Efficacy of ipilimumab 3mg/kg following progression on low dose ipilimumab in metastatic melanoma.
Authors: Lai-Kwon Julia Elizabeth , Jacques Sarah , Carlino Matteo S. , Benannoune Naima , Robert Caroline , Allayous Clara , Baroudjian Barouyr , Lebbe Celeste , Zimmer Lisa , Eroglu Zeynep , Ozturk Topcu Turkan , Dimitriou Florentia , Haydon Andrew Mark , Lo Serigne N. , Menzies Alexander M. , Long Georgina V. 
Published: June 2022

e21533

Background: Anti-cytotoxic T lymphocyte-associated antigen 4 inhibitors, such as ipilimumab (IPI), are commonly used in melanoma management. Whilst a clear dose-toxicity relationship exists, and a dose-response relationship is seen with monotherapy in people with anti PD-1 antibody-naïve melanoma, there is no data on the outcomes of patients who progress following low dose IPI and are subsequently treated with standard dose IPI. We conducted a multicentre, retrospective review to assess the efficacy of this strategy. Methods: Patients with resected stage III, unresectable stage III or IV melanoma who received low dose IPI (< 3mg/kg) with an anti-PD1 antibody in the neoadjuvant, adjuvant or metastatic setting with recurrence (neo/adjuvant) or progressive disease (metastatic) as best response, who then received standard dose IPI (3mg/kg, IPI3) alone or in combination with an anti-PD1 antibody were eligible. IPI dose, frequency and best investigator-assessed RECIST response were collected. Progression free survival (PFS) and overall survival (OS) were analysed using the Kaplan Meier method. Results: 36 patients from 8 centres; 27 (75%) male, BRAF V600 mutant (18, 50%). All patients received low dose IPI with an anti-PD1 antibody, 18 (50%) in the neo/adjuvant and 18 (50%) in the metastatic setting; 15 (42%) received IPI 1mg/kg every 6 weeks, 13 (36%) IPI 1mg/kg every 3 weeks, 3 (8%) IPI 50mg every 6 weeks or 100mg every 12 weeks respectively, and 2 (6%) IPI 1mg/kg every 8 weeks. 23 (64%) received >1 intervening line of systemic therapy prior to IPI3. The most common intervening therapy was BRAF/MEK inhibitors; 14/23 (61%) as 2nd line treatment, 4/8 (50%) as 3rd line treatment, and all progressed. All patients received standard dose IPI3 for unresectable stage III or stage IV melanoma; median age 60 (29-78), 18 (50%) had M1d disease, 32 (89%) ECOG 0-1, 18 (50%) normal lactate dehydrogenase. 35 (97%) received IPI3 with nivolumab and 1 received single agent IPI3. 15 (42%) received 4 cycles of IPI3. The most common reason for IPI3 cessation was progressive disease (16, 44%). The response rate to IPI3 following progression on low dose IPI was 9/36 (25%); the disease control rate was 12/36 (33%). 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. 13/36 (36%) had grade 3-4 immune-related adverse events (irAE). In 3/36 (8%), the same irAE was observed at low dose IPI and IPI3, and 1 patient had the same irAE (rash) at a higher grade with IPI3 compared to low dose IPI. Conclusions: Standard dose IPI3 following progression on low dose IPI has clinical activity.This is a reasonable treatment strategy for patients who progress on low dose IPI and provides further evidence of a dose-response relationship for IPI. Further research is needed to manage resistance to IPI with anti-PD1.