Background: Immune-checkpoint inhibition targeting the programmed cell death protein 1 (PD1) axis continues to reshape the therapeutic landscape of classical Hodgkin lymphoma (HL). The randomized phase II GHSG NIVAHL trial previously investigated nivolumab-based 1st-line treatment of early-stage unfavorable HL. With either fully concomitant (4x nivo-AVD) or sequential (4x nivolumab, 2x nivo-AVD, 2x AVD) treatment, each followed by 30Gy involved-site radiotherapy (IS-RT), good tolerability and outstanding 3-year progression-free (PFS) and overall survival (OS) of 99% and 100%, respectively, were reported (Bröckelmann PJ et al. JCO 2023). Additionally, correlative studies on tumor (re-)biopsies, longitudinal blood samples and metabolic tumor volume dynamics indicated very early complete remissions in both treatment arms. The upcoming GHSG phase II INDIE trial will investigate an individualized immunotherapy with the anti-PD1 antibody tislelizumab in this setting.
Trial design: INDIE is an investigator-sponsored open-label phase II trial conducted at 35 GHSG trial sites in Germany. Patients with newly diagnosed early-stage unfavorable HL by GHSG criteria will receive two initial infusions of tislelizumab followed by PET-based restaging. Patients in complete metabolic remission will continue treatment with four additional tislelizumab infusions. Patients with residual metabolic activity will receive concomitant treatment with four cycles of AVD and tislelizumab. In the main cohort of N=100 patients aged 18–60 years, consolidative 30Gy IS-RT will only be applied in case of PET-positive residues. In an exploratory cohort of N=20 patients >60 years of age, 30Gy IS-RT will be applied irrespective of remission status at end of systemic treatment. Primary endpoint is the 1-year PFS and 3-year PFS, OS, feasibility and safety, patient-reported outcomes and correlative studies are secondary endpoints. The trial is registered at clinicaltrials.gov (NCT04837859), financially supported by BeiGene and started recruitment in May 2024.
Outlook: INDIE is the first trial to investigate an individualized immunotherapy in treatment naïve early-stage unfavorable HL, potentially omitting both chemo- and radiotherapy in optimally responding patients. Together with extensive correlative studies on longitudinal tumor biopsies, blood and stool samples, this trial will generate critical insights into response-adapted 1st-line HL immunotherapy.
Paul J. Bröckelmann, Helen Kaul, Michael Fuchs, Carsten Kobe, Christian Baues, Wolfram Klapper, Bastian von Tresckow, Peter Borchmann