Phase 2b randomized, blinded, placebo-controlled trial to investigate the efficacy and safety of visugromab added to pembrolizumab, pemetrexed, and carboplatin in first-line metastatic non-squamous NSCLC: GDFATHER-NSCLC-01.

Abstract

TPS8665 Background: Immune checkpoint inhibitors (ICIs) have improved outcomes in NSCLC, yet primary and secondary resistance remain common, limiting durable benefit. Growth differentiation factor 15 (GDF-15) has been implicated in ICI resistance. Clinical data for the anti–GDF-15 antibody visugromab in combination with nivolumab have been presented, demonstrating reinvigoration with deep and durable responses in relapsed/refractory solid tumors and increased efficacy in an ICI-naïve neoadjuvant setting, strongly supporting further evaluation in ICI-naïve NSCLC. This trial estimates the added clinical activity and safety of visugromab with standard chemo-immunotherapy and addresses primary immune resistance in first-line metastatic non-squamous NSCLC. Methods: GDFATHER-NSCLC-01 is a phase 2b, multicenter trial with an initial safety-run-in (SRI) followed by a randomized, double-blind, placebo-controlled part, conducted at >40 sites in seven countries across the US and Europe. The SRI employs a 3+3 dose escalation (two predefined visugromab dose levels; DLT window of 21 days) to determine the recommended dose for expansion; an independent data monitoring committee oversees escalation and the selection of the expansion dose. In the randomized part, participants with untreated metastatic non-squamous NSCLC (no actionable driver mutations), ECOG 0–1, are assigned 2:1 to receive visugromab or placebo in combination with pembrolizumab, pemetrexed, and carboplatin (21-day cycles). Brain metastases are allowed if untreated, asymptomatic and clinically stable, or if previously treated and stable per protocol. Patients are stratified according to PD-L1 tumor proportion score (<1% vs 1–49% vs ≥50%). The primary endpoint of the trial is objective response rate (RECIST v1.1). Key secondary endpoints include duration of response, progression-free survival, overall survival, safety, pharmacokinetics, and patient-reported outcomes; exploratory biomarker analyses are planned. The randomized part is not powered for statistical significance; the planned sample size is 90 participants, enabling descriptive estimation of effect sizes to inform future pivotal development. Enrollment status: The SRI has been completed. The randomized part is open to accrual; first patient pending. Clinical trial information: NCT07098988 .