Background: Although thin, T1 melanomas have an excellent cure rate with surgery alone, ~2% recur and lead to patient death within 10 years of diagnosis. This results in >25% of melanoma deaths originating from thin melanomas (TMs), with more patients dying from TMs than thick (T4) melanomas. There is, therefore, an urgent need to improve the identification and management of patients with TMs at high risk of recurrence.Methods: Patients with T1 melanoma and recurrence ≤ 2 years of diagnosis (T1 rapid group) were compared to patients with T1 melanoma and recurrence ≥10 years after diagnosis (T1 late group). Demographics, disease characteristics, recurrence patterns and survival were studied. Results: 442 patients from 14 sites were included: 310 and 132 patients in the T1 rapid and late groups, respectively. Median age at primary melanoma diagnosis was 51 years [15-85], 272 (62%) male, 254 (58%) superficial spreading and 101 (23%) head/neck primary. The majority (73%) of recurrences in the T1 rapid group were locoregional. Using univariable logistic regression analysis, age >65 years (p<0.0001), lentigo maligna (LM) melanoma subtype (p=0.025), head/neck primary site (p=0.0065), mitoses ≥1/mm2 (p=0.0181) and ulceration (p=0.0087) were significantly associated with T1 rapid recurrence compared to T1 late recurrence. Using multivariable analysis, age >65 years (p=0.0010), mitoses ≥1/mm2 (p=0.049) and ulceration (p=0.037) remained significant.Conclusions: Rapid recurrence of TM is associated with age >65 years, LM subtype, head/neck primary site, mitoses ≥1/mm2 and ulceration. Such patients may benefit from more aggressive management of their primary melanoma and closer subsequent surveillance.

Abstract Introduction: Most patients that die from melanoma do so after recurrence of early stage disease. There is, therefore, an urgent need to improve the identification and management of patients with early stage melanoma at high risk of recurrence. The tumour microenvironment (TME), subclonal tumour cell intrinsic features and cellular interactions likely play key roles in melanoma recurrence. Spatial transcriptomics (ST) is optimally positioned to characterize these factors and may provide novel insights and strategies to overcome early stage melanoma recurrence. Methods: We examined 12 early stage (thick, T4b) FFPE primary melanoma samples with extreme clinical outcomes, identified from the prospectively collected Melanoma Research Victoria database. Of these, 7 patients had T4b melanoma with an unexpectedly good outcome of no recurrence ≤5 years of diagnosis and 5 patients had T4b melanoma with an expectedly poor outcome of recurrence ≤5 years of diagnosis (late and early recurrence groups, respectively). Samples were interrogated using 10X CytAssist Visium with comparisons between the two groups. Comprehensive bioinformatics analyses were performed including Bayespace and Harmony for initial spot clustering; SingleR for cluster annotation; RCTD deconvolution to refine cluster identification; edgeR on pseudo-bulk counts and gene set testing of differentially expressed genes (DEG); sscomp for differential cellular composition; SPIAT for spatial immune-tumor architecture analysis and non-negative matrix factorization (NMF) and SpaceMarkers for exploration of gene expression patterns and interacting regions. Results: Key cell types were revealed within each sample, including tumor cells, diverse immune cell subsets, fibroblasts, macrophages and keratinocytes. Tissue architecture including dermis, epidermis and invasive tumour front were well characterised. DEG identified downregulation of SLC5A10, PFKFB2, FBXO32, GABRB3, SMIM38 and CDH7 in the late group relative to the early group. Gene set analysis revealed upregulation of the hallmark hypoxia, angiogenesis, EMT, glycolysis, IL2, TNFa and TGFb pathways in the late relative to the early group. Cellular compositions varied across the two groups, with the late group having significantly lower tumour purity and higher abundance of immune cells than the early group. NMF revealed specific patterns associated with tumor and immune cells, with significant downregulation of IGHA2, CYP4X1, RBMXL3 and AIRE at the interacting region between tumor and immune cells in the late relative to the early group. Conclusion: This study is one of the first to analyze primary melanoma samples with extreme clinical outcomes using ST. Our results reveal that differences in cellular composition of primary melanomas as well as differential expression of key genes involved in immune activation, inflammation and metabolism may be associated with melanoma recurrence. Citation Format: Prachi Bhave, Marie Trussart, Anthony T. Papenfuss, Grant A. McArthur. Spatial transcriptomic analysis of primary melanomas with extreme clinical outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1215.

Abstract Background Although thin, T1 melanomas have an excellent cure rate with surgery alone, >25% of melanoma deaths originate from thin melanomas (TMs). There is, therefore, an urgent need to improve the identification and management of patients with TMs at high risk of recurrence. Methods Patients with T1 melanoma and recurrence ≤ 2 years of diagnosis (T1 rapid group) were compared to patients with T1 melanoma and recurrence ≥10 years after diagnosis (T1 late group). Results 442 patients from 14 sites were included: 310 and 132 patients in the T1 rapid and late groups, respectively. Median age at primary melanoma diagnosis was 51 years [15-85], 272 (62%) male, 254 (58%) superficial spreading and 101 (23%) head/neck primary. The majority (73%) of recurrences in the T1 rapid group were locoregional. Using univariable logistic regression analysis, age >65 years (p<0.0001), lentigo maligna (LM) melanoma subtype (p=0.025), head/neck primary site (p=0.0065), mitoses ≥1/mm 2 (p=0.0181) and ulceration (p=0.0087) were significantly associated with T1 rapid recurrence compared to T1 late recurrence. Using multivariable analysis, age >65 years (p=0.0010), mitoses ≥1/mm 2 (p=0.049) and ulceration (p=0.037) remained significant. Conclusions Rapid recurrence of TM is associated with age >65 years, LM subtype, head/neck primary site, mitoses ≥1/mm 2 and ulceration.

TPS2703 Background: Inimmune has developed INI-4001, a novel TLR7/8 agonist as an immunotherapy treatment for cancer. Pre-clinically, the lead formulation of INI-4001 was able to eliminate Lewis Lung Carcinoma (LLC) flank tumors in mice after just two treatments. Moreover, INI-4001 slowed the growth of MC38 and B16F10 tumors and synergized when combined with anti-PD-1 therapy, leading to an increased cure rate in both MC38 and B16F10 flank tumors in mice when both drugs were used compared to either treatment alone. In July of 2024, we dosed our first patient in a Phase 1 clinical trial in patients with advanced solid tumors. Methods: INI-4001 will be evaluated in a Phase Ia/Ib, open-label, dose-escalation, and dose expansion study. This study will be conducted in two parts: Phase Ia (dose escalation) and Phase Ib (dose expansion). Phase Ia will initially seek to establish the MTD or OBD of INI-4001 administered as monotherapy. Using a BOIN design, we have planned six ascending 1-3-subject cohorts with weekly dosing on continuous 21-day cycles. Imaging shall occur after each 3 cycles, and combination therapy with a checkpoint inhibitor is allowable under certain conditions after 3 cycles of monotherapy. Combination with checkpoint inhibitor is allowed if the subject has progressed or achieved stable disease according to iRECIST criteria and has a tumor type for which a checkpoint inhibitor is approved. Following identification of the MTD or OBD, Phase 1b allows any dose level at or below the MTD to be expanded with up to 20 additional subjects to further explore the safety, PK, PD, and preliminary efficacy of INI-4001 alone or as combination therapy. Currently in Phase Ia, Cohorts 1, 2, and 3 have been completed without DLT. Enrollment to Cohort 4 will begin in February 2025. INI-4001 may continue as monotherapy or combination as long as the subject receives benefit. Following cessation of INI-4001, patients will be requested to participate in long-term follow-up to assess overall survival. Clinical trial information: NCT06302426 .

TPS2671 Background: T-cell Engagers (TCEs) are emerging as a promising immuno-therapeutic modality in the treatment of solid tumors, demonstrating outstanding potency and a manageable safety profile. Claudin 6 (CLDN6) is an oncofetal protein that has recently emerged as a particularly attractive tumor-associated antigen (TAA) for TCE therapy because of its highly tumor-restricted pattern of expression. ARC101 is a bispecific antibody that targets CLDN6 on tumor cells with high specificity and selectivity, and CD3 on T cells. In pre-clinical models, ARC101 demonstrated potent cytolytic activity at low concentrations against a panel of CLDN6-expressing tumor cells in vitro and an ovarian cancer xenograft in vivo. Methods: First-in-human, multicenter, phase 1 study ARC101-P1-101 (NCT06672185) aims to determine the optimal dosing, safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor efficacy of ARC101 as monotherapy in patients with locally advanced or metastatic CLDN6 expressing solid tumors. The study will be conducted according to the Bayesian Optimal Interval (BOIN) design in two parts: Part 1 (dose escalation) and Part 2 (dose expansion). Part 1 is designed to select the Maximum Tolerated Dose (MTD), Recommended-Phase 2-Dose (RP2D) and dosing schedule of ARC101. Part 1 will start with an ‘Accelerated Titration Phase’, with cohorts of at least one, but no more than three patients and a fixed dose, intravenous regimen. Once a single event of clinically significant toxicity of Grade ≥2 occurs, the ‘Standard Titration Phase’ will be initiated with cohorts of at least three patients per ARC101 target dose level. Once immune-related toxicity is observed, the regimen may be changed to a ‘Fractionated Step-up Dosing’ IV regimen. The study design allows for backfill cohorts and intra-patient dose escalations. Part 2 will further explore the safety, PK/PD characteristics, and preliminary efficacy of ARC101 administered at the RP2D and schedule identified in Part 1 in patients with testicular and ovarian cancer. Key eligibility criteria include patients with any advanced or refractory solid tumor malignancy that expresses CLDN6 and is metastatic or unresectable. Patients must be ≥18 years of age and have Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Patients must have received standard therapy for advanced or metastatic disease, and disease must be measurable per Response Criteria in Solid Tumors (RECIST) v1.1 or evaluable. Mandatory requirement of a pre-study tumour sample for IHC analysis will facilitate the exploratory objective of biomarker analysis, including correlating CLDN6 expression with treatment response. The study is actively enrolling participants for the dose escalation phase. Contact clinicaltrials@thirdarcbio for additional information. Clinical trial information: NCT06672185 .

IMPORTANCE:Acral (AM) and mucosal melanomas (MM) are rare subtypes with a poor prognosis. In those with advanced disease, anti-PD-1 (PD1) therapy has reduced activity compared to that seen in non-acral cutaneous melanoma. OBJECTIVE:To determine the efficacy of adjuvant PD1 in resected AM or MM. DESIGN:An international, retrospective cohort study SETTING: Data up to November 2021 collected from 20 centres across 10 countries. PARTICIPANTS:One hundred and ninety four patients with resected stage III or IV1 AM or MM who received adjuvant PD1 were included and compared to matched patients from the Melanoma Institute Australia (MIA) database using a propensity score matching analysis. MAIN OUTCOMES AND MEASURES:Recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and overall survival (OS) were investigated. RESULTS:Forty five of 139 (32%) AM and 9 of 55 (16%) MM patients completed adjuvant therapy. The main reason for early treatment cessation in both groups was disease recurrence: 51 (37%) and 30 (55%) in the AM and MM groups, respectively. In the AM group adjuvant PD1 was associated with a longer RFS [HR-0.69 (0.52-0.92, p = 0.0127)], DMFS [HR0.58 (0.38-0.89, p = 0.0134)] and OS [HR of 0.59 (0.38-0.92, p-value 0.0196)] when compared to the historical cohort. In the MM group there was no statistical difference in RFS [HR1.36 (0.69-2.68,p-value 0.3799], DMFS or OS. CONCLUSION AND RELEVANCE:After adjuvant PD1, both AM and MM have a high risk of recurrence. Our data suggests a benefit to using adjuvant PD1 therapy in resected AM but not in resected MM. Additional studies to investigate the efficacy of adjuvant PD1 for MM are needed.

Australia has one of the highest incidences of cutaneous melanoma in the world.1 Indeed, melanoma is so common that it is estimated to be the third most diagnosed cancer in Australia in 2022 and is the most common cancer in people aged 20–39 years.1 The management of melanoma continues to evolve, with significant advances being made over historical approaches, resulting in improved patient outcomes. This review provides a concise overview of the screening, diagnosis and management of melanoma in Australia. We conducted a literature search on the MEDLINE and PubMed electronic databases for articles published from 2000 to 2022 to include updated data on the management of melanoma. Articles in English and studies involving humans only were included. The search included combinations of the keywords "melanoma", "cutaneous melanoma", "metastatic melanoma", "risk assessment", "risk models", "risk prediction", "risk stratification", "polygenic risk", "genome wide association studies", "diagnosis", "imaging", "biopsy", "surgery", "resection", "excision", "immunotherapy", "checkpoint inhibitors", "targeted therapy", "adjuvant therapy" and "neoadjuvant therapy". Specialist society publications and guidelines were also reviewed, including those from Cancer Council Australia, the American Society of Clinical Oncology and the European Society for Medical Oncology. There were no exclusions on article type, and abstracts, review articles, letters and editorials were considered. There is currently insufficient evidence to assess the impact of skin cancer screening on melanoma mortality,2 with a recent Australian study finding that skin screening increases the risk of biopsy and melanoma in situ without increasing the detection rate of invasive melanoma compared with unscreened individuals.3 However, most clinical practice guidelines recommend regular skin checks and prevention advice for people at high risk of melanoma or other skin cancers.4-6 A targeted approach to screening high risk individuals may be cost-effective,7, 8 but further evidence is needed. To identify individuals at high risk, clinicians have historically relied on phenotypic features such as naevi and pigmentation (skin, hair and eye colour) as well as personal and family history of skin cancer. Epidemiology studies on twins have demonstrated that about 58% of melanoma incidence is attributable to genetic variation.9 Although 10% of individuals with melanoma will have an affected first degree relative,10 only 10% of those cases will have a strong family history (ie, three or more cases related in the first or second degree).11, 12 Therefore, familial melanoma accounts for a relatively small portion of melanoma heritability. Familial risk in some families can be explained by the presence of high penetrance variants in the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene, by clustering of low penetrance variants across multiple genes or by behavioural factors.13, 14 Large genome-wide association studies have evaluated the frequency of common genetic variants among people with and without melanoma. The most recent meta-analysis of these studies revealed 68 independent genetic variations (single nucleotide polymorphism) in 54 loci as being associated with modest melanoma risk.15 As would be expected from the clinical risk factors above, some of the genes associated with these single nucleotide polymorphisms are implicated in pigmentation or naevus susceptibility.15 More recently, risk prediction models have been developed to improve the accuracy of risk stratification,16 and several Australian melanoma risk tools are freely available online and can be used to guide informed discussions between clinicians and patients about prevention, screening and treatment.17-19 It is important to note, however, that most risk prediction models rely on self-reporting and only a few of these models have been externally validated. Of those that have, acceptable discriminatory ability has been shown, thus enabling risk stratification and tailored prevention in clinical practice.20-23 However, most models demonstrated poor calibration, suggesting that the methods for estimating absolute risk need careful consideration to ensure accurate prediction of the number of cases in the population,22 which is relevant for population screening programs.20, 21, 23 By combining the odds ratios and frequencies of genome-wide association studies of single nucleotide polymorphisms, it is possible to generate an individual's polygenic risk score. Studies have shown that melanoma polygenic risk scores have similar risk prediction performance to models based on traditional risk factors,24 and, when combined, they result in a modest incremental improvement in discrimination, sensitivity and specificity.25 Further research is needed to guide the integration of sociodemographic, clinical and genomic risk factors into risk prediction models and their implementation in practice. In the absence of evidence to support implementation of a formal melanoma screening program, screening is currently opportunistic and not necessarily targeted towards individuals at highest risk. The current screening procedure relies on a full skin examination by a clinician. Diagnostic accuracy varies between clinicians according to experience and training.26 In addition, high discordance between pathologists in identifying benign naevi versus melanoma has also been observed.27, 28 Variable accuracy is one factor contributing to the high burden of benign "just in case" biopsies as well as missed opportunities for early detection.8, 29 Rates of melanoma in situ diagnosis are increasing significantly without a corresponding reduction in mortality.30 Therefore, there is increasing concern about overdiagnosis (finding lesions that would not cause harm) and the impact of this on patient wellbeing and health system costs as well as the phenomenon of "diagnostic drift" (the tendency to upstage borderline or precursor lesions as malignant over time).31, 32 Emerging software applications powered by machine learning have the potential to improve the inter- and intra-observer variability in the diagnosis of skin lesions using images from professional total body photography through to "selfies" from modern smartphones.33 There is observational evidence to support the use of total-body photography for surveillance of high risk individuals to improve both early detection and reduce unnecessary biopsies.8, 34, 35 However, imaging is costly, not widely or consistently used, and not currently covered by Medicare. An Australian randomised control trial is currently underway to evaluate the clinical impact and cost effectiveness of using melanoma surveillance photography for those at high risk of melanoma, from a health system perspective, run through melanoma and skin cancer trials (ClinicalTrials.gov, NCT04385732). Although advanced diagnostic imaging technology is currently being implemented, there is a relative lack of evidence supporting its clinical efficacy and cost-effectiveness.36 For example, machine learning algorithms are integrated into imaging systems that can detect change in individual lesions and provide risk assessments for malignancy. Despite impressive data on algorithm performance compared with dermatologists in experimental settings, there are several unknowns about machine learning performance in the real world.37-39 Studies have shown, for example, that machine learning algorithms are most beneficial to improve accuracy of diagnosis for inexperienced clinicians but less helpful for experienced clinicians.39 Inaccurate machine learning algorithms may therefore inappropriately influence clinicians and must be used with caution.39 Other unanswered questions include whether machine learning algorithms developed overseas remain accurate and robust in the Australian population, where machine learning fits into the diagnostic paradigm (eg, as a triage or second opinion system), patient trust in the technology, and how machine learning will affect doctor–patient interactions.39 An increasing number of consumer smartphone applications (apps) are commercially available for melanoma prevention and early detection. A 2019 review of major smartphone app stores found 66 apps available for melanoma prevention and early detection.40 Consumer apps mostly promoted skin self-examination and early detection behaviours, and others provided telehealth and machine learning diagnostic capabilities and prevention education. Very few apps had been evaluated in randomised trials, and it is uncertain whether they improve patient outcomes compared with current best practice.41 Favourable results have also been found for consumer-led mobile teledermoscopy apps that link patients with a doctor.42 However, when providing risk assessments or diagnostic advice based on machine learning algorithms (without clinician input), there are concerns regarding reliability due to a lack of quality standards or regulatory oversight. Over time, technological advancements are expected to improve machine learning algorithms within apps but these will require clinical trials to assess their effectiveness and limitations in real-world settings. It is critical for end-users to understand how algorithms are trained.43 Issues of generalisability and transparency are particularly important, including the accuracy of machine learning in all populations, skin types and tumour subsites (scalp, nails), and whether the machine learning output is explainable.44 A significant challenge is to determine whether the use of machine learning will further compound current rates of overdiagnosis. These issues require further research before such technology can be recommended for routine clinical use. A multidisciplinary approach is central to ensuring appropriate care. Correct pathological diagnosis and accurate staging are imperative, as they dictate the treatment approach. Excisional biopsy with a 2 mm margin is the most reliable method to accurately diagnose and guide the management of suspicious skin lesions.45, 46 Incisional biopsy carries the risk of an incomplete diagnosis but can be appropriate in selected patients depending on the site and size of the lesion (eg, the face or acral regions). Following diagnosis, wide local excision is curative for most cases.45 The recommended radial excision margins are 5 mm for melanoma in situ, 1 cm for T1 (≤ 1.0 mm thickness), 1–2 cm for T2 (> 1.0–2.0 mm), and 2 cm margins for T3 and T4 (> 2.0 mm) melanoma.45, 46 Recent availability of adjuvant systemic therapy for resected disease highlights the need for adequate surgical staging.45 For a subset of people with invasive melanoma, sentinel lymph node biopsy (SLNB) is the gold standard for regional lymph node assessment and should be performed at the time of the definitive primary melanoma wide local excision.47, 48 SLNB is generally recommended for people with melanoma that is > 1 mm thick, or 0.8–1 mm thick with adverse features such as ulceration, who clinically do not have lymphadenopathy.49 SLNB provides accurate staging and prognostic information49, 50 and should be performed at centres with radiological and surgical expertise to reduce false negative and false positive rates.49 Tumour thickness, ulceration and the presence of melanoma in the sentinel lymph node are the most important prognostic factors for patient survival.47 Importantly, SLNB involvement and/or the presence of satellites upstages disease to stage III. Currently, patients with resected stage IIIB/C/D51 or resected stage IV melanoma can access adjuvant therapy including immune checkpoint inhibitors (ICIs) and targeted therapy. Thus, with the advent of adjuvant therapy, SLNB is no longer a purely prognostic tool but also aids in the therapeutic management of patients with high risk primary disease. Until recently, proceeding to completion lymph node dissection (CLND) was recommended as standard of care for patients found to have a positive SLNB. However, two trials that randomly assigned patients with a positive SLNB to either observation with ultrasound surveillance or immediate CLND found no survival benefit with CLND.47, 49 Therefore, the default for patients with a positive SLNB is now surveillance with clinical examination and nodal basin ultrasound, with CLND reserved for clinically apparent or imaging-detected regional disease or for patients who choose to have the procedure after counselling.47-50 The management of in-transit or distant metastases should be discussed in a multidisciplinary setting. Adjuvant therapy aims to treat residual micrometastatic disease after histologically complete resection, thus decreasing the chance of recurrence and in turn improving survival.52 The first trial to explore the use of adjuvant ICIs compared four doses of ipilimumab with placebo in patients with completely resected stage III melanoma. Although a significant improvement in recurrence-free survival and overall survival was demonstrated, 45% of patients developed severe adverse events.53 Following this, two clinical trials individually explored nivolumab and pembrolizumab as adjuvant monotherapy, administered for one year after surgery.54, 55 Both trials reported similar results, with a halving of the risk of melanoma recurrence after surgery compared with observation and less toxicity compared with ipilimumab, and, thus, both nivolumab and pembrolizumab are available on the Pharmaceutical Benefits Scheme (PBS) as adjuvant therapy. Importantly, both trials are yet to demonstrate whether this decrease in recurrence rate translates to improved overall survival. Adjuvant B-Raf proto-oncogene (BRAF)/MEK inhibition with dabrafenib/trametinib combination has also been shown to halve the risk of melanoma recurrence, providing an alternative to adjuvant ICIs in patients with BRAF V600 mutant disease.56 This trial has shown a trend towards improved overall survival, although data are not yet mature.56 The prognosis of patients with advanced melanoma has significantly improved over the past decade with the advent of novel therapies, including ICIs and BRAF/MEK inhibiting targeted therapy, taking patient survival from the order of months to potentially many years.57 Anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immune checkpoint inhibitor: ipilimumab. Ipilimumab was the first ICI to demonstrate improved survival of patients with advanced melanoma. Several trials have compared ipilimumab to chemotherapy, vaccine therapy or other historical agents in both treatment-naïve patients and in those who had received prior therapy.58-60 Ipilimumab was found to improve survival by several months over the alternatives. Importantly, survival rates plateaued with long term follow-up, and, thus, ipilimumab was the first agent to demonstrate that ICIs had the potential of inducing durable disease control. Anti-programmed cell death 1 (PD-1) immune checkpoint inhibitors: nivolumab and pembrolizumab. Several large clinical trials have demonstrated that both nivolumab and pembrolizumab improve survival over ipilimumab, and these agents are therefore considered standard of care and are commonly used in clinical practice, either as monotherapy or in combination with ipilimumab.61, 62 Patients treated with anti-PD-1 monotherapy have a five-year overall survival rate of about 44%, with less toxicity than ipilimumab.61, 62 Anti-CTLA-4 and anti-PD-1 combination therapy. Anti-CLTA-4/anti-PD-1 combination therapy was studied in a three-arm trial that randomly assigned patients with previously untreated advanced melanoma to either ipilimumab/nivolumab, nivolumab or ipilimumab. The overall survival at 7.5 years was 48%, 42% and 22% for ipilimumab/nivolumab, nivolumab and ipilimumab respectively, demonstrating that both ipilimumab/nivolumab and nivolumab monotherapy were superior to ipilimumab alone.62-64 Although the trial was not powered to compare the two nivolumab arms, an exploratory analysis did demonstrate improved survival outcomes with combination therapy. Combination ICI significantly increases the rates of immune-related adverse events compared with anti-PD-1 monotherapy; therefore, the decision to treat with either of these options is made after careful assessment of an individual's risks versus benefits.62-64 Patients harbouring a BRAF V600 mutation are eligible for treatment with oral agents targeting the BRAF and MEK genes. BRAF polymerase chain reaction sequencing is typically performed on tissue following confirmation of advanced (stage III+) disease. BRAF/MEK inhibitors classically display a rapid onset of action. In patients with previously untreated advanced melanoma, combination therapy leads to five-year overall survival rates of about 34%, significantly greater than single agent BRAF or MEK inhibition.65 Thus, these agents are rarely administered individually, and current options available in Australia include dabrafenib/trametinib, vemurafenib/cobimetinib and encorafenib/binimetinib. These agents have a unique toxicity profile, including drug fevers, gastrointestinal upset, and skin reactions. Overall, the data supporting all three combination options are similar in terms of efficacy, and, therefore, decisions on which option to prescribe are often based on factors such as toxicity profile and pill burden.66, 67 Recent data have demonstrated that overall survival is improved in patients initially treated with ICIs rather than targeted therapy, and thus patients with treatment-naïve BRAF mutant disease are generally recommended to receive first line immunotherapy.68, 69 With the extraordinary advances described above, the treatment landscape of melanoma continues to be a topic of much interest, with novel therapies and approaches being explored in several clinical trials. Here, we summarise a few of these. A recent trial demonstrated an improvement in recurrence-free survival with the use of adjuvant pembrolizumab in patients with high risk stage II disease. Although pembrolizumab is not yet available on the PBS for this indication, this trial provides promising early evidence that adjuvant ICIs may be beneficial in earlier stage disease.70 The use of adjuvant targeted therapy in earlier stage melanoma is also being explored. The Columbus-AD trial is currently recruiting patients across multiple Australian sites, investigating the benefit of adjuvant encorafenib and binimetinib in high risk stage II melanoma with a BRAF mutation (ClinicalTrials.gov, NCT05270044). CTLA-4 and PD-1 represent only two of many potential immunotherapy targets. Recently, the combination of relatlimab (a lymphocyte activation gene-3 [LAG-3] inhibitor) and nivolumab was shown to improve progression-free survival compared with nivolumab alone.71 Furthermore, this combination resulted in fewer high grade immune-related adverse events compared with previous studies of combination ipilimumab and nivolumab. Although overall survival results are not yet mature, this represents an exciting potential new treatment option in the armamentarium against advanced melanoma. Neoadjuvant therapy represents a new approach to melanoma management and involves administering systemic therapy for a short duration before surgery in patients with resectable stage III disease. Several advantages are provided by neoadjuvant over adjuvant therapy, including assessment of treatment response, allowing treatment alteration in patients with a poor response at surgery, tumour shrinkage leading to higher rates of complete surgical resection, and potentially greater immunological effect due to the presence of macroscopic tumour.57 In a pooled analysis of patients who achieved an excellent pathological response, two-year recurrence-free survival rates of 96% and 79% with neoadjuvant ICI and targeted therapy, respectively, were demonstrated.72 Despite this comparing favourably to the two-year recurrence-free survival of about 60% seen with adjuvant ICIs and targeted therapy, a head-to-head comparison of adjuvant versus neoadjuvant therapy is needed to explore which approach is most beneficial. Recently presented results from the phase 2 SWOG S1801 trial demonstrated that three cycles of neoadjuvant pembrolizumab followed by 15 cycles of adjuvant pembrolizumab is superior to 18 cycles of adjuvant pembrolizumab, with significantly better two-year event-free survival (72% v 49%; hazard ratio, 0.58; P = 0.004). These are the first data to suggest that neoadjuvant ICI may become the new standard of care over adjuvant ICI therapy.73 Several other neoadjuvant trials are currently underway including the randomised phase 3 NADINA trial that is recruiting across multiple Australian sites (ClinicalTrials.gov, NCT04949113).74 Neoadjuvant therapy represents an exciting prospect for the management of resectable disease, as patients may be able to receive only a few weeks of systemic therapy followed by surgery and then proceed to surveillance alone. It should be noted, however, that neoadjuvant therapy is currently limited to clinical trials. Due to the significant advances in melanoma treatment, numerous patients are now surviving many years, if not decades, after diagnosis. This has resulted in a new era of cancer care, involving melanoma survivorship, with a large community of survivors now coming together to contribute to and advance the management of melanoma. Several institutions across Australia actively involve consumers in research and education committees; for example, the Australian Melanoma Consumer Alliance consists of representatives from the Melanoma and Skin Cancer Advocacy Network, Melanoma Patients Australia, Melanoma Institute Australia, Melanoma and Skin Cancer Trials, the Australian Melanoma Research Foundation, Melanoma Research Victoria, Melanoma Western Australia and Melanoma Tasmania, with consumer groups reviewing research proposals and providing feedback.75 This integration of consumers and of those affected by melanoma into research efforts reflects the fact that their insights and experiences are increasingly valued in improving the quality and relevance of research and models of care.76 A recent State of the Nation report jointly commissioned by Melanoma Institute Australia and Melanoma Patients Australia notes that, despite ongoing efforts to improve supportive care, there is much to be done.77 Current challenges for all patients with cancer and long term survivors, not just those with melanoma, include lack of screening for supportive care, a shortage of disease-specific nurse consultants, no structured models for survivorship, and high out-of-pocket costs for long term survivors.77 Importantly, advances in supportive care require patient engagement to help with the design and creation of interventions. Treatment approaches need to adopt a holistic approach, with care for the whole person rather than just care of their cancer, and survivorship care plans should evolve into supportive care plans developed with the patient's input.78 Although survivorship is the accepted medical term, it is artificially defined to commence once treatment finishes and a patient transitions from active anticancer treatment to post-treatment care and disease surveillance.79 However, the physical, emotional and financial implications begin at diagnosis, not after treatment completion, and thus supportive care plans should commence at diagnosis. Furthermore, support should be provided in a dynamic fashion, adapting as a person's quality of life indicators evolve and need change. This personalisation of supportive care focused on the whole person is not necessarily expensive. Once educated, and with appropriate supports from a nurse, or even trained volunteers, the patient is generally able to direct the right level of care they need.80 The management of cutaneous melanoma has been revolutionised in the past decade, with ongoing efforts to improve patient outcomes centred on rich translational research endeavours and robust clinical trials. Adoption of personalised risk assessment tools to tailor screening, treatment and surveillance will ensure appropriate escalation and de-escalation of care to provide the greatest benefit with minimal risk and toxicity, including physical, emotional and financial benefits. Decision-support tools are likely to become more reliable and accessible as algorithms derived from big datasets, including imaging, histopathology, genetic and outcome data, are validated in the clinical setting. In turn, reduced variability in diagnostic accuracy and management decisions will lead to earlier and more accurate melanoma detection and personalised approaches to treatment, with the ultimate goals of disease prevention and more efficient health system usage. Finally, the increasing importance of consumer engagement cannot be overlooked. Encouraging patients to be involved in the development of their own management and supportive care plan will enable holistic care, leading to superior quality of life and clinical outcomes. Prachi Bhave has received a National Health and Medical Research Council (NMHRC) postgraduate scholarship and an Australian Melanoma Research Foundation LEK Melanoma Research Grant. Anne Cust has received an NHMRC Investigator Grant (2008454). Victoria Mar is the recipient of an NHMRC Early Career Fellowship. The Australian Centre of Excellence in Melanoma Imaging and Diagnosis (ACEMID) has received funding from the Australian Cancer Research Foundation; an NHMRC Clinical Trials and Cohort Studies Grant (2001517); an NHMRC Centre of Research Excellence Grant (2006551); and an NHMRC Synergy Grant (2009923). No funding sources had a role in the planning, writing or publication of this work. We acknowledge the contributions and guidance from Andrew M Haydon (Alfred Health, Monash University), B Mark Smithers (Princess Alexandra Hospital, University of Queensland), Peter Ferguson (Melanoma Institute Australia, University of Sydney, ACEMID), Caitlin Horsham (University of Queensland, ACEMID), Rodney Flude (Melanoma Institute Australia, ACEMID), Peter Soyer (University of Queensland, ACEMID), Rachael Morton (University of Sydney, ACEMID), Pablo Fernández-Peñas (Westmead Hospital, University of Sydney, ACEMID), Grant McArthur (Peter MacCallum Cancer Centre, University of Melbourne), and the ACEMID Consortium. Open access publishing facilitated by Monash University, as part of the Wiley - Monash University agreement via the Council of Australian University Librarians. Prachi Bhave has received conference sponsorship from Bristol-Myers Squibb (manufacturer of nivolumab), MSD (manufacturer of pembrolizumab) and Novartis (manufacturer of dabrafenib/trametinib), and speaker fees from Novartis and MSD. Victoria Mar has received speaker fees from Novartis, Bristol Myers Squibb, Merck and Janssen, and conference sponsorship from L'Oreal. Commissioned; externally peer reviewed.

9578 Background: Adjuvant (adj) radiotherapy (RT) halves the risk of locoregional (LR) recurrence in patients (pts) with high risk stage III melanoma after lymphadenectomy (CLND), however its role in the adj immunotherapy (IO) era without CLND is unknown. Methods: Pts with resected stage III melanoma who received adj IO and recurred with resectable LR only disease were studied. After resection of this 1st recurrence, adj RT may or may not have been administered. Disease characteristics, treatment at relapse and outcomes were examined. Results: 71 pts from 9 centres were included. Prior to adj IO, median age was 60y, 59% male, 56% BRAF mutant, 61% stage IIIC (AJCC V8), 52% underwent CLND and 17% had in-transit (IT) only disease. Adj IO included: 90% single agent anti-PD1, 8% ipilimumab-nivolumab (IN) and 1% nivolumab or IN (blinded on trial). Median duration of adj IO was 5 months. 21(30%) pts had high risk stage III disease at diagnosis, per previously established TROG criteria; 3 (4%) received upfront adj RT prior to recurrence. Median time to 1st recurrence was 7 months. 49 (69%) pts recurred during and 22 (31%) after cessation of adj IO. At 1st recurrence, 9 (13%) pts had stage IIIB disease, 55 (77%) IIIC, 7 (10%) IIID and 8 (11%) continued prior adj IO, 31 (44%) commenced therapy and 32 (45%) had no systemic therapy. 24 (34%) pts received adj RT after resection of 1st recurrence and 47 (66%) did not (Table). Adj RT was associated with a reduced risk of any 2nd recurrence (7/24, 29% vs 26/47, 55%, p=0.03) and LR 2nd recurrence (2/24, 8% vs 17/47, 36%, p=0.012). Whilst pts who received adj RT at 1st recurrence were more likely to have LN only disease, extra nodal extension and involved surgical margins, these factors did not significantly affect overall risk of 2nd recurrence on multivariate analysis. Of note, 70% of pts who did not receive adj RT at 1st recurrence had IT only disease, and though this did not significantly affect rate of 2nd recurrence (p=0.19), this likely reflects an inherent selection bias in this study. RT toxicity occurred in 16 (67%) pts, 10 with dermatitis only, and all grade 1 or 2. Median follow up was 22 months. Median recurrence free survival to 2nd recurrence was 23 months for all pts, not reached for those who had adj RT at 1st recurrence and 19 months for those who did not have adj RT (p=0.047). Median overall survival was not reached. Conclusions: Whilst adj RT appears to reduce 2nd recurrences, this may have been influenced by an unavoidable selection bias in the data, particularly an imbalance in the percentage of pts with IT disease. Prospective data with larger cohorts is needed to validate our results.[Table: see text]

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.

Background: Mucosal melanoma (MM) is a rare melanoma subtype with distinct biology and poor prognosis. Data on the efficacy of immune checkpoint inhibitors (ICIs) are limited. We determined the efficacy of ICIs in MM, analyzed by primary site and ethnicity/race. Patients and methods: A retrospective cohort study from 25 cancer centers in Australia, Europe, USA and Asia was carried out. Patients with histologically confirmed MM were treated with anti-programmed cell death protein 1 (PD-1) +/- ipilimumab. Primary endpoints were response rate (RR), progression-free survival (PFS), overall survival (OS) by primary site (naso-oral, urogenital, anorectal, other), ethnicity/race (Caucasian, Asian, Other) and treatment. Univariate and multivariate Cox proportional hazards model analyses were conducted. Results: In total, 545 patients were included: 331 (63%) Caucasian, 176 (33%) Asian and 20 (4%) Other. Primary sites included 113 (21%) anorectal, 178 (32%) urogenital, 206 (38%) naso-oral and 45 (8%) other. Three hundred and forty-eight (64%) patients received anti-PD-1 and 197 (36%) anti-PD-1/ipilimumab. RR, PFS and OS did not differ by primary site, ethnicity/race or treatment. RR for naso-oral was numerically higher for anti-PD-1/ipilimumab [40%, 95% confidence interval (CI) 29% to 54%] compared with anti-PD-1 (29%, 95% CI 21% to 37%). Thirty-five percent of patients who initially responded progressed. The median duration of response (mDoR) was 26 months (95% CI 18 months-not reached). Factors associated with short PFS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) >= 3 (P < 0.01), lactate dehydrogenase (LDH) more than the upper limit of normal (ULN) (P = 0.01), lung metastases (P < 0.01) and >= 1 previous treatments (P < 0.01). Factors associated with short OS were ECOG PS >= 1 (P < 0.01), LDH > ULN (P = 0.03), lung metastases (P < 0.01) and >= 1 previous treatments (P < 0.01). Conclusions: MM has poor prognosis. Treatment efficacy of anti-PD-1 f ipilimumab was similar and did not differ by ethnicity/race. Naso-oral primaries had numerically higher response to anti-PD-1/ipilimumab, without difference in survival. The addition of ipilimumab did not show greater benefit over anti-PD-1 for other primary sites. In responders, mDoR was short and acquired resistance was common. Other factors, including site and number of metastases, were associated with survival.

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.

Background Clinical trials of immunotherapy have excluded patients with pre-existing autoimmune disease. While the safety and efficacy of single agent ipilimumab and anti-PD1 antibodies in patients with autoimmune disease has been examined in retrospective studies, no data are available for combination therapy which has significantly higher toxicity risk. We sought to establish the safety and efficacy of combination immunotherapy for patients with advanced melanoma and pre-existing autoimmune diseases.Methods We performed a retrospective study of patients with advanced melanoma and pre-existing autoimmune disease who received combination ipilimumab and anti-PD1 at 10 international centers from March 2015 to February 2020. Data regarding the autoimmune disease, treatment, toxicity and outcomes were examined in patients.Results Of the 55 patients who received ipilimumab and anti-PD1, the median age was 63 years (range 23–83). Forty-six were treated with ipilimumab and nivolumab and nine with ipilimumab and pembrolizumab.Eighteen patients (33%) had a flare of their autoimmune disease including 4 of 7 with rheumatoid arthritis, 3 of 6 with psoriasis, 5 of 10 with inflammatory bowel disease, 3 of 19 with thyroiditis, 1 of 1 with Sjogren’s syndrome, 1 of 1 with polymyalgia and 1 of 1 with Behcet’s syndrome and psoriasis. Eight (44%) patients ceased combination therapy due to flare. Thirty-seven patients (67%) had an unrelated immune-related adverse event (irAE), and 20 (36%) ceased combination immunotherapy due to irAEs. There were no treatment-related deaths. Patients on immunosuppression (OR 4.59; p=0.03) had a higher risk of flare.The overall response rate was 55%, with 77% of responses ongoing. Median progression free survival and overall survival were 10 and 24 months, respectively. Patients on baseline immunosuppression had an overall survival of 11 months (95% CI 3.42 to 18.58) compared with 31 months without (95% CI 20.89 to 41.11, p=0.005).Conclusions In patients with pre-existing autoimmune disease, not on immunosuppression and advanced melanoma, combination ipilimumab and anti-PD1 has similar efficacy compared with previously reported trials. There is a risk of flare of pre-existing autoimmune disorders, particularly in patients with inflammatory bowel disease and rheumatologic conditions, and patients on baseline immunosuppression.

Diagnostic evaluation of metastatic non-small cell lung cancer (NSCLC) requires confirmation of malignancy, identification of histological subtype, provision of tumour staging and to identify targets for systemic treatments through molecular characterisation. The optimal diagnostic test sequence to achieve a timely diagnosis whilst minimising invasive procedures in metastatic NSCLC remains unclear. We sought to explore the impact of diagnostic test sequencing in metastatic NSCLC on efficiency, effectiveness, timeliness and survival.

AM is a rare melanoma subtype with poor prognosis. While retrospective data suggests low activity of PD1 alone, no data are available on the efficacy of combination PD1/CTLA4 in AM. AM primary site is associated with differences in tumour mutation burden, which may impact CPI activity. We examined the efficacy of CPIs in AM, and in primary site subgroups. Patients (pts) with unresectable stage III/IV AM treated with at least one line of CPI (PD1 and/or ipilimumab (Ipi) were studied. Disease/patient characteristics and therapy were examined. Multivariable logistic and Cox regression analysis were conducted. Primary outcomes were objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). 369 pts were included; median age at first diagnosis was 63yrs (20-88), 80% Caucasian, 53% male, 12% BRAF, 13% NRAS, 7% KIT mutant; 41 had received prior adjuvant CPI. Median time from primary diagnosis to development of advanced disease was 19.6 months [1.8-260.6]. Primary site of AM was 260 (70%) plantar, 25 (7%) palmar and 84 (23%) subungual. Excluding 41 pts who received adjuvant CPI, 1st line systemic therapy included 151 (46%) PD1, 51 (15%) Ipi, 54 (16%) combination CPI and 72 (22%) other therapies (e.g. chemotherapy, targeted therapy). At commencement of 1st-line therapy, 30% were stage M1c, 53% ECOG 0 and 19% had elevated LDH. Median follow up was 8.1yrs (7.68-10.66). ORR was highest with combination CPI; this remained significant in multivariate analysis (Table). PFS was significantly associated with 1st-line therapy, however PFS was not significantly different between PD1 and combination CPI (p=0.42) (Table). Median OS was 2.3yrs (95% CI 1.9-2.6) and did not vary by 1st-line therapy received (p=0.57). No outcome differences were found between primary sites.Table: 1047POR = Odds ratio HR = Hazard ratioPD1 (N=151)CTLA4 (N=51)PD1+CTLA4 (N=54)ORR26%12%44%Univariable OR10.43 (95%CI, 0.19-0.97), p=0.00092.24 (95%CI, 1.24-4.07), p=0.0023Multivariable OR10.45 (95%CI, 0.20-1.03), p=0.00152.38 (95%CI, 1.30-4.36), p=0.0015PFS (months)7.0 (95%CI, 5.3-1.5)4.9 (95%CI, 4.1-6.2)7.3 (95%CI, 4.9-13.2)Univariable HR11.57 (95%CI, 1.15-2.14), p=0.00420.91 (95%CI, 0.66-2.14), p=0.56Multivariable HR11.64 (95%CI, 1.20-2.24), p=0.00190.87 (95%CI, 0.63-1.21), p=0.42 Open table in a new tab CPIs are active in pts with advanced AM, with superiority of combination CPI over PD1 alone in terms of ORR but not PFS or OS. Primary AM site did not impact CPI efficacy.

BackgroundMelanoma brain metastases (MBMs) are a challenging clinical problem with high morbidity and mortality. Although first-line dabrafenib–trametinib and ipilimumab–nivolumab have similar intracranial response rates (50%–55%), central nervous system (CNS) resistance to BRAF-MEK inhibitors (BRAF-MEKi) usually occurs around 6 months, and durable responses are only seen with combination immunotherapy. We sought to investigate the utility of ipilimumab–nivolumab after MBM progression on BRAF-MEKi and identify mechanisms of resistance.MethodsPatients who received first-line ipilimumab–nivolumab for MBMs or second/third line ipilimumab–nivolumab for intracranial metastases with BRAFV600mutations with prior progression on BRAF-MEKi and MRI brain staging from March 1, 2015 to June 30, 2018 were included. Modified intracranial RECIST was used to assess response. Formalin-fixed paraffin-embedded samples of BRAFV600mutant MBMs that were naïve to systemic treatment (n=18) or excised after progression on BRAF-MEKi (n=14) underwent whole transcriptome sequencing. Comparative analyses of MBMs naïve to systemic treatment versus BRAF-MEKi progression were performed.ResultsTwenty-five and 30 patients who received first and second/third line ipilimumab–nivolumab, were included respectively. Median sum of MBM diameters was 13 and 20.5 mm for the first and second/third line ipilimumab–nivolumab groups, respectively. Intracranial response rate was 75.0% (12/16), and median progression-free survival (PFS) was 41.6 months for first-line ipilimumab–nivolumab. Efficacy of second/third line ipilimumab-nivolumab after BRAF-MEKi progression was poor with an intracranial response rate of 4.8% (1/21) and median PFS of 1.3 months. Given the poor activity of ipilimumab–nivolumab after BRAF-MEKi MBM progression, we performed whole transcriptome sequencing to identify mechanisms of drug resistance. We identified a set of 178 differentially expressed genes (DEGs) between naïve and MBMs with progression on BRAF-MEKi treatment (p value <0.05, false discovery rate (FDR) <0.1). No distinct pathways were identified from gene set enrichment analyses using Kyoto Encyclopedia of Genes and Genomes, Gene Ontogeny or Hallmark libraries; however, enrichment of DEG from the Innate Anti-PD1 Resistance Signature (IPRES) was identified (p value=0.007, FDR=0.03).ConclusionsSecond-line ipilimumab–nivolumab for MBMs after BRAF-MEKi progression has poor activity. MBMs that are resistant to BRAF-MEKi that also conferred resistance to second-line ipilimumab–nivolumab showed enrichment of the IPRES gene signature.

9571 Background: Adjuvant anti-PD1 therapy reduces the risk of recurrence in resected stage III/IV melanoma and is now standard care. Limited data exist beyond registration trials. We sought to explore the use of adjuvant immunotherapy in routine clinical practice. Methods: Patients (pts) from 11 Australian centres who received adjuvant nivolumab (nivo) for resected stage III/IV melanoma were included in this study. Efficacy, toxicity, surveillance, recurrence characteristics, management and further treatment outcomes were examined. Results: 471 pts received adjuvant nivo between 8/2018 to 3/2020. 318 (68%) were male, median age 64y (range 17-94), 28 (6%) were AJCC v8 IIIA, 194 (41%) IIIB, 175 (37%) IIIC, 11 (2%) IIID, and 63 (13%) IV. 65 (14%) pts had in-transit only disease, 152 (37%) pts were sentinel lymph node biopsy (SLNB+) and only 9 (6%) of these had CLND. 128 (27%) had BRAF mutant (BRAFmt) melanoma. Median time from resection to start of adjuvant nivo was 1.8 months (mo) (range 0.2-4.0). Median FU was 17.5 mo. 256 (54%) pts completed 12 months of nivo, 86 (18%) ceased early for toxicity, 76 (16%) for disease recurrence, 25 (5%) other reasons (COVID-19 8, co-morbidities 7, pt choice 10); 28 (6%) pts were still receiving nivo at data cut. Median duration of treatment was 10.4 mo (range 0-16.8). 117 (25%) pts recurred; 76 (65%) while ON nivo and 41 (35%) OFF nivo ( > 1 month after last dose, including 20 pts who stopped early for toxicity). 24 mo RFS was 69%. Median time to recurrence was 6.0 mo (95% CI 5.1, 7.5). 56 (48%) had first recurrence with locoregional (LR) disease only and 61 (52%) had distant +/- LR recurrence. Of those who recurred with LR disease only, 46/56 (82%) underwent surgery, 15/46 (33%) then had adjuvant radiotherapy, and 15/46 (33%) had ‘second adjuvant’ therapy with BRAF/MEK inhibitors (15/21, 71% BRAFmt pts). 10/56 (37%) pts who recurred with LR disease subsequently recurred distantly. 58/80 (73%) pts received systemic therapy at either 1st or subsequent unresectable recurrence. For recurrences ON nivo, 18 pts received combination ipilimumab (ipi) and nivo (ORR 44%), 4 pts had ipi monotherapy (ORR 0%), 7 pts had anti-PD1 + investigational agent (ORR 57%), 11 pts had BRAF/MEK inhibitors (ORR 82%). 1 pt had PD with ongoing PD1 monotherapy. For recurrences OFF nivo, no patients responded to PD1 alone (n = 1) or with an investigational agent (n = 1), ipi+nivo (n = 3), ipi monotherapy (n = 4) or chemotherapy (n = 2); 6 pts received BRAF/MEK inhibitors (ORR 50%). 2-year OS was 92%. Conclusions: Despite higher rates of discontinuation due to toxicity compared with clinical trial cohorts, the efficacy data appear similar. Most early recurrences are distant, and many with LR recurrence soon recur distantly thereafter. Second line adjuvant BRAF/MEK inhibitors are frequently used for resected LR recurrence. Both ipi+nivo and BRAF/MEK inhibitors appear to have activity after distant recurrence.

•After treatment of solitary melanoma progression, 44% had no subsequent progression.•Solitary progression is not necessarily the harbinger of widespread progression.•Local therapy of solitary progression may contribute to favourable long-term outcomes.