Chiorean et al. Page 6314

Pancreatic ductal adenocarcinoma remains one of the deadliest cancer subtypes. Preclinical evidence has suggested that PARP inhibitors are synergistic with topoisomerase inhibitors, and clinical effectiveness of the PARP inhibitor veliparib plus modified FOLFIRI (mFOLFIRI; no 5-FU bolus) was observed. Chiorean and colleagues conducted a randomized phase II clinical trial assessing second-line veliparib and mFOLFIRI versus FOLFIRI in patients with metastatic pancreatic adenocarcinoma. An interim futility analysis revealed that veliparib plus mFOLFIRI was unlikely to improve prognosis but was more likely to cause grade 3/4 toxicity. Interestingly, trends were detected indicating that FOLFIRI treatment may improve PFS and OS in patients with alterations in homologous recombination DNA damage repair. Further clinical study is necessary to determine if this subgroup of patients will benefit from FOLFIRI treatment.

Opat et al. Page 6323

Marginal zone lymphoma (MZL) is a rare non-Hodgkin lymphoma reliant on B-cell receptor signaling. Opat and colleagues conducted a phase II clinical trial to assess the efficacy and safety of zanubrutinib, a next-generation selective Bruton tyrosine kinase inhibitor, in patients with relapsed/refractory MZL. An objective response rate of 68.2% was observed, with 25.8% of patients showing complete response to treatment. Furthermore, zanubrutinib showed a favorable safety profile, with most adverse events being grade 1 or 2. These results suggest that zanubrutinib may be an appropriate therap. for patients with relapsed/refractory MZL, although further study is needed, especially to develop predictive biomarkers for treatment.

Zhang et al. Page 6384

B-cell maturation antigen (BCMA) chimeric antigen receptor T (CAR-T) cell therapy for relapsed/refractory multiple myeloma is highly efficacious. However, many patients recur, and factors associated with long-term prognosis remain unclear. To this end, Zhang and colleagues conducted a clinical trial of anti-BCMA CAR-T cell therapy in patients with relapsed/refractory multiple myeloma. The objective response rate was 98.3%, with 70.3% of patients showing a complete response. Further analyses revealed extramedullary disease, light chain multiple myeloma, and high-risk cytogenetic factors as important independent predictors of a poor prognosis after anti-BCMA CAR-T cell therapy. These results will inform future treatment of relapsed/refractory multiple myeloma, although further clinical validation is warranted.

Schwenzer et al. Page 6500

ProTide modification of nucleoside analogues is designed to overcome the cellular resistance mechanisms that limit their efficacy. In this study, Schwenzer and colleagues describe a novel ProTide, NUC-7738. NUC-7738 was generated through chemical modification of 3′-deoxyadenosine (3′-dA). 3′-dA is rapidly deaminated by adenosine deaminase, leading to a short plasma half-life. NUC-7738 is resistant to this deamination event. NUC-7738 promoted apoptosis pathways and decreased NF-κB signaling. These findings were validated in samples from patients in an ongoing first-in-human trial of NUC-7738. Additional confirmation of these results is necessary for this encouraging novel agent.