PURPOSE:Angiosarcoma and epithelioid hemangioendothelioma (EHE) are two rare vascular sarcomas with limited therapeutic options. Prior reports have shown sensitivity to microtubule-targeting agents in these histologies. We report the efficacy and safety of eribulin in these vascular sarcomas in a pooled analysis of two parallel phase 2 studies. PATIENTS AND METHODS:Patients more than age 18 years with metastatic or recurrent angiosarcoma or EHE were treated with eribulin (1.4 mg/m2 on days 1 and 8 of a 21-day cycle) until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by RECIST 1.1. RESULTS:Twenty-nine patients were accrued to the study, with 25 (85%) having had prior taxane exposure. We observed an ORR of 17% for angiosarcomas, with 6 of 23 (26%) patients achieving disease stability for greater than 6 months, and an ORR of 33% (2/6) for EHE, with two of six continuing treatment for over 12 months. Five patients experienced a >1.3-fold time to progression ratio (TTP2/TTP1) on eribulin compared with the immediately prior therapy. Eribulin tolerability was consistent with published data. CONCLUSIONS:Eribulin showed clinical activity in this largely taxane-pretreated population. Future studies will be needed to confirm activity. See related commentary by Chen, p. 2130.

Abstract Background: D3S-002 is a potent, selective oral ERK1/2 inhibitor, purposefully designed as a combination partner for KRAS G12X inhibitors to overcome feedback MAPK activation induced by these agents. In KRAS G12Ci resistant models, D3S-002 combined with D3S-001, a next-generation KRAS G12Ci, demonstrated significantly improved efficacy compared with either D3S-001 or D3S-002 alone, supporting clinical evaluation of this combination. Methods: This ongoing phase 1/2, open-label, dose-escalation and dose expansion study (NCT05886920) was designed to evaluate safety, tolerability, pharmacokinetics (PK) and recommended phase 2 dose of D3S-002 monotherapy or combination therapy in adult patients with advanced solid tumors harboring MAPK pathway mutations. The dose escalation part of D3S-002 monotherapy has been completed. The PK and safety profiles were evaluated with D3S-002 QD at 8 dose levels from 10mg to 240mg under BOIN design. Results: Thirty-two patients were enrolled in the dose escalation part of D3S-002 monotherapy across 10 sites in the US (n=2), Australia (n=15), and China (n=15). The No. of patients receiving 10mg, 20mg, 40mg, 60mg, 90mg, 135mg, 180mg or 240mg D3S-002 QD were 3, 3, 3, 3, 5, 3, 6, 6 respectively. The median duration of exposure was 1.3m (0.2-5.6). D3S-002 exhibits a dose-proportional PK profile with dose-dependent exposure increases from 10 mg to 240 mg QD and minimal accumulation after repeated dosing. Tmax was 1-3 hours, and terminal half-life of ∼3-5 hours was consistent across dose levels. This PK behavior aligns with D3S-002’s intentionally designed preclinical pharmacology, supporting pulsatile ERK inhibition that allows drug-free intervals in normal tissues while maintaining effective MAPK pathway suppression in tumors with elevated ERK activity. D3S-002 was well tolerated, with ≥Grade 3 TRAEs observed in 18.8% (6/32) of patients. No Grade 5 TRAEs were reported. TRAEs occurred in ≥10% of patients including AST/ALT increase and nausea. No significant correlation was observed between PK and changes in liver enzymes. Unlike other ERKi(s), skin toxicities (dermatitis acneiform: 6.5%, rash: 3.1%) and ocular toxicities (6.5%) are uncommon. The maximum tolerated dose was reached at 240 mg QD. Among 27 efficacy evaluable patients, the DCR was 25.9%. Tumor shrinkage was observed in 3 patients, including 1 unconfirmed partial response (PR). Guided by PK/safety profile, D3S-002 combination with D3S-001 will be initiated at 40 mg QD. Conclusions: D3S-002 demonstrates predictable, dose-proportional PK consistent with its preclinically designed pulsatile exposure profile, supporting its development as an optimal ERKi partner for synergistic combination with other MAPK pathway-targeted therapies. A clinical study evaluating D3S-002 in combination with D3S-001 for the treatment of patients with KRAS G12C-mutant NSCLC is currently underway. Citation Format: Yi-Long Wu, Michael Millward, Yanqiao Zhang, Matteo S. Carlino, Xian Wang, Amitesh Roy, Jun Zhang, Jun Zhao, Zhen Wang, Amy Weise, Debora Doroshow, Shaonan Wang, Zifei Fan, Rong Su, Jing Zhang, Jia Wang, Wenqian Wang, Cheng Chen, Qian Chen, Hui Wang, Zhijian Chen. First in human phase 1 study of D3S-002, a purposely designed ERK1/2 inhibitor, in advanced solid tumors with MAPK pathway mutations [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 CT060.

Abstract Recent genome-wide screens have identified ERK as a central signaling hub in KRAS-mutant tumors and a key driver of resistance to KRAS-targeted therapies. However, prior clinical development of ERK1/2 inhibitors has been hindered by narrow therapeutic windows and on-target toxicity. Consequently, achieving clinical success in targeting this critical kinase has long been a major challenge in oncology. With the modest durability of first-generation KRAS G12C inhibitors (G12Ci), combining ERK1/2 inhibitors with G12Ci represents a strong mechanistic approach. Notably, analyses of post-progression tumor tissue and ctDNA from G12Ci-refractory patients revealed diverse resistance mechanisms converging on ERK1/2, further supporting this combination strategy. We hypothesize that effective combination therapy requires a potent, selective G12Ci as the foundation, with the ERK1/2 inhibitor primarily suppressing non–KRAS G12C–mediated feedback rather than compensating for incomplete inhibition by suboptimal G12Ci. D3S-001, a next-generation G12Ci achieving complete target coverage at its clinical dose, has demonstrated robust activity in NSCLC patients who are G12Ci-naïve (ORR 67%, DCR 100%) or previously treated with other G12C inhibitors (ORR 30%, DCR 80%). These findings support evaluating whether ERK1/2 inhibition can further improve outcomes in G12Ci-refractory disease. D3S-002 is an ERK1/2 inhibitor purposefully optimized as a combination partner for D3S-001. It shows potent enzymatic inhibition, high selectivity, a target-residence t1/2 of ∼30 minutes and a plasma PK t1/2 of 1–4 hours across species. This profile enables pulsatile ERK blockade, allowing drug-free intervals in normal tissues while maintaining effective MAPK pathway suppression in G12Ci–pretreated tumors with elevated ERK signaling. In preclinical xenograft models resistant to first-generation G12Ci, D3S-001 monotherapy achieved tumor stasis, whereas the addition of D3S-002 induced marked tumor regression with minimal body-weight loss. In resistance models driven by KRAS amplification, low-dose D3S-002 (25 mg/kg QD) combined with D3S-001 significantly extended disease control compared with D3S-001 alone, supporting clinical evaluation of this combination strategy. The safety and PK of D3S-002 were evaluated in a global Phase 1 trial (NCT05886920) enrolling 32 patients in the United States (n=2), Australia (n=15), and China (n=15). D3S-002 was well tolerated, with Grade ≥3 treatment-related adverse events in 18.8% (6/32), and a MTD of 240 mg QD. PK analyses showed transient Cmax pulses (Tmax 1–3 hours), near-zero Ctrough, and a plasma t1/2 of 2–4 hours, consistent with the intended pulsatile profile. These results demonstrate that D3S-002’s preclinical design has translated into favorable tolerability and the desired PK characteristics, supporting its development as a clinical combination partner for D3S-001. A Phase I/II proof-of-concept study evaluating the D3S-002/D3S-001 combination in KRAS G12C–mutant NSCLC patients who progressed on prior G12Ci therapy is now in preparation. Citation Format: Jing Zhang, Wenqian Wang, Zhiqiang Zheng, Xin Xiong, Shaonan Wang, Jia Wang, Zifei Fan, Hui Wang, Qian Chen, Cheng Chen, Michael Millward, Zhen Wang, Jun Zhao, Jun Zhang, Amy Weise, Rong Su, Zhi Jian Chen, Yi-Long Wu. D3S-002: A Purposefully Designed ERK1/2 Inhibitor Achieving Low-Dose, Pulsatile Target Inhibition for Combination with D3S-001, a New-Generation KRAS G12C Inhibitor [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr A005.

Importance:The clinical utility of matching therapies to genomic biomarkers based on varying levels of evidence remains uncertain, particularly for patients with rare and refractory cancers. Objective:To assess whether a tiered, evidence-based framework for matching genomic biomarkers to therapies is associated with differential overall survival in patients with advanced solid tumors. Design, Setting, and Participants:This multicenter cohort study was conducted within the Molecular Screening and Therapeutic program, a nationwide precision oncology program in Australia. Patients aged 18 years and older with advanced, refractory solid tumors and adequate Eastern Cooperative Oncology Group Performance Status were enrolled from June 2016 to December 2021, with follow-up through July 2022. Data were analyzed from July 2022 to July 2024. Exposures:Systemic therapy following comprehensive genomic profiling. Therapies were classified as matched or unmatched using the TOPOGRAPH (Therapy-Oriented Precision Oncology Guidelines for Recommending Anticancer Pharmaceuticals) knowledge base, which stratifies biomarker-drug pairs by level of evidence (tiers 1-3A, prospective trial evidence; tiers 3B/4, investigational/repurposed). Main Outcome and Measures:The primary outcome was overall survival from date of molecular profiling results. The hypothesis was tested using a time-dependent multivariable Cox proportional hazards model, adjusted for age, Eastern Cooperative Oncology Group Performance Status, cancer type, prior therapy, and prior receipt of matched therapy. Results:Of 3383 patients (mean [SD] age 57.1 [14.3] years; 1792 [53.0%] female), 1270 (37.5%) had a clinically active (tiers 1-3A) biomarker. Among patients with a tier 1 to 3A biomarker receiving treatment, those receiving matched therapy had a longer median overall survival than those receiving unmatched therapy (21.2 months [95% CI, 17.1-26.8 months] vs 12.8 months [95% CI, 11.7-13.9 months]; adjusted hazard ratio [aHR], 0.60; 95% CI, 0.44-0.82; P = .001). In contrast, among patients receiving therapy matched to investigational evidence (tiers 3B/4), there was not an associated survival benefit compared with unmatched therapy (14.5 months [95% CI, 12.6-18.4 months] vs 12.8 months [95% CI, 12.0-14.7 months]; aHR, 1.04; 95% CI, 0.84-1.29; P = .71). Patients who received therapies repurposed from other cancer types based solely on a biomarker and lacking direct evidence (tier 3B) did not experience longer survival compared with those receiving unmatched therapy (13.6 months [95% CI, 8.0-16.8 months] vs 12.5 months [95% CI, 11.3-13.5 months]; aHR, 1.40; 95% CI, 1.00-1.96; P = .047). Conclusions and Relevance:In this cohort study of patients with advanced solid tumors, matching therapies to genomic biomarkers was associated with improved survival only when supported by prospective clinical trial evidence. These findings support using an evidence-based framework to prioritize genomically guided therapies.

Background Garsorasib (D-1553) is an orally administered selective KRAS G12C inhibitor. We report results from group 1 of the phase 1b D1553-101 study assessing garsorasib plus pembrolizumab and platinum-based chemotherapy in participants with KRAS G12C‒mutated advanced or metastatic NSCLC. Methods Eligible participants had locally advanced or metastatic NSCLC with KRAS G12C mutation and were candidates for pembrolizumab plus platinum-based chemotherapy. Participants received garsorasib 600 mg once daily (QD) or twice daily (BID) combined with pembrolizumab 200 mg once every 3 weeks plus 4 to 6 cycles of cisplatin or carboplatin and pemetrexed (nonsquamous histology) or carboplatin and paclitaxel (squamous histology). The primary endpoints were safety and incidence of dose-limiting toxicities (DLTs). Results As of February 24, 2024, 17 participants received garsorasib 600 mg QD (n = 10) or BID (n = 7) combined with pembrolizumab plus platinum-based chemotherapy. Overall, 94% of participants experienced grade ≥3 treatment-related adverse events (AEs) and 88% had a dose reduction or interruption due to treatment-related AEs. One participant in the BID group experienced a DLT of grade 2 diarrhea; no other DLTs occurred. Among all participants, the objective response rate was 59% and median progression-free survival was 7.4 months. Conclusion In participants with KRAS G12C‒mutated locally advanced or metastatic NSCLC, despite an encouraging signal of efficacy, the incidence of treatment-related AEs with garsorasib plus pembrolizumab and platinum-based chemotherapy was high, and participants had frequent dose modification or interruption due to treatment-related AEs. Based on these findings, the study did not proceed into phase 2. (NCT04585035)

2608 Background: The acidic tumor micro-environment is linked to immune suppression and insensitivity to immunotherapy. The G protein-coupled receptor, GPR65, is activated in this low pH environment, driving the increased transcription of myeloid immune-suppressive genes and reduced transcription of T- and NK-cell functional and effector genes. Against the backdrop of this target validation, PTT-4256, a first-in-class, potent, orally-bioavailable, allosteric, small molecule inhibitor of GPR65, is being developed as a potential treatment of solid tumors. In mouse syngeneic cancer models, oral administration of PTT-4256 as monotherapy delivers pronounced efficacy, which is enhanced in combination with an anti-PD-1 antibody. Transcriptomic analysis shows that PTT-4256 effectively reverses the acidic immune suppression in mice tumors. Methods: RAISIC-1 is a multi-modular Phase 1/2 clinical trial in adults with histologically confirmed advanced/metastatic solid malignancies who have previously received standard of care therapies. Phase 1 (Module A) is aimed to evaluate safety (treatment emergent and related adverse events – TEAE/TRAE; dose limiting toxicity – DLT; maximum tolerated dose-MTD), pharmacokinetics, pharmacodynamics, preliminary efficacy (as per RECIST 1.1) and estimate the optimal biological dose (OBD) / recommended Phase 2 dose (RP2D). PTT-4256 is administered orally in 21-day cycles until disease progression or unacceptable toxicity. A comprehensive biomarker program is included to detect immune-related changes in blood/plasma. Results: As of 7 January 2026, 14 participants (3 ongoing) have been treated with one of 5 dose-levels (10, 20, 40, 80 and 160 mg/day). PTT-4256 was well-tolerated with no DLTs. TRAEs were reported in ten participants, with fatigue (n = 8), nausea (n = 4), rash (n = 4), reduced appetite (n = 4), vomiting (n = 2) reported in more than 1 participant. All were grade 1 or 2 except one transient episode ( < 1 day) of grade 3 hypertension. Tumor shrinkage and stable disease have been observed at doses 40mg and above in six participants, of which two (nasopharyngeal cancer and renal cell cancer (RCC)) are ongoing in treatment > 5 months. Transcriptomics and proteomics analyses show dose-dependent changes in immune-related markers in blood/plasma following PTT-4256 treatment that are consistent with preclinical data and the mode of action. Conclusions: Enrollment at dose levels ≥ 300 mg is ongoing. Phase 2 (Module B) as PTT-4256 monotherapy or in combination with anti-PD1 in RCC and head & neck squamous cell cancer (HNSCC) will commence upon identification of RP2D. Clinical trial information: NCT06634849 .

2501 Background: Despite anti-PD-1/PD-L1 therapy success, 60-70% of patients develop progression with limited options (ORR 6-8% to retreatment). Upregulation of inhibitory receptors LILRB1/2 and KIR3DL1 mediates immune escape in anti-PD-1/PD-L1-resistant tumors. IOS-1002, a novel LILRB1/2 and KIR3DL1 antagonist, restores anti-tumor immunity when combined with pembrolizumab. Methods: Open-label, multicenter, dose-escalation Phase 1a study (NCT05235308) evaluated IOS-1002 (300-1800mg, Q2W IV) plus pembrolizumab 400mg (Q6W IV) in advanced solid tumors progressing on prior anti-PD-1/PD-L1 therapy. Primary endpoints: safety, tolerability; secondary: ORR, DCR, duration of response (DOR). Comprehensive biomarker analysis included serial cytokine profiling, target receptor expression (LILRB1/2, KIR3DL1), and tumor immune score (TIS) by gene expression analysis. Responses were assessed by RECIST v1.1. Results: As of January 1st, 2026, 28 patients received combination treatment with 16 anti-PD-1/PD-L1-relapsed/refractory patients (median age 65, ECOG 0-1). 3 confirmed PRs (tumor reduction -35% to -58% from baseline) leading to an ORR of 20% (3/15 evaluable) were noted with a DCR of 54% at week 12 (7/13) and 40% at week 24 (4/10), respectively. Durable responses included: 1 metabolic CR (urothelial cancer), 1 pathological CR confirmed by repeat biopsy showing absence of viable tumor cells (cutanteous SqCC), and 1 cervical cancer patient achieving -29% tumor reduction with concomitant > 90% decline in CA-125 tumor marker. Median treatment DOR was 30+ weeks (range 12-46+); 8 patients remain on treatment. Biomarker analysis demonstrated strong predictive value for TIS and target receptor expression achieving 75% ORR (3/4) versus 0% in dual-low patients (0/5). Combined biomarker score significantly correlated with depth of response (R² = 0.72, p = 0.008) and progression-free survival (HR 0.31, 95% CI 0.11-0.88, p = 0.04). Safety profile was favorable with no increase in grade≥3 immune-related adverse events beyond pembrolizumab monotherapy. Conclusions: IOS-1002 plus pembrolizumab demonstrated clinically meaningful efficacy in pretreated anti-PD-1/PD-L1-relapsed/refractory patients. Biomarker-driven patient selection using dual-high TIS and target receptor expression enhanced ORR to 75% and strongly predicted response depth, durability, and survival benefit. The favorable safety profile with no incremental immune-related toxicity, coupled with durable responses and high disease control rates, provides compelling rationale for Phase 1b expansion in biomarker-selected PD-1/PD-L1-refractory solid tumors. Clinical trial information: NCT05235308 . Endpoint Result ORR (evaluable) 20% (3/15) DCR Week 12 54% (7/13) DCR Week 24 40% (4/10) Biomarker-selected ORR 75% (3/4) Ongoing treatment 8/16 (50%)

DATA SUPPLEMENT Adjuvant Nivolumab Versus Ipilimumab in Resected Stage III/IV Melanoma: 5-Year Efficacy and Biomarker Results From CheckMate 238

TPS904 Background: Activating FGFR3 gene alterations have been identified in up to 20% of advanced/metastatic urothelial cancers (mUC). The pan-FGFR inhibitor erdafitinib (erda) is approved for the treatment of mUC with susceptible FGFR3 genetic alterations whose disease has progressed on or after at least one line of prior systemic therapy. Since pan-FGFR inhibitors target all four isoforms of FGFR (1-4), their lack of FGFR isoform specificity can lead to off-target toxicity (e.g., hyperphosphatemia, stomatitis, ocular toxicity, skin and nail toxicity) and loss of activity due to development of on-target resistance mutations (e.g., V555M/L gatekeeper). TYRA-300 has been designed to be more selective for FGFR3 over FGFR1/2/4 to minimize off-target toxicity and to avoid interactions with known FGFR3 gatekeeper mutations. TYRA-300 is in development for the treatment of FGFR3 + mUC and other solid tumors (SURF301 - NCT05544552). Methods: SURF301 is a first-in-human, open-label, Phase 1/2 global study in several parts: dose escalation in participants with advanced malignancies, with/without FGFR3 alterations (Phase 1, Part A); dose expansion in participants with FGFR3 -activating mutations or fusions (Phase 1, Part B); and select tumor expansion cohorts with FGFR3 activating mutations or fusions (Phase 2). The purpose of Phase 1 is to evaluate the safety, tolerability, pharmacokinetics (PK), preliminary antitumor activity of TYRA-300, and identify the recommended Phase 2 dose (RP2D). Phase 2 will enroll participants in FGFR3 + mUC and other tumor types to further explore the anti-tumor activity and safety of TYRA-300. SURF301 study began enrolling patients in November 2022 and is ongoing in Australia, the United States, France, and Spain. Clinical trial information: NCT05544552 .

Constitutive YAP activation resulting from dysregulated Hippo signaling drives tumor progression in mesothelioma and other cancers. VT3989, a first-in-class potent oral TEAD palmitoylation inhibitor, disrupts YAP transcriptional activity. Here we report the first-in-human phase 1/2 trial findings evaluating VT3989 in refractory solid tumors with a focus on mesothelioma. This study is ongoing, and we report results from the dose escalation and non-prespecified interim efficacy results of the expansion cohorts for which recruitment is ongoing. Dose escalation (n = 85) and expansion (n = 87) cohorts included 172 patients (135 mesothelioma). VT3989 exhibited a favorable safety profile with mostly grade 1-2 toxicities, including increased urine albumin:creatinine ratio (UACR), proteinuria, peripheral edema and fatigue. Proteinuria was reversible with dose adjustment and did not result in renal impairment. The overall response rate (ORR) was 26% in 47 patients with mesothelioma treated at clinically optimized doses, whereas the ORR was 32% (disease control rate 86%; median progression-free survival 10 months) in 22 patients with mesothelioma when clinically optimized doses and UACR thresholds were incorporated. These data provide the first early clinical proof of concept for effectively drugging the Hippo-YAP-TEAD pathway. VT3989 was recently awarded orphan drug designation and fast-track designation for the treatment of mesothelioma by the US Food and Drug Administration (FDA). ClinicalTrials.gov Identifier: NCT04665206 .

AXA-042 is a novel, systemically delivered synthetic toll-like receptor (TLR) 2/6 agonist in development for the treatment of advanced solid tumors. A first-in-human study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of AXA-042 as monotherapy and in combination with a checkpoint inhibitor in subjects with advanced solid tumors is currently ongoing (ACTRN12622000993796). Cytometry by time-of-flight (CyTOF) analysis was performed to characterize AXA-042 immune modulation signatures in patient whole blood samples. AXA-042 was administered intravenously q21d. Informed consent was obtained and whole blood samples were collected pre-dose on C1D1, and 24h and 168h post-treatment (C1D2, C1D15) across three dose levels of AXA-042. Stabilized whole blood samples were immunophenotyped using a 43-marker CyTOF panel. In pre-dose samples, TLR2 was most frequently expressed on Monocytes (>80%), cDCs (47%) and in 20-30% of CD8, CD4 and γδ-T cell subsets. AXA-042 treatment led to the re-distribution of neutrophil, monocyte and cDC subset frequencies on C1D2, consistent with the expected acute inflammation response to a TLR2 agonist. Furthermore, AXA-042 increased the frequency of activated CD69+ cytolytic NK cells and γδ-T cells on C1D2. A general immune reset to baseline levels occurred for most populations on C1D15. Notably, a decrease in CTLA4+ Tregs and an increase in T-bet+ NK, γδ-T cells and TCF1+ CD8, CD4 T-cell subset frequencies, indicating a potential increase in Th1 polarization and preservation of effector function, was observed on C1D15 (Table 1 Table 1. Subset Frequency Timepoint Median % Change (* FDR<0.05, ** FDR<0.01) Dose Level 1 (n=6) Dose Level 2 (n=3) Dose Level 3 (n=3) ↑CD16lo Neutrophils C1D2 8.7** 38.8** 48.3 ** ↓CD16hi Neutrophils C1D2 -7.8** -37.8** -48.6 ** ↑CD44+ Neutrophils C1D2 13.2 23.6** 17.4** ↓CD39+ Monocytes C1D2 -20.1** -15.9** -29.5** ↓CD39+ cDCs C1D2 -14.9** -12.8* -5.0* ↓HLA-DR+ Monocytes C1D2 -17.5** -15.6** -0.9* ↓CD11b+ Monocytes C1D2 -8.6** -17.3* -27.3** ↑CD69+ Cytolytic NKs C1D2 10.5 36.5** 16.7** ↑CD69+ γδ-T C1D2 -0.7 * 14.4 18.2 ** ↓CTLA4+ Tregs C1D15 -2.3 * -11.1 ** -15.9 ** ↑Tbet+ Cytolytic NK C1D15 5.5* 30.5** 23.9** ↑Tbet+ γδ-T C1D15 4.4 16.2** 13.1** ↑TCF1+ CD8 TCM T cells C1D15 2.6 14.5* 12.9** ↑TCF1+ CD4 TCM T cells C1D15 0.03 14.5* 9.8** ↑TCF1+ CD8 Naïve T cells C1D15 0.42 21.1* 15.5** ↑TCF1+ CD4 Naïve T cells C1D15 5.3 15.6** 14.7** ↑HLA-DR+ ncMonocytes C1D15 -4.1 9.0* 25.9** ↑HLA-DR+ cDCs C1D15 -0.2 7.4* 32.5* ). The whole blood immunophenotyping analysis identified early pharmacodynamic markers of innate immune response engagement in response to AXA-042 and demonstrated sustained presence of Th1-polarized NK and T cell subsets with potential for enhanced cytotoxicity and effector function on C1D15. Ben Tran, Sophia Frentzas, Charlotte Rose Lemech, Michael Millward, Daphne Day, Jayesh Desai, Ardian Latifi, Paul Wabnitz, Phil Kearney, Anna V. Galkin. AXA-042, a systemically administered TLR2/6 agonist, demonstrates innate immune engagement and Th1 polarization in patients with advanced solid tumors [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 5850.

BACKGROUND:In the CheckMate 238 trial, patients with resected stage IIIB-C or stage IV melanoma who were treated with nivolumab had longer recurrence-free survival than those who received ipilimumab. Data were needed on longer-term survival. METHODS:We randomly assigned patients in a 1:1 ratio to receive an intravenous infusion of nivolumab (at a dose of 3 mg per kilogram of body weight every 2 weeks) or ipilimumab (at a dose of 10 mg per kilogram every 3 weeks for four doses, then every 12 weeks) for up to 1 year or until disease recurrence or the occurrence of unacceptable toxic effects. Randomization was stratified according to disease stage and status with respect to programmed cell death ligand 1. The primary end point was recurrence-free survival; secondary end points included overall and distant metastasis-free survival and safety. RESULTS:At a minimum follow-up of nearly 9 years (107 months), the median duration of recurrence-free survival was 61.1 months with nivolumab and 24.2 months with ipilimumab (hazard ratio for recurrence or death, 0.76; 95% confidence interval [CI], 0.63 to 0.90); 9-year recurrence-free survival was 44% and 37%, respectively. The median duration of distant metastasis-free survival in patients with stage III melanoma was more than 9 years with nivolumab and 83.8 months with ipilimumab, with 9-year survival of 54% and 48%, respectively (hazard ratio for distant metastasis or death, 0.81; 95% CI, 0.65 to 1.00). The median overall survival was more than 9 years in both trial groups, with 9-year survival of 69% in the nivolumab group and 65% in the ipilimumab group (hazard ratio for death, 0.88; 95.03% CI, 0.69 to 1.11). The rates of death from melanoma at 9 years were 26% with nivolumab and 30% with ipilimumab (hazard ratio, 0.87; 95% CI, 0.67 to 1.13). Subsequent systemic therapy was administered to fewer patients in the nivolumab group than in the ipilimumab group (37.3% vs. 44.6%). No new late adverse events were reported. CONCLUSIONS:The 9-year final data support a sustained finding of longer recurrence-free survival with nivolumab than with ipilimumab. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 238 ClinicalTrials.gov number, NCT02388906; Eudra-CT number, 2014-002351-26.).

BACKGROUND:Cell-free, circulating tumour DNA (ctDNA) is an established measure of minimal residual disease; however, it is not utilised in melanoma management. We investigated whether ctDNA measurements could predict survival outcomes during adjuvant targeted therapy or placebo treatment in stage III melanoma, thereby identifying patients at high risk and low risk of recurrence. METHODS:Analytically validated mutation-specific droplet digital PCR assays were used to measure BRAFV600E or BRAFV600K ctDNA in patients aged 18 years or older who were enrolled in the COMBI-AD trial, which was a double-blind, randomised, phase 3 study of oral dabrafenib (150 mg twice daily) plus oral trametinib (2 mg once daily) combination therapy versus two matched placebos in resected BRAFV600-mutant stage III melanoma. Patients were screened for enrolment between Jan 31, 2013, and Dec 11, 2014, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and were randomly assigned (1:1) to the two treatment groups. The primary endpoint was recurrence-free survival, and the results from final analysis have been previously published and will not be described here. Biomarker analysis was a prespecified exploratory endpoint and performed in the intention-to-treat population. We compared associations between survival outcomes and baseline (post-resection) ctDNA copies per mL, tumour mutational burden and interferon gamma (IFNG) gene expression. In a subset of patients, ctDNA quantities during follow-up or at recurrence were measured. The trial is registered with ClinicalTrials.gov, NCT01682083, and has been completed. FINDINGS:Baseline plasma samples were available for 597 of 870 patients (331 male patients and 266 female patients) and samples for assessing the ctDNA positivity rate at landmark follow-up timepoints of 3 months, 6 months, 9 months, and 12 months after treatment initiation were available for 94 of 870 patients. Additionally, samples were available from 118 of 870 patients within a 2-month timeframe before or after clinical or radiographic recurrence. Median follow-up for the biomarker analyses was 60 months (IQR 39-66) in the combination therapy group and 58 months (21-66) for the placebo group. ctDNA was detectable in 79 (13%) of 597 baseline samples. ctDNA positivity rate and mutant copies per mL plasma were significantly higher in patients with higher disease substages. As a binary variable, ctDNA detection was associated with worse recurrence-free survival (placebo group: median 3·71 months [95% CI 2·39-6·89] vs 24·41 months [17·28-43·13]; hazard ratio [HR] 2·91 [95% CI 1·99-4·25], p<0·0001); combination therapy group: median 16·59 months [95% CI 12·02-26·80] vs 68·11 months [50·36-not reached]; HR 2·98 [1·95-4·54], p<0·0001) and overall survival (placebo group: median 33·90 months [13·96-not reached] vs not reached; HR 3·35 [2·01-5·55], p<0·0001); combination therapy group: median 40·31 months [24·90-not reached] vs not reached; HR 4·27 [2·50-7·27], p<0·0001) in the placebo group and combination therapy groups. Baseline ctDNA was more strongly associated with survival outcomes than IFNG gene expression or tumour mutational burden. Patients with adverse longitudinal ctDNA kinetics (molecular relapse or persistently positive) had markedly shorter median recurrence-free survival (8·31 months [95% CI 5·39-12·20] and 5·32 months [2·79-not reached], respectively) compared with patients with favourable kinetics (ie, undetectable after positive baseline result: 19·25 months [16·39-not reached]; and durable undetectable: not reached [38·44-not reached], p<0·0001). INTERPRETATION:Droplet digital PCR measurements of ctDNA to assess minimal residual disease before adjuvant targeted therapy and during follow-up can identify patients at high risk of early recurrence. Additional studies using ctDNA measurements to guide therapeutic interventions might lead to improvements in the management of resected stage III melanoma. FUNDING:Novartis.

INTRODUCTION:Metastatic melanoma carries a poor prognosis. Immune checkpoint inhibitors (ICIs) have improved outcomes, but responses remain variable, highlighting the need for simple prognostic biomarkers. Inflammatory markers such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lactate dehydrogenase (LDH) reflect tumour burden and inflammation, though their clinical utility is unstandardised. METHODS:We retrospectively analysed 103 metastatic melanoma patients treated with anti-PD-1 monotherapy at two centres in Western Australia (2014-2020). Baseline NLR, PLR, and LDH were assessed within 30 days pre-treatment. Outcomes included clinical benefit, progression-free survival (PFS), and overall survival (OS). RESULTS:Poor ECOG performance status (PS ≥2) (RR 2.39, 95% CI 1.48-3.86) and elevated LDH (≥250 U/L) (RR 1.68, 95% CI 1.21-2.31) were associated with no clinical benefit (p < 0.001). NLR ≥5 predicted significantly worse OS (9.1 vs 28.2 months; HR 8.54, 95% CI 2.58-28.32; p < 0.001). Elevated LDH predicted shorter OS (6.0 vs 50.3 months; HR 3.68, 95% CI 1.65-8.21; p = 0.002) and PFS (19.0 months vs not reached; HR 2.51, 95% CI 1.37-4.72; p = 0.004). CONCLUSION:ECOG PS ≥2 and elevated NLR were associated with no clinical benefit, while elevated NLR and LDH independently predicted poorer survival. These markers may serve as practical prognostic tools in metastatic melanoma treated with ICIs.