To determine the maximum tolerated dose (MTD) of stereotactic ablative radiotherapy (SABR) in combination with immunotherapy for the treatment of metastatic melanoma. The study also investigates the effects of timing and dosing of SABR on clinical efficacy.
Metastatic melanoma patients with at least two metastases received SABR to a single metastatic site. All patients had standard dose immunotherapy with anti-PD1 and/or anti-CTLA4 at the discretion of their treating clinician. Following a standard 3+3 design, patients were escalated through three SABR doses (10 Gy, 15 Gy and 20 Gy) delivered at three different time points (with Cycle 1, 2, or 3 of immunotherapy). Dose limiting toxicities (DLT) was defined as Grade 3 or higher toxicity within three months of first treatment and assessed by an independent data safety monitoring committee (IDSMC). Logistic or Cox regressions were used to assess the impact of SABR dose and timing on the progression-free (PFS) and overall survival (OS) of this cohort.
24 patients were enrolled with a median clinical follow-up of 28 months. Four patients (16.7%) developed DLTs, one occurred at a SABR treated site, and all received 15Gy. On this basis the IDSMC recommended stopping the trial and the MTD was defined at 10Gy. The 2-year PFS was 21.9% (95% CI, 7.1%-41.8%) and 2-year OS was 49.6% (95% CI, 28.7%-67.6%). The median PFS for those receiving 10 Gy was numerically higher than those receiving 15Gy, 8.3 months vs. 2.1 months (p=0.38). The only treatment related factor associated with both improved PFS (HR=0.08 p<0.01) and OS (HR=0.008, p=<0.01) was receiving SABR with Cycle 3. SABR dose (PFS p=0.17, OS p=0.50) was not significant.
SABR at 10Gy can be safely combined with immunotherapy. SABR timing appears to influence efficacy more than dose and warrants consideration in research attempting to optimise synergism.

Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.

References

PubMed