Abstract 3271: Different pathologic response rates between Australia and Europe in macroscopic stage III melanoma patients upon neoadjuvant ipilimumab plus nivolumab in the phase II OpACIN-neo trial
Authors: Irene L. Reijers, Elisa A. Rozeman, Alexander M. Menzies, Judith M. Versluis, Bart A. van de Wiel, Karolina Sikorska, Hanna Eriksson, Kerwin Shannon, Carolien Bierman, Harm van Tinteren, Maria Gonzalez, Andrew J. Spillane, Robyn P. Saw, Alexander C. van Akkooi, Richard A. Scolyer, Johan Hansson, Georgina V. Long, Christian U. Blank
Journal: Cancer Research (2020)

Abstract Background In the multicenter investigator-initiated OpACIN-neo trial, patients (pts) with macroscopic stage III melanoma were randomized (stratified by center) to three different dosing schemes of neoadjuvant ipilimumab (IPI) + nivolumab (NIVO). Two cycles IPI 1 mg/kg + NIVO 3 mg/kg was identified as the most favorable regimen with 20% grade 3-4 adverse events and a pathologic response rate (pRR) of 77%. After a median follow-up of 17.7 months, relapses were observed in 1/64 (2%) of the pts with a pathologic response, and in 13/21 (62%) of the non-responders. Post-hoc analyses according to continent of study inclusion were conducted to investigate potential differences between pts treated in Europe (EU) and in Australia (AUS). Methods We evaluated baseline patient characteristics, safety and efficacy in terms of pathologic response in pts treated in EU (n=48) and AUS (n=38). Mutational (mut) load of baseline biopsies was assessed using whole exome sequencing. Multivariate analyses were performed using the logistic regression method. Median follow-up was 18.2 months for EU pts and 16.6 months for AUS pts. Results Baseline characteristics (AUS vs EU) differed in age (median 60 vs 53 year [yr], p=0.017). There were numerically more male pts in the Australian cohort (65.8 vs 50.0%, p=0.142) and more pts with unknown primary melanoma (36.8 vs 20.8%, p=0.100). A numerical higher pRR was observed in AUS pts vs EU pts (84.2% vs 64.7%, OR 2.50, p=0.092). The pRR was significantly higher for older pts (OR per yr 1.059, p=0.003), males (83.7% vs 63.9%, OR 2.90, p=0.041), and pts with higher mut load (OR per mutation 1.002, p=0.014). Mut load was higher in pts with pathologic response (p=0.0013) and in AUS pts (p=0.0003). There was a positive correlation between age and mut load (R=0.26, p=0.043). Multivariate analysis including continent, age, gender and mut load revealed that only mut load was significantly associated with response (OR 1.002, p=0.037).The frequency of grade 3-5 toxicities was the same in pts &amp;lt;60 compared to pts &amp;gt;60 yr (42.3% vs 32.4%, p=0.353). Conclusion The numerical higher pRR in AUS vs EU melanoma pts upon neoadjuvant IPI + NIVO appears mostly driven by a higher mut load found in the melanomas of AUS pts. AUS pts were older and there was a positive correlation between age and mut load, indicating that the higher mut load in AUS pts might be explained by higher age. It remains to be elucidated if continental variance in sun exposure also contributed to the difference in mut load. The fact that older pts achieve a higher response rate in absence of increased toxicity rates indicates that older pts should not be withheld neoadjuvant IPI + NIVO. Citation Format: Irene L. Reijers, Elisa A. Rozeman, Alexander M. Menzies, Judith M. Versluis, Bart A. van de Wiel, Karolina Sikorska, Hanna Eriksson, Kerwin Shannon, Carolien Bierman, Harm van Tinteren, Maria Gonzalez, Andrew J. Spillane, Robyn P. Saw, Alexander C. van Akkooi, Richard A. Scolyer, Johan Hansson, Georgina V. Long, Christian U. Blank. Different pathologic response rates between Australia and Europe in macroscopic stage III melanoma patients upon neoadjuvant ipilimumab plus nivolumab in the phase II OpACIN-neo trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3271.