Background: Programmed death-1 (PD-1) inhibitors are effective in relapsed/refractory classic Hodgkin lymphoma (R/R cHL) with monotherapy CRR 16-28% and median PFS 14-15 months. Hodgkin Reed Sternberg (HRS) cells exhibit near-universal chromosome 9p24.1/CD274 (PD-L1) copy gains, a genetic basis for sensitivity to PD-1 blockade. We recently found that tumor-associated macrophages in proximity to HRS cells express SIRP-alpha, the CD47 ligand. Additionally, HRS cells express CD47, which limits macrophage-mediated phagocytosis following SIRP-alpha engagement (“don’t eat me signal”). These findings provide a preclinical rationale for dual targeting of the PD-1 & CD47 immune checkpoints. In this phase II trial we assessed safety & preliminary efficacy of the anti-CD47 antibody magrolimab with pembrolizumab in R/R cHL.
Methods: Eligible patients had R/R cHL with ECOG PS0-1 & ≥2 prior therapies. Prior anti-PD-1 was permitted if ≥6 months prior. Prior allo-SCT & systemic autoimmune disease were excluded. Patients received magrolimab ramp-up during C1/C2, 45mg/kg from C3, & pembrolizumab 200mg each 21-day cycle. Response was assessed with PET/CT by Lugano & LYRIC criteria. Treatment continued up to 24 months or until progression, toxicity, or transplant.
Results: 8 patients have been enrolled at 2 centers. Median age was 34 years (25-59) & median prior lines of therapy were 2 (2-18). All patients were post auto-SCT. 5/8 received prior PD-1 with 40% refractory to last CPi. The ORR (3 CR, 3 PR) was 75% and 2 with SD. For PD-1 exposed patients the ORR was 60% (1 CR, 2 PR). At a median follow-up of 13 months, treatment is ongoing in 5 patients. Therapy was discontinued in 3 patients: 1) worsening radiotherapy-related mucositis, 2) G3 hepatotoxicity attributed to pembrolizumab, 3) allo-SCT in CR. Transient anemia occurred in 75% of patients (G1-2 62.5%, G3 12.5%). Other G≥3 TRAEs included lymphopenia (n=2) & increased ALT & bilirubin (n=1). An interim safety analysis after the first 6 patients found no DLTs. There were no fatal AEs, G≥3 infectious AEs, or treatment-related deaths. One patient died off study due to PD.
Conclusions: Magrolimab with pembrolizumab is well tolerated and demonstrates promising response rates in patients with R/R cHL, supporting preclinical translational data. The combination of anti-PD-1 & CD47-directed therapies warrants further investigation in R/R cHL. Correlative studies (ctDNA, tumor microenvironment) are planned.
Joseph Schroers-Martin, Michael Spinner, Reid Merryman, Cheryl Chang, Austin Yeung, Chandley Silin, May Powell, Philippe Armand, Margaret A. Shipp, Ranjana H. Advani