In this PACUPod update, Britany and Seth review Wang et al.'s phase II, single-arm trial of chidamide (an HDAC inhibitor) combined with tislelizumab (a PD-1 inhibitor) and platinum-based chemotherapy as first-line therapy for treatment-naïve, driver-gene-negative advanced NSCLC. They discuss the rationale for combining epigenetic therapy with immunotherapy and chemotherapy, the reported efficacy (ORR 80%, disease control rate 100%, median progression-free survival 11 months, median overall survival 17.5 months) and safety profile (55% of patients experienced grade 3 or higher treatment-related adverse events, primarily leukopenia and neutropenia), patient selection criteria, and pharmacologic considerations (CYP3A4 metabolism and potential drug interactions). The hosts place these findings in the context of prior HDAC inhibitor–immunotherapy studies and emphasize study limitations (small sample size, single-arm design) and the need for larger randomized trials and biomarker-driven patient selection to validate and refine this triplet therapy for NSCLC.

In this PACUPod update, Britany and Seth dive into a Phase I/II trial evaluating donor-derived WT1-targeted cytotoxic T lymphocytes (CTLs) for relapse prevention in children undergoing haploidentical hematopoietic stem cell transplantation. The discussion covers trial design (open-label, dose-escalation, single-arm), safety focus on graft-versus-host disease, and early signals of efficacy including relapse rates and CTL persistence. They highlight GMP manufacturing, timing within 60 days post-transplant, and the supporting preclinical and adult clinical data. The episode references Montagna et al.’s Frontiers in Immunology 2025 study (PubMed ID: 40547030).

In this PACUPod episode, we dissect the BREAKWATER phase 3 trial that adds encorafenib and cetuximab to mFOLFOX6 as first-line therapy for patients with BRAF V600E-mutated metastatic colorectal cancer. The discussion covers study design, endpoints, and results comparing the triplet to standard chemotherapy (with or without bevacizumab). Key findings include improved progression-free survival (12.8 vs 7.1 months; HR 0.53) and overall survival (30.3 vs 15.1 months; HR 0.49), as well as a higher objective response rate (65.7% vs 37.4%). We also examine safety signals (higher grade 3–4 toxicities, including hematologic, dermatologic, and GI events) and management considerations, such as monitoring for hepatotoxicity, electrolyte disturbances, and QT prolongation, plus drug interactions (notably CYP3A4 with encorafenib). The episode discusses limitations (open-label design, early stop of the triplet-alone arm) and the clinical implications for precision oncology and routine molecular profiling per ASCO guidelines. Finally, we highlight future directions, including long-term outcomes, resistance mechanisms, and potential biomarker-driven strategies beyond BRAF V600E.