PET IMAGING IN NOVEL ESCALATION OF RADIOTHERAPY DOSE AND TREATED VOLUME AUGMENTS IMMUNOTHERAPY IN B-CELL LYMPHOMA: RESULTS FROM A PHASE I TRIAL (RADD STUDY).

Abstract

Aim: Relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) have limited effective therapies yet are highly radiosensitive. PD-1/PD-L1 inhibitor monotherapy is relatively ineffective in B-cell lymphoma but evidence suggests synergy with cytotoxics and enhanced radiotherapy abscopal effects. We undertook a phase I study escalating radiotherapy dose and volumes with PD-L1i, and explored tumour response with 18F-FDG PET, and radiolabelled anti-CD8 and durvalumab PET. Method(s): Thirty-four enrolled adult eligible patients (29 transplantineligible DLBCL; 5 FL) received external-beam radiotherapy (2.5-30 Gy, 5 or 10 fractions (#)) to between one and three target sites, with standard-dose durvalumab commencing day two of radiotherapy (RT) until progression (RT-Durvalumab). Primary endpoint was radiotherapy recommended phase II dose (RP2D). 18F-FDG PET studies were performed at baseline and for response assessment, with calculation of SUVmax, SUVmean, total metabolic tumour volume (TMTV) and total lesion glycolysis (TLG). A subset of patients underwent PET biodistribution studies of 89Zr-durvalumab & CD8 minibody 89Zr-Dfcrefmirlimab. Result(s): Radiotherapy RP2D was 20 Gy/5# for FL and 30 Gy/10# for DLBCL to 3 sites each with no dose-limiting toxicities. In PET/CT evaluable patients, 66% achieved reduction in target lesions, with 33% achieving shrinkage of >50%. FL overall response was 60% (CR 3 40%), and DLBCL was 14% (CR 10%). RT treatment field responses (TMTV, TLG) were observed in 100% of patients receiving 10Gy or above, and abscopal effect was observed in 21% of patients in these cohorts. There was no association between baseline 18F-FDG PET SUVmax and TMTV and disease response. Baseline tumour CD8 T-cell presence on CD8 PET as measured by SUVmax, and in gene expression profiling of baseline biopsy samples, both correlated with response to therapy (p < 0.05). Conclusion(s): RT-Durvalumab with up to 30Gy/10# radiotherapy to three disease sites is safe with minimal toxicity and offers promising responses in FL. Higher tumour CD8 T-cell presence identified on baseline anti- CD8-PET and tumour tissue correlates with RT-Durvalumab response. These results have direct implication for the design of immune therapy trials in lymphoma patients.