Durvalumab and Acalabrutinib for Relapsed/Refractory (r/r) High-Grade B-Cell Lymphoma: MoST15, Open Label Phase II Sub-Study of the Molecular Screening and Therapeutics in Leukaemia and Lymphoma (MoST-LLy) Framework
Authors: Blunt Danielle N , Harrup Rosemary , Amor Gerlinda , Christensen Helen , Finlayson Sarah , Lin Frank , Ross David M , Dobbins Julia , Brown Anna , Scott Hamish S , Lane Steven W 
Published: December 2024

Participants with high-grade B-cell lymphoma who relapse after frontline immunochemotherapy have a dismal prognosis. Chimeric antigen receptor T-cell (CAR-T) and bispecific T-cell antibodies are effective treatments. However, access remains limiting for many participants and further effective regimens with tolerable safety profiles are needed.

Methods:

MoST15 (ACTRN12621000507886) is an open-label single arm multicentre phase IIa signal-seeking trial embedded within the MoST-LLy master trial framework. As part of this framework, 155 participants with advanced hematological malignancy have received baseline tumour genomic screening with the TSO500 (Illumina) panel. Ethnicity of this cohort was predominantly Australian of European ancestry, but also included Asian, African, and Pacific Islands ancestry.

MoST15 inclusion criteria include high grade relapsed/refractory B-cell lymphoma with ECOG 0-2 and clinical or radiological measurable disease assessed by Response Evaluation Criteria in Lymphoma 2017 (RECIL). Participants are not permitted to have prior treatment PD1/PD-L1 or BTK inhibitor, however prior CAR-T therapy is permitted. The primary endpoint is to determine the combined clinical activity of durvalumab and acalabrutinib, defined as at least 8 of 32 participants achieving response assessed by RECIL. Secondary endpoints include overall and progression-free survival (OS and PFS). Exploratory analysis of predictive biomarkers includes mutational patterns, tumour mutational burden (TMB), and PD-L1 expression. The data cut-off for this interim analysis was 13 Jun 2024.

Study treatment: Durvalumab is a monoclonal antibody that blocks PD-L1 (programmed cell death ligand-1) to restore T-cell activation and anti-tumour responses. Acalabrutinib inhibits Bruton Tyrosine Kinase (BTK), an essential component of oncogenic signalling in many B-cell malignancies. Durvalumab was administered at 1500mg IV every 28 days and acalabrutinib 100mg orally twice daily until progression. Survival was estimated using Kaplan-Meier methods. Results:

21 participants (9 female) received study treatment. The median age was 76yrs (range 53-87). The median prior lines of systemic therapy was 3 (range 1-5). All participants received prior chemotherapy, with 62% also receiving prior radiotherapy. Median follow-up was 10 months (range 0.56 to 18.83). Overall response rate was 29% (including one complete response after 4 cycles, and 5 participants (24%) achieved a partial response). Median PFS was 2.0 months (95% CI: 1.54-5.16). Mean duration of therapy was 3.9 months (4 cycles, range 1-19). The median OS was 17.61 months (95% CI: 5.45-18.83). There have been 9 Grade 3-5 serious adverse events (predominantly infection). 10 participants have died, 9 of disease progression and 1 from pneumonia. There were 3 immune related AEs. 5 participants withdrew from treatment (4 clinician, 1 participant decision). Preliminary correlative analysis revealed TMB at baseline ranged from 3.9-24.6 mutations/megabase (median: 9.4). TP53 mutations were prevalent (9/21 treated) in this heavily pretreated cohort and were associated with a reduced likelihood of response (0% vs 46%) and significantly worse PFS (median 1.6 months [mutant] vs 5.6 months [wildtype], Hazard Ratio for progression or death, 3.8 [95% CI: 1.2-11.8], p=0.02).

Conclusion:

The combination of durvalumab and acalabrutinib showed encouraging preliminary clinical activity in a heavily pre-treated cohort with relapsed/refractory aggressive B-cell lymphoma. The combination was well tolerated and deliverable to a predominantly elderly and frail population and warrants further study in this context.