Phase 2 trial of nivolumab combined with stereotactic body radiotherapy in patients with metastatic or locally advanced inoperable melanoma
Mené sur 20 patients atteints d'un mélanome métastatique ou d'un mélanome inopérable de stade localement avancé, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse globale au niveau des lésions non irradiées, et la toxicité d'un traitement combinant nivolumab et radiothérapie corporelle stéréotaxique
Purpose : Nivolumab improves survival in metastatic melanoma patients. Unfortunately, most patients do not respond to this treatment. Preclinical data indicates that radiotherapy 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 (RECISTv1.1). Stereotactic body radiotherapy (SBRT), 3x8Gy to the largest lesion, was delivered prior to the second nivolumab cycle. Primary endpoint was overall response rate (ORR) in the non-irradiated lesions (RECISTv1.1). 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 non-irradiated lesions exhibited a local complete response in the irradiated lesion. Treatment-related adverse events (AEs) grade 1-2 occurred in 17 patients; 3 patients experienced AEs grade 3 (lymphopenia, gastro-enteritis and bullous pemphigoid). No AEs grade 4-5 occurred. ctDNA was detected in 8 patients and changes corresponded to clinical response and suggested that a subset of patients, with a low PD-L1 score, only started responding after SBRT. Conclusion : 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. Albeit underpowered, our data therefore does not indicate a substantial abscopal response. Nonetheless, serial ctDNA analyses suggest that a subset of patients responded only after the addition of SBRT.
https://www.redjournal.org/article/S0360-3016(19)30568-1/fulltext 2019