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To assess efficacy and toxicity of combination immunotherapy with ipilimumab plus nivolumab in routine practice in a retrospective multicentre cohort of patients with advanced melanoma.This retrospective analysis included patients with advanced melanoma treated with ipilimumab and nivolumab between October 2015 and January 2020 at six centres in Australia, Europe and the United States of America. We describe efficacy outcomes (overall survival [OS], progression-free survival [PFS] and objective response rate [ORR]) in treatment-naïve and pre-treated patients, with and without brain metastases, plus treatment-related adverse events (trAEs) in all patients treated.A total of 697 patients were identified; 472 were treatment-naïve of which 138 (29.2%) had brain metastases, and 225 were previously treated of which 102 (45.3%) had brain metastases. At baseline, 32.3% had stage M1c and 34.4% stage M1d disease. Lactate dehydrogenase was high in 280 patients (40.2%). With a median follow-up of 25.9 months, median OS in the 334 treatment-naïve patients without brain metastases was 53.7 months (95% confidence interval [CI] 40.8-NR) and 38.7 months (95% CI 18.6-NR) for the 138 treatment-naïve patients with brain metastases. For the entire cohort the ORR was 48%, for treatment-naïve patients without brain metastases ORR was 56.6% with a median PFS of was 13.7 months (95% CI 9.6-26.5). Median PFS was 7.9 months (95% CI 5.8-10.4) and OS 38 months (95% CI 31-NR) for the entire cohort. Grade 3-4 trAE were reported in 44% of patients, and 4 (0.7%) treatment-related deaths (1 pneumonitis, 2 myocarditis and 1 colitis) were recorded.The outcome and toxicity of combination immunotherapy with ipilimumab and nivolumab in a real-world patient population are similar to those reported in pivotal trials.

PURPOSE Currently, there are no robust biomarkers that predict immunotherapy outcomes in metastatic melanoma. We sought to build multivariable predictive models for response and survival to anti-programmed cell death protein 1 (anti–PD-1) monotherapy or in combination with anticytotoxic T-cell lymphocyte-4 (ipilimumab [IPI]; anti–PD-1 ± IPI) by including routine clinical data available at the point of treatment initiation. METHODS One thousand six hundred forty-four patients with metastatic melanoma treated with anti–PD-1 ± IPI at 16 centers from Australia, the United States, and Europe were included. Demographics, disease characteristics, and baseline blood parameters were analyzed. The end points of this study were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The final predictive models for ORR, PFS, and OS were determined through penalized regression methodology (least absolute shrinkage and selection operator method) to select the most significant predictors for all three outcomes (discovery cohort, N = 633). Each model was validated internally and externally in two independent cohorts (validation-1 [N = 419] and validation-2 [N = 592]) and nomograms were created. RESULTS The final model for predicting ORR (area under the curve [AUC] = 0.71) in immunotherapy-treated patients included the following clinical parameters: Eastern Cooperative Oncology Group Performance Status, presence/absence of liver and lung metastases, serum lactate dehydrogenase, blood neutrophil-lymphocyte ratio, therapy (monotherapy/combination), and line of treatment. The final predictive models for PFS (AUC = 0.68) and OS (AUC = 0.77) included the same variables as those in the ORR model (except for presence/absence of lung metastases), and included presence/absence of brain metastases and blood hemoglobin. Nomogram calculators were developed from the clinical models to predict outcomes for patients with metastatic melanoma treated with anti–PD-1 ± IPI. CONCLUSION Newly developed combinations of routinely collected baseline clinical factors predict the response and survival outcomes of patients with metastatic melanoma treated with immunotherapy and may serve as valuable tools for clinical decision making.

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.

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.

Aim: Immune checkpoint inhibitor-induced encephalitis (ICI-iE) is a rare but life-threatening toxicity of immune checkpoint inhibitor treatment. We aim to identify the characteristics of ICI-iE and describe factors that discriminate it from herpes simplex virus (HSV)-1 encephalitis and anti-leucine-rich glioma-inactivated 1 (anti-LGI1) encephalitis, as two alternative entities of encephalitis. Methods: In this retrospective multicentre cohort study, we collected patients with ICI-iE reported to the Side Effect Registry Immuno-Oncology from January 2015 to September 2021 and compared their clinical features and outcome with 46 consecutive patients with HSV-1 or anti-LGI1 encephalitis who were treated at a German neurological referral centre. Results: Thirty cases of ICI-iE, 25 cases of HSV-1 encephalitis and 21 cases of anti-LGI1 encephalitis were included. Clinical presentation of ICI-iE was highly variable and resembled that of HSV-1 encephalitis, while impairment of consciousness (66% vs. 5%, p = .007), confusion (83% vs. 43%; p = .02), disorientation (83% vs. 29%; p = .007) and aphasia (43% vs. 0%; p = .007) were more common in ICI-iE than in anti-LGI1 encephalitis. Antineuronal antibodies (17/18, 94%) and MRI (18/30, 60%) were mostly negative in ICI-iE, but cerebrospinal fluid (CSF) showed pleocytosis and/or elevated protein levels in almost all patients (28/29, 97%). Three patients (10%) died of ICI-iE. Early immunosuppressive treatment was associated with better outcome (r = 0.43). Conclusions: ICI-iE is a heterogeneous entity without specific clinical features. CSF analysis has the highest diagnostic value, as it reveals inflammatory changes in most patients and enables the exclusion of infection. Early treatment of ICI-iE is essential to prevent sequelae and death.

Background: Immune checkpoint inhibitor (ICI) immunotherapies have revolutionized the treatment of melanoma, although drug resistance or concurrent immune-related adverse events (irAEs) still impact many patients. There is growing evidence that immunotherapy outcomes are influenced by the gut microbiome. This includes differential associations for key bacterial groups such as Bacteroidaceae and Ruminococacceae. However, how gut microbes interact with the immune system to influence the success of ICIs and/or the development of irAEs remains unclear. Methods: We longitudinally profiled the gut microbiome and circulating immune cell subsets in stage III melanoma patients from Australia and the Netherlands (n=126) treated on trial with combination anti-PD-1/anti-CTLA-4 immunotherapy in the neo-adjuvant setting (NCT02977052). Paired pre- and post-treatment (baseline/week 6) stool samples were analyzed using 16S rRNA gene sequencing (n=126) and matched PBMCs were comprehensively profiled using mass cytometry (n=71). Results: Treatment with anti-PD-1/anti-CTLA-4 immunotherapy was associated with an increase in the frequency (% total CD45+) of CD8+ effector memory T cells (Tem) (CD45RA- CCR7-) (P= 0.0096) and a reduction in regulatory T cells (Tregs) (CD25+FoxP3+) (P= 0.0029) between baseline and week 6. The reduction in Tregs was dominantly observed in responders (P= 0.0016) compared to non-responders (P= 0.9515). However, patients who developed severe irAEs were also particularly deficient in Tregs at week 6 compared to patients with no or mild toxicities (P= 0.0293). Notably, in patients where circulating Tregs were reduced, the degree of reduction in Tregs positively correlated with the baseline relative abundance of Bacteroides (P< 0.0001). Higher pre-treatment Bacteroides abundance was also linked to the development of more severe irAEs (P= 0.0472) and overall steroid use (P= 0.0345) prior to week 6. Thus, while Bacteriodes here is linked to a response-associated parameter (reduction in Tregs), it is also linked to severe, early irAEs. In contrast, a higher abundance of Ruminococcaceae was protective, and overall a greater proportion of patients with Ruminococcaceae dominated microbiomes were responders, highlighting a role for both bacterial groups in shaping ICI outcomes. Conclusions: While response to ICI therapy was associated with a decrease in circulating Tregs, excessive reduction in Tregs was observed in patients that develop severe irAEs. Together, this highlights the delicate balance between immune activation and regulation in facilitating anti-tumor immune responses whilst avoiding irAEs. Our data suggests that the gut microbiome may have a role in establishing immune tone prior to and during immunotherapy and may influence this “tipping point” and the risk of developing irAEs. Citation Format: Rebecca C. Simpson, Erin R. Shanahan, Marcel Batten, Ines P. Silva, Irene L. Reijers, Judith M. Versluis, Alexander M. Menzies, Maria Gonzalez, Umaimainthan Palendira, Andrew Holmes, James S. Wilmott, Christian U. Blank, Richard A. Scolyer, Georgina V. Long. Longitudinal microbiome-immune dynamics in melanoma patients treated with immune checkpoint inhibitor immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3463.

9501 Background: In the OpACIN-neo study, 2 cycles neoadjuvant (neoadj) IPI 1mg/kg + NIVO 3mg/kg (I1N3) have been identified as most favorable dosing scheme with a pathologic response rate (pRR) of 77% and 20% grade 3-4 irAEs. After 24.6 months median follow-up (FU), the 2-year (2y) RFS was 96.9% for patients (pts) with pathologic response versus 35.5% for non-responders (>50% viable tumor; pNR). These data raised the question whether therapeutic lymph node dissection (TLND) could be safely omitted in pts achieving a major pathologic response (MPR; ≤10% viable tumor) in their index node (ILN; largest LN metastasis at baseline), and if additional adjuvant (adj) therapy could improve the outcome of pNR pts. Methods: PRADO is an extension cohort of the phase 2 OpACIN-neo study aiming to confirm the pRR and safety of neoadj I1N3 and to test response-driven subsequent therapy. Pts with stage III melanoma were included to receive 2 cycles neoadj I1N3 after marker placement in the ILN. ILN resection was planned at week 6. Pts that achieved MPR in the ILN did not undergo TLND; pts with partial response (pPR; >10 – ≤50% viable tumor) underwent TLND; and pts with pNR underwent TLND and received adj NIVO or dabrafenib plus trametinib (D+T) for 52 weeks ±radiotherapy (RT). Primary endpoints were pRR in the ILN and RFS at 2y. The 2y RFS rates were calculated using a Kaplan Meier based method. Results: Between Nov 2018 and Jan 2020, 99 patients were enrolled and treated with at least 1 cycle of neoadj I1N3. We previously showed a pRR of 72% (95% CI 62 - 80), including 60 (61%) pts with MPR and 11 (11%) pts with pPR. TLND omission in MPR pts resulted in significant reduced surgical morbidity and improved quality of life. There were 27 non-responders of whom 6 developed distant metastasis before ILN resection. Of the other 21 pNR pts, 7 received adj NIVO, 10 adj D+T, 3 no adj therapy, and 1 was lost to FU. After a median FU of 27.9 months (data cutoff Jan 31, 2022), the estimated 2y RFS rate for MPR pts was 93.3% (95% CI 87.2 – 99.9), with 4/60 pts developing a regional relapse. Distant metastasis-free survival (DMFS) was 100%. Of the 11 pPR pts, 4 developed a relapse (all distant), resulting in a 2y RFS and DMFS rate of 63.6% (95% CI 40.7 – 99.5). The 2y RFS rate of the pNR pts was 71.4% (95% CI 54.5 – 93.6), and DMFS 76.2%. At data cutoff, relapse occurred in 2/7 pNR pts with adj NIVO and 3/10 with adj D+T. Final data cutoff is planned mid Feb, 2022. Conclusions: MPR pts in whom TLND was omitted showed a 2y RFS rate of 93.3% and DMFS of 100%, indicating that the ILN procedure and omitting adj therapy could become a safe approach in these pts. Adj systemic therapy in pNR pts seems to improve RFS as compared to historic control (OpACIN-neo), thus should be considered in this unfavorable pNR group. The DMFS rate of 63.6% observed in the pPR group advocates the consideration of adj therapy also for this subgroup in the future. Clinical trial information: NCT02977052.

9572 Background: OpACIN was the first trial testing neoadjuvant ipilimumab (IPI) + nivolumab (NIVO) versus the same combination given adjuvant. An unexpected high pathologic responses of 78% was observed in the neoadjuvant arm with a 2-year relapse-free survival (RFS) rate of 80%. The subsequent OpACIN-neo trial tested 3 different dosing schedules of neoadjuvant IPI + NIVO and identified 2 cycles IPI 1 mg/kg + NIVO 3 mg/kg q3w as most favorable schedule with a pathologic response rate of 77% and 20% grade 3-4 immune-related adverse events. Long-term data on the durability of the pathologic (path) responses upon neoadjuvant checkpoint inhibition are lacking so far. Therefore, we present here the updated RFS and overall survival (OS) data of both trials. Methods: In OpACIN 20 macroscopic stage III melanoma pts were randomized to receive either IPI 3 mg/kg + NIVO 1 mg/kg q3w 4 cycles adjuvant after lymph node dissection or split 2 cycles neoadjuvant and 2 adjuvant. In OpACIN-neo 86 macroscopic stage III melanoma pts were randomized to arm A (2x IPI 3 mg/kg + NIVO 1 mg/kg q3w, n=30), arm B (2x IPI 1 mg/kg + NIVO 3 mg/kg q3w, n=30), or arm C (2x IPI 3 mg/kg q3w followed by 2x NIVO 3 mg/kg q2w, n=26) followed by lymph node dissection in week 6. RFS and OS were estimated using Kaplan Meier method. All comparative efficacy endpoints are descriptive for OpACIN, since the trial was not powered for comparison of the arms. Results: After a median follow-up (FU) of 68.6 months for OpACIN (minimum FU of 59.8 months), median RFS and OS were not reached. Only 1/7 patients (pts) with a pathologic response on neoadjuvant therapy has relapsed. Estimated 5-year RFS and OS rates for the neoadjuvant arm were 70.0% (95%CI: 46.7-100.0) and 90.0% (95%CI: 73.2-100.0) versus 60.0% (95%CI 36.2-99.5) and 70.0% (95%CI: 46.7-100.0) for the adjuvant arm. After a median FU of 46.8 months for OpACIN-neo (minimum FU of 38.2 months), median RFS and OS were not reached. Of pts with path response on neoadjuvant therapy, 3/64 (4.7%) had an event (2 pts relapsed, 1 pt died due to toxicity), versus 14/21 (66.7%) without path response. This resulted in a 3-year RFS rate of 95.3% (95%CI: 90.3-100.0) for responding versus 36.8% (95%CI: 20.4-66.4) for non-responding pts (p

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.

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.

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]