Phase 2 Trial of Nivolumab Combined With Stereotactic Body Radiation Therapy in Patients With Metastatic or Locally Advanced Inoperable Melanoma

Nora Sundahl, Teofila Seremet, Jo Van Dorpe, Bart Neyns, Liesbeth Ferdinande, Annabel Meireson, Lieve Brochez, Vibeke Kruse, Piet Ost

Research output: Contribution to journalArticle

23 Citations (Scopus)


PURPOSE: Nivolumab improves survival in patients with metastatic melanoma. Unfortunately, most patients do not respond to this treatment. Preclinical data indicate that radiation therapy could work synergistically with nivolumab and improve response rates.

METHODS AND MATERIALS: We conducted a phase 2 trial in 20 patients with inoperable or metastatic melanoma with ≥2 measurable lesions (Response Evaluation Criteria in Solid Tumors v1.1). Stereotactic body radiation therapy (SBRT) of 3 × 8 Gy to the largest lesion was delivered before the second nivolumab cycle. The primary endpoint was overall response rate (ORR) in the nonirradiated lesions (Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints included toxicity. An exploratory endpoint was mutant BRAF and NRAS circulating tumor DNA (ctDNA) on serial blood samples.

RESULTS: An ORR of 45% was noted with 3 complete and 6 partial responses. Three patients experienced stable disease and 7 had progressive disease as best response. All patients with a complete response in the nonirradiated lesions exhibited a local complete response in the irradiated lesion. Grade 1 to 2 treatment-related adverse events (AEs) occurred in 17 patients; 3 patients experienced grade 3 AEs (lymphopenia, gastroenteritis, and bullous pemphigoid). No grade 4 to 5 AEs occurred. ctDNA was detected in 8 patients, and changes corresponded to clinical response and suggested that a subset of patients with a low programmed death ligand-1 score only started responding after SBRT.

CONCLUSIONS: We conclude that the combination treatment was well tolerated and led to an ORR of 45% in patients with metastatic or inoperable melanoma, similar to historical response rates of nivolumab monotherapy. Although underpowered, our data therefore do not indicate a substantial abscopal response. Nonetheless, serial ctDNA analyses suggest that a subset of patients responded only after the addition of SBRT.

Original languageEnglish
Pages (from-to)828-835
Number of pages8
JournalInternational Journal of Radiation Oncology, Biology, Physics
Issue number4
Publication statusPublished - 15 Jul 2019

Bibliographical note

Copyright © 2019 Elsevier Inc. All rights reserved.


  • Adult
  • Aged
  • Antineoplastic Agents, Immunological/adverse effects
  • Biomarkers, Tumor/blood
  • Chemoradiotherapy/adverse effects
  • DNA, Neoplasm/blood
  • Drug Administration Schedule
  • Female
  • GTP Phosphohydrolases/blood
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Melanoma/blood
  • Membrane Proteins/blood
  • Middle Aged
  • Nivolumab/adverse effects
  • Programmed Cell Death 1 Receptor/blood
  • Progression-Free Survival
  • Proto-Oncogene Proteins B-raf/blood
  • Radiosurgery/adverse effects
  • Response Evaluation Criteria in Solid Tumors
  • Skin Neoplasms/blood


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