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.

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We assessed the safety, tolerability, PK, PD and efficacy of the PKC inhibitor LXS196 in patients with metastatic uveal melanoma (MUM). As of 30 Sep 2018, 68 patients received LXS196 at doses ranging from 100 to 1000 mg once daily (QD; 38 patients) and 200 to 400 mg twice daily (BID; 30 patients). All patients in the QD regimen had discontinued treatment due to progressive disease. Five patients in the BID regimen remain on study. LDH was > ULN in 38 patients (55.9%), and 60 patients (88.2%) had liver involvement. Dose limiting toxicities (DLTs) in cycle 1 were reported in 7 of 38 patients on the QD schedule and in 2 of 17 patients on the BID schedule who were evaluable for the dose determination. The most common DLT was hypotension, manageable with LXS196 interruption and dose reduction. The most frequent AEs (all grades, in ≥ 20% of patients) suspected to be related to LXS196 in patients across both dosing schedules (n = 68) included nausea (66.2%), diarrhea (45.6%), vomiting (30.9%), hypotension (22.1%), increased ALT (22.1%), and fatigue (20.6%). The majority of gastrointestinal and constitutional AEs were of low grade (grade 1 or 2). Grade 3 or 4 AEs suspected to be related to LXS196 were reported in 17 patients (25.0%), the most frequent being hypotension (8.8%). BID dosing was better tolerated than QD dosing with fewer grade 3 or 4 AEs reported (20% with BID vs 28.9% with QD dosing) and fewer drug-related SAEs (6.7% with BID vs 15.8% with QD). In this study, MTDs were determined at 500mg QD and 400 mg BID and the RDE was declared at 300mg BID. The most common AEs suspected to be related to LXS196 (any grade, in >15% of patients) at the RDE (n = 18) included nausea (77.8%), diarrhea (61.1%), vomiting (38.9%), increased ALT (27.8%), asthenia, dry skin and rash (22.2% each), hypotension, fatigue, increased AST, dermatitis acneiform, and peripheral edema (16.7% each). Clinical PK demonstrates rapid absorption of LXS196 with Tmax of ~1 hr post dose and consistent terminal T1/2 across different doses (~ 11 hr). Exposure at doses above 300 mg QD and 200 mg BID are in the efficacious range from preclinical projections. LXS196 results in reduction of pMARCKS and pPKC delta, evident of target engagement in on-treatment tumor biopsies. Overall, amongst 66 evaluable patients, per RECIST v1.1, 6 had a PR (2 in QD; 4 in BID) and 45 had SD as their best response. At the RDE, of 17 evaluable patients, 2 had confirmed PRs and 12 had SD as their best response (including 2 patients with > 30% tumor reduction/unconfirmed PRs). The median duration of exposure is 3.71 months (range; 1.81 - 15.28 months) and 4.6 months (range; 0.33 - 20.01 months) for patients in the QD and BID regimens, respectively. Of the 5 ongoing patients in the BID regimen, 2 maintain a PR (200 and 300 mg BID) and 3 have SD (all at 300 mg BID). All 5 patients have remained on study for > 13 months. These results suggest encouraging clinical activity of LXS196 as a single agent with manageable toxicity profile in patients with MUM. Citation Format: Ellen Kapiteijn, Matteo Carlino, Valentina Boni, Delphine Loirat, Frank Speetjens, John Park, Emiliano Calvo, Richard Carvajal, Marta Nyakas, Juan Gonzalez-Maffe, Xu Zhu, Ramu Thiruvamoor, Padmaja Yerramilli-Rao, Sophie Piperno-Neumann. A Phase I trial of LXS196, a novel PKC inhibitor for metastatic uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT068.

TPS9605 Background: Adjuvant (adj) immune checkpoint inhibition (ICI) improves relapse free survival (RFS) in stage III melanoma patients (pts). However, preclinical and translational data suggest that neo-adjuvant (neoadj) treatment might be favorable due to broader immune activation. The phase 1b OpACIN study comparing neoadj to adj IPI plus NIVO demonstrated a high pathological response rate (pRR) of 78% complicated by 90% gr 3-4 immune-related adverse events (irAEs). The phase 2 OpACIN-neo trial tested safety and efficacy of three different schemes of neoadj IPI+NIVO and identified two cycles of IPI 1mg/kg + NIVO 3mg/kg as well tolerated (20% gr 3-4 irAEs), with a high pRR of 77%. In both trials, none of the pts with a pathologic response have relapsed after a median follow-up of 30 and 8.3 months. In stage IV melanoma, long-term benefit is observed in patients achieving CR with ICI, even after cessation of therapy. This raises the question of whether a therapeutic lymph node dissection (TLND) can be omitted when a deep pathologic response with neoadj IPI+NIVO is achieved. Methods: The aim of this international multi-center investigator-initiated phase 2 PRADO extension study is to confirm the pRR and toxicity of 2 cycles of neoadjuvant IPI 1mg/kg + NIVO 3mg/kg (the preferred OPACIN-neo regimen) and to test response-driven subsequent therapy i.e. omitting surgery and adjuvant ICI based on the pathological response. 100-110 pts with stage IIIB/C melanoma and a measurable lymph node (≥15mm according to RECIST 1.1) will receive two cycles of IPI 1mg/kg + NIVO 3mg/kg after marker placement into the largest lymph node metastasis. After six weeks, pts will undergo resection of the index lymph node. For pCR/near pCR, pts will not undergo TLND; For pPR, pts will undergo TLND; and for pNR, pts will undergo TLND and start adjuvant NIVO or targeted therapy +/- radiotherapy for 52 weeks. Primary endpoints are pRR of marked lymph node and RFS at 24 months. Baseline biopsies, blood samples (week 0, 6, 12) and faeces (week 0, 6) will be collected for translational research analyses. The first patient in this trial was included in October 2018; 22 patients have been enrolled. Clinical trial information: NCT02977052.

TPS9605 Background: Adjuvant treatment with anti-PD1 therapy improves the recurrence free survival (RFS) in resectable stage III melanoma. The Checkmate-238 and KEYNOTE-054 trials respectively reported a 4-year RFS of 52.5% for adjuvant nivolumab and a 3-year RFS of 63.7% for adjuvant pembrolizumab. Despite these improved outcomes, a considerable proportion of patients have a relapse in the years after therapeutic lymph node dissection (TLND). The OpACIN trial showed that neoadjuvant treatment with nivolumab (NIVO) plus ipilimumab (IPI) is feasible and induces a stronger and broader T-cell response. The subsequent OpACIN-neo trial identified 2 cycles of NIVO 3mg/kg + IPI 1mg/kg as a neoadjuvant dosing scheme with decreased toxicity and preserved high pathologic response rates (77%), which was confirmed in the PRADO trial. A favorable 2-year RFS (83,6%) was achieved in the overall OpACIN-neo population, although patients with a pathological partial or non-response have a worse prognosis and may therefore benefit from additional adjuvant therapy. The efficacy of neoadjuvant checkpoint inhibition versus the current standard of adjuvant therapy needs to be confirmed in a phase III trial, before neoadjuvant therapy can be considered as a standard option for this patient population. Methods: This international, randomized phase 3 trial aims to compare the efficacy of neoadjuvant IPI + NIVO with adjuvant NIVO in macroscopic stage III melanoma. In total 420 patients diagnosed with recurrent or de novo melanoma, with at least one pathologically proven, clinically detectable lymph node (up to 3 in-transit metastases (ITMs) allowed), will be randomized to neoadjuvant or adjuvant treatment. The population will be stratified by BRAF mutation, continent and the presence of ITMs. Patients in arm A will receive 2 cycles of IPI 80mg + NIVO 240mg and will undergo TLND at week 6. In the case of pathological partial response or non-response, surgery will be followed by adjuvant NIVO (11 cycles) or adjuvant dabrafenib + trametinib (46 weeks) if BRAFV600-mutation is present. Patients in arm B will undergo upfront TLND followed by 12 cycles of NIVO 480mg. The primary endpoint will be the event free survival (EFS) defined as the time from randomization until progression to unresectable stage III or stage IV melanoma, recurrent melanoma, a new primary melanoma or death due to melanoma or treatment. Final analysis will be performed after 132 events have been observed, or at latest 2 years after the last patient is included. Baseline biopsies and blood samples (screening, week 0, 3, 6, 9 and 12) will be collected for translational research. Quality of Life questionnaires and electronic Patient Reported Outcomes will be collected using the Kaiku application. The first patient was enrolled on the 23rd of July 2021. Clinical trial information: NCT04949113.