Evaluation of three dosing schemes alternating levels of neoadjuvant ipilimumab and nivolumab administered to patients with resectable stage III melanoma and lymph node metastasis has yielded an optimal regimen that reduces toxicity while maintaining high response rates in this patient population. Findings were presented at the ESMO 2018 Congress in Munich, Germany.
Christian Blank, Medical Oncologist, The Netherlands Cancer Institute in Amsterdam, Netherlands pointed out that patients with high-risk stage III melanoma generally have poor outcomes and have a 5-year overall survival rate of less than 50%.
In the previous phase Ib OpACIN study, neoadjuvant ipilimumab plus nivolumab treatment provided a pathological response rate (pRR) of 78%, and none of the patients in the trial demonstrating pathologic response have relapsed to date. However, toxicity was high, with 90% of patients experiencing grade 3/4 immune related adverse events (irAEs), leading the investigators to evaluate alternative dosing regimens that could preserve this high response rate while minimising toxicity.
The subsequent multicentre phase II, OpACIN-neo (NCT02977052) trial randomly assigned patients with resectable macroscopic stage III melanoma 1:1:1 to receive standard therapy comprising 2 doses of ipilimumab at 3 mg/kg plus nivolumab at 1 mg/kg every 3 weeks (arm A), or 2 doses of ipilimumab at 1 mg/kg plus nivolumab at 3 mg/kg every 3 weeks (arm B), or to receive 2 doses of ipilimumab at 3 mg/kg every 3 weeks followed immediately by 2 doses of nivolumab at 3 mg/kg every 2 weeks (arm C). Eligible patients were required to have one or more measurable lymph node metastases (RECIST v1.1), no in-transit metastases within the last 6 months, and normal LDH. Complete lymph node dissection was scheduled at week 6.
The primary endpoints were grade ≥3 irAEs within the first 12 weeks, radiologic RR according to RECIST v1.1, and pRR, which was defined as less than 50% of viable tumour cells.
Of the86 patients randomised, 30 patients in arm A and B, and 26 in arm C had evaluable data and were included in this analysis.
At a median follow-up of 7.7 months, the Data Safety Monitoring Board recommended early closure of arm C due to toxicity.
Grade ≥3 irAEs had occurred in 40%, 20%, and 50% of patients in arms A, B, and C, respectively.
The radiologic and pathologic response was also lowest in arm C; the radiologic RR was 60%, 60%, and 42%, and the pRR was 80%, 77%, and 68% in arms A, B, and C, respectively.
Durable pathological complete responses were achieved with all dosing regimens
Pathological complete response (pCR) was achieved by 47% of patients in arm A, 57% in arm B, and by 23% of patients in arm C.
None of the patients achieving pathologic response have relapsed; however, relapse has been reported in 9 of 21 patients demonstrating no pathologic response (pNR).
Two deaths occurred in in arm A; one patient who had not a pathologic response died of melanoma and one pCR patient died due to complications after experiencing immune-related encephalitis at 9.5 months following the initiation of therapy.
Caroline Robert who discussed the study findings commented about pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma. Furthermore, she questioned if pathological complete response accurately predicts long term survival which is not a case in neoadjuvant treatments for breast or pancreatic cancers, but they are neoadjuvant chemotherapies. Early trial of neoadjuvant ipilimumab plus nivolumab identifies the regimen with optimal benefit/risk ratio. However, long term benefit value of pCR remains to be proven. It is about a period of intense “paradigm shaking”, and place of surgery should be revisited according to Dr Robert.
Data from the OpACIN-neo study led the investigators to conclude that the arm B combination of neoadjuvant ipilimumab at 1 mg/kg plus nivolumab at 3 mg/kg resulted in less toxicity than the standard dosing regimen. Furthermore, the high response rate was preserved with this regimen.
They suggest that this schedule is an attractive candidate to be tested against adjuvant PD-1 blockade agents in a phase III study.
This trial was sponsored by Bristol Meyers Squibb.
LBA42 - Rozeman EA, Menzies AM, van de Wiel BA, et al. OpACIN-neo – A Multicenter Phase 2 Study to identify the Optimal neo-Adjuvant Combination scheme of Ipilimumab (IPI) and Nivolumab (NIVO).