1500TiP - REFINE-Lung is a multicentre phase III study to determine the optimal frequency of pembrolizumab in non-small cell lung cancer utilising a novel multi-arm design

Background

Standard regimens for anti-PD1 agents nivo and pembro may result in overtreatment. These agents have high target affinity, saturate PD1 at low concentrations, occupy PD1 long after discontinuation and have a flat dose-response relationship across a wide range tested. Lower doses or longer administration frequency may retain efficacy. New approaches to optimise treatment regimens are required to enhance cost-effectiveness, pt quality of life and toxicity. However, conventional 2-arm non-inferiority designs are inefficient for this. We present a new multi-arm trial design to tackle the problem, implemented in the UK multicentre phase III REFINE-Lung study that aims to determine the optimal treatment frequency of pembro in NSCLC. Pts progression free after 6 months of standard therapy are randomised to 5 pembro frequency reduced arms (q6w, q9w, q12w, q15w and q18w). By evaluating the frequency-response relationship, the longest frequency that is equivalent to standard of care within a pre-defined margin will be determined.

Trial design

The REFINE-Lung trial (NCT05085028) is a multicentre, randomised open-label, phase III trial in advanced NSCLC, utilising a novel Multi-Arm Multi-Stage Response Over Continuous Interventions (MAMS-ROCI) design. 1750 pts aged ≥18 and progression free at six months of 1st line pembro and planning to continue, will be enrolled from up to UK 35 hospital groups. Pts will be randomised equally to 5 dose frequency arms, starting with q6w (control) vs. q12w arms for an interim analysis of safety. If q12w PFS is not significantly reduced, remaining q9w, q15w and q18w arms will be opened. Pts who progress may re-escalate to q6w therapy. Primary objective is to determine the optimal dose frequency of pembro, defined as the longest dose interval non-inferior to standard therapy using 2-year survival as the primary outcome. Secondary endpoints include OS, PFS, toxicity, quality of life and cost effectiveness. An exploratory sub-study will explore fundamental aspects of cancer immunotherapy and develop novel biomarkers of response, resistance and toxicity. The trial is currently open at 26 centres.

Clinical trial identification

Sponsor Protocol No.: C/41/2021; EudraCT: 2021-004908-18; NCT05085028.

Editorial acknowledgement

Legal entity responsible for the study

Imperial College of Science, Technology and Medicine.

Funding

National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme.

Disclosure

E. Ghorani: Financial Interests, Personal, Other, patent associated with T cell dysfunction: N/A. F. Blackhall: Financial Interests, Personal, Invited Speaker, Educational Symposium lecture: AstraZeneca; Financial Interests, Personal, Advisory Board, NTRK Advisory Board and guidelines for diagnosis: Bayer; Financial Interests, Personal, Other, IDMC Chair: AstraZeneca; Financial Interests, Personal, Advisory Board, Small cell Advisory Board Oct 2020 : Amgen; Financial Interests, Personal, Invited Speaker, ESMO Satellite Symposium November 2020 : Takeda; Financial Interests, Personal, Other, Consultancy for RETinhibitor development: Blueprint; Financial Interests, Personal, Other, Real world evidence research study design and analysis (EGFR): Janssen; Financial Interests, Institutional, Invited Speaker, Institutional payment for clinical trial activities: Amgen, Pfizer; Financial Interests, Institutional, Invited Speaker, Payment for clinical trial activities: Mirati; Financial Interests, Institutional, Invited Speaker, Clinical trial activities: BMS; Financial Interests, Institutional, Funding, Real world evidence research programme: Roche; Non-Financial Interests, Advisory Role, Application of genotyping platforms in lung cancer: Guardant Health; Non-Financial Interests, Advisory Role, Clinical trials of IMPs in lung cancer and translational lung cancer biomarkers: AstraZeneca. M.E.R. O'Brien: Financial Interests, Personal, Royalties, Fast Facts: Non small cell lung cancer, edition 1 and 2: Karger Publisher; Financial Interests, Personal, Advisory Board: MSD, Amgen, Puma, Pierre Fabre, Iteos, AstraZeneca, Sanofi; Financial Interests, Personal, Other, Lecture to Chinese oncologist sponsored by Lilly and by Roche.: Lilly and Roche; Financial Interests, Personal, Other, Attendance at ASCO 2022: MSD; Financial Interests, Personal, Other, Attendance at ESMO 2022: ESMO; Financial Interests, Personal, Advisory Board, IDMC member - Lagoon Trial: PharmaMar Lurbinectinib. C.H.H. Ottensmeier: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Roche Genentech; Financial Interests, Personal, Other, consulting: Sebastian Bio; Financial Interests, Personal, Other, member of SAB: Neuvogen; Financial Interests, Institutional, Research Grant, trial funding: Verastem, Merck Sharp and Dohme; Financial Interests, Institutional, Invited Speaker, phase I trial: Transgene; Financial Interests, Institutional, Invited Speaker: Delcath Systems, PsiOxus, Touchlight Genetics. J. Spicer: Financial Interests, Institutional, Advisory Role: 4D Pharma, Apobec, Avacta, AstraZeneca, BMS, Roche; Financial Interests, Personal, Stocks/Shares, Co-founder: Epsilogen Ltd; Financial Interests, Institutional, Principal Investigator: Achilles, BergenBio, Boehringer, IO Biotech, MSD, Roche, RS Oncology, SeaGen, Starpharma; Non-Financial Interests, Personal, Other, Attendance at scientific meetings: Amgen; Non-Financial Interests, Personal, Other, Attendance at scientific meeting: BMS; Non-Financial Interests, Personal, Officer, Attendance at scientific meeting: Janssen. C. Milner-Watts: Financial Interests, Personal, Other, Honoraria: AstraZeneca. M.J. Seckl: Financial Interests, Personal and Institutional, Research Grant: NIHR. All other authors have declared no conflicts of interest.