Abstract Background: SCIB1 and iSCIB1+ are off the shelf DNA vaccines incorporating CD8 and CD4 epitopes from TRP2/gp100 into an antibody framework to allow Fc targeting of activated dendritic cells. SCIB1 and iSCIB1+ potentially have a synergistic effect on advanced unresectable melanoma when combined with checkpoint inhibitors (CPI). SCIB1 was successfully evaluated as monotherapy in a phase 1/2 in stage 3/4 melanoma patients. SCIB1 induced T cell responses in 88% patients, 75% RFS at 39 months cut off (n=16) versus 63% for Pembrolizumab (Keynote 054). The current Phase 2 trial tests the hypothesis that unresectable patients may have an improved response when the vaccine is combined with CPI. SCIB1 induced T cell responses in HLA-A2 patients, iSCIB1+ has a modified Fc and contains additional epitopes covering more HLA haplotypes, HLA-A2, A3, A31, Bw4, B35 and B44 representing 80% of the population. Methods: In a Phase 2 trial patients with advanced unresectable melanoma were treated with SCIB1 or iSCIB1+ (i.m) in combination with nivolumab and ipilimumab. Clinical response was assessed by RECIST 1.1. T cell responses to SCIB1 and iSCIB1+ were assessed using a cultured IFNγ ELISpot assay, single cell RNA- and TCR-seq analysis. Results: 41 patients received SCIB1 and had a PFS of 55% and OS of 77% at 26 months. 39 patients received iSCIB1+ and had an improved PFS of 74% at 16 months when compared to SCIB1, possibly due to the modified Fc and additional epitopes. This compares favorably with CPI alone in checkmate 067 which had a median PFS of 11.5 months and similar patient demographics. Among 200 grade 3 or greater adverse events only 4 (uveitis), were solely related to vaccine and were rapidly resolved upon treatment. Vaccine induced T cell responses peaked at 25 weeks and strongly correlated with PFS and DCR. Patients that generated a strong T cell response to both gp100 and TRP2 peptides post-vaccination exhibited better tumor control, with tumors reducing in size or disappearing (PR/CR, 70%). Seventy percent (23/32) of patients responded to both TRP2 and gp100 making antigen loss less likely. iSCIB1+ specific TCRs cloned from these patients confirmed epitope and HLA restriction and showed strong recognition and killing of melanoma target cells. T cells expressing iSCIB1+ specific TCRs showed a strong cytotoxic and polyfunctional Tpex transcriptional profile. Conclusions: iSCIB1+ in combination with nivolumab and ipilimumab as first line treatment for unresectable melanoma showed improved PFS of 74% at 16 months without an increase in clinically meaningful adverse events. Clinical benefit was correlated with strong iSCIB1+ induced T cell responses. These data support a registrational, randomized, controlled trial of iSCIB1 + with potential to redefine frontline therapy for unresectable advanced melanoma. Citation Format: Joseph Chadwick, Samantha Paston, Kate Young, Heather Shaw, Pippa Corrie, Sarah Danson, Miranda Payne, Poulam Patel, Maria Marples, Ioannis Karydis, Satish Kumar, Clare Barlow, Rebecca Lee, Martin Highley, Kellati Prasad, Georgia Goodhew, Olivia Howard, Joe Thornton, Nermeen Varawalla, Lindy Durrant. SCOPE, A phase 2 clinical trial with off-the-shelf DNA plasmid vaccine in first line advanced melanoma combined with check point blockade, shows good T cell responses which correlate with long progression free survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT237.

Background Circulating tumor DNA (ctDNA) is a promising biomarker in melanoma, with higher sensitivity for tumor burden detection than conventional diagnostics. While well established in research, clinical routine implementation remains pending. Key global questions concern optimal clinical applications and barriers to adoption. Methods A web-based survey of 116 members of the Melanoma World Society Study Group assessed international expert opinions on ctDNA utility across predefined clinical scenarios. The questionnaire included 18 general questions on ctDNA use and 5 clinical vignettes with de-identified patient data and retrospectively obtained ctDNA results. Results ctDNA was rated most valuable for detecting minimal residual disease (mean score 3.63), surveillance of recurrent disease (3.85), and stage IV melanoma (3.82), with limited utility in early stages. Experts considered ctDNA superior to S100 and LDH for early relapse detection and identifying progressive disease. Most participants (80%) agreed that ctDNA correlates with radiographic response, and 82% favored its integration into routine follow-ups. In urgent high-tumor-burden settings, 82.8% would initiate BRAFi/MEKi therapy based on ctDNA if tissue analysis was pending, and 93.9% if unavailable. For central nervous system lesions, 62% did not support blood ctDNA, while 66% considered cerebrospinal fluid valuable. Pragmatic approaches with small to mid-size targeted panels and short turnaround times were preferred. Major barriers included the need for prospective trials (85%), standardized guidelines (83%), and reimbursement policies (82%). Conclusion Key opinion leaders regarded ctDNA as a valuable adjunct selected melanoma scenarios. Validation through prospective studies, guideline development, and reimbursement frameworks are essential for broader clinical implementation.

9535 Background: Targeting melanoma by T cells drives anti-tumor responses. We previously showed that SCIB1, a DNA vaccine incorporating T cell epitopes from TRP-2/gp100 into an antibody framework to allow Fc targeting of activated dendritic cells, was successful as monotherapy in a Phase 1/2 trial in Stage III/IV melanoma patients. Disease control was achieved in 60% of cases of unresectable melanoma. In addition, 88% of 20 Stage III/IV patients treated with SCIB1 who had had a previous successful tumor resection, were disease free for 5 years. 1st line combination treatment with nivolumab and ipilimumab in advanced melanoma has a reported ORR of 50%. The current SCOPE trial tests the hypothesis that patients with unresectable melanoma may improve response rate when SCIB1 is given with checkpoint inhibitors (CPI). Methods: Previously untreated patients with unresectable Stage III/IV melanoma were treated with nivolumab with ipilimumab and SCIB1 (8 mg) i.m. using needle-free injections at a fixed dosing schedule for a total of 10 doses over 24 months. The CPI therapy was administered in accordance with respective SmPC. ORR, as measured by RECIST 1.1 in the intention-to-treat population, is the primary endpoint. The study is designed using Simon's two stage methodology with 80% power when the ORR of no interest is 50% and the true ORR is 70% with an overall type I error of 5%. In the 1st stage, 15 patients have been enrolled and as there were more than 8 clinical responses (ORR [CR or PR]) within 25 weeks of the 1st SCIB1 dose. Having passed Simon Stage 1, further recruitment continues. The null hypothesis will be rejected if 27 or more responses are observed in 43 patients. Results: To date, 23 patients have received the combination of SCIB1 with nivolumab and ipilimumab. At study entry, all patients were Stage IV. 13 patients have reached the first imaging timepoint at 13 weeks, the objective response rate is 11/13 (85%). 11/11 responses were confirmed in a subsequent scan (1 CR and 10 PRs); DCR 12/13 (92%) and 1 PD. Patients showed a 40-100% reduction in tumor volume at 13 and/or 25 weeks. Most of the SCIB1 adverse reactions were Grade 1/2 injection site related or headaches. 3 patients reported Grade 3 events (rash, neutropenia and raised GGT) all related to the CPIs. Observed toxicity frequency and intensity was in line with reported figures from ipilimumab/nivolumab therapy. Serious adverse reactions to date have all been related only to the CPIs. Conclusions: SCIB1 given with nivolumab and ipilimumab, as 1st line treatment in unresectable melanoma, improved the ORR to 85% without an increase in clinically meaningful adverse events. These results, if confirmed in the larger ongoing patient cohort, provide confidence in initiating a randomized registration program in unresectable melanoma patients with this novel DNA plasmid technology. Clinical trial information: NCT04079166 .

The gut microbiome of cancer patients impacts response to immune checkpoint inhibitor (CPI) therapy. We have recently identified nine species of gut commensal bacteria that are all strongly associated with CPI response in four independent cohorts of advanced melanoma patients. A consortium of nine strains, each representing one of these species, synergistically inhibited tumor growth in combination with anti-PD1 in a syngeneic tumor model thereby demonstrating these bacteria as active drivers of the anti-tumor immune response. The mechanisms by which each of the nine bacteria exert their systemic anti-tumor effects was investigated using in vitro assays with primary human immune cells. Eight of the strains triggered dendritic cells maturation, which led to the induction of CD8+ Cytotoxic T Lymphocytes (CTLs) with very potent tumoricidal activity. In addition, metabolites derived from four of the bacterial species, from two different phyla, triggered CTLs to upregulate the expression of granzyme B (GzB) and Interferon (IFN)γ and kill tumor cells in vitro. Furthermore, the bacterial metabolites derived from a different species were able to counteract the CD8+ T cell inhibitory effects of in vitro generated tumor-associated macrophages (TAMs), restoring CTL cell proliferation and the expression of GzB and IFNγ. In summary, nine species of gut commensal bacteria were identified as being associated with CPI response in melanoma. All species directly activated dendritic cells to trigger potently tumoricidal CTLs. Certain bacteria promoted anti-tumor effects through metabolites that can either promote CTL activation or hinder the inhibitory effects of TAM within the tumor microenvironment. This demonstrates that different bacteria associated with CPI response can interact with the immune system in distinct ways to enhance the efficacy of CPIs. All nine strains have now been combined to create a Live Biotherapeutic Product, MB097. MELODY-1 (NCT06540391) is an ongoing phase 1b study to evaluate MB097 in combination with pembrolizumab in advanced melanoma patients. Citation Format: Ghaith Bakdash, Amy Popple, Dominika Klisko, Robyne Hudson, Laure Castan, Clelia Villemin, Fernanda Schreiber, Chiara Berlato, Pippa Corrie, Tim Sharpington, Trevor D Lawley, Matthew J Robinson. Clinical response to checkpoint inhibitors is associated with distinct gut bacteria that promote anti-tumor immunity through different mechanisms [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B102.

Abstract Background Pancreatic cancer (PDAC: pancreatic ductal adenocarcinoma, the commonest form), a lethal disease, is best treated with surgical excision but is feasible in less than a fifth of patients. Around a third of patients presentlocally advanced, inoperable, non-metastatic (laPDAC), whose stadrd of care is palliative chemotherapy; a small minority are down-sized sufficiently to enable surgical excision. We propose a phase II clinical trial to test whether a combination of standard chemotherapy (gemcitabine & nab-Paclitaxel: GEM-NABP) and repurposing All Trans Retinoic Acid (ATRA) to target the stroma may extend progression-free survival and enable successful surgical resection for patients with laPDAC, since data from phase IB clinical trial demonstrate safety of GEM-NABP-ATRA combination to patients with advanced PDAC with potential therapeutic benefit. Methods Patients with laPDAC will receive at least six cycles of GEM-NABP with 1:1 randomisation to receive this with or without ATRA to assess response, until progression or intolerance. Those with stable/responding disease may undergo surgical resection. Primary endpoint is progression free survival (PFS) defined as the time from the date of randomisation to the date of first documented tumour progression (response evaluation criteria in solid tumours [RECIST] v1.1) or death from any cause, whichever occurs first. Secondary endpoints include objective response rate (ORR), overall survival (OS), safety and tolerability, surgical resection rate, R0 surgical resection rate and patient reported outcome measures (PROMS) as measured by questionnaire EQ-5D-5L. Exploratory endpoints include a decrease or increase in CA19-9 and serum Vitamin A over time correlated with ORR, PFS, and OS. Discussion STARPAC2 aims to assess the role of stromal targeting in laPDAC. Trial registration EudraCT: 2019–004231-23; NCT04241276; ISRCTN11503604.

Until recently, cisplatin/gemcitabine was standard of care for the first-line treatment of patients with advanced biliary tract cancer (BTC). The addition of durvalumab, an immune checkpoint inhibitor, to the combination of cisplatin/gemcitabine has demonstrated an overall survival (OS) benefit and is now a standard of care first-line treatment option. BTCs exhibit immunogenic features may develop through an accumulation of genetic and epigenetic alterations, and can be influenced by microbial exposure. Microbiota can influence inflammation and immunity, and its disruption may impair tumor response to immunotherapy and chemotherapy. Here, the rationale and design of the multi-center, single-arm ABC-12 trial (ISRCTN11210442) is described, which investigates the role of the microbiome in patients with advanced BTC in a first-line study of durvalumab (MEDI4736) in combination with cisplatin/gemcitabine. The primary objective is to determine the difference in baseline alpha diversity between "responders" (partial or complete response) and "non-responders" at 18 weeks (RECIST 1.1) in patients treated with cisplatin/gemcitabine/durvalumab. Secondary objectives include investigating the association between microbiome parameters and objective response rate, tumor control (partial, complete response, and stable disease), progression-free and OS, and investigating the interaction between treatment effect and microbiome parameters on clinical outcomes.

The gut microbiome of cancer patients impacts the response to immune checkpoint inhibitor (CPI) therapy. Using high precision microbiome profiling, we have recently identified 9 diverse species of gut commensal bacteria that are all consistently and strongly associated with CPI response across 4 independent cohorts of melanoma patients. These 9 species represent all 3 of the major phyla in the human intestinal microbiome, and include 4 novel species. A consortium of 9 strains, each representing 1 of these species, is being developed as a live biotherapeutic product (LBP), MB097. In the MCA-205 syngeneic tumor model, MB097 demonstrated synergistic tumor growth inhibition in combination with anti-PD1. The mechanisms by which each of the 9 species exert their anti-tumor effects were investigated, using in vitro assays with primary human immune cells. The bacteria strongly activate dendritic cells (DCs) inducing interleukin (IL)-12. These DCs stimulated by the bacterial strains very potently triggered CD8+ Cytotoxic T Lymphocytes (CTLs) to upregulate Granzyme B and interferon (IFN)γ and kill tumor cells in vitro. Similarly, bacteria-stimulated DCs prompted natural killer (NK) cell activation, as demonstrated by increased expression of IFNγ and elevated capacity for killing tumor cells. DC stimulation by 3 of the 9 strains markedly skewed the cytokine profile to higher IL-12 and lower IL-10, and also led to particularly potent CTL and NK cell activation. These strains represent 3 different families of Firmicutes. Blocking IL-12 reversed the activation and tumor killing effect of DCs stimulated with these strains of Firmicutes. Moreover, the bacterial metabolites derived from 4 different strains triggered CTLs to upregulate the expression of granzyme B and IFNγ and kill tumor cells in vitro. In summary, we have identified 9 gut commensal bacteria as being consistently associated with response to CPI in metastatic melanoma. These bacteria can interact directly with DCs to potently activate CTLs and NK Cells, and some strains of Firmicutes do this via induction of IL-12. Other strains also release metabolites that directly enhance CTL activation. These data begin to identify the different mechanisms by which gut commensal bacteria drive immunotherapy response in human systems. MELODY-1 (NCT06540391) is an ongoing interventional phase 1b study to evaluate MB097 in combination with pembrolizumab in advanced melanoma patients. Matthew James Robinson, Laure Castan, Fernanda Schreiber, Clelia Villemin, Chiara Berlato, David J. Adams, Pippa Corrie, Tim Sharpington, Trevor D. Lawley, Ghaith Bakdash. Clinical response to immune checkpoint inhibitors in melanoma is associated with distinct gut bacterial species that promote anti-tumor immunity by different mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2219.

Targeting melanoma with T cells drives anti-tumor responses. We previously showed that a DNA vaccine, SCIB1, incorporating T cell epitopes from TRP-2/gp100 into an antibody framework to allow Fc targeting of activated dendritic cells, was successfully as a monotherapy in Stage 3/4 melanoma patients in a Phase 1/2 clinical study. Unresectable melanoma patients showed a 60% ORR and 88% of patients treated with SCIB1, post tumor resection, remained disease free for 5 years [1]. The current SCOPE trial tests the hypothesis that unresectable patients may have an improved response when SCIB1 is combined with checkpoint inhibitors (CPI) compared to CPI alone. Patients are treated with nivolumab with ipilimumab and SCIB1 (8mg) i.m. using needle-free injection at a fixed dosing schedule for up to 10 doses over 24 months. The CPI therapy is administered i.v. in accordance with their respective SmPC. ORR as measured by RECIST 1.1 in the overall intention-to-treat population is the primary endpoint. The study is designed using Simon's two stage methodology with 80% power when the true response rate is 70% versus 50% RR of no interest with an overall type I error of 5%. In the first stage, 15 patients needed to be enrolled and if there are eight or fewer clinical responses (RECIST 1.1 objective response [CR or PR] within 25 weeks of the first dose of SCIB1), further recruitment would have been stopped. The null hypothesis will be rejected if 27 or more responses are observed in 43 patients. T cell responses are assessed using a cultured ELISpot assay following TRP-2 or gp100 peptides stimulation To date, 43 patients received the combination of SCIB1 with nivolumab and ipilimumab. 25 patients had reached 25 weeks, and had 80% PFS, 84% DCR and 72% ORR with 20% of patients showing a complete response. 94% (16/17) of the clinical responders had a T cell response, 80% (4/5) of the patients with stable disease had a T cell response, 33% (1/3) of patients with progressive disease had a T cell response. T cell receptors isolated from patients showed strong, peptide, ImmunoBody® and tumor recognition. Of interest was that in a patient who showed a pre-vaccinated response to the encoded epitope a different TCR was stimulated by the vaccine. Most of the SCIB1-related adverse events were Grade 1/2. The only Grade 3 related events were a rash, pulmonary embolism, neutropenia and raised GGT. No exacerbation of immune-mediated adverse events was observed when SCIB1 was added to nivolumab with ipilimumab . SCIB1 in combination with nivolumab and ipilimumab as first line treatment for unresectable Stage 3/4 melanoma resulted in 80% 6-month PFS with strong vaccine specific T cell responses without an increase in clinically meaningful adverse events. These results, if confirmed, in a larger patient cohort provide confidence in initiating a randomized registration program in unresectable melanoma patients with our novel DNA plasmid technology. Heather Shaw, Poulam Patel, Miranda Payne, Satish Kumar, Sarah Danson, Martin Highley, Clare Barlow, Prasad Kellati, Ioannis Karydis, Maria Marples, Kate Young, Pippa Corrie, Robert Miller, Georgia Goodhew, Samantha Paston, Gaelle Cane, Joseph Chadwick, Sabaria Shah, Lindy G. Durrant, Nermeen Varawalla. A DNA plasmid melanoma cancer vaccine, SCIB1, combined with nivolumab + ipilimumab in patients with advanced unresectable melanoma: Efficacy and safety results from the open-label Phase 2 SCOPE Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB214.

Background: Targeting melanoma by T cells drives anti-tumour responses. Previously in a phase 1/2 study we successfully evaluated a DNA vaccine, SCIB1, incorporating CD8 and CD4 T cell epitopes from TRP-2/gp100 into an antibody framework to allow Fc targeting of activated dendritic cells. In stage 3/4 unresectable melanoma patients receiving SCIB1 as a monotherapy we showed a 60% disease control rate (DCR) and 88% of patients treated with SCIB1 post tumour resection remained disease free for 5 years. Checkpoint inhibitor (CPI) therapies are now standard of care for melanoma, with nivolumab and ipilimumab being the most used combination. The current Phase 2 SCOPE trial tests the hypothesis that unresectable patients may have an improved response when SCIB1 is combined with CPI. In patients enrolled in this trial, the induction of SCIB1 specific T cell responses is also being evaluated. Methods: Patients were treated with nivolumab, ipilimumab and SCIB1 (8mg) i.m. using needle-free injection at a fixed dosing schedule for a total of 10 doses over 24 months. CPI therapy was administered i.v. in accordance with their respective SmPC. Vaccine specific T cell responses to SCIB1 were assessed via a combination of IFNγ ELISpot, single-cell RNA- & TCR-seq and TCR repertoire analysis. Results: From 41 patients enrolled in the SCOPE study, we will present data on functional T cell responses to the TRP2 and gp100 peptides incorporated within SCIB1. Characterization of these T cell responses showed SCIB1 induces both CD4 and CD8 mediated responses. For three patients, we have isolated CD8 TCRs which are reactive to the SCIB1 epitopes incorporated in the vaccine. Single-cell RNA- & TCR-seq was performed on sorted CD8+ IFNγ+ cells with RNA-seq analysis revealing several expanded TCR clonotypes in CD8 T cell populations with a cytotoxic transcriptional profile. Using Lentivirus-TCR transduced T cells we have successfully shown that six isolated CD8 TCRs react specifically to the TRP-2 or gp100 epitopes incorporated into SCIB1. We have characterized the T cell responses and have mapped the minimal epitope and the presenting HLA allele. Bulk TCR repertoire sequencing revealed that, in two out of three patients, the isolated SCIB1 specific TCRs were undetectable in peripheral CD8 T cells collected from pre-vaccination samples. The same TCRs were detectable in the post-vaccination CD8 TCR repertoire. Conclusions: SCIB1 in combination with nivolumab and ipilimumab consistently induced functional CD4 and CD8 T cell responses, with demonstratable vaccine induced expansion of SCIB1 specific TCR clonotypes. Citation Format: Joseph Chadwick, Gaëlle Cane, Sabaria Shah, Katie Mann, Patrick Copeland, Daisy Weston, Jordan Wright, Leanne Toon, Heather Shaw, Poulam Patel, Miranda Payne, Satish Kumar, Sarah Danson, Martin Highley, Clare Barlow, Kellati Prasad, Ioannis Karydis, Maria Marples, Kate Young, Pippa Corrie, Robert Miller, Rachael Metheringham, Georgia Goodhew, Nermeen Varawalla, Samantha Paston, Lindy Durrant. A DNA plasmid melanoma cancer vaccine, SCIB1, combined with nivolumab + ipilimumab induces functional CD4 and CD8 T cell responses in patients with advanced unresectable melanoma [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B119.

Proof-of-principle studies have identified circulating tumor DNA (ctDNA) in small volumes of whole blood, even dried blood spots (DBS) collected by finger-prick sampling from patients with advanced cancer. This minimally invasive sampling method offers ease, frequency and low cost of collection, simplified shipping and long-term room temperature stability. Adopting DBS for ctDNA collection and whole genome sequencing (WGS) analysis may support novel clinical trial design and increase real-world utility of liquid biopsies, especially where traditional phlebotomy is a barrier. We collected sample quartets comprising serial DBS, and matching plasma, tumor, and buffy coat from ∼125 patients with multiple cancer types including oesophageal, lung, head & neck, melanoma, ovarian, colorectal and pancreatic cancer. Collections were in diverse settings at hospitals in the UK and Ethiopia, and by patients at home in the UK. DNA isolated from DBS was size-selected using bead-based enrichment to remove genomic DNA. Libraries were generated from DBS size-selected DNA, and DNA extracted from plasma, tumor and buffy coat samples had paired-end WGS at depth of ∼1X, 10X, and 50X respectively. Using bioinformatic pipelines for tumor-informed and tumor-agnostic detection, WGS data was analyzed for somatic copy number aberrations (SCNAs), fragment length, and tumor-specific single nucleotide variants (SNVs). We detected SNVs and SCNAs in DBS reflective of genomic changes in matching tumor DNA and plasma, from patients with Stage II-IV cancers. We observed concordant changes to the levels of those SNVs and SCNAs in plasma and DBS samples collected before and after systemic treatment compared with clinical and radiological measures. With tumor-informed analysis, utilizing patient-specific lists of 5, 930-51, 927 SNVs identified from tumor DNA, limit of detection for ctDNA was 34 ppm in plasma, and 95 ppm in DBS, comparable to commercially available assays for ctDNA. DBS collected in hospital by healthcare professionals, remotely in Ethiopia and at-home by patients in the UK with transportation at room temperature showed ctDNA can be extracted for analysis from diverse settings. Our data highlights the promising role of DBS in advancing non-invasive cancer diagnostics and monitoring. The versatility of DBS in capturing ctDNA from various cancer types, coupled with its accessibility for collecting samples, is a significant step forward in blood-based cancer detection. This offers potential to enhance cancer monitoring and early detection strategies in both tumor-informed and tumor-agnostic settings. DBS is a cost-effective, user-friendly sampling strategy allowing at-home collection, enabling large-scale research and development programs needed to bring biomarker methods into widespread use. Amit Roshan, Fazlur R. Talukdar, Angela An, Emma-Jane Ditter, Ze Zhou, Paulius D. Mennea, Linfang Wu, Maria C. Neofytou, Anita Balakrishnan, Claire M. Connell, Gabriel Funingana, Giovanni Codacci-Pisanelli, Girma Mulisa, Tamrat Abebe, Constanza Linossi, Hui Zhao, Wendy N. Cooper, Huiqi Yang, Rajesh Jena, James D. Brenton, Pippa Corrie, Rebecca C. Fitzgerald, Simon Pacey, Richard Baird, Nitzan Rosenfeld. Dried blood sot sampling as a minimally invasive and accessible method for investigating circulating tumor DNA in diverse cancer settings [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4550.

Little more than 10 years ago, metastatic melanoma was considered to have one of the poorest cancer outcomes, associated with a median overall survival of 6-8 months. Cytotoxic chemotherapy offered modest response rates of 20%-30%, but no clear survival benefit. Patients were routinely enrolled in clinical trials as their first-line therapy in the search for effective novel therapeutics. Remarkable developments in molecular biology, cancer genomics, immunology, and drug discovery have dominated the early part of the 21st century, and nowhere have the benefits been better realized than in the transformation of outcomes for patients with metastatic melanoma: since 2011, 14 new agents have been approved that significantly increase survival, with long-term remissions and, possibly now, potential for cure. Even so, there is still much work to be done, given that most treated patients still die of their disease. Although most survival gains have so far been realized for cutaneous melanoma, improving treatment options for those 10% of patients with rarer, noncutaneous melanomas is a high priority. Key novel therapeutic approaches aimed at improving outcomes with potential for curing patients with melanoma are considered.

Mucosal (MM) and acral melanomas (AM) are rare melanoma subtypes of unmet clinical need; 15%-20% harbor KIT mutations potentially targeted by small-molecule inhibitors, but none yet approved in melanoma. This multicenter, single-arm Phase II trial (NICAM) investigates nilotinib safety and activity in KIT mutated metastatic MM and AM. KIT mutations are identified in 39/219 screened patients (18%); of 29/39 treated, 26 are evaluable for primary analysis. Six patients were alive and progression free at 6 months (local radiology review, 25%); 5/26 (19%) had objective response at 12 weeks; median OS was 7.7 months; ddPCR assay correctly identifies KIT alterations in circulating tumor DNA (ctDNA) in 16/17 patients. Nilotinib is active in KIT-mutant AM and MM, comparable to other KIT inhibitors, with demonstrable activity in nonhotspot KIT mutations, supporting broadening of KIT evaluation in AM and MM. Our results endorse further investigations of nilotinib for the treatment of KIT-mutated melanoma. This clinical trial was registered with ISRCTN (ISRCTN39058880) and EudraCT (2009-012945-49).

AimsThe MAPK pathway is constitutively activated in uveal melanoma (UM). Selumetinib (AZD6244, ARRY-142886), a MEK inhibitor, has shown limited activity as monotherapy in metastatic UM. Pre-clinical studies support synergistic cytotoxic activity for MEK inhibitors combined with taxanes, and here we sought to assess the clinical efficacy of combining selumetinib and paclitaxel.Patients and MethodsSeventy-seven patients with metastatic UM who had not received prior chemotherapy were randomised to selumetinib alone, or combined with paclitaxel with or without interruption in selumetinib two days before paclitaxel. The primary endpoint was progression free survival (PFS). After amendment, the combination arms were combined for analysis and the sample size adjusted to detect a hazard ratio (HR): 0.55, 80% power at 1-sided 5% significance level.ResultsThe median PFS in the combination arms was 4.8 months (95% CI: 3.8 - 5.6) compared with 3.4 months (2.0 - 3.9) in the selumetinib arm (HR 0.62 [90% CI 0.41 - 0.92], 1-sided p-value = 0.022). ORR was 14% and 4% in the combination and monotherapy arms respectively. Median OS was 9 months for the combination and was not significantly different from selumetinib alone (10 months) with HR of 0.98 [90% CI 0.58 - 1.66], 1-sided p-value = 0.469. Toxicity was in keeping with the known profiles of the agents involved.ConclusionsSelPac met its primary endpoint, demonstrating an improvement in PFS for combination selumetinib and paclitaxel. No improvement in OS was observed, and the modest improvement in PFS is not practice changing.