PMID- 30951807
OWN - NLM
STAT- MEDLINE
DCOM- 20191219
LR  - 20191219
IS  - 1879-355X (Electronic)
IS  - 0360-3016 (Linking)
VI  - 104
IP  - 4
DP  - 2019 Jul 15
TI  - Phase 2 Trial of Nivolumab Combined With Stereotactic Body Radiation Therapy in 
      Patients With Metastatic or Locally Advanced Inoperable Melanoma.
PG  - 828-835
LID - S0360-3016(19)30568-1 [pii]
LID - 10.1016/j.ijrobp.2019.03.041 [doi]
AB  - 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 x 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.
CI  - Copyright (c) 2019 Elsevier Inc. All rights reserved.
FAU - Sundahl, Nora
AU  - Sundahl N
AD  - Department of Radiation Oncology, Ghent University Hospital, Belgium; Cancer 
      Research Institute Ghent (CRIG), Belgium. Electronic address: 
      nora.sundahl@ugent.be.
FAU - Seremet, Teofila
AU  - Seremet T
AD  - Department of Medical Oncology, Oncology Centre, University Hospital Brussels, 
      Brussels, Belgium.
FAU - Van Dorpe, Jo
AU  - Van Dorpe J
AD  - Cancer Research Institute Ghent (CRIG), Belgium; Department of Pathology, Ghent 
      University Hospital, Belgium.
FAU - Neyns, Bart
AU  - Neyns B
AD  - Department of Medical Oncology, Oncology Centre, University Hospital Brussels, 
      Brussels, Belgium.
FAU - Ferdinande, Liesbeth
AU  - Ferdinande L
AD  - Department of Pathology, Ghent University Hospital, Belgium.
FAU - Meireson, Annabel
AU  - Meireson A
AD  - Department of Dermatology and Dermatology Research Unit, Ghent University 
      Hospital, Belgium.
FAU - Brochez, Lieve
AU  - Brochez L
AD  - Cancer Research Institute Ghent (CRIG), Belgium; Department of Dermatology and 
      Dermatology Research Unit, Ghent University Hospital, Belgium.
FAU - Kruse, Vibeke
AU  - Kruse V
AD  - Cancer Research Institute Ghent (CRIG), Belgium; Department of Medical Oncology, 
      Ghent University Hospital, Belgium.
FAU - Ost, Piet
AU  - Ost P
AD  - Department of Radiation Oncology, Ghent University Hospital, Belgium; Cancer 
      Research Institute Ghent (CRIG), Belgium.
LA  - eng
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190403
PL  - United States
TA  - Int J Radiat Oncol Biol Phys
JT  - International journal of radiation oncology, biology, physics
JID - 7603616
RN  - 0 (Antineoplastic Agents, Immunological)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (DNA, Neoplasm)
RN  - 0 (Membrane Proteins)
RN  - 0 (PDCD1 protein, human)
RN  - 0 (Programmed Cell Death 1 Receptor)
RN  - 31YO63LBSN (Nivolumab)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
RN  - EC 3.6.1.- (GTP Phosphohydrolases)
RN  - EC 3.6.1.- (NRAS protein, human)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antineoplastic Agents, Immunological/adverse effects/*therapeutic use
MH  - Biomarkers, Tumor/blood
MH  - Chemoradiotherapy/adverse effects/*methods
MH  - DNA, Neoplasm/blood
MH  - Drug Administration Schedule
MH  - Female
MH  - GTP Phosphohydrolases/blood
MH  - Humans
MH  - Kaplan-Meier Estimate
MH  - Male
MH  - Melanoma/blood/pathology/secondary/*therapy
MH  - Membrane Proteins/blood
MH  - Middle Aged
MH  - Nivolumab/adverse effects/*therapeutic use
MH  - Programmed Cell Death 1 Receptor/blood
MH  - Progression-Free Survival
MH  - Proto-Oncogene Proteins B-raf/blood/genetics
MH  - Radiosurgery/adverse effects/*methods
MH  - Response Evaluation Criteria in Solid Tumors
MH  - Skin Neoplasms/blood/pathology/*therapy
EDAT- 2019/04/06 06:00
MHDA- 2019/12/20 06:00
CRDT- 2019/04/06 06:00
PHST- 2019/01/17 00:00 [received]
PHST- 2019/03/12 00:00 [revised]
PHST- 2019/03/27 00:00 [accepted]
PHST- 2019/04/06 06:00 [pubmed]
PHST- 2019/12/20 06:00 [medline]
PHST- 2019/04/06 06:00 [entrez]
AID - S0360-3016(19)30568-1 [pii]
AID - 10.1016/j.ijrobp.2019.03.041 [doi]
PST - ppublish
SO  - Int J Radiat Oncol Biol Phys. 2019 Jul 15;104(4):828-835. doi: 
      10.1016/j.ijrobp.2019.03.041. Epub 2019 Apr 3.