RT Journal Article
SR Electronic
T1 Ipilimumab alone or in combination with nivolumab in patients with advanced melanoma who have progressed or relapsed on PD-1 blockade: clinical outcomes and translational biomarker analyses
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e003853
DO 10.1136/jitc-2021-003853
VO 10
IS 1
A1 Claire F Friedman
A1 Christine Spencer
A1 Christopher R Cabanski
A1 Katherine S Panageas
A1 Daniel K Wells
A1 Antoni Ribas
A1 Hussein Tawbi
A1 Katy Tsai
A1 Michael Postow
A1 Alexander Shoushtari
A1 Paul Chapman
A1 Joyson Karakunnel
A1 Samantha Bucktrout
A1 Pier Gherardini
A1 Travis J Hollmann
A1 Richard O Chen
A1 Margaret Callahan
A1 Theresa LaVallee
A1 Ramy Ibrahim
A1 Jedd Wolchok
YR 2022
UL http://jitc.bmj.com/content/10/1/e003853.abstract
AB Background There are no validated biomarkers that can aid clinicians in selecting who would best benefit from anticytotoxic T lymphocyte-associated antigen 4 monotherapy versus combination checkpoint blockade in patients with advanced melanoma who have progressive disease after programmed death 1 (PD-1) blockade.Methods We conducted a randomized multicenter phase II trial in patients with advanced melanoma. Patients were randomly assigned to receive either 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab or 3 mg/kg of ipilimumab every 3 weeks for up to four doses. Patients were stratified by histological subtype and prior response to PD-1 therapy. The primary clinical objective was overall response rate by week 18. Translational biomarker analyses were conducted in patients with blood and tissue samples.Results Objective responses were seen in 5 of 9 patients in the ipilimumab arm and 2 of 10 patients in the ipilimumab+nivolumab arm; disease control rates (DCRs) (66.7% vs 60.0%) and rates of grade 3–4 adverse events (56% vs 50%) were comparable between arms. In a pooled analysis, patients with clinical benefit (CB), defined as Response Evaluation Criteria in Solid Tumors response or progression-free for 6 months, showed increased circulating CD4+ T cells with higher polyfunctionality and interferon gamma production following treatment. Tumor profiling revealed enrichment of NRAS mutations and activation of transcriptional programs associated with innate and adaptive immunity in patients with CB.Conclusions In patients with advanced melanoma that previously progressed on PD-1 blockade, objective responses were seen in both arms, with comparable DCRs. Findings from biomarker analyses provided hypothesis-generating signals for validation in future studies of larger patient cohorts.Trial registration number NCT02731729.Data are available upon reasonable request. Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplementary information. The corresponding author may be contacted with any requests.