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 Journal Article
| Authors: | Friedman, C. F.; Spencer, C.; Cabanski, C. R.; Panageas, K. S.; Wells, D. K.; Ribas, A.; Tawbi, H.; Tsai, K.; Postow, M.; Shoushtari, A.; Chapman, P.; Karakunnel, J.; Bucktrout, S.; Gherardini, P.; Hollmann, T. J.; Chen, R. O.; Callahan, M.; Lavallee, T.; Ibrahim, R.; Wolchok, J. |
| Article Title: | 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 |
| Abstract: | 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. © |
| Keywords: | adult; clinical article; treatment response; aged; overall survival; cancer recurrence; advanced cancer; diarrhea; drug efficacy; drug safety; monotherapy; paclitaxel; cancer patient; flow cytometry; nuclear magnetic resonance imaging; translation initiation; t lymphocyte; biological marker; interleukin 2; ipilimumab; cancer immunotherapy; melanoma; progression free survival; phase 2 clinical trial; gene expression; randomized controlled trial; interleukin 13; interleukin 21; interleukin 4; interleukin 5; interleukin 7; interleukin 8; cohort analysis; genetic transcription; enzyme linked immunosorbent assay; histology; arthralgia; pruritus; alanine aminotransferase; aspartate aminotransferase; hypokalemia; hyponatremia; hypotension; maculopapular rash; granzyme b; immunotherapy; gamma interferon; drug combination; multicenter study; cd4+ t lymphocyte; urinary tract infection; heparin; erythema; transforming growth factor beta1; tumor immunity; upregulation; interleukin 17; th17 cell; disease control; interleukin 15; peripheral blood mononuclear cell; tumor necrosis factor; rna sequence; programmed death 1 ligand 1; programmed death 1 receptor; anaplastic lymphoma kinase; adrenal insufficiency; tumor microenvironment; cd69 antigen; hypophysitis; mucosal melanoma; rantes; overall response rate; macrophage inflammatory protein 1alpha; vein puncture; dabrafenib; nivolumab; very elderly; intention to treat analysis; human; male; female; article; circulating tumor dna; interleukin 9; pembrolizumab; whole exome sequencing; mass cytometry |
| Journal Title: | Journal for ImmunoTherapy of Cancer |
| Volume: | 10 |
| Issue: | 1 |
| ISSN: | 2051-1426 |
| Publisher: | Biomed Central Ltd |
| Date Published: | 2022-01-01 |
| Start Page: | e003853 |
| Language: | English |
| DOI: | 10.1136/jitc-2021-003853 |
| PUBMED: | 35074903 |
| PROVIDER: | scopus |
| PMCID: | PMC8788323 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2022 -- Source: Scopus |
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