ctDNA results from an exploratory analysis in this study. Methods: C5851001 is a phase 1 study in advanced solid tumors. Pts with NSCLC must have prior exposure to platinum and anti–PD-(L)1 agents, targeted therapies for tumors expressing AGAs, and measurable disease per RECIST 1.1. PD-L1 expression status by tumor proportion score (TPS) was reported by local sites. Paired baseline (T0) and on-treatment (T1; C2D15 to C3D1) ctDNA samples were used for ctDNA analyses using a methylation-based tissue-free assay (Guardant Infinity). Tumor fraction (TF) was quantified by methylation score. Changes in ctDNA from T0 to T1 were compared between subgroups using the Wilcoxon test. Results: As of Nov 22, 2025, 55 pts with 2L+ NSCLC received PDL1V: median age 63 yrs, 70.9% ECOG PS 1, 29.1% squamous (SQ) histology, 67.3% TPS ≥1%. The median number of prior lines of therapy was 2.0 (range, 1-8). The investigator-assessed confirmed objective response rate (ORR) was 32.4% (95% CI, 18.0-49.8) in pts with TPS ≥1% NSCLC (n=37) and 0% in TPS <1% (n=18). Grade 3-4 TRAEs occurred in 32.6%. Paired T0 and T1 samples were available in 47/55 pts. ctDNA analysis showed 46/47 pts (98%) had detectable ctDNA at baseline. At T1, ctDNA TF decreased in 36/46 pts (78%) and became nondetectable in 7/46 (15%). Pts with complete or partial responses (CR/PR) had a greater median ctDNA reduction from T0 to T1 than nonresponders (−99% vs −37%, p<0.001). Pts with TPS ≥1% NSCLC had a greater median ctDNA reduction than pts with TPS <1% NSCLC (−77% vs −4%, P =0.0023). For pts with TPS ≥1% NSCLC, there was no significant difference in median ctDNA reduction between nonsquamous (NSQ) and SQ histology (–73% vs –87%, p=0.48). Conclusions: PDL1V monotherapy showed promising antitumor activity with a manageable safety profile in pts with 2L+ TPS ≥1% NSCLC. Most pts had ctDNA reduction with PDL1V treatment, with greater ctDNA reduction in pts with radiographic response and TPS ≥1% NSCLC. These data further support evaluation of PDL1V in the ongoing phase 3 trial in 2L+ PD-L1+ NSCLC, SQ and NSQ (NCT07144280/PADL1NK-005) and the continued use of ctDNA for response monitoring and potential early prediction of clinical benefit. Clinical trial information: NCT05208762 . Subgroup n ctDNA reduction (%) from T0 to T1median (lower/upper quartile) By ORR CR/PR 12 −99 [−100 to −93] SD/PD 34 −37 [−72 to 5] By PD-L1 status TPS <1% 14 −4 [−36 to 26] TPS ≥1% 32 −77 [−98 to −39] TPS 1%-49% 17 −72 [−82 to −38] TPS ≥50% 15 −91 [−100 to −41] By histology TPS ≥1% NSQ 24 -73 [-95 to -38] SQ 8 -87 [-98 to -70]