Andrea Riccardo Filippi

Radiation-free treatment for early-stage classic Hodgkin lymphoma (eHL) has been shown to be less effective than standard combined-modality treatment (CMT; chemotherapy plus involved-node radiotherapy (INRT)), which achieves long-term disease control of 94–95%. Approximately 70% of patients can be cured with chemotherapy alone, whereas about 5% fail CMT. Identifying patients who can safely receive chemotherapy alone and those requiring intensified CMT could enable a risk-adapted treatment strategy. The RAFTING trial (NCT04866654; EudraCT 2020-002382-33) is an international, prospective, phase 2, non-inferiority study enrolling patients 18–70 years, stage I–IIA eHL without bulky disease, B symptoms, or extranodal involvement. Low-risk (LR) patients are defined by total metabolic tumor volume (TMTV) <84 mL and negative PET-2. Those with at least one modified EORTC (mEORTC) risk factor, in which bulky disease is replaced by a large nodal mass (5–10 cm), receive four ABVD cycles, while those without risk factors receive two ABVD cycles alone. High-risk (HR) patients, defined by TMTV ≥84 mL and/or positive PET-2, receive “triple therapy”: 4 ABVD cycles, INRT (20/30 Gy), and nivolumab (240 mg q2w, ≤doses). LR patients are monitored using cfDNA. Limited relapse is treated with INRT (36 Gy) and nivolumab. The RAFTING trial is the first prospective eHL study to personalize treatment using TMTV and PET-2. It aims to omit radiotherapy in LR patients, intensify treatment in HR patients, and spare relapsed LR patients high-dose chemotherapy and autologous transplantation. CfDNA is being evaluated as a relapse marker. Despite the protocol’s complexity, this study exemplifies personalized medicine and could transform treatment practices.

Background: The PACIFIC study established the standard of care for unresectable, stage III non-small cell lung cancer (NSCLC). The DEDALUS trial is a phase 2, open-label, multicenter study enrolling patients who are eligible for sequential chemo-radiation therapy (CRT) plus immunotherapy. Methods: Patients had unresectable stage IIIA-C NSCLC, regardless of PD-L1 status. After 3 cycles of chemo-durvalumab, responders received hypo-fractionated thoracic radiotherapy (45 Gy over 3 weeks) with durvalumab, then continued durvalumab for up to 12 months or until disease progression. Primary endpoint was safety, assessed by the incidence of grade 3 and 4 possibly related adverse events (PRAEs) within 6 months. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and quality of life (NCT05128630). Results: Between February 2022 and August 2024, 28 patients were screened, and 25 enrolled across 3 Italian centers. Enrollment was halted early due to low recruitment. We recorded 9 grade 3-4 PRAEs, which accounted for 6.4% of all AEs; 7 patients (28%) experienced at least 1 grade 3-4 PRAE. Only 1 was immune-related, while the remaining PRAEs were related to chemotherapy, none to RT. Median PFS was 13.2 months (95% CI = 4.9 to 18.6), median OS was 17.5 months (95% CI = 10.7 to 18.6). Among the 16 patients who started maintenance without progression median PFS was 18.6 months (95% CI = 12.8 to not reached), median OS was not reached. Conclusions: The early closure of the study and the reduced sample size make it difficult to draw significant conclusions. However, feasibility and safety seem to be acceptable, and early PFS and OS data are promising, especially for patients who completed the full treatment sequence.