104TiP Phase Ib/IIa study of ATR inhibitor tuvusertib + anti-PD-1 cemiplimab in patients with advanced non-squamous (nsq) non-small cell lung cancer (NSCLC) that has progressed on prior anti-PD-(L)1 and platinum-based therapies

Immune checkpoint inhibitors (ICI) have improved outcomes in NSCLC, but primary or acquired resistance limits treatment options for patients with disease progression on anti-PD-(L)1 and platinum-based therapies. Growing evidence indicates that ataxia telangiectasia and Rad3-related protein kinase inhibition (ATRi) modulates antitumor immunity, and the ATRi + ICI combination is active in patients with ICI-resistant tumours. ATRi + ICI may have the potential to overcome ICI resistance and induce antitumor immune responses in patients with advanced NSCLC, particularly in tumours harbouring ATRi-sensitizing mutations. This open-label, multicentre, phase Ib/IIa study (NCT05882734) evaluates the efficacy, safety, tolerability, and pharmacokinetics of tuvusertib + cemiplimab. Eligible patients have nsq NSCLC that has progressed on prior anti-PD-(L)1 and platinum-based therapies, with a response of stable disease or better to prior anti PD-(L)1-therapy. Patients with tumours harbouring actionable EGFR or ALK genomic alterations are excluded. In the randomised phase Ib, two dosing regimens, tuvusertib 100 mg once-daily (QD) + cemiplimab 350 mg Q3W (n=30) or tuvusertib 180 mg QD 2 weeks on/1 week off + cemiplimab 350 mg Q3W (n=30), are being evaluated. Based on a totality of evidence approach, the most favourable regimen will be selected for investigation in phase IIa, in which patients will be treated in 3 separate strata based on genetic alterations detected in ctDNA: stratum A (n=40), STK11 or KEAP1; stratum B (n=40), ATM or ARID1A or SMARCA4 or PBRM1; stratum C (n=40), any other/no alterations. Tumour genetic characteristics will be assessed by a central liquid biopsy assay. Primary endpoints are investigator-assessed objective response (OR; RECIST v1.1), occurrence of adverse events (AE), and treatment-related AEs in phase Ib, and OR in phase a. Secondary endpoints in both phases include duration of response, progression-free survival, and overall survival. The study is open for enrollment in centres across the USA, Italy, Spain, France, Japan and Korea. EU Trial Number: 2022-502010-85-00; 10 May 2023/Version 2.1-EU NCT05882734. Medical writing services (funded by Merck) were provided by Mario Pahl of Bioscript Group, Macclesfield, UK. Merck Healthcare KGaA. Merck Healthcare KGaA, Frankfurter Strasse 250, Darmstadt, 64293, Germany.