The development of effective allele-specific and RAS-ON multiselective direct RAS inhibitors for pancreatic ductal adenocarcinoma (PDAC) represents unprecedented progress in systemic therapy for a devastating disease. These drugs are already changing the standard of care in PDAC, and their development raises important questions about how ongoing and future trials of local therapies such as radiotherapy (RT) may be affected. Although RT remains part of the therapeutic armamentarium for pancreatic ductal adenocarcinoma (PDAC), particularly in locally advanced disease and the adjuvant setting, decades of clinical trials have raised more questions than they have answered. One major challenge has been the concurrent evolution of systemic therapies, complicating the design, interpretation, and clinical relevance of RT trials. Here, we review how changes in systemic therapy have influenced seminal trials of RT for PDAC and will consider implications for ongoing and future trials in this space. These considerations, already relevant when options were more limited, are even more critical with the emergence of novel RAS-targeted therapies.
Introduction Anti-CD19 CAR T-cell therapy has improved outcomes in B-cell non-Hodgkin lymphoma (B-NHL), but only about half of patients achieve durable benefit. As CD20 is expressed in > 90% of B-NHL, this phase I trial evaluated the CD20-directed CAR T-cell product MB-CART20.1 in adults with relapsed/refractory CD20-positive B-NHL without curative treatment options. Methods In this phase I dose-escalation trial, patients received 1.0 × 10⁵ cells/kg body weight (BW) MB-CART20.1 at the safety dose level (SDL) or 1.0 × 10⁶ cells/kg BW at dose level 1 (DL1). Results Recruitment was terminated early because of the COVID-19 pandemic after nine heavily pretreated patients had received MB-CART20.1 (SDL n = 7; DL1 n = 2). Diagnoses included transformed follicular lymphoma (n = 4), diffuse large B-cell lymphoma (n = 3), Richter transformation from chronic lymphocytic leukemia (CLL, n = 1), and small lymphocytic lymphoma (n = 1). One dose-limiting toxicity (DLT; grade 4 neutropenia) occurred at DL1; the maximum tolerated dose was not determined. No grade ≥ 3 cytokine release syndrome occurred (grade 1: n = 4; grade 2: n = 1). One patient developed grade 2 immune effector cell-associated neurotoxicity syndrome. The best overall response rate was 56%, including 33% complete responses (CR; SDL n = 1; DL1 n = 2). CRs were durable, with one maintained through 5 years of follow-up. CAR T-cells showed robust expansion, with higher Cmax at DL1 than SDL (125.9 vs. 3.1 cells/µL). Cmax and AUC0–28D were higher in responders (p = 0.0369). Conclusion With manageable toxicity, no DLTs at SDL, and preliminary signs of efficacy in the overall trial cohort, these findings warrant further investigation of CD20-directed CAR T-cell therapy in relapsed/refractory B-NHL.
