A djuvant immune checkpoint inhibition (CPI) and BRAF/ MEK-targeted therapies after therapeutic lymph node dissection (TLND) have improved relapse-free survival (RFS) in patients with clinical stage III nodal melanoma. Despite these improvements, approximately 40-50% of patients have a relapse within 3-5 years after TLND 1-3 . Preclinical and early clinical trial data suggest that neoadjuvant CPI leads to superior anti-tumor immunity and survival benefit compared to adjuvant CPI 4,5 . Similarly to stage IV melanoma, the combination of anti-CLTA-4 and anti-PD-1 appears to be superior to anti-PD-1 monotherapy in the neoadjuvant setting 6,7 . Previous clinical trials (OpACIN (NCT02437279) and OpACIN-neo (NCT02977052)) testing neoadjuvant ipilimumab (anti-CTLA-4) plus nivolumab (anti-PD-1) in stage III melanoma demonstrated high pathologic response rates (pRRs; 74-78%) and a strong association between pathologic response and RFS, with 94-100% of responding patients remaining free of relapse at 2 years 5,7-9 . Similarly, long-term benefit was observed upon complete response to CPI in stage IV melanoma, even after cessation of CPI [10][11][12] .The association between response and survival; the observed ongoing responses after cessation of therapy in stage IV melanoma; and the substantial morbidity from TLND [13][14][15][16] that impairs

No abstract

10002 Background: OpACIN-neo tested 3 dosing schemes of neoadjuvant (neoadj) IPI+NIVO and identified 2 cycles of IPI 1mg/kg + NIVO 3mg/kg (I1N3) as the most favorable with a pathologic (path) response rate (pRR) of 77% and 20% grade 3-4 irAEs. After 17.6 months median FU, 1/64 (2%) patients (pts) with path response vs 13/21 (62%) of the non-responders ( > 50% viable tumor cells; pNR) had relapsed. We hypothesized that therapeutic lymph node dissection (TLND) could be omitted in pts achieving a complete or near-complete path response (≤10% viable tumor cells; major path response, MPR) in the index node (largest LN metastasis: ILN), whereas additional adjuvant (adj) therapy might improve the outcome of pNR pts. Methods: PRADO is an extension cohort of the multi-center phase 2 OpACIN-neo study that aims to confirm the pRR and safety of neoadj I1N3 and to test response-driven subsequent therapy. Pts with RECIST 1.1 measurable clinical stage III melanoma were included to receive 2 cycles of neoadj I1N3 after marker placement in the ILN. ILN resection was planned at wk 6. Pts that achieved MPR in the ILN did not undergo TLND; pts with pPR ( > 10 – ≤50% viable tumor cells) underwent TLND; and pts with pNR underwent TLND and received adj NIVO or targeted therapy (TT) for 52 wks +/- radiotherapy (RT). Primary endpoints were pRR in the ILN and 24-month RFS. Estimated toxicity rates at wk 12 were calculated using a Kaplan Meier based method. Results: Between Nov 16, 2018 and Jan 3, 2020, 99 of 114 screened pts were eligible and enrolled. So far, 86 pts had ≥12 wks FU. 70/99 pts achieved a path response in the ILN (pRR 71%, 95% CI 61% - 79%); 60 (61%) had MPR. TLND was omitted in 58 (97%) of the MPR pts. There were 28 non-responders; 7 developed distant metastasis before ILN resection. To date, 8 of the 21 pNR pts had adj NIVO, 7 had adj TT and 7 had adj RT. The estimated grade 3-4 irAE rate at wk 12 was 24%. Due to toxicity, 10 pts (10%) received only 1 cycle I1N3 and in 3 pts ILN resection was not performed: 2 of these pts underwent TLND at wk 9 and one pt was not evaluated for path response. At data cutoff, the surgery-related grade 1,2 and 3 AE rates were 29%, 10% and 0% in pts who underwent ILN resection only vs 21%, 30% and 9% in pts who underwent subsequent TLND (p = 0.004). At ASCO 2020 all pts will have reached ≥12 wks FU. Conclusions: Neoadj I1N3 treatment induced a high pRR with tolerable toxicity. TLND was omitted in a major subset of pts, reducing surgical morbidity. Longer FU is needed to report safety and RFS when TLND is omitted in MPR pts. Clinical trial information: NCT02977052.

BackgroundAcral melanoma is a rare melanoma subtype with poor prognosis. Importantly, these patients were not identified as a specific subgroup in the landmark melanoma trials involving ipilimumab and the anti-programmed cell death protein-1 (PD-1) agents nivolumab and pembrolizumab. There is therefore an absence of prospective clinical trial evidence regarding the efficacy of checkpoint inhibitors (CPIs) in this population. Acral melanoma has lower tumor mutation burden (TMB) than other cutaneous sites, and primary site is associated with differences in TMB. However the impact of this on the effectiveness of immune CPIs is unknown. We examined the efficacy of CPIs in acral melanoma, including by primary site.MethodsPatients with unresectable stage III/IV acral melanoma treated with CPI (anti-PD-1 and/or ipilimumab) were studied. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was objective response rate (ORR); secondary outcomes were progression-free survival (PFS) and overall survival (OS).ResultsIn total, 325 patients were included: 234 (72%) plantar, 69 (21%) subungual and 22 (7%) palmar primary sites. First CPI included: 184 (57%) anti-PD-1, 59 (18%) anti-PD-1/ipilimumab combination and 82 (25%) ipilimumab. ORR was significantly higher with initial anti-PD-1/ipilimumab compared with anti-PD-1 (43% vs 26%, HR 2.14, p=0.0004) and significantly lower with ipilimumab (15% vs 26%, HR 0.49, p=0.0016). Landmark PFS at 1 year was highest for anti-PD-1/ipilimumab at 34% (95% CI 24% to 49%), compared with 26% (95% CI 20% to 33%) with anti-PD-1 and 10% (95% CI 5% to 19%) with ipilimumab. Despite a trend for increased PFS, anti-PD-1/ipilimumab combination did not significantly improve PFS (HR 0.85, p=0.35) or OS over anti-PD-1 (HR 1.30, p=0.16), potentially due to subsequent therapies and high rates of acquired resistance. No outcome differences were found between primary sites.ConclusionWhile the ORR to anti-PD-1/ipilimumab was significantly higher than anti-PD-1 and PFS numerically higher, in this retrospective cohort this benefit did not translate to improved OS. Future trials should specifically include patients with acral melanoma, to help determine the optimal management of this important melanoma subtype.

TPS10087 Background: Previous OpACIN and OpACIN-neo studies, investigating neoadjuvant ipilimumab (IPI) plus nivolumab (NIVO), demonstrated high pathologic response rates (74-78%) and favorable long-term outcomes in patients (pts) achieving pathologic response; at 36 and 18 months follow-up, respectively, only 1/71 (1.4%) pts with response has relapsed. In contrast, pts without pathologic response (pNR) have a poor prognosis; 15/23 (65.2%) have relapsed so far. This emphasizes the need for baseline biomarkers predictive of non-response and new neoadjuvant treatment combinations for these pts. In our previous studies, baseline interferon-gamma (IFN-γ) signature low pts were less likely to respond to neoadjuvant IPI plus NIVO. The DONIMI study tests the combination of NIVO +/- IPI with domatinostat (DOM), a class 1 histone deacetylase inhibitor, according to the IFN-γ signature in the tumor. Based on the signature previously described by Ayers et al. we have developed a neoadjuvant IFN-γ signature algorithm that will be used for the first time to classify pts in this prospective trial. Methods: The aim of this two-center investigator-initiated phase 1b study is to assess the safety and feasibility of neoadjuvant NIVO +/- DOM +/- IPI in 45 stage III melanoma pts with RECIST 1.1 measurable de-novo or recurrent disease. IFN-γ signature high pts (n = 20) will be randomized (stratified by center) to Arm A (2 cycles NIVO 240mg q3wk) or Arm B (2 cycles NIVO 240mg q3wk + DOM 200mg twice daily (BID), d1-14, q3wk). IFN-γ signature low pts (n = 25) will be randomized to Arm C (2 cycles NIVO 240mg q3wk + DOM 200mg BID, d1-14, q3wk) or Arm D (2 cycles NIVO 240mg q3wk + IPI 80mg q3wk + DOM 200mg once daily (OD), d1-14, q3wk). Based on safety data of the first 5 pts in arm D, the remaining pts will be treated with either a higher dosing scheme (200mg BID, d1-14, q3wks), a lower dosing scheme (100mg OD, d1-14, q3wks) or the same dosing scheme (200mg OD, d1-14, q3wks). The primary endpoint is safety and feasibility. A treatment arm will be declared as not feasible if 2/5 or 3/10 pts cannot adhere to the preplanned time of surgery (week 6 +/- 1week) due to treatment-related adverse events. Biopsies (week 0, 3), blood samples (week 0, 3, 6, 12) and feces (week 0, 3, 6) will be collected for translational research. The first patient was enrolled on January 23th, 2020. Clinical trial information: NCT04133948.