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Introduction: In patients with metastatic melanoma, progression of a single tumour lesion (solitary progression) after response to immune checkpoint inhibition (ICI) is increasingly treated with local therapy. We evaluated the role of local therapy for solitary progression in melanoma.Patients and methods: Patients with metastatic melanoma treated with ICI between 2010 and 2019 with solitary progression as first progressive event were included from 17 centres in 9 countries. Follow-up and survival are reported from ICI initiation.Results: We identified 294 patients with solitary progression after stable disease in 15%, partial response in 55% and complete response in 30%. The median follow-up was 43 months; the median time to solitary progression was 13 months, and the median time to subsequent progression after treatment of solitary progression (TTSP) was 33 months. The estimated 3-year overall survival (OS) was 79%; median OS was not reached. Treatment consisted of systemic therapy (18%), local therapy (36%), both combined (42%) or active surveillance (4%). In 44% of patients treated for solitary progression, no subsequent progression occurred. For solitary progression during ICI (n = 143), the median TTSP was 29 months. Both TTSP and OS were similar for local therapy, ICI continuation and both combined. For solitary progression post ICI (n = 151), the median TTSP was 35 months. TTSP was higher for ICI recommencement plus local therapy than local therapy or ICI recommencement alone (p = 0.006), without OS differences.Conclusion: Almost half of patients with melanoma treated for solitary progression after initial response to ICI had no subsequent progression. This study suggests that local therapy can benefit patients and is associated with favourable long-term outcomes. & ordf;2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Background Patients with synchronous clinical stage III melanoma can present with primary melanoma lesions, locally recurrent melanoma or in-transit metastases. Neoadjuvant ipilimumab plus nivolumab induces high pathologic response rates and an impressive relapse-free survival in patients with nodal macroscopic stage III melanoma. Whether primary site melanoma and in-transit metastases respond similarly to lymph node metastases with neoadjuvant immunotherapy is largely unknown. Such data would clarify whether surgical excision of these melanoma lesions should be performed before neoadjuvant therapy or whether it could be deferred and performed in conjunction with lymphadenectomy following neoadjuvant immunotherapy. Patients Patients with synchronous clinical stage III melanoma were identified from the OpACIN, OpACIN-neo and PRADO neoadjuvant trials, where all patients were treated with ipilimumab plus nivolumab. An additional case treated outside those clinical trials was included. Results Seven patients were identified; six patients had a concordant response in primary site melanoma lesions or in-transit metastasis and the lymph node metastases. One patient had concordant progression in both the primary and nodal tumour lesions and developed stage IV disease during neoadjuvant treatment, and thus, no resection was performed. Conclusion Pathologic response following neoadjuvant ipilimumab plus nivolumab in primary site melanoma lesions or in-transit metastasis is concordant with a response in the lymph node metastases, indicating that there may be no need to perform upfront surgery to these melanoma lesions prior to neoadjuvant treatment.

Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN ( NCT02437279 ) and phase 2 OpACIN-neo ( NCT02977052 ) studies1,2. While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response (n = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo (n = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (P

Background The previous OpACIN and OpACIN-neo studies investigating neoadjuvant IPI plus NIVO have demonstrated high pathologic response rates (74–78%) and favorable long-term outcomes for patients (pts) with a pathological response; at 36 and 18 months follow up only 1/71 (1.4%) responders has relapsed. In contrast, pathological non-responders 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 IFN-γ signature high pts were more likely to respond to IPI plus NIVO. The DONIMI study tests the combination of NIVO ± IPI combined with a class 1 histone deacetylase inhibitor, domatinostat (DOM), according to the pts IFN-γ signature. We have developed a neoadjuvant IFN-γ signature, based on the signature previously described by Ayers et al., that will be used for the first time to classify pts in this prospective trial. Trial design This two-center investigator-initiated phase 1b study aims to assess the safety and feasibility of neoadjuvant NIVO ± DOM ± IPI in 45 stage III melanoma pts with macroscopic de-novo or recurrent disease. IFN-γ signature high pts (n=20) will be randomized (stratified by center) to Arm A (2 cycles NIVO 240 mg q3wk) or Arm B (2 cycles NIVO 240 mg q3wk + DOM 200 mg twice daily (BID), d1-14, q3wk). IFN-γ signature low pts (n=25) will be randomized to Arm C (2 cycles NIVO 240 mg q3wk + DOM 200 mg BID, d1-14, q3wk) or Arm D (2 cycles NIVO 240 mg q3wk + IPI 80 mg q3wk + DOM 200 mg 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 (200 mg BID, d1-14, q3wks), a lower dosing scheme (100 mg OD, d1-14, q3wks) or the same dosing scheme (200 mg 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 patients cannot adhere to the planned 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. To date, 7 patients have been enrolled. Clinical trial information NCT04133948 Disclosure Information I.L.M. Reijers: None. E.A. Rozeman: None. P. Dimitriadis: None. O. Krijgsman: C. Other Research Support (supplies, equipment, receipt of drugs or other in-kind support); Modest; BMS. L.J.W. Bosch: None. S. Cornelissen: None. J. Bouwman: None. J.M. Versluis: None. D. Rao: None. B. van de Wiel: None. A.J. Spillane: None. R.A. Scolyer: F. Consultant/Advisory Board; Modest; MSD, Neracare, Myriad, Novartis. A.M. Menzies: F. Consultant/Advisory Board; Modest; BMS, MSD Oncology, Novartis, Pierre Fabre, Roche. A.C.J. van Akkooi: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; Amgen, BMS, Novartis. F. Consultant/Advisory Board; Modest; Amgen, BMS, Novartis, MSD, Merck, Merck-Pfizer, 4SC. G.V. Long: F. Consultant/Advisory Board; Modest; Aduro, Amgen, BMS, Mass-Array, Pierre-Fabre, Novartis, Merck MSD, Roche. C.U. Blank: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; BMS, Novartis, Nanostring. F. Consultant/Advisory Board; Modest; BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, Genmab, Pierre Fabre.

Background Before adjuvant checkpoint inhibition the 5-year overall survival (OS) rate was poor ( Materials and Methods The phase 1b OpACIN trial included 20 stage IIIB/IIIC melanoma patients, which were randomized to receive IPI 3 mg/kg plus NIVO 1 mg/kg either adjuvant 4 cycles or split 2 cycles neoadjuvant and 2 adjuvant. In the phase 2 OpACIN-neo trial, 86 patients were randomized to 2 cycles neoadjuvant treatment, either in arm A: 2x IPI 3 mg/kg plus NIVO 1 mg/kg q3w (n=30), arm B: 2x IPI 1 mg/kg plus NIVO 3 mg/kg q3w (n=30), or arm C: 2x IPI 3 mg/kg q3w followed immediately by 2x NIVO 3 mg/kg q3w (n=26). Pathologic response was defined as Results Only 1 of 71 (1.4%) patients with a pathologic response on neoadjuvant therapy had relapsed, versus 16 of 23 patients (69.6%) without a pathologic response, after a median follow-up of 36 months for the OpACIN and 24 months for the OpACIN-neo trial. In the OpACIN trial, the estimated 3-year RFS rate for the neoadjuvant arm was 80% (95% CI: 59%-100%) versus 60% (95% CI: 36%-100%) for the adjuvant arm. Median RFS was not reached for any of the arms within the OpACIN-neo trial. Estimated 24-months RFS rate was 84% for all patients (95% CI: 76%-92%); 90% for arm A (95% CI: 80%-100%), 78% for arm B (95% CI: 63%-96%) and 83% for arm C (95% CI: 70%-100%). Baseline interferon-γ gene expression score and tumor mutational burden predict response. Conclusions OpACIN for the first time showed a potential benefit of neoadjuvant IPI plus NIVO versus adjuvant immunotherapy, whereas the OpACIN-neo trial confirmed the high pathologic response rates that can be achieved by neoadjuvant IPI plus NIVO. Both trials show that pathologic response can function as a surrogate markers for RFS. Clinical trial information NCT02437279, NCT02977052 Disclosure Information J.M. Versluis: None. E.A. Rozeman: None. A.M. Menzies: F. Consultant/Advisory Board; Modest; BMS, MSD, Novartis, Roche, Pierre-Fabre. I.L.M. Reijers: None. O. Krijgsman: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; BMS. E.P. Hoefsmit: None. B.A. van de Wiel: None. K. Sikorska: None. C. Bierman: None. P. Dimitriadis: None. M. Gonzalez: None. A. Broeks: None. R.M. Kerkhoven: None. A.J. Spillane: None. J.B.A.G. Haanen: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; BMS, MSD, Neon Therapeutics, Novartis. F. Consultant/Advisory Board; Modest; BMS, MSD, Novartis, Pfizer, AZ/MedImmune, Rocher/Genentech, Ipsen, Bayer, Immunocore, SeattleGenetics, Neon Therapeutics, Celsius Therapeutics, Gadet, GSK. W.J. van Houdt: None. R.P.M. Saw: None. H. Eriksson: None. A.C.J. van Akkooi: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; Amgen, BMS, Novartis. F. Consultant/Advisory Board; Modest; Amgen, BMS, Novartis, MSD Merck, Merck-Pfizer, 4SC. R.A. Scolyer: F. Consultant/Advisory Board; Modest; MSD, Neracare, Myriad, Novartis. T.N. Schumacher: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; MSD, BMS, Merck. E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; AIMM Therapeutics, Allogene Therapeutics, Amgen, Merus, Neogene Therapeutics, Neon Therapeutics. F. Consultant/Advisory Board; Modest; Adaptive Biotechnologies, AIMM Therapeutics, Allogene Therapeutics, Amgen, Merus, Neon Therapeutics, Scenic Biotech. Other; Modest; Third Rock Ventures. G.V. Long: F. Consultant/Advisory Board; Modest; Aduro, Amgen, BMS, Mass-Array, Pierre-Fabre, Novartis, Merck MSD, Roche. C.U. Blank: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; BMS, Novartis, NanoString. E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Uniti Cars, Neon Therapeutics, Forty Seven. F. Consultant/Advisory Board; Modest; BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre-Fabre.

Neoadjuvant chemo(radio)therapy is part of the established standard of care in cancer treatment; neoadjuvant application of immunotherapy, however, is only performed within recent trials. Combination of programmed cell death protein 1 and cytotoxic T lymphocyte antigen 4 blockade shows promising results with high pathologic response rates in the neoadjuvant setting and a very low relapse rate in the responding patients. In addition, neoadjuvant administration allows direct determination of treatment efficacy within the individual patient, and offers easy access to paired tumor material, both pretherapy and post-therapy, thus facilitates the rational development of new combinations driven by preclinical analyses. Patient-derived human tumor explant systems such as a recently developed human patient-derived tumor fragment platform can provide an additional tool to further rationalize the development of new treatment combinations. We will discuss neoadjuvant immunotherapy as a unique opportunity for rational trial design, the development of immune signatures for non-responding patients to steer clinical trial development, and the use of patient-derived ex vivo models to identify new personalized immunotherapy combinations. In this context, we propose the ‘Lombard Street Approach’, a back and forth approach of characterizing non-responders on neoadjuvant immunotherapy combinations, identifying promising new combinations for this group in the tumor fragment platform, and performing subsequently signature-driven small proof-of-concept combination trials. Repeating this approach with smaller and smaller groups of non-responders will step by step increase the percentage of patients benefiting from neoadjuvant immunotherapy in a rational and fast manner.

Introduction: In patients with metastatic melanoma, progression of a single tumour lesion (solitary progression) after response to immune checkpoint inhibition (ICI) is increas

10014 Background: Anti-PD1 therapy (PD1), either alone or in combination with anti-CTLA4, has high initial response rates, but 20% of patients (pts) with complete response (CR) and 60% with partial response (PR) experience disease progression by 5 years. The nature and best management of this acquired resistance (AR) remains unknown. Methods: Consecutive pts from 16 centers who achieved CR or PR to PD1-based therapy and who later progressed were examined. Demographics, disease characteristics, nature of progression and subsequent treatments were examined. Results: 300 pts were identified, median age was 64y, 133 (44%) BRAF mutant and 55 (18%) had target therapy (TT) prior to PD1-based therapy. 173 (58%) received PD1 alone, 114 (38%) PD1+CTLA4 and 13 (4%) PD1 + an investigational drug. 89 (30%) pts had CR, 210 (70%) pts had PR. Median time to AR was 12.6 mo (95% CI, 11.3, 14.2) and 142 (47%) progressed while still on drug. Most pts (N = 194, 65%) progressed in a single organ site, and in a solitary lesion (N = 154, 51%). 38 (25%) progressed in the brain only. AR was in new lesion in 136 (45%), existing lesions in 106 (35%), and both new and existing lesions in 58 (19%). For those with solitary lesion progression, 51 (33%) had local (L) treatment alone, 54 (35%) had local and systemic (L+ST), 46 (30%) had systemic therapy alone (ST) and 3 (2%) had no further treatment (BSC). If progression was non-solitary, 89 (61%) had ST, 33 (23%) L+ST, 17 (12%) L alone and 7 (5%) BSC. For those who received ST after AR, first ST (ST1) was PD1 alone in 130 (51%) [53, 41% continuation, 77, 59% reinduction], PD1+CTLA4 in 31 (12%), CTLA4 alone in 15 (6%), targeted therapy in 49 (19%) and investigational drugs in 29 (11%). Median follow-up from AR was 20 mo (95% CI 18-22). The ORR to ST1 was 46% for PD1 alone (56% continuation, 42% reinduction), 56% for PD1+ CTLA4, 0% for CTLA4 alone, 20% for investigational drugs and 67% for TT. Median OS from AR was 38 mo (95% CI, 34.6-NR). 2y-OS was 69% in those with solitary progression compared to 55% for the pts that had a non-solitary progression (p < 0.001). There was no difference in OS by ST1 class. Detailed analyses including nature and management of AR while on PD1 or after discontinuation will be presented, as will site-specific AR outcomes. Conclusions: Acquired resistance to PD1-based therapy in melanoma is usually oligometastatic, occurring approximately one year after PD1 start. Most pts with isolated progression have local therapy, and the most frequent subsequent systemic therapy is PD1-alone. Patients with AR can have meaningful survival, with median OS over 3 years from AR.

Neoadjuvant checkpoint inhibition, in which the therapy is administered before surgery, is a promising new approach to managing bulky but resectable melanoma, and is also being explored in other cancers. This strategy has a high pathologic response rate, which correlates with survival outcomes. The fact that biopsies are routinely available provides a unique opportunity for understanding the responses to therapy and carrying out reverse translation in which these data are used to select therapies in the clinic or in trials that are more likely to improve patient outcomes. In this Perspective, we discuss the rationale for neoadjuvant immunotherapy in resectable solid tumors based on preclinical and human translational data, summarize the results of recent clinical trials and ongoing research, and focus on future directions for enhancing reverse translation.

A 61-year-old man, without noteworthy medical history, presented with complaints of progressive fatigue and flushes. Diagnostic imaging revealed a large tumour in the stomach with liver metastases, and histopathological examination showed a well-differentiated gastric neuroendocrine tumour (NET). After chemotherapy, everolimus was administered, and upon progression, PD-1 inhibitor PDR001 was started. Two weeks after the first gift, he was admitted with loss of consciousness and a blood glucose level of 1.6 mmol/L. Plasma insulin was below 0.5 mU/L, C-peptide level was 250 pmol/L, insulin-like growth factor (IGF)-II was 804 ng/mL, and pro-IGF-IIE level was 80 µg/L. Based on the clinical findings, the patient was diagnosed with non-islet cell tumour hypoglycaemia (NICTH) with an overproduction of pro-IGF-IIE and eventually IGF-II due to progressive metastatic well-differentiated gastric NET. NICTH is a very rare condition. It has been reported in several tumour types but has never been described as a consequence of NET.

9579 Background: Recently, trials have shown the benefit of adjuvant aPD-1 therapy in macroscopic stage III melanoma patients. This treatment has been incorporated in daily clinical practice, however, a substantial part of patients still does not benefit from this therapy, as they develop recurrences. The aim of this study is to evaluate the results of adjuvant aPD-1 therapy and the potency of the IFNγ signature as a prognostic or predictive marker, as it has proven to be predictive of response in neoadjuvant trials. Methods: Patients participating in an ongoing biobank study and naïve for systemic therapy were included, between 10-2017 and 06-2020, after complete resection of macroscopic stage III melanoma. Approval and reimbursement of adjuvant therapy in the Netherlands started in 12-2018, resulting in 2 cohorts of similar high risk patients: prior to availability of adjuvant aPD-1 (cohort A) and thereafter (cohort B). Data cut-off for clinical data was January 1st 2021. Transcriptome sequencing was performed on samples of stage III melanoma by CeGaT GmbH, IFNγ signature was determined on these data with the median as cut-off. Clinical data were compared between cohort A and B as intention-to-treat population, including patients with a recurrence before adjuvant therapy start (n=10). Results: In total, 99 patients were included: 50 in cohort A and 49 in cohort B. Majority of included patients had thick primary melanomas (Breslow >2mm in 59.6%) and stage IIIC/IIID disease (83.3%) according to AJCC 8th edition. At a median follow-up of 20.6 months (95% confidence interval [CI] 16.6-24.7), median recurrence-free survival (RFS) was 6.1 months (95%CI 3.9-8.4) versus 22.8 months (95%CI 8.7-36.9), significantly in favor of cohort B (p=0.011). Median overall survival (OS) was not reached in both patient groups, but was overall significantly different (p=0.040), favoring cohort B. RNA sequencing was performed in 25 patients who received adjuvant therapy and in 24 who did not, excluding patients with an early recurrence (

9533 Background: First line IPI+PD1 induces long-term response in 36% of MM patients (pts); however, the majority of pts will progress and may require further treatment, which is yet to be established. We studied the patterns of progressive disease (PD) on 1st line IPI+PD1, and the management and outcomes in MM pts. Methods: Demographics, disease characteristics, nature of PD, subsequent treatments and outcomes were examined in MM pts with PD on 1st line IPI+PD1. Multivariable analyses (MVA) identified factors associated with patterns of PD: innate resistance (IR) = PD as best response or stable disease (SD) < 6 mo; acquired resistance (AR) = PD after initial response or SD ≥ 6 mo. Results: 310 MM pts from 14 melanoma centres were included; 208 (67%) had PD during and 102 (33%) after ceasing IPI+PD1. Overall med. progression-free survival (mPFS) was 2.8 mo (CI 95% 2.7 – 3.0); 187 pts (60%) had IR (mPFS 2.2 [2.1 – 2.5]), 112 pts (36%) had AR (mPFS 8.5 [7.2 – 10.2]) and 11 pts (4%) had pseudoprogression, i.e. PD followed by response without changing treatment (mPFS 2.7 mo [1.4 – NA]). On MVA, pts with ECOG PS ≥ 1 were more likely to have IR vs AR; and within IR pts, those with head & neck primary melanomas and lung metastases were more likely to have PD < 1.5 mo. Most pts with IR (68%) had PD in multiple sites, while 61% AR pts had PD in a single site. Brain was most common site of single organ PD; 49% of IR and 41% of AR. Med. follow-up from PD was 32.7 mo (28.1 – 36.8). After PD, 61 pts (20%) had best supportive care (26% of IR and 11% of AR pts). 259 pts (80%) received further treatment: 39% IR pts had systemic treatment (ST) only and 27% had ST + local; 31% AR pts had ST only and 39% had ST + local. Of 200 pts (65%) who had ST(+/-local), 54% had 1 line of ST and 46% had ≥ 2; 1st line ST (ST1) was BRAF/MEKi in 36% of pts, PD1 in 32%, IPI+PD1 in 7%, investigational drugs in 11%, chemotherapy in 9% and others in 5%. ORR in IR pts was lower than in AR pts for every type of ST1 (see Table). Med. OS from PD was 11.4 mo (CI 95% 9.6 – 16.1); IR 6.4 mo (CI 95% 5.6 – 10.2) and AR 26.1 mo (CI 95% 17.1 – NA). Conclusions: These data suggest longer OS from PD for AR vs IR pts independent of ST type. BRAF/MEKi, rechallenge with PD1+/-IPI and investigational drugs showed activity after PD on IPI+PD1, while chemotherapy has no role in this context.[Table: see text]

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 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.

Introduction The outcome of high-risk stage III melanoma patients was poor with a 5-year overall survival (OS) rate of Methods The phase 1b OpACIN trial randomized 20 stage IIIB/IIIC melanoma patients to receive either 4 cycles of adjuvant IPI 3 mg/kg plus NIVO 1 mg/kg or 2 cycles of neoadjuvant IPI plus NIVO at the same dose followed by 2 cycles adjuvant IPI plus NIVO. In the OpACIN-neo trial, 86 patients were randomized to 2 cycles neoadjuvant in arm A: 2x IPI 3 mg/kg plus NIVO 1 mg/kg q3w (n=30), arm B: 2x IPI 1 mg/kg plus NIVO 3 mg/kg q3w (n=30), and arm C: 2x IPI 3 mg/kg q3w followed immediately by 2x NIVO 3 mg/kg q3w (n=26). Pathologic response was defined as Results After a median follow-up of 36 months for the OpACIN and 18 months for the OpACIN-neo trial, only 1 of 71 patients (1.4%) with a pathologic response on neoadjuvant therapy had relapsed, versus 15 of 23 patients (65.2%) without a pathologic response. The estimated 3-year RFS rate for the neoadjuvant arm was 80% (95% CI: 59%-100%) versus 60% (95% CI: 36%-100%) for the adjuvant arm in the OpACIN trial. The median RFS was not reached in any of the arms within the OpACIN-neo trial. Estimated 18-months RFS rate was 85% (95% CI: 78%-93%) for all patients; for arm A 90% (95% CI: 80%-100%), for arm B 82% (95% CI: 70%-98%) and for arm C 83% (95% CI: 70%-100%). Translational analyses showed that tumor mutational burden and interferon-γ gene expression score at baseline, both separate and combined, can function as predictors of response. Conclusions OpACIN showed for the first time a potential benefit of neoadjuvant versus adjuvant immunotherapy, while OpACIN-neo confirmed the high pathologic response rates which can be achieved by neoadjuvant IPI plus NIVO. Both trials argue for pathologic response as a surrogate markers for RFS. Clinical trial information: NCT02437279, NCT02977052 Citation Format: Christian U. Blank, Judith M. Versluis, Elisa A. Rozeman, Alexander M. Menzies, Irene L. Reijers, Oscar Krijgsman, Esmée P. Hoefsmit, Bart A. van de Wiel, Karolina Sikorska, Carolien Bierman, Petros Dimitriadis, Maria Gonzalez, Annegien Broeks, Ron M. Kerkhoven, Andrew J. Spillane, John B. Haanen, Winan J. van Houdt, Robyn P. Saw, Hanna Eriksson, Alexander C. van Akkooi, Richard A. Scolyer, Ton N. Schumacher, Georgina V. Long. 36-months and 18-months relapse-free survival after (neo)adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma patients - update of the OpACIN and OpACIN-neo trials [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 3412.

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.

10064 Background: Neoadjuvant ipilimumab and nivolumab induces high pathologic response rates of 74-78% (OpACIN and OpACIN-neo trial), thus the role of Therapeutic Lymph Node Dissections (TLND) in patients with major pathologic responses (MPR: pathological (near) complete response) is now unclear. In the PRADO trial, TLND was omitted in patients with MPR in their index lymph node ((ILN), the largest LN marked prior to neoadjuvant therapy). We sought to determine if less extensive surgery is associated with better Health Related Quality of Life (HRQoL). These are the first results of the comparison of HRQoL between patients undergoing a TLND or less extensive ILN excision. Methods: HRQoL was assessed with the European Organisation for Research and Treatment of Cancer QoL questionnaire-C30 (QLQ-C30). A generalized estimation equation was used to assess the difference in HRQoL outcomes between patients who underwent TLND (pathological non- and partial-responders, pNR/pPR) versus those who did not (pathological (near)complete responders, pNCR/pCR). Differences were adjusted for age, gender and follow-up (FU, in weeks), but not for pathological responses (pNR, pPR, pNCR & pCR). Differences in QLQ-C30 scores were classified as clinically important according to published guidelines. Results: A total of 49 patients from the PRADO study had reached at least 24 weeks FU, and were included in the first explorative analysis. The median age of this study population was 58 years (range, 22-84). Questionnaire completion rates were high: 94% at baseline, 100%, 90%, 88% at week 6, 12 and 24, respectively. Sixteen (33%) patients underwent TLND versus 33 (67%) who had ILN excision only. Over a FU period of 24 weeks, patients who underwent TLND scored significantly lower on global (68 vs 78, adjusted difference (diff) = -9.53, p = .005), physical (84 vs 94 diff = -11.1, p = < .001), emotional (69 vs 83, diff = -11.7, p = .001), role (70 vs 85, diff = -13, p = .004), and social functioning (81 vs 91, diff = -8.9, p = .016) and had a higher symptom burden of fatigue (35 vs 23, diff = 11.1, p = .004), insomnia (38 vs 18, diff = 16.6, p = .002) and financial impact (12 vs 4, diff = 7.9, p = .027) than patients undergoing ILN excision only. These differences were indicated as clinically relevant. Conclusions: First results from PRADO suggest that reducing the extent of surgery following neoadjuvant immunotherapy might result in better HRQoL of high-risk stage III melanoma patients. Clinical trial information: NCT02977052.

10038 Background: Only a subset of advanced melanoma patients respond to anti-PD-1 (aPD1) monotherapy. Upfront identification of (non-)responsiveness would help guide first-line treatment decisions, prevent overtreatment and unnecessary risk for toxicities. T cell density and expression of T cell related genes have been associated with response to aPD1, but are imperfect predictors. We investigated whether spatial proximity of CD8 T cells to tumor cells improves upon the predictive value of T cell density alone. Methods: Pretreatment tumor specimens from melanoma patients treated with aPD1 in the Netherlands Cancer Institute were stained for DAPI, SOX10/Melan-A, CD4, CD8, FOXP3 and PD-1 by multiplex immunofluorescence. Sections were imaged on Vectra and analyzed using HALO to optimize marker thresholds and demarcate tumor and stroma. T cell proximity to tumor cells was evaluated as difference in area under the curve between i) a spatial G-function quantifying T cell density around tumor cells in tumor areas and ii) analogous null distributions obtained by random permutation of cell labels. This assessment of co-clustering is independent of cell density and heterogeneity therein and does not reflect repulsion of T cells to stromal/marginal areas. Clinical characteristics, RECIST response and survival were collected from patient records. Associations between T cell density, T cell proximity to Sox10/Melan-A+ tumor cells, other clinical biomarkers (LDH, M stage and WHO performance status) and response were examined in a Bayesian hierarchical logistic regression. Results: Tumor specimens of 98 patients were included, of whom 45 were treated with aPD1 as first-line therapy and 33 had an objective response. CD8 T cell proximity to tumor cells was associated with response in an independent, comparatively strong, and tissue dependent manner (cutaneous tissue: 2.78 [2.45, 3.17], visceral: 2.30 [1.95, 2.72], lymphoid: 2.12 [1.88, 2.40], format: maximal posteriori odds ratio [89% equal-tailed credibility interval]), in a multivariate model correcting for CD8 T cell density (1.74 [1.62, 1.88]), LDH (1.93 [1.72, 2.16]), M stage (0.92 [0.87, 0.98]) and WHO performance status (0.79 [0.72, 0.88]). Our model achieved an area under the ROC curve of 77.7%, whereas an analogous model omitting the proximity variable achieved 73.1%. Conclusions: Our analyses show that spatial proximity of CD8 T cells to tumor cells functions as an independent biomarker for response to aPD1 and suggests that preexisting CD8 T cell tumor reactivity is reflected by this spatial proximity.

10021 Background: Continuous combination of MAPK inhibition (MAPKi) and anti-PD-(L)1 has been investigated by several trials to improve outcome of BRAFV600 mutated melanoma patients. A major obstacle for continuous combination is the high frequency (~60%) of grade 3-4 treatment-related adverse events (TRAE) for which many patients need to discontinue (~40%). In a preclinical model we showed that short‐time MAPKi induces T cell infiltration and is synergistic with anti-PD‐1. In patients T cell infiltration increased after short-term MAPKi, while after > 2 weeks this was often diminished. The aim of this phase 2b study was to identify the optimal duration of MAPKi with dabrafenib (BRAFi) + trametinib (MEKi) in combination with pembrolizumab (anti-PD-1) in terms of safety, feasibility and immune-activating capacity. Methods: Treatment-naïve BRAFV600E/K mutant advanced melanoma patients started pembrolizumab (PEM) 200mg Q3W and were randomized in week 6 to continue PEM only (cohort 1) or to receive in addition intermittent dabrafenib (D) 150 mg BID + trametinib (T) 2mg QD for 2 x 1 week (cohort 2), 2 x 2 weeks (cohort 3), or continuous for 6 weeks (cohort 4). All cohorts continued PEM for up to 2 years. Primary endpoints were safety and treatment-adherence. Secondary endpoints were objective response rate (ORR, RECIST 1.1) at week 6, 12, 18 compared to baseline and PFS. Results: Between June 2016 and August 2018, 32 patients have been included; 56% were male, 50% had M1c disease and the majority had a BRAFV600E mutation (81%) and a baseline LDH level > ULN (87%). Grade 3-4 TRAE were observed in 12%, 12%, 50%, and 62% of patients in cohort 1, 2, 3, and 4, respectively. All planned D+T was given in 88%, 63%, and 38% of patients in cohort 2, 3, and 4. Most patients needed to interrupt or discontinue D+T due to fever or elevated liver enzymes. ORR at week 6, week 12, and week 18 were 38%, 62%, and 62% in cohort 1, 25%, 62%, and 75% in cohort 2, 25%, 50%, and 75% in cohort 3 and 0%, 62%, and 50% in cohort 4. After a median follow-up of 17.4 months, the median PFS of patients treated with PEM monotherapy was 10.6 months compared to 27.0 months for patients treated with PEM and short-term/intermittent D+T (p = 0.13). Conclusions: Combination of PEM plus intermittent D+T seems more feasible and tolerable than continuous triple therapy. Intermittent short-time combination therapy might be equally effective, enables therapy with MAPKi as a second line, and therefore warrants further investigation in a larger patient cohort. Clinical trial information: NCT02625337.

Background In stage III melanoma patients, adjuvant immune checkpoint inhibition (ICI) has shown to improve relapse free survival. However, preclinical and translational data suggest that neoadjuvant (neoadj) ICI might be more beneficial due to broader immune activation. In the OpACIN and OpACIN-neo trials with neoadj IPI+NIVO, high pathologic (path) response rates (pRR) were observed (78% and 77%, respectively). Furthermore, neoadj ICI could reduce tumor burden, making surgery less mutilating. In patients presenting with synchronous lymph node (LN) metastases, neoadj ICI might improve surgical resectability of both sites. To date, response of these primary melanoma lesions upon neoadj IPI+NIVO is not reported. Methods Here we report on four stage III melanoma patients with melanoma at the primary site and synchronous LN metastases that were treated with neoadj IP+NIVO. Results Four stage III melanoma patients were identified. In the OpACIN-neo trial, one patient treated with 2 courses IPI 1 mg/kg + NIVO 3 mg/kg showed a path partial response (33% viable tumor cells) in the in-scar recurrence and a complete response (CR) in the LN metastasis, and one patient treated with 2 courses IPI 3 mg/kg followed by 2 courses NIVO 3 mg/kg showed no pathological response in both the in-scar recurrence (60% viable tumor cells) and LN metastasis (59% vital tumor). In the PRADO extension cohort, one patient treated with 2 courses IPI 1 mg/kg + NIVO 3 mg/kg demonstrated a path CR in both the axillar LN metastases and the primary melanoma on digit 4 of his right hand, preventing finger amputation. The results of another PRADO patient with a large primary on the shoulder and axillar LN metastases are pending (expected June 2019). Conclusions Neoadjuvant IPI+NIVO induces comparable responses in LN metastases and at the primary melanoma location. In the light of the high LN response upon neoadj IPI+NIVO, postponing the resection of the primary or recurrent melanoma should be considered, improving surgical resectability and reducing morbidity. Clinical trial identification NCT02977052. Legal entity responsible for the study Netherlands Cancer Institute. Funding BMS. Disclosure E.A. Rozeman: Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: NanoString. A.C.J. van Akkooi: Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: MSD Merck; Advisory / Consultancy: Merck-Pfizer; Advisory / Consultancy: 4SC. G.V. Long: Advisory / Consultancy: Aduro; Advisory / Consultancy: Amgen; Advisory / Consultancy: BMS; Advisory / Consultancy: Merck MSD; Advisory / Consultancy: Mass-Array; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Roche. C.U. Blank: Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (self): BMS; Advisory / Consultancy: Roche; Advisory / Consultancy: GSK; Advisory / Consultancy, Research grant / Funding (self): Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: GenMab; Advisory / Consultancy: Lilly; Research grant / Funding (self): NanoString; Advisory / Consultancy: Pierre Fabre. All other authors have declared no conflicts of interest.

Background Outcome of high-risk stage III melanoma patients (pts) was poor with a 5-year OS rate of Methods Between Augustus 2015 and October 2016, 20 stage IIIB/IIIC melanoma pts with palpable nodal disease were included in the phase Ib feasibility OpACIN trial. Pts were randomized to receive IPI 3 mg/kg + NIVO 1 mg/kg, either adj 4 courses or split 2 courses neoadj and 2 adj. Path response, as reviewed by a blinded pathologist, was defined as Results After a median FU of 36.7 months (minimum 28.3 months FU of pts alive) none of the 7 pts with a path response in the neoadj arm have relapsed. Both non-responding pts in the neoadj have relapsed versus 4 pts in the adj arm. One pt has died in the neoadj arm and 3 in the adj arm. The estimated 3-year RFS rate was 80% for the neoadj arm and 60% for the adj arm. The 3-year OS rates were 90% and 67%, respectively. Of the 18 (90%) pts that had developed 1 or more grade 3-4 adverse events all have recovered to ≤ grade 1, except for grade 2 endocrine toxicities needing hormonal supplementation therapy that are ongoing in 8 (50%) of 16 pts alive. Conclusions OpACIN was the first trial investigating neoadj IPI + NIVO in pts with macroscopic stage III melanoma, thus having the longest FU. At 3 years FU, no new safety events occurred and none of the pts with a path response have relapsed, suggesting that path response could be considered as surrogate marker for RFS and OS in neoadjuvant checkpoint inhibitor trials. Clinical trial identification NCT02437279. Legal entity responsible for the study Netherlands Cancer Institute. Funding BMS. Disclosure C.U. Blank: Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Roche; Advisory / Consultancy: GSK; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: GenMab; Advisory / Consultancy: Lilly; Research grant / Funding (institution): NanoString; Advisory / Consultancy: Pierre Fabre. J.V. van Thienen: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis. J.B.A.G. Haanen: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AZ/MedImmune; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Immunocore; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy, Research grant / Funding (institution): Neon Therapeutics; Advisory / Consultancy: Celsius Therapautics; Advisory / Consultancy: Gadet; Advisory / Consultancy: GSK. A.C.J. van Akkooi: Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: MSD Merck; Advisory / Consultancy: Merck-Pfizer; Advisory / Consultancy: 4SC. T.N. Schumacher: Advisory / Consultancy: Adaptive Biotechnologies; Advisory / Consultancy, Shareholder / Stockholder / Stock options: AIMM Therapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Allogene Therapeutics; Advisory / Consultancy: Amgen; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Merus; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Neon Therapeutics; Advisory / Consultancy: Scenic Biotech; Research grant / Funding (institution): MSD; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck KGaA; Shareholder / Stockholder / Stock options: Neogene Therapeutics; Shareholder / Stockholder / Stock options, Venture partner: Third Rock Venture. E.A. Rozeman: Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: NanoString. All other authors have declared no conflicts of interest.

Background In the multi-center investigator-initiated OpACIN-neo trial, patients (pts) with macroscopic stage III melanoma were randomized (stratified by center) to 3 different dosing schemes of neoadjuvant (neoadj) IPI+NIVO. Two cycles IPI 1mg/kg + NIVO3mg/kg was identified as the most favorable regimen with 20% grade 3-4 adverse events and a pathological response rate (pRR) of 77%. After a median follow-up (FU) of 8.3 months (mo) none (0/86) of the pts with a pathologic (path) response had relapsed, while 9/21 (43%) without a path response relapsed. Post-hoc analyses were conducted to investigate potential differences between pts treated in Europe (EU) and in Australia (AUS). Methods Baseline patient characteristics, safety and efficacy in terms of path response were evaluated in pts treated in EU (n=48) and AUS (n=38). Multivariate analyses were performed using logistic regression method. Median FU was 9.3mo for EU pts and 6.9mo for AUS pts. Results Baseline characteristics (AUS vs EU) differed in age (median 60 vs 53 year [yr], p=0.017) and AUS pts were more likely to be male (65.8 vs 50.0%, p=0.142) and have an unknown primary melanoma (36.8 vs 20.8%, p=0.100); no difference in PD-L1 expression was observed. There was a trend to a higher pRR for AUS pts than for EU pts (84.2% vs 68.1%, OR 2.50, p=0.092). pRR was also higher for pts >60yr compared to £60yr (91.2% vs 64.7%, OR 5.64, p=0.010) and males vs females (83.7% vs 63.9%, OR 2.90, p=0.041). Multivariate analysis including continent, age and gender showed an adjusted OR for path response of 1.85 (p=0.289) for AUS vs EU pts, an OR of 4.89 (p=0.021) for pts >60yrs vs £60yrs and an OR of 2.50 (p=0.095) for males vs females. The frequency of high grade toxicity was the same in pts 60yr (42.3% vs 32.4%, p=0.353). Conclusions The continental difference in path response appears mostly driven by differences in age and gender. It remains to be elucidated whether the higher pRRs in elderly pts and pts from AUS can be explained by differences in mutational burden (analysis in progress and will be presented). Our data also indicate that neoadj IPI+NIVO is safe and highly effective in the elderly. Clinical trial identification NCT02977052. Legal entity responsible for the study Netherlands Cancer Institute. Funding BMS. Disclosure E.A. Rozeman: Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: NanoString. A.M. Menzies: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre. R.A. Scolyer: Advisory / Consultancy: MSD; Advisory / Consultancy: Neracare; Advisory / Consultancy: Novartis. A.C.J. van Akkooi: Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Merck MSD; Advisory / Consultancy: Merck-Pfizer; Advisory / Consultancy: 4SC. J. Hansson: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis. G.V. Long: Advisory / Consultancy: Aduro; Advisory / Consultancy: Amgen; Advisory / Consultancy: BMS; Advisory / Consultancy: Merck MSD; Advisory / Consultancy: Mass-Array; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Roche. C.U. Blank: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Lilly; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Pfizer; Advisory / Consultancy: GSK; Advisory / Consultancy: GenMab; Research grant / Funding (institution): NanoString. All other authors have declared no conflicts of interest.

A 73-year-old man, without any medical history, had presented with dark urine and pale stool without pain. Diagnostic imaging revealed a tumour in the pancreas with liver metastases. Histopathological examination showed a well-differentiated pancreatic neuroendocrine tumour. After a stable 2.5 years on everolimus, progression of the liver metastases was seen and a switch was made to chemotherapy. Three months later, he developed progressive spinal neurological symptoms. MRI of the spine and brain revealed leptomeningeal contrast-enhancing lesions. Cytopathological examination of the cerebrospinal fluid showed malignant epithelial cells compatible with well-differentiated neuroendocrine tumour. Epithelial cell-adhesion molecule-based flow cytometry of the cerebrospinal fluid confirmed the presence of epithelial tumour cells. Based on these results, the diagnosis of leptomeningeal metastases of an originally well-differentiated neuroendocrine tumour of the pancreas was made.

10016 Background: Adjuvant targeted therapy (TT) improves relapse free survival (RFS) in patients (pts) with BRAF mutant stage 3 melanoma. The outcomes and optimal management of pts who relapse after adjuvant TT is unknown. Methods: Pts from 21 centres with recurrent melanoma after adjuvant TT were included. Disease characteristics, adjuvant therapy, recurrence, treatment at relapse and outcomes were examined. Results: 87 pts developed recurrent melanoma; 21 (24%) during and 66 (76%) after cessation of adjuvant TT. Median time to 1st recurrence was 16.3 months with median follow up after 1st recurrence of 31 months. 30 (34%) pts recurred locoregionally, 51 (59%) pts developed distant recurrence and 6 (7%) pts had both. Of those who recurred locoregionally, 23/30 (77%) pts underwent surgery to no evidence of disease, only 3 (13%) of which received adjuvant anti-PD1 therapy, and 15/30 (50%) subsequently developed distant disease. 29 (33.3%) pts have died. 75 (86%) pts received systemic therapy at either 1st or subsequent recurrence. 40 (46%) pts received 1st line anti-PD1 based therapy (single agent anti-PD1, anti-PD1 with ipilimumab or anti-PD1 with investigational agent), 12 (14%) pts received ipilimumab monotherapy, 18 (21%) pts received retreatment with combination BRAF/MEK inhibitors and 5 (6%) pts received other agents (chemotherapy, TVEC). 57 (66%) pts had disease that was assessable for response rate (RR). RR after relapse was 69.7% (23/33) to 1st line anti-PD-1 based therapy, 46% (6/13) to TT and 9% (1/11) to ipilimumab monotherapy (Table). Median overall survival (OS) from date of 1st recurrence for all pts was not reached. OS varied by drug class received as 1st line systemic therapy after relapse. 3 year OS was 79% for anti-PD-1 based therapy, 55% for TT and 25% for ipilimumab. Conclusions: This study demonstrates that pts who relapse after adjuvant TT may respond to subsequent immunotherapy at similar rates to the treatment naïve setting. [Table: see text]