Background: Immune-checkpoint blockade targeting the programmed cell death protein 1 (PD1) axis continue to reshape the therapeutic landscape of classical Hodgkin lymphoma (HL). The randomized phase II GHSG NIVAHL trial investigated nivolumab-based 1st-line treatment of early-stage unfavorable HL, either fully concomitant (4x nivo-AVD) or sequential (4x nivolumab, 2x nivo-AVD, 2x AVD) each followed by 30Gy involved-site radiotherapy (IS-RT; Bröckelmann PJ et al. JAMA Oncol 2020). The most recent update continued to show feasibility, a favorable safety profile and outstanding efficacy with 2-year progression-free (PFS) and overall survival (OS) of 99% and 100%, respectively (Bröckelmann PJ et al. ASH 2020). 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 (200mg Q3W) followed by an FDG-PET/CT based restaging. Patients in complete metabolic remission will continue treatment with four additional tislelizumab infusions (300mg Q4W). Patients with residual metabolic activity will receive concomitant treatment with four cycles of AVD at standard dose and tislelizumab (300mg Q4W, tis-AVD). 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 (Figure 1). In an exploratory 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 with 1- and 3-year OS, 3-year PFS, feasibility and safety, patient-reported outcomes and correlative studies being secondary endpoints. The trial is registered at clinicaltrials.gov (NCT04837859) and financially supported by BeiGene.
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.