Stereotactic Radiation Therapy Combined With Immunotherapy Against Metastatic Melanoma: Long-Term Results of a Phase 1 Clinical Trial

Gishan Ratnayake, Simone Reinwald, Mark Shackleton, Maggie Moore, Mark Voskoboynik, Jeremy Ruben, Menno C. van Zelm, Di Yu, Rachel Ward, Robin Smith, Andrew Haydon, Sashendra Senthi

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Purpose: To determine the maximum tolerated dose (MTD) of stereotactic ablative radiation therapy (SABR) in combination with immunotherapy for the treatment of patients with metastatic melanoma. The study also investigates the effects of timing and dosing of SABR on clinical efficacy. Methods: Metastatic melanoma patients with at least 2 metastases received SABR to a single metastatic site. All patients had standard dose immunotherapy with anti-PD1 or anti-CTLA4 at the discretion of their treating clinician. Following a standard 3 + 3 design, patients were escalated through 3 SABR doses (10 Gy, 15 Gy, and 20 Gy) delivered at 3 different time points (with cycle 1, 2, or 3 of immunotherapy). Dose-limiting toxicities (DLT) were defined as grade 3 or higher toxicity within 3 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. Results: Twenty-four patients were enrolled with a median clinical follow-up of 28 months. Four patients (16.7%) developed DLTs; 1 DLT occurred at a SABR-treated site, and all patients received 15 Gy. On this basis the IDSMC recommended stopping the trial and the MTD was defined at 10 Gy. 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 for those receiving 15 Gy, 8.3 months versus 2.1 months (P =.38). The only treatment-related factor associated with both improved PFS (HR 0.08, P <.01) and OS (HR 0.008, P ≤.01) was receiving SABR with cycle 3. SABR dose (PFS P =.17, OS P =.50) was not significant. Conclusions: SABR at 10 Gy can be safely combined with immunotherapy. SABR timing appears to influence efficacy more than dose and warrants consideration in research attempting to optimize synergism.

Original languageEnglish
Pages (from-to)150-156
Number of pages7
JournalInternational Journal of Radiation Oncology, Biology, Physics
Volume108
Issue number1
DOIs
Publication statusPublished - 1 Sep 2020

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