Abstract 3062
Background
Outcomes of high risk stage III melanoma patients (pts) are poor, with a 5-year overall survival (OS) rate of <50%. Adjuvant (adj) IPI improved 5-year recurrence-free survival (RFS) and OS, and adj NIVO or pembrolizumab improved RFS further. OpACIN, a phase 1b study of neoadjuvant (neoadj) vs adj IPI + NIVO, demonstrated a pathological response rate (pRR) of 78% in the neoadj arm with an increased expansion of tumor-resident TCR clones vs adj. None of the pts with a pathologic response have yet relapsed. However, toxicity was high with 90% grade 3/4 immune-related adverse events (irAEs). This raised the question whether alternative scheduling of neoadj IPI + NIVO may reduce toxicity, but preserve efficacy.
Methods
In this multi-center phase 2 trial (OpACIN-neo) pts with resectable stage III melanoma were randomized 1:1:1 to arm A: 2x IPI 3mg/kg + NIVO 1mg/kg Q3W; arm B: 2x IPI 1mg/kg + NIVO 3mg/kg Q3W; and arm C: 2x IPI 3mg/kg Q3W followed immediately by 2x NIVO 3mg/kg Q2W. Complete lymph node dissection was scheduled at week 6. Primary endpoints were grade ≥3 irAEs within the first 12 weeks, radiologic RR (RECIST 1.1), and pRR (<50% viable tumor cells). Major inclusion criteria were: ≥1 measurable lymph node metastases (RECIST 1.1), no in-transit metastases in the last 6 months, and normal LDH.
Results
86 patients were evaluable; 30 pts in arm A and B, and 26 in arm C. Median follow up was 7.7 months. On advice of the DSMB, arm C was closed earlier due to toxicity. Grade ≥3 irAEs occurred in 40%, 20%, 50% of pts in arm A, B, and C, respectively. Radiologic RR was 60%, 60%, and 42%, whilst pRR was 80% (43% pCR), 77% (57% pCR), and 68% (24% pCR). None of the pts with a pathologic response have relapsed, while 9/21 pts with no pathologic response (pNR) have relapsed. Two pts have died, one (arm A, pNR) of melanoma and one (arm A, pCR) due to complications after an immune-related encephalitis 9.5 months after start of therapy. Baseline IFN-signature biomarker analyses will be presented.
Conclusions
Neoadj IPI 1 mg/kg + NIVO 3 mg/kg is less toxic than the standard dosing regimen. The high response rate was preserved, making this schedule an attractive candidate to be tested against adj PD-1 blockade in a phase 3 study.
Clinical trial identification
NCT02977052