PFS and OS by detection of BRAF V600 alterations in ctDNA at (A and B) baseline and (C and D) on treatment. Only patients with BRAF V600 alteration detections at baseline are shown in C and D. Bini, binimetinib; D, detectable; Enco, encorafenib; ND, nondetectable; Vemu, vemurafenib.

PURPOSE:Treatment with encorafenib ± binimetinib is associated with improved survival versus vemurafenib in patients with BRAF V600E/K-mutant advanced melanoma. We retrospectively analyzed genomic and transcriptomic data from the phase III COLUMBUS trial to identify molecular correlates of benefit with encorafenib ± binimetinib. EXPERIMENTAL DESIGN:In COLUMBUS, patients with BRAF V600E/K-mutant locally advanced, unresectable, or metastatic melanoma (n = 921) were randomized to receive encorafenib plus binimetinib, encorafenib, or vemurafenib. We used whole-exome sequencing (n = 666), whole-transcriptome sequencing (RNA sequencing; n = 514), and assessment of circulating tumor DNA (ctDNA) at baseline (n = 336) and on treatment (cycle 2 day 1, n = 184) to evaluate biomarker associations with progression-free and overall survival. RESULTS:Survival benefits with encorafenib plus binimetinib versus vemurafenib were greatest in patients with higher tumor mutational burden (TMB) and those with evidence of tumor immune infiltration (i.e., higher cytolytic score, PD-L1 expression, or IFNγ gene signature scores). Clustering of gene expression profiles identified three tumor subgroups, including an "immune" subgroup associated with improved survival. Detection of BRAF V600 alterations in baseline ctDNA was associated with shorter survival; clearance of BRAF V600 alterations at cycle 2 day 1 was associated with improved survival across arms. CONCLUSIONS:The greatest benefits of encorafenib plus binimetinib were observed in patients with evidence of high TMB and/or tumor-immune infiltration, suggesting potential immune contributions to efficacy, which were not observed with vemurafenib. BRAF V600 detectability in ctDNA seems to have utility as a marker of prognosis and response in this population.

PFS and OS for encorafenib plus binimetinib or encorafenib vs. vemurafenib by (A and B) TMB and (C and D) cytolytic score. E, Volcano plots of univariable gene expression associations with OS in each arm based on z-scored gene expression values. F, Gene-set enrichment analysis of gene expression associations against hallmark gene signatures; signatures with greatest average NES across arms shown. Bini, binimetinib; BM, biomarker; CYT, cytotoxic score; Enco, encorafenib; NES, normalized enrichment scores; Vemu, vemurafenib.

Background Therapeutic options for BRAFV600-mutant melanoma in patients who progress on BRAF/MEK-inhibitors (BRAF/MEKi) and immune-checkpoint-inhibitor (ICI) therapy, are limited. We conducted a retrospective registry study to investigate post-ICI rechallenge with BRAF/MEKi, stratified by type of initial BRAF/MEKi therapy. Methods This retrospective study analysed patients from the EUMelaReg registry, who received adjuvant or first-line (1L) BRAF/MEKi in the advanced setting, followed by ICI therapy and were later retreated with BRAF/MEKi. Overall response rate (ORR) for rechallenge served as primary endpoint, disease-control rate (DCR), progression-free survival (PFS), and overall survival (OS) were further endpoints. A covariate-matched control group of patients who received BRAF/MEKi only after 1L ICI failure was selected for comparison. Results Among patients previously treated with adjuvant (n=42) or non-adjuvant (n=142) BRAF/MEKi, rechallenge after one interim ICI line resulted in ORRs of 26.2% and 30.3% and DCRs of 42.9% and 61.8%, respectively. Median PFS was 8.4 and 5.1 months, median OS 13.8 and 8.6 months, respectively. Overall, the rechallenge group had a 1-year OS of 43.2%, lower than the matched control (58.9%). The adjuvant subgroup was similar to control (55.4%), while the advanced subgroup showed notably poorer survival (39.9%). Subgroup analyses showed that both the pre-ICI response to BRAF/MEKi treatment and progressive disease prior to ICI were associated with outcome of the BRAF/MEKi rechallenge. Conclusion Rechallenge with BRAF/MEKi therapy under real-world conditions for advanced melanoma provides a valid treatment option. For patients who received their initial BRAF/MEKi therapy as adjuvant therapy there seems to be only limited impairment of outcomes.

BACKGROUND:Immunosuppression mechanisms mediated by regulatory T cells (Tregs) can lead to poor clinical outcomes in patients undergoing immune-based therapies. Activation markers, such as inducible T-cell co-stimulator (ICOS), are highly expressed on the surface of tumor-infiltrating Tregs and present as relevant targets for targeted depletion of these cells. Here, we present clinical outcomes from a Phase 1 study (NCT03829501) of an anti-ICOS antibody of alomfilimab (SAR445256 or KY1044) as monotherapy and in combination with the anti-programmed death-ligand 1 (PD-L1) antibody, atezolizumab, in patients with advanced solid tumors. METHODS:Alomfilimab was administered intravenously once every 3 weeks (Q3W) ±3 days at six dose levels (DLs; 0.8 mg to 240 mg) as monotherapy and five DLs (0.8 mg to 80 mg) in combination with atezolizumab (1,200 mg Q3W ±3 days). Eligible patients must have had advanced metastatic disease as determined by Response Evaluation Criteria in Solid Tumors V.1.1 and no viable treatment options according to National Comprehensive Cancer Network guidelines. RESULTS:Overall 38 patients were enrolled in the monotherapy cohort, and 102 patients were enrolled in the combination therapy cohort. Alomfilimab had a manageable safety profile and showed a trend toward modest efficacy in tumor growth control when combined with anti-PD-L1 in selected malignancies. At least one treatment-emergent adverse event was reported in 35 patients (89.7%) in the monotherapy cohort, and in 99 (98%) patients in the combination cohort. Objective response was not observed in the monotherapy cohort. In the combination cohort, seven patients had an objective response. Median time to progression-free survival was 2 months for both cohorts. Furthermore, alomfilimab showed evidence of target engagement on T-cell subsets, specifically cluster of differentiation (CD)4+memory cells, in both single-agent and in combination treatment with atezolizumab. This was accompanied by transient elevation of granulocyte-macrophage colony-stimulating factor, interferon-γ, and tumor necrosis factor-α levels and dose-dependent reduction of ICOS+Tregs in the tumor microenvironment. CONCLUSIONS:Alomfilimab treatment was associated with an acceptable safety profile across both mono and combination approaches, accompanied by decreased ICOS+Tregs populations and enhanced CD4+ and CD8+ effector T cells cell activity. Limited clinical activity was observed despite evidence of biological activity. TRIAL REGISTRATION NUMBER:NCT03829501.

MONETTE study design, Baseline tumor sample and blood samples, DoR, best percentage change from baseline in target lesion size, OS in PD-L1 and CD8/Ki67 biomarker evaluable populations, micrographs of PD-L1 expression and CD8+/Ki67 cells, baseline area of CD8+ T cells, Ki67+ cells, and proliferating CD8+ Ki67 + T cells in the central tumor region, OS in the baseline circulating immune cell biomarker population, longitudinal pharmacodynamic effects on T cells, OS in GDF-15 biomarker population and baseline GDF-15 as a prognostic marker for OS in monotherapy and combination therapy.

Abstract Cancer vaccines have recently emerged as promising anti-cancer therapies that complement immune checkpoint blockade by stimulating targeted anti-tumor immunity. Their efficacy critically depends on including tumor antigens that can elicit a potent, cancer-specific T-cell response. To achieve this, Evaxion developed the proprietary AI-Immunology™ platform to identify highly immunogenic tumor antigens and design personalized cancer vaccines based on patient-specific sequencing data, optimized for maximal immune activation.The AI-platform identifies somatic mutations and indels in the tumor mutanome, considering tumor expression, clonality and HLA loss to select neoantigens with highest immunogenic potential. EVX-01, the first vaccine candidate generated from this AI-platform, was evaluated in a phase 2 clinical study (NCT05309421) in advanced melanoma. EVX-01 was administered in combination with pembrolizumab, following a 12-week run-in period with pembrolizumab as monotherapy. Patients received in total 10 EVX-01 doses, split into 6 priming and 4 booster immunizations. Primary endpoint was RECIST 1.1-based response improvement of the objective response rate (ORR). For immunogenicity and biomarker analysis peripheral blood was collected before, during and after treatment and processed to peripheral blood mononuclear cells (PBMC). Vaccine-specific T-cell responses were assessed by Interferon-gamma ELISpot and intracellular cytokine staining and flow cytometry, both ex vivo and after in vitro stimulation. Non-vaccine antigens were tested to investigate potential epitope spreading. At the two-year read out, the ORR was 75% (12/16) in the overall cohort. Of the responders, 92% (11/12) continued to respond at 24 month follow up. The treatment was well-tolerated, and the manufacturing success rate was 100%. Additionally, of 13 patients with stable disease (SD) or partial response (PR) after a the 12-week pembrolizumab induction, 54% (7/13) deepened the response upon initiation of EVX-01. The final immunogenicity analysis showed that EVX-01 priming induced strong vaccine-specific T-cell responses in the 15 assessable patients, with booster doses sustaining response magnitudes until last assessment at week 102. Both CD4+ and CD8+ T cells contributed to the response, with CD4+ T cells predominating. 84% of tested neoantigens elicited a specific immune response and AI-Immunology™ platform-assigned immunogenicity scores correlated with the magnitude of T-cell reactivity. In conclusion, the AI-Immunology™ platform can effectively identify highly immunogenic neoantigens, design manufacturable and safe personalized cancer vaccines with pharmacodynamic activity. Combined with PD-1 blockade, EVX-01 achieves a 75% ORR and induces durable, vaccine-specific T-cell immunity in all treated patients, validating the platforms predictive precision. Citation Format: Mads Lausen, Michail Angelos Pavlidis, Ohrt Andersen Rasmus, Thuesen Nikolas, Nadia Viborg, Georgina V. Long, Adnan Khattak, Paolo A Ascierto, Carolina Cimminiello, Thomas Trolle, Christian Garde, Michael J. Chisamore, Benjamin Wolthers, Stine Friis Thorsen, Birgitte Rønø, Daniela Kleine-Kohlbrecher. AI-designed personalized neoantigen vaccine, EVX-01, induces durable de novo T-cell responses in advanced melanoma patients [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 7741.

BACKGROUND:Heterodimeric IL-15 (NIZ985) shows rapid and indirect effects on different myeloid cells but may upregulate PD-1 (programmed cell death-protein 1) on CD8 + T cells, limiting its therapeutic potential. Combining IL-15 with an anti-PD-1 antibody is known to enhance antitumor immune response and prolong survival in mice. METHODS:This was a phase I/Ib, open-label, multicenter study (NCT04261439) of NIZ985 single agent (SA) or with an anti-PD-1/CPI agent in patients with advanced solid tumors or lymphoma (responded and progressed on prior anti-PD-1) in a dose escalation (SA/with spartalizumab) and a dose expansion (with tislelizumab) arm. Primary objectives were to assess safety and tolerability including DLTs in cycle 1, adverse events (AEs) and serious AEs, dose interruptions, reductions, and dose intensity of NIZ985 SA and combination therapy. The recommended dose for expansion (RDE) for further investigations was determined. RESULTS:NIZ985 was safe and well-tolerated, with a safety profile consistent with a previous investigation. Most common AEs with SA were injection site reaction, pyrexia, and transaminase increase. With combination therapy, AEs leading to dose adjustment/interruption were higher with NIZ985 16mg/kg compared to 8mg/kg and 12 mg/kg. NIZ985 exposure after the first dose increased with dose increases and was not affected by concomitant administration of CPIs. The RDE was determined to be 12 µg/kg NIZ985 QW (3 weeks on-1week off). CONCLUSIONS:While NIZ985 is safe to use in combination with PD-1 inhibitors and showed biological activity, preliminary antitumor efficacy was limited in patients who previously progressed on an anti-PD-1/CPI agent.

9540 Background: Sonidegib is an efficacious treatment of LA laBCC but is associated with a high risk of treatment-related adverse events (TRAEs) causing treatment discontinuation. Following a CR, treatment discontinuation rate reaches up to 60% after a year, leading to 3 years relapse free survival rate of 35%. We aimed at evaluating sonidegib tailored schedule (TS) after CR to increase treatment duration by reducing TRAEs, thus allowing CR maintenance. Methods: We conducted a multicenter, open-label, single-arm phase II study enrolling adult patients (pts) with laBCC who obtained a CR to sonidegib regardless of the tumor’s subtype and burden. Eligible pts received TS1 with sonidegib 14 days on and 14 days off. Pts on TS1 who experienced grade 2-3 toxicity (except alopecia) lasting >28 days moved to TS2 (7 days on and 21 days off). Treatment continued until progression or unacceptable toxicity. Primary endpoint was the rate of pts maintaining sonidegib 12 months after study enrolment (H0 31%, H1 60%). Evaluable pts were defined as all pts who were either on treatment or suspended treatment for reasons other than treatment-unrelated adverse events or death. Secondary endpoints were safety, treatment compliance, rate of disease relapse at 1 and 2 years, overall survival, quality of life, use of concomitant medications and of medical resources, and translational analysis. Results: Between Jan 2021 and Dec 2023, 22 pts from 10 Italian centers were enrolled; the data cut-off was Jan 2025. Pts characteristics are reported in table 1. The median follow-up was 22 months (range 2-33). Three disease and treatment-unrelated deaths occurred before completing 1 year of TS and therefore 19 pts were evaluable. At data cut-off, 12 pts had discontinued treatment: 26% (5) due to disease progression, 11% (2) to sonidegib’s unacceptable toxicity, the remaining either to personal or physician’s choice. Twelve out of 19 evaluable pts (63%) were still on treatment after 1 year from TS start (median duration 20 months, range 2-29), meeting the primary endpoint. The most common TRAEs episodes were muscle cramps (13), alopecia (6), dysgeusia (5) with overall TRAEs grade G1 (29), G2 (11), G3 (3). Twelve pts had dose reduction to TS2. Conclusions: Tailored maintenance schedule with pulsed sonidegib allows for longer treatment duration and fewer relapses in CR laBCC pts. Study follow up to evaluate secondary endpoints outcome and translational analysis are ongoing. Clinical trial information: 2020-002613-17 . Patient characteristics. Characteristic N (%) Male : Female 14 (64) : 8 (36) Median age 76y (range 56-93y) ECOG PS 0-1 15 (68): 7 (32) Histology sub-type Nodular 8 (36) Superficial 2 (9) Infiltrative 7 (32) Mixed 1 (5) Other 4 (18)

Importance:Patients with melanoma are at risk of developing subsequent cutaneous malignant neoplasms, and the effect of prior immunotherapy is unknown. Objective:To analyze new skin cancers in participants with high-risk stage II melanoma treated with adjuvant pembrolizumab or placebo. Design, Setting, and Participants:The multicenter double-blind, phase 3 KEYNOTE-716 randomized clinical trial enrolled 976 participants 12 years or older with completely resected stage IIB or IIC cutaneous melanoma between September 23, 2018, and November 4, 2020. Follow-up was completed on February 16, 2024. This analysis was not prespecified in the trial protocol. Interventions:Participants were randomly assigned to receive intravenous pembrolizumab, 200 mg (2 mg/kg for pediatric participants), or placebo, every 3 weeks for no more than 17 cycles. Main Outcomes and Measures:Secondary analyses of incidence and time to diagnosis of new melanoma or other cutaneous malignant neoplasm, sensitivity analysis of recurrence-free survival (RFS) with new primary melanoma counted as an event, and incidence of immune-mediated severe skin reactions. Results:A total of 976 participants were assigned to treatment (487 to pembrolizumab and 489 to placebo), of whom 589 (60.3%) were male (median age at diagnosis, 61 [IQR, 52-69] years). The median follow-up was 52.8 (range, 39.4-64.8) months. In the pembrolizumab group, 37 participants (7.6%) were diagnosed with new skin cancers (median time to diagnosis, 168.0 [range, 1.0-1182.0] days); 12 (2.5%) had new invasive primary melanoma, 6 (1.2%) had new primary melanoma in situ, 19 (3.9%) had basal cell carcinoma (BCC), and 9 (1.8%) had cutaneous squamous cell carcinoma (cSCC). In the placebo group, 56 participants (11.5%) were diagnosed with new skin cancers (median time to diagnosis, 177.0 [range, 1.0-1043.0] days); 9 (1.8%) had new invasive primary melanoma, 9 (1.8%) had new primary melanoma in situ, 26 (5.3%) had BCC, and 17 (3.5%) had cSCC. Median RFS with new primary melanoma counted as an event was not reached with pembrolizumab and was 59.2 months (95% CI, 53.9 months to not reached) with placebo (hazard ratio, 0.65; 95% CI, 0.52-0.80); 48-month RFS was 68.7% and 56.5%, respectively. Immune-mediated severe skin reactions occurred in 16 of 483 participants (3.3%) in the pembrolizumab group and 3 of 486 (0.6%) in the placebo group (grade 3 or 4: 14 [2.9%] vs 3 [0.6%]). Conclusions and Relevance:In this secondary analysis of a randomized clinical trial, the incidence of new primary melanoma was not different between groups, whereas nonmelanoma skin cancers were more common with placebo. The RFS benefit of pembrolizumab remained after accounting for new primary melanomas. Immune-mediated severe skin reactions occurred infrequently and were manageable. These findings support the use of adjuvant pembrolizumab in high-risk stage II melanoma. Trial Registration:ClinicalTrials.gov Identifier: NCT03553836.

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.

A false-negative diagnosis of cancer can lead to a delay in effective treatment and a poorer prognosis. Here, we use the example of cutaneous melanoma to examine how many years of life are lost after a false-negative diagnosis compared to a primarily correct diagnosis. From 1996 to 2015, 9,063 patients are prospectively registered in the German Central Malignant Melanoma Registry and followed up until December 2023. A false-negative diagnosis is found in 206 (2.3%) patients. The median time to correct diagnosis is 24.0 months. The 10-year recurrence-free survival probabilities are 32.9% for false-negative diagnoses and 76.2% for correct diagnoses (p < 0.001). The 10-year melanoma-specific survival probabilities are 62.1% versus 85.0% (p < 0.001). On average, each person with an initial false-negative diagnosis loses 8.2 years of life compared to people with a correct diagnosis. This high number of years of life lost raises the question of whether similar results also apply to other types of cancer.

PURPOSE:Stage IIB/IIC melanoma has a high risk of recurrence after resection. Combined BRAF/MEK inhibitor therapy showed benefit in resected high-risk stage III and advanced melanoma. The objective of this study was to investigate its role in stage IIB/IIC. METHODS:Adult patients with resected stage IIB/IIC cutaneous melanoma which had a BRAF V600E/K mutation were randomized 1:1 to receive encorafenib (enco) 450 mg QD + binimetinib (bini) 45 mg BID orally for one year or placebo. The study planned to randomize 815 patients and was designed to demonstrate superiority regarding recurrence-free survival (RFS). Following a premature termination of accrual, the study was amended with safety as the primary endpoint and RFS as secondary endpoint. RESULTS:Between June 9, 2022, and October 9, 2023, 339 patients were screened for a BRAF mutation and 110 randomized. Data cutoff was 19 Nov. 2024, after the last patient discontinued study participation. Among randomized patients, 87 (79%) had a BRAF V600E mutation, and 39 (35%) AJCC8 stage IIC. Median follow-up was 12 and 7 months for enco/bini and placebo arms, respectively. Among 54 patients who initiated enco + bini, grade ≥ 3 treatment-related adverse events (AE) occurred in 13 (24%) patients, and 18 (33%) patients had an AE leading to permanent treatment discontinuation. RFS at 12 months was 86% (95% CI: 65-95%) in the enco + bini and 70% (95% CI: 46-85%) in the placebo arm, distant metastasis-free survival at 12 months was 92% (95% CI: 77-97%) for enco + bini and 82% (95% CI: 55-93%) for placebo. CONCLUSION:EORTC 2139 - Columbus-AD demonstrated a consistent and manageable safety profile and encouraging efficacy results for the combination of enco and bini in resected stage IIB/C BRAF V600E/K-mutated cutaneous melanomas.

BACKGROUND:Pegenzileukin (SAR444245), a pegylated non-alpha recombinant human interleukin (IL)-2 variant, avoids engagement of the IL-2 receptor α subunit (IL-2Rα) chain and associated toxicities, while retaining engagement of IL-2Rβγ, for activation of effector T cell and natural killer (NK) cell. The first-in-human study of pegenzileukin with pembrolizumab showed initial efficacy and tolerable safety in advanced and metastatic solid tumors. In this study, we evaluate pegenzileukin with cemiplimab for advanced or metastatic melanoma (MM) and cutaneous squamous cell carcinoma (CSCC). METHODS:This phase 1/2, open-label, multicenter study evaluated drug combinations in patients with MM (Cohort A) and CSCC (Cohort B). Pegenzileukin was given at two dose levels (16 µg/kg: Cohort A1 and B1 and 24 µg/kg: Cohort A2 and B2) during dose escalation and recommended phase 2 dose (RP2D) during dose expansion, while cemiplimab was given at a dose of 350 mg; both drugs were administered every 3 weeks as a 30-minute intravenous infusion. The primary endpoint was the objective response rate (ORR); secondary endpoints included dose-limiting toxicities (DLTs), progression-free survival (PFS), safety, and exploratory biomarker endpoints. RESULTS:A total of 46 patients were enrolled. At the RP2D of pegenzileukin (16 µg/kg, n=20 in Cohort A1 and n=16 in Cohort B1), the ORR was 40% in Cohort A1 and 56.3% in Cohort B1. In Cohort A1, one patient achieved a complete response, and seven achieved a partial response (PR). In Cohort B1, nine patients achieved a PR. At the RP2D, 75.0% and 85.7% responders, respectively, in Cohort A1 and Cohort B1 had a duration of response of ≥12 months. The PFS rate at 6 months was 55.0% in Cohort A1 and 70.7% in Cohort B1. Five DLTs occurred in four patients: Cohort A had one case of ≥3 Grade thrombocytopenia and one of Grade 2 cytokine release syndrome, while Cohort B had one case of ≥3 Grade alanine transaminase/aspartate transaminase increases and one infusion-related reaction (IRR). Grade 1 or 2 IRRs were the most common adverse events. Treatment led to robust expansion of NK and CD8 T-cells, without an increase of regulatory T cells. CONCLUSION:Pegenzileukin in combination with cemiplimab at the RP2D of 16 µg/kg showed a manageable safety profile and promising translational data supporting its mechanism of action. TRIAL REGISTRATION NUMBER:NCT04913220.

Background Randomised trials recently showed that sequencing of first-line (1L) immune checkpoint inhibitor (ICI) and second-line (2L) BRAF-MEK-inhibitor (BRAF/MEKi) combination therapy provides better clinical outcomes in BRAFV600-mutated, irresectable/metastatic melanoma than the inverse sequence. However, efficacy benchmark data for 2L BRAF/MEKi are limited as the combination was developed for 1L use, lacking estimates for the impact of prior ICI. Methods This retrospectively study analysed 2,343 patients from the EUMelaReg registry with BRAFV600-mutated melanoma who received BRAF/MEKi either as 2L after failing 1L ICI (n=654) or as 1L treatment (n=1,689). Patients with prior adjuvant ICI or BRAF/MEKi were excluded. Prognostic imbalances between the two groups were adjusted using 1:1 inverse propensity score matching. Key efficacy outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and time on treatment (TOT). Results Patients in the 2L cohort achieved outcomes from start of treatment at least equivalent to the matched 1L BRAF/MEKi cohort. Kaplan-Meier estimates demonstrated longer median PFS (8.4 vs 7.7 months; p=0.01) and longer median TOT (7.8 vs 6.2 months; p=0.002) for patients treated with 2L BRAF/MEKi compared to 1L. Median OS from start of 2L (17.2 months) or 1L (16.0 months) BRAF/MEKi was similar (p=0.73) despite inherent bias from differing index dates. ORR among both groups (56.4% vs 53.5%; p=0.32) was equal. Conclusion This study further supports the recommended sequencing of ICI as 1L and BRAF/MEKi as 2L therapy for patients with BRAFV600-mutated melanoma. It shows that prior failure of ICI does not compromise the efficacy of BRAF/MEKi treatment.

Characterization of tumor samples to identify candidate molecular subtypes by K-means clustering and distribution of subtypes by biopsy site. A, Heatmap showing K-means cluster and the expression of key marker genes (AXL and MITF) and cell type scores generated by xCell. B, Distribution of K-means subgroups across biopsy sites. C, OS by K-means subgroup and treatment arm. Bini, binimetinib; Vemu, vemurafenib.

Aim Anti-programmed death-1/ligand-1 (anti-PD-(L)1) therapies are effective for advanced cSCC. This international study examines response patterns and subsequent management strategies following anti-PD-(L)1 therapy. Method This retrospective cohort study involved 10 centres across 6 countries. Key outcomes included objective response rate (ORR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS) for anti-PD-(L)1 and subsequent therapy. Results One-hundred and fifty-nine patients with advanced cSCC who received anti-PD-(L)1 were evaluated. At median follow-up of 19.3 months (95% CI; 17.5 – 22.2), ORR was 67%. The 12-month and 24-month PFS rates were 62% (95% CI: 55 - 70) and 55% (95% CI: 47 - 64), while 12-month and 24-month OS rates were 81% (95% CI: 75- 88) and 71% (95% CI: 63 – 80). Disease progression occurred in 47 patients (30%); 11% who progressed within 6 weeks of receiving anti-PD-(L)1 therapy, 55% with primary resistance, 28% with secondary resistance, 6% with late progression. Among 21 patients who received subsequent systemic therapies; 8 received cetuximab monotherapy (ORR 50%, DOR 8.5 months [95% CI; 6.9 - NR]) and 5 received anti-PD-(L)1 rechallenge (ORR 20%, one responder with response duration of 3.2 months). In multivariate analysis, a head and neck primary tumour site was associated with higher ORR, and prolonged PFS. Conclusion Our real-world findings reinforce the efficacy of anti-PD-(L)1 therapy in patients with advanced cSCC, with outcomes influenced by primary tumour location. The heterogeneity of subsequent treatments highlights an unmet need in the management of patients who progress on these therapies.

PURPOSE:Data suggest that ceralasertib, a potent and selective oral inhibitor of the ataxia-telangiectasia and Rad3-related (ATR) DNA damage response kinase, may overcome resistance to prior immunotherapy. PATIENTS AND METHODS:In this phase II study, patients with unresectable or metastatic melanoma of cutaneous, acral, or mucosal subtype and confirmed progression during anti-PD-(L)1 therapy with or without anti-CTLA-4 were randomized 2:1 to ceralasertib 240 mg twice daily on days 1 to 7 and then durvalumab 1,500 mg intravenously on day 8, every 28 days or ceralasertib 240 mg twice daily on days 1 to 7, every 28 days. The primary endpoint was objective response rate (ORR). Key secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Exploratory analyses of baseline (tumor and circulating) and on-treatment (circulating only) biomarkers were conducted. RESULTS:ORR was 9.3% [95% confidence interval (CI), 4.3-16.9] for ceralasertib plus durvalumab (below the prespecified minimum threshold) and 5.8% (95% CI, 1.2-15.9) for ceralasertib monotherapy; median PFS was 2.0 months (95% CI, 1.9-3.5) versus 1.9 months [95% CI, 1.9-3.1; hazard ratio (HR), 0.80; 95% CI, 0.54-1.18]; and median OS was 16.0 months [95% CI, 10.5-not calculated (NC)] versus 12.3 months (95% CI, 9.5-NC; HR, 0.81; 95% CI, 0.49-1.37). Both regimens were well tolerated. Exploratory analyses indicated a possible link between higher baseline pretreatment tumor CD8+ T-cell counts and improved OS across both arms and suggested that ceralasertib treatment may induce transient, cyclical changes in circulating CD14+ monocytes and GDF-15 plasma levels. CONCLUSIONS:Both ceralasertib plus durvalumab and ceralasertib monotherapy demonstrated low response rates in anti-PD-(L)1-resistant advanced melanoma.