Abstract 104TiP
Background
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.
Trial design
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.
Clinical trial identification
EU Trial Number: 2022-502010-85-00; 10 May 2023/Version 2.1-EU NCT05882734.
Editorial acknowledgement
Medical writing services (funded by Merck) were provided by Mario Pahl of Bioscript Group, Macclesfield, UK.
Legal entity responsible for the study
Merck Healthcare KGaA.
Funding
Merck Healthcare KGaA, Frankfurter Strasse 250, Darmstadt, 64293, Germany.
Disclosure
L. Paz-Ares: Financial Interests, Institutional, Full or part-time Employment: Hospital Universitario 12 de Octubre; Financial Interests, Personal, Invited Speaker: Amgen. F. Cappuzzo: Financial Interests, Personal, Full or part-time Employment: Azienda Unità Sanitaria Locale, AUSL della Romagna, Ravenna, Italy; Financial Interests, Personal, Principal Investigator: Merck; Financial Interests, Personal, Sponsor/Funding: Merck. N. Yamamoto: Financial Interests, Personal and Institutional, Full or part-time Employment: National Cancer Center Hospital, Tokyo, Japan; Financial Interests, Personal, Speaker’s Bureau: ONO, Chugai, Daiichi Sankyo, Eisai; Financial Interests, Personal, Advisory Board: Eisai, Takeda, Boehringer Ingelheim, Cmic, Chugai, MERCK, Healios; Financial Interests, Personal and Institutional, Other, Research Grant: Astellas, Chugai, Eisai, Taiho, BMS, Pfizer, Novartis, Eli Lilly, AbbVie, Daiichi Sankyo, Bayer, Boehringer Ingelheim, Kyowa Kirin, Takeda, ONO, Janssen Pharma, MSD, Merck, GSK, Sumitomo Pharma, Chiome Bioscience, Otsuka, Carna Biosciences, Genmab, Shiono; Financial Interests, Institutional, Principal Investigator: Merck; Financial Interests, Personal, Sponsor/Funding: Merck. N. Vokes: Financial Interests, Personal, Full or part-time Employment: University of Texas, MD Anderson Cancer Center, Houston, USA; Financial Interests, Personal, Principal Investigator: Merck; IDEAYA; Regeneron; Financial Interests, Personal and Institutional, Sponsor/Funding: Merck; Financial Interests, Personal, Advisory Role: Sanofi, OncoCyte, Eli Lilly, Regeneron, Amgen, Xencor, AstraZeneca, Tempus. J.E. Gray: Financial Interests, Personal, Full or part-time Employment: Moffitt Cancer Center, Tampa, USA; Financial Interests, Personal, Advisory Board: AbbVie; AstraZeneca; Blueprint Medicines; Daiichi Sankyo, Inc; EMD Serono - Merck KGaA; Gilead Sciences, Inc; IDEOlogy Health; Janssen Scientific Affairs; Jazz Pharmaceuticals; Loxo Oncology Inc; Merck & Co, Inc; Novartis; OncoCyte Biotechnology; Spectrum; Financial Interests, Personal, Member of Board of Directors: ISLAC Board of Directors; SWOG Lung Committee Chair; Financial Interests, Personal, Principal Investigator: Merck; Financial Interests, Personal, Sponsor/Funding: Merck. T.K. Owonikoko: Financial Interests, Personal, Full or part-time Employment: University of Pittsburgh, Pittsburgh, USA, University of Maryland, Baltimore, MD; Financial Interests, Personal, Stocks/Shares: Coherus Biosciences; GenCART; Cambium Oncology; Taobob LLC.; Fortess Biotech; Exelixis; Financial Interests, Personal, Advisory Board: Novartis; Lilly; Eisai; Bristol Myers Squibb; Amgen; AstraZeneca; Boehringer Ingelheim; EMD Serono; XCovery; Bayer; Merck; Oncocyte; Takeda; Jazz Pharmaceuticals; Zentalis; Ipsen; Daiichi Sankyo; Janssen; BeiGene; Genentech; Coherus; GenCART; Heat Biologi; Financial Interests, Personal, Officer: ASCO; Financial Interests, Personal, Member of Board of Directors: ASCO; Financial Interests, Personal, Principal Investigator: Merck, Ymabs, Inc.; Amgen; AstraZeneca; Calithera Biosciences; Novartis; Boehringer Ingelheim; Cyclacel; Financial Interests, Personal, Sponsor/Funding: Merck. R. Ariyasu: Financial Interests, Personal, Full or part-time Employment: Cancer Institute Hospital of JFCR, Tokyo, Japan; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Chugai Pharmaceutical, Bristol Myers Squibb; Financial Interests, Personal, Principal Investigator: Merck; Financial Interests, Personal, Sponsor/Funding: Merck. H. Ishii: Financial Interests, Personal, Full or part-time Employment: Kurume University Hospital, Kurume, Japan; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Principal Investigator: Merck, Sanofi; Financial Interests, Personal, Sponsor/Funding: Merck. J.H. Kang: Financial Interests, Personal, Full or part-time Employment: Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim, Roche, MSD, Takeda; Financial Interests, Personal, Advisory Board: Yoohan, BeiGene AstraZeneca, Daiichi Sankyo, Novartis; Financial Interests, Personal, Research Grant: Yoohan, BeiGene AstraZeneca, Daiichi Sankyo, Novartis. S. Lee: Financial Interests, Personal, Full or part-time Employment: Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Financial Interests, Personal and Institutional, Principal Investigator: Merck; Financial Interests, Personal, Sponsor/Funding: Merck. R. Hallwachs: Financial Interests, Personal, Full or part-time Employment: Merck Healthcare KGaA, Darmstadt, Germany; Financial Interests, Personal, Stocks/Shares: Merck KGaA. A. Coenen-Stass: Financial Interests, Personal, Full or part-time Employment: Merck Healthcare KGaA, Darmstadt, Germany. B. Sarholz: Financial Interests, Personal, Full or part-time Employment: the healthcare business of Merck KGaA, Darmstadt, Germany; Financial Interests, Personal, Stocks/Shares: Merck. L.A. Pudelko: Financial Interests, Personal, Full or part-time Employment: Merck Healthcare KGaA, Darmstadt, Germany. J. Mukker: Financial Interests, Personal, Full or part-time Employment: EMD Serono, Billerica, MA USA. C. Moulin Correa: Financial Interests, Personal, Full or part-time Employment: Ares Trading SA, Eysins, Switzerland, an affiliate of Merck KGaA. I. Gounaris: Financial Interests, Personal, Full or part-time Employment: Merck Serono Ltd., Feltham, UK, an affiliate of Merck KGaA, Darmstadt, Germany; Financial Interests, Personal, Stocks/Shares: Novartis, Alcon and Sandoz. L. Villaruz: Financial Interests, Personal, Full or part-time Employment: University of Pittsburgh, USA; Financial Interests, Personal, Sponsor/Funding: Merck; Financial Interests, Personal, Other, Consulting fees: Takeda, Janssen, Intervenn Biosciences, Sanofi, Daiichi Sankyo, Jazz, BMS, Gilead, Johnson and Johnson, EMD Serono.