- •Ipilimumab 3 mg/kg after recurrence/progression on low-dose ipilimumab (IPI) has clinical activity.
- •The response rate was 9/36 (25%).
- •In primary resistance to low-dose IPI, the response rate was 6/20 (30%).
- •In acquired resistance to low-dose IPI, the response rate was 3/16 (18.5%).
- •This provides further evidence of the dose–efficacy relationship for IPI.
Differing doses of ipilimumab (IPI) are used in combination with an anti-PD1 antibody in advanced melanoma. There is no data on the outcomes of patients who progress following low-dose IPI (< 3 mg/kg) and are subsequently treated with IPI 3 mg/kg (IPI3). We conducted a multicentre retrospective survey to assess the efficacy of this strategy.
Patients with resected stage III, unresectable stage III or IV melanoma who received low dose IPI (< 3 mg/kg) with an anti-PD1 antibody with recurrence (neo/adjuvant) or progressive disease (metastatic), who then received IPI3 ± anti-PD1 antibody were eligible. Best investigator-determined Response Evaluation Criteria in Solid Tumours response, progression-free survival (PFS) and overall survival (OS) were analysed.
Total 36 patients received low-dose IPI with an anti-PD1 antibody, 18 (50%) in the neo/adjuvant and 18 (50%) in the metastatic setting. Of which, 20 (56%) had primary resistance and 16 (44%) had acquired resistance. All patients received IPI3 for unresectable stage III or IV melanoma; median age 60 (29–78), 18 (50%) M1d disease, 32 (89%) Eastern Cooperative Oncology Group performance status 0–1. Around 35 (97%) received IPI3 with nivolumab and 1 received IPI3 alone. The response rate to IPI3 was 9/36 (25%). In patients with primary resistance, the response rate was 6/20 (30%). After a median follow-up of 22 months (95% CI: 15–27 months), the median PFS and OS were not reached in patients who responded; 1-year PFS and OS were 73% and 100%, respectively.
IPI3 following recurrence/progression on low dose IPI has clinical activity, including in primary resistance. IPI dosing is therefore critical in a subset of patients.
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- Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.N Engl J Med. 2015; 373: 23-34
- Five-year survival with combined nivolumab and ipilimumab in advanced melanoma.N Eng J Med. 2019; 381: 1535-1546
- Overall survival with combined nivolumab and ipilimumab in advanced melanoma.N Eng J Med. 2017; 377: 1345-1356
- Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial.Lancet. 2020; 395: 1558-1568
- Abstract CT004: adjuvant therapy with nivolumab (NIVO) combined with ipilimumab (IPI) vs NIVO alone in patients (pts) with resected stage IIIB-D/IV melanoma (CheckMate 915).Cancer Res. 2021; 81: CT004
- Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC).Nat Med. 2021; 27: 301-309
- Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma.Nat Med. 2021; 27: 256-263
- Neoadjuvant systemic therapy in melanoma: recommendations of the International Neoadjuvant Melanoma Consortium.Lancet Oncol. 2019; 20: e378-e389
- Risk and incidence of fatal adverse events associated with immune checkpoint inhibitors: a systematic review and meta-analysis.Ther Clin Risk Manag. 2019; 15: 293-302
- Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis.BMC Med. 2015; 13: 211
- Phase III study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon Alfa-2b for resected high-risk melanoma: North American Intergroup E1609.J Clin Oncol: Off J Am Soc Clin Oncol. 2020; 38: 567-575
- Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial.Lancet Oncol. 2017; 18: 611-622
- Standard-dose pembrolizumab plus alternate-dose ipilimumab in advanced melanoma: KEYNOTE-029 Cohort 1C, a phase 2 randomized study of two dosing schedules.Clin Cancer Res: Off J Am Assoc Cancer Res. 2021;
- Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial.Lancet Oncol. 2017; 18: 1202-1210
- Evaluation of two dosing regimens for nivolumab in combination with ipilimumab in patients with advanced melanoma: results from the phase IIIb/IV CheckMate 511 trial.J Clin Oncol: Off J Am Soc Clin Oncol. 2019; 37: 867-875
- Ipilimumab combination dosing: less is more.Clin Cancer Res. 2021;
- Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial.Lancet Oncol. 2019; 20: 948-960
- Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in high-risk stage III melanoma: the PRADO trial.Nat Med. 2022; 28: 1178-1188
- Efficacy and safety of retreatment with ipilimumab in patients with pretreated advanced melanoma who progressed after initially achieving disease control.Clin Cancer Res: Off J Am Assoc Cancer Res. 2013; 19: 2232-2239
- Survival follow-up and ipilimumab retreatment of patients with advanced melanoma who received ipilimumab in prior phase II studies.Ann Oncol: Off J Eur Soc Med Oncol. 2014; 25: 2277-2284
- Risks and benefits of reinduction ipilimumab/nivolumab in melanoma patients previously treated with ipilimumab/nivolumab.J ImmunoTher Cancer. 2021; 9e003395
- Re-induction ipilimumab following acquired resistance to combination ipilimumab and anti-PD-1 therapy.Eur J Cancer. 2021; 153: 213-222
- Management of early melanoma recurrence despite adjuvant anti-PD-1 antibody therapy(☆).Ann Oncol: Off J Eur Soc Med Oncol. 2020; 31: 1075-1082
- Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce.J ImmunoTher Cancer. 2020; 8e000398
- Efficacy and safety of retreatment with ipilimumab in patients with pretreated advanced melanoma who progressed after initially achieving disease control.Clin Cancer Res. 2013; 19: 2232-2239
- Ipilimumab retreatment in patients with pretreated advanced melanoma: the expanded access programme in Italy.Br J Cancer. 2014; 110: 1721-1726
- Site-specific response patterns, pseudoprogression, and acquired resistance in patients with melanoma treated with ipilimumab combined with anti–PD-1 therapy.Cancer. 2020; 126: 86-97
- Atypical patterns of response to immune checkpoint inhibitors: interpreting pseudoprogression and hyperprogression in decision making for patients’ treatment.. 2018; 11: 35-38
- Pseudoprogression and hyperprogression during immune checkpoint inhibitor therapy for urothelial and kidney cancer.World J Urol. 2018; 36: 1703-1709
- Patterns of response and progression to immunotherapy.American Society of Clinical Oncology Educational Book. 2018; 38 (American Society of Clinical Oncology Annual Meeting): 169-178
- The value of immunotherapy for survivors of stage IV non-small cell lung cancer: patient perspectives on quality of life.J Cancer Surviv: Res Pract. 2020;
- Nivolumab for patients with advanced melanoma treated beyond progression: analysis of 2 phase 3 clinical trials.JAMA Oncol. 2017; 3: 1511-1519
Published online: March 10, 2023
Accepted: March 4, 2023
Received in revised form: February 15, 2023
Received: December 11, 2022
Publication stageIn Press Uncorrected Proof
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