Is Local Ablative Stereotactic Radiation Therapy a Valuable Rescue Strategy for Time on Drug in Patients Enrolled in Phase I Trials?

Purpose: Patients with advanced tumors enrolled in phase I trials display strong treatment expectations and few therapeutic alternatives. When oligoacquired resistance (OAR; <= 3 lesions of disease progression) occurs, local ablative stereotactic radiation therapy (SRT) could allow disease control and continuing the experimental systemic treatment. Methods and Materials: Data from patients enrolled in phase I trials evaluating systemic treatments, who experienced OAR while on the phase I systemic therapy and subsequently received SRT between January 2014 and April 2023, were retrospectively analyzed. Progression-free survival (PFS)1 (trial entry to OAR), PFS2 (SRT to first subsequent relapse), time to next systemic treatment (TTNT), and overall survival (OS) were assessed. First subsequent patterns of relapse after SRT were distinguished as OAR2, which could be locally rechallenged, or systemic acquired resistance (SAR; > 3 lesions of disease progression). When available, correlations between molecular profile and pathway enrichments of OAR and SAR were explored. Results: Forty-two patients with 52 oligoprogressive lesions were analyzed. The median follow-up was 24 months. SRT allowed a median PFS2 of 7.1 months and a median TTNT of 12.8 months. PFS2 included 49% OAR2 and 51% SAR. Median time to fi rst subsequent relapse (9.6 vs 3.5 months; P = .014) and TTNT (22.4 vs 7.6 months; P < .001) were longer for OAR2 compared with that for SAR. No severe toxicities were reported. A PFS1 of < 6 months and de novo oligoprogressive lesions were associated with the presence of SAR. More diverse enriched gene pathways were observed for SAR compared with that for OAR2. Conclusions: In patients enrolled in phase I trials, OAR managed with SRT may increase time on investigational systemic treatments. Predictive factors reflecting tumor aggressiveness and clonal heterogeneity could help deciphering OAR2 from SAR and maximize SRT output in the oligoprogressive setting. (c) 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.