CIRCULATING TUMOR DNA SEQUENCING REVEALS RAPID RESPONSE KINETICS TO ANTI-PD1 BASED FIRST-LINE TREATMENT OF HODGKIN LYMPHOMA: MOLECULAR INSIGHTS FROM THE GHSG NIVAHL TRIAL

Abstract

P. J. Bröckelmann, S. Borchmann equally contributing authors.

Anti-PD1 immune checkpoint blockade (ICB) has been incorporated into first-line treatment of classic Hodgkin lymphoma (HL) in several clinical trials recently. The GHSG NIVAHL trial demonstrated high response rates to both sequential and concomitant treatment with ICB and chemotherapy (Bröckelmann, JCO, 2023). However, it remains unclear whether some patients might achieve long-term remission following ICB alone and how to identify them without risking treatment failure. Recently, two studies established a circulating tumor (ct)DNA-based biologic classification of HL including subtypes with an immune escape phenotype that might be particularly sensitive to ICB (Alig, Nature, 2024; Heger, JCO, 2024). Despite these advances, the role of biologic HL classifiers and ctDNA-based minimal residual disease (MRD) kinetics during anti-PD1 first-line treatment have not yet been studied.

The multicenter, randomized GHSG phase II NIVAHL trial evaluated an either sequential or concomitant combination of AVD with the anti-PD1 antibody nivolumab (N) in 109 patients with previously untreated, early-stage unfavorable HL. ctDNA sequencing was applied to plasma samples obtained at baseline, one week after treatment initiation and at all three imaging response assessments as previously described (Heger, JCO, 2024).

Samples were available from 69 (baseline), 23 (after 1xN-AVD or 1xN), 30 (first restaging after 2xN-AVD or 4xN), 24 (end of systemic therapy after cumulatively 4xN-AVD) and 24 (following 30 Gy IS-RT) patients, respectively. Patient characteristics of this subset were representative of the whole study cohort. Strikingly, 6/19 (31.6%) patients achieved MRD negativity following just one infusion of nivolumab. Patients with Inflammatory immune escape HL or Virally-driven HL had higher rates of MRD negativity after just one infusion of nivolumab compared with patients with Oncogene-driven HL (50% versus 23.1%, Figure 1A). At later timepoints, assessment of MRD allowed for the detection of complete molecular response also in patients with remaining metabolic activity by Deauville-score based PET assessment: At the end of systemic therapy, 8/24 (33.3%) patients were PET positive, while MRD indicated complete molecular remission in 24/24 (100%) of patients (Figure 1B). Importantly, with a median follow-up of 41 months, none of the 8 PET positive patients relapsed or died.

Here, we present the first study evaluating the impact of biologic HL classifiers and very early MRD kinetics in HL patients receiving ICB first-line treatment. Our results suggest that molecular risk stratification might allow to select HL patients with exceptional benefit from anti-PD1 ICB alone. In these patients, chemotherapy might be reduced or omitted in future clinical trials. At the end of systemic anti-PD1 based first-line treatment, MRD might allow for more reliable detection of complete remission despite residual PET-positivity and thus spare patients from consolidative radiotherapy.

Research funding declaration: Deutsche Forschungsgemeinschaft EN179/13-1, BO5316/2-1, BO5316/3-1 (BvT, SB); Else Kröner Forschungskolleg Clonal Evolution in Cancer Cologne; Mildred Scheel Nachwuchszentrum Grant 70113307 (JMH, PJB)

Keywords: liquid biopsy; diagnostic and prognostic biomarkers; Hodgkin lymphoma

Potential sources of conflict of interest:

J. Heger

Consultant or advisory role: Incyte, Roche, Miltenyi Biotec, Novartis, SOBI, SERB Pharmaceuticals

Honoraria: Incyte, Roche, Miltenyi Biotec, SOBI, SERB Pharmaceuticals

Educational grants: SOBI, SERB Pharmaceuticals

Other remuneration: Incyte, MorphoSys, Novartis

B. von Tresckow

Consultant or advisory role: Allogene, Amgen, BMS/Celgene, Cerus, Gildead Kite, Incyte, IQVIA, Janssen-Cilag, Lilly, Merck Sharp & Dohme, Miltenyi, Novartis, Noscendo, Pentixapharm, Pfizer, Pierre Fabre, Qualworld, Regeneron, Roche, Sobi, Takeda

Honoraria: AbbVie, AstraZeneca, BMS/Celgene, Gilead Kite, Incyte, Janssen-Cilag, Lilly, Merck Sharp & Dohme, Novartis, Roche, Serb, Takeda

Educational grants: AbbVie, AstraZeneca, Gilead Kite, Janssen-Cilag, Lilly, Merck Sharp & Dohme, Pierre Fabre, Roche, Takeda, Novartis

Other remuneration: Esteve (Inst), Merck Sharp & Dohme (Inst), Novartis (Inst), Takeda (Inst)