PT  - JOURNAL ARTICLE
AU  - Claire F Friedman
AU  - Christine Spencer
AU  - Christopher R Cabanski
AU  - Katherine S Panageas
AU  - Daniel K Wells
AU  - Antoni Ribas
AU  - Hussein Tawbi
AU  - Katy Tsai
AU  - Michael Postow
AU  - Alexander Shoushtari
AU  - Paul Chapman
AU  - Joyson Karakunnel
AU  - Samantha Bucktrout
AU  - Pier Gherardini
AU  - Travis J Hollmann
AU  - Richard O Chen
AU  - Margaret Callahan
AU  - Theresa LaVallee
AU  - Ramy Ibrahim
AU  - Jedd Wolchok
TI  - 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
AID  - 10.1136/jitc-2021-003853
DP  - 2022 Jan 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - e003853
VI  - 10
IP  - 1
4099  - http://jitc.bmj.com/content/10/1/e003853.short
4100  - http://jitc.bmj.com/content/10/1/e003853.full
SO  - J Immunother Cancer2022 Jan 01; 10
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.