title: Efficacy and Safety of Nivolumab in Patients With BRAF V600 Mutant and BRAF Wild-Type Advanced Melanoma: A Pooled Analysis of 4 Clinical Trials.
abstract: OBJECTIVE
  The anti-PD-1 therapeutic antibody, nivolumab, has demonstrated clinical activity in patients with advanced melanoma. The activity of nivolumab in subgroups of patients with tumors which have wild-type BRAF kinase vs patients with tumors having mutant BRAF has not systematically been explored in a large dataset.
  
  
  OBJECTIVE
  To evaluate the efficacy and safety of nivolumab in patients with wild-type BRAF and mutant BRAF metastatic melanoma.
  
  
  METHODS
  This was a retrospective analysis of data pooled from 4 clinical trials of nivolumab in 440 adult patients with unresectable stage III or stage IV melanoma, who had been tested for BRAF mutational status while participating in one of the studies.
  
  
  METHODS
  The investigational drug, nivolumab, was administered intravenously to study participants over a 60-minute period, at doses of 0.1, 0.3, 1.0, 3.0, or 10.0 mg/kg every 2 weeks until disease progression, discontinuation owing to adverse events, withdrawal, or end of study. Most patients (83%) received nivolumab at a dosage of 3 mg/kg.
  
  
  METHODS
  Best overall response by modified World Health Organization or Response Evaluation Criteria In Solid Tumors criteria and safety profile.
  
  
  RESULTS
  Of a total of 440 patients from 4 nivolumab clinical trials included in the analysis, 334 were BRAF wild-type and 106 were positive for BRAF V600 mutation. With the exception of prior BRAF inhibitor therapy, the demographics were well balanced between the 2 cohorts. In patients evaluable for response, the objective response rates were 34.6% (95% CI, 28.3-41.3) for the 217 patients with wild-type BRAF status and 29.7% (95% CI, 19.7-41.5) for the 74 with mutant BRAF status. The objective response rates did not seem to be affected by prior BRAF inhibitor therapy, prior ipilimumab therapy, or PD-L1 status of the tumor. The median duration of objective response was 14.8 months (95% CI, 11.1-24.0 months) for wild-type BRAF and 11.2 months (95% CI, 7.3-22.9 months) for mutant BRAF. Median time to objective response was 2.2 months in both patient groups. The incidence of treatment-related adverse events of any grade was 68.3% in the wild-type BRAF group and 58.5% in the mutant BRAF group, with grade 3 or 4 adverse events in 11.7% and 2.8% of patients, respectively. Treatment-related AEs of any grade that occurred in at least 5% of patients in either group were fatigue, pruritus, rash, and diarrhea.
  
  
  CONCLUSIONS
  The results of this retrospective analysis suggest that nivolumab has similar efficacy and safety outcomes in patients with wild-type or mutant BRAF, regardless of prior BRAF inhibitor or ipilimumab treatment.
authors.affiliation: Department of Medical Oncology, Royal Marsden Hospital, London, England.
authors.forename: James
authors.initials: J
authors.lastname: Larkin
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor3Department of Dermatology, University of Michigan, Ann Arbor.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Lao
authors.affiliation: Earle A. Chiles Research Institute at Providence Cancer Center, Portland, Oregon.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Urba
authors.affiliation: Department of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: David F
authors.initials: DF
authors.lastname: McDermott
authors.affiliation: Bristol-Myers Squibb Co, Princeton, New Jersey.
authors.forename: Christine
authors.initials: C
authors.lastname: Horak
authors.affiliation: Bristol-Myers Squibb Co, Hopewell, New Jersey.
authors.forename: Joel
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, New York9Weill-Cornell Medical College, New York, New York.
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D002986:Clinical Trials as Topic; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007262:Infusions, Intravenous; D000074324:Ipilimumab; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000556:secondary; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D000077594:Nivolumab; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000074324:Ipilimumab; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D047428:Protein Kinase Inhibitors; D000077594:Nivolumab; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf