All treatment-emergent adverse events

TPS2677 Background: Nivolumab/ipilimumab is standard of care for advanced melanoma patients based on Phase III randomized data from the CheckMate 067 trial. The recent 10-year outcomes results were reported with a melanoma specific survival for Nivolumab/ipilimumab of 52%. These data are very encouraging, but 50% of patients still succumb to their disease by 10-years. Preclinical data suggests that the circadian rhythm may influence the anatomic localization, function and activity of T cells, the target of immunotherapy. More T cells in the tumor or tumor-draining lymph node during initial immunotherapy administration may improve clinical responses and long-term outcomes. To investigate this idea, we performed a retrospective analysis, the MEMOIR study, finding that more evening infusions of immunotherapy were associated with significantly worse progression free and overall survival for metastatic melanoma patients. These findings have now been reproduced in other cancer histologies, in a larger meta-analysis, and in pre-clinical mechanistic studies. Considering these data, we hypothesize that evening infusions of immunotherapy will have worse progression free survival than either morning or midday infusions. Methods: The TIME trial is a three-arm phase II study of time-of-day specified administration of standard dose nivolumab/ipilimumab for metastatic melanoma. For newly diagnosed metastatic melanoma patients enrolled on study, they will be randomized to receive 4 cycles every 3 weeks of nivolumab/ipilimumab between 8:00-11:00 (Arm A), 11:00-14:00 (Arm B), or 14:00-17:00 (Arm C). Following these 4 cycles, they will receive standard of care maintenance nivolumab in a time-of-day agnostic fashion. Eligible patients must have stage IV unresectable cutaneous, acral or mucosal melanoma, no prior immunotherapy within 1 year, ECOG performance status of 0-1, age ≥ 18, no symptomatic or hemorrhagic brain metastases with none greater than 2 cm. The primary objective is to determine whether progression free survival for Arm A or Arm B is superior to Arm C. Secondary objectives include assessments of adverse events, melanoma specific survival and overall survival. We will evaluate the immune profiles of blood and tumor to assess the impact of time of drug administration on the circulating immune responses and the tumor immune microenvironment. 99 patients will be enrolled to detect a HR of 0.50 with at least 80% power and a Type 1 error rate of 0.1 (2-sided) for a comparison of A vs. C, and B vs. C. The study is open at Emory and has enrolled 3 patients; the study is undergoing regulatory review at MGH and Cedars-Sinai. Clinical trial information: NCT07155317 .

PURPOSE:MEDI1191 is a lipid nanoparticle-formulated mRNA designed to induce local interleukin-12 production and intensify antitumor T cell responses. We report dose-escalation results from a first-in-human, open-label, phase I study of intratumoral MEDI1191 plus intravenous durvalumab (NCT03946800). METHODS:Patients were ≥18 years with advanced/metastatic solid tumors and had progressed on ≥1 line of prior therapy (immunotherapy permitted). Cutaneous/subcutaneous (Parts 1A and 1B) or deep-seated lesions (Part 1D) were injected; patients had ≥1 noninjected lesions measurable per RECIST v1.1. Target lesions were noninjected. MEDI1191 and durvalumab were given sequentially (Part 1A) or concurrently (Parts 1B and 1D). Primary objectives were safety and determination of maximum tolerated dose (MTD). Secondary objectives included efficacy. RESULTS:As of February 27, 2023, 61 patients were treated. Patients had a median of 4 prior regimens (range, 1-17); 39 (63.9%) received prior anti-PD-(L)1 immunotherapy. Treatment-emergent adverse events (TEAEs) occurred in 96.7% of patients and 41.0% experienced Grade 3/4 TEAEs. There were no dose-limiting toxicities. The MTD was not reached. Objective response rate was 9.8%, including 1 confirmed complete response and 5 confirmed partial responses (PRs). Duration of response was 2.7-22.3 months; median was not reached. Responses occurred in injected lesions, local noninjected lesions, and distant lesions. Three of the 39 patients with prior anti-PD-(L)1 therapy had PRs. CONCLUSIONS:MEDI1191 and durvalumab were tolerated. Preliminary antitumor activity was encouraging in these heavily pretreated patients, including patients previously treated with immune checkpoint inhibitors.

Abstract Background Adjuvant treatment with PD-1 inhibitors for 12 months has been the established standard of care for patients with resected stage IIB-IV cutaneous melanoma. In other solid tumours (e.g. breast and colorectal), a shorter duration of adjuvant chemotherapy has been shown to be non-inferior with improved toxicity profile. More recently, neoadjuvant immunotherapy with immune checkpoint inhibitors for clinically detectable stage III and stage IV disease has been introduced. There is no clear biological rationale for the chosen duration, and no studies have investigated duration of adjuvant treatment with immune checkpoint inhibitors. A reduced duration of adjuvant therapy could lead to less toxicity from reduced drug exposure, patients returning to normal life sooner, significantly lower drug costs and better healthcare resource utilization. There remains significant interest from patients and clinicians to address this important question. Methods Grand SLAM is a prospective phase III randomised, controlled international multi-centre non-inferiority study. The primary objective is to investigate if short (6 months) has equal efficacy as long (12 months) duration of (neo-)adjuvant immune checkpoint inhibition in relation to distant metastasis-free survival and relapse-free survival at landmark analysis at 2 years. After radical surgery of stage IIB-C, III or IV cutaneous melanoma, patients are randomly assigned 1:1 to short or long adjuvant treatment with either nivolumab or pembrolizumab. Patients who have received neoadjuvant treatment with major pathological response are excluded. The sample size of 1,880 patients was determined based on a non-inferiority margin of 4%, a significance level of 0.045 and 80% statistical power. An interim analysis will be conducted when 2/3 of patients are accrued. Biomarkers and the role of food supplements for relapse (MelKo) will be investigated in prespecified substudies. Discussion This is the first randomised study to assess a shorter duration of adjuvant anti PD-1 antibody in cutaneous melanoma patients. As of March 2026, the study is recruiting patients in the Nordic countries. Centres in other countries will open shortly. Trial registration NCT06488482. Date of registration: 2024-06-10.

Taxonomic differences from baseline between treatment arms at after antibiotic preconditioning and at C1D1

2634 Background: Checkpoint blockade achieves durable long term responses in about 30-50% of patients with malignant melanoma (MM). However, a substantial proportion of patients either fail to respond or develop resistance after initial response. As a result, many MM patients undergo multiple sequential immunotherapeutic treatments in an attempt to achieve clinical benefit. However, the effects of repeated rounds of immunotherapy on the immune system remain poorly understood. We herein report that prior anti-CTLA-4 blockade within 12 months of analysis associated with a hyperactive immunosuppressive immune signature involving IL-6, in 24 patients with anti-PD-1 refractory metastatic MM enrolled in a Phase I/II trial. Methods: The patients received continued checkpoint inhibition with an anti-PD-L1 antibody in combination with an immunostimulatory gene therapy based on replication-competent adenovirus targeting the CD40 and 4-1BB pathways (LOKON003, NCT04123470). Using unsupervised clustering, plasma biomarker profiles at baseline and post treatment initiation was evaluated and correlated to clinical parameters. Results: Two plasma protein profiles were identified at baseline among enrolled patients and one of those included immunosuppressive biomarkers. While patients with this hyperactive immunosuppressive signature (n=8) at baseline experienced a median overall survival (mOS) of 4.0 months, patients without this baseline signature (n=15) had a mOS of 28.1 months. The hyperactive immunosuppressive signature was not related to M1 status, sex, age, or number of prior treatments, but prior anti-CTLA-4 treatment within a year of enrollment was more prevalent in patients with this signature. If dividing the patients only based on receiving anti-CTLA-4 therapy within 12 months (n=10) versus later or not at all (n=14), mOS was 5.3 and 30.7 months, respectively. Patients that had received recent anti-CTLA-4 treatment, presented with a plasma protein signature resembling the hyperactive immunosuppressive signature with IL-6 as a central node among the upregulated proteins. Patients who did not receive anti-CTLA-4 blockade during the past 12 months responded to the combination of the immunostimulatory gene therapy and continued checkpoint blockade with upregulation of biomarkers associated with T cell activation and cell killing capacity, which may have supported the better survival outcome in this patient group. Conclusions: The findings highlight the need for further clinical evaluation of the consequences of repeated immunotherapeutic treatments, IL-6 inhibition in this population, and consideration for a wash-out period from further immunotherapy to allow for immune system recovery post anti-CTLA-4 treatment. Clinical trial information: NCT04123470 .

CD8 intra-tumoral infiltration percentage by IHC

PURPOSE:IMC-C103C is an ImmTAC bispecific (MAGE-A4×CD3) T cell engager targeting a peptide from the cancer-testis antigen MAGE-A4 presented by HLA-A*02:01. This phase 1/2 study in advanced solid tumors (IMC-C103C-101; NCT03973333) investigated the safety and preliminary anti-tumor activity of IMC-C103C. METHODS:HLA-A*02:01+ patients with previously treated advanced solid tumors received IMC-C103C by weekly intravenous infusion, with step-up dosing introduced at higher dose levels. Dose-escalation decisions were guided by the mTPI-2 method. Key objectives included evaluating safety and preliminary anti-tumor activity; pharmacokinetics, pharmacodynamics, and biomarkers were also assessed. RESULTS:68 patients were enrolled in 10 dose-escalation cohorts (n=56; 64% ovarian carcinoma (OC)) and one OC expansion cohort (n=12). In dose escalation, patients received doses ranging from 0.5 to 240 µg. The dose-limiting toxicity rate at the two highest dose levels (1/6 and 2/10) did not exceed the maximum tolerated dose. A lower-dose regimen of 15-45-140 µg, with clinical activity, and a more favorable tolerability profile, was selected as the expansion dose. There were no treatment-related discontinuations or deaths. The most common treatment-related adverse events were cytokine-mediated, including grade 1/2 cytokine release syndrome and associated symptoms. While MAGE-A4 expression was observed in most patient's tumors (71% positive), the level of expression was low (median H-score=16). Initial clinical and pharmacodynamic activity was observed at doses of 15 µg, with more consistent activity observed at doses ≥90 µg. At doses ≥90 µg, patients with MAGE-A4+ OC had deeper reductions in tumor size and circulating tumor DNA and trended to have longer overall survival than patients with MAGE-A4- OC. CONCLUSIONS:IMC-C103C was well tolerated at doses up to 140 µg, induced dose-dependent pharmacodynamic changes, and demonstrated clinical activity in multiple patients with MAGE-A4+ solid tumors. Clinical activity was dependent on MAGE-A4 expression; however, expression was especially low in the higher dosing cohorts, limiting adequate efficacy assessment. TRIAL REGISTRATION NUMBER:NCT03973333.

9527 Background: Brenetafusp (brene) is an ImmTAC bispecific (PRAME × CD3) therapy that promotes T cell recruitment into tumors. Initial Phase (Ph) 1 data showed acceptable safety, robust T cell activation at target doses (TD) ≥ 20 mcg and promising clinical activity in multiple tumors including heavily pretreated cutaneous melanoma (CM) (Hamid 2022, 2024; NCT04262466]). We present updated monotherapy (mono) and PD1 immune checkpoint inhibitor (ICI) combination (combo) safety and efficacy results supporting brene dose selection in Mel (CM, mucosal [Mu] or acral [Ac]). Methods: HLA-A*02:01+ Mel patients (pts) who exhausted standard treatments were eligible. Primary objectives: safety and recommended dose; additional objectives included efficacy, biomarkers and ctDNA response. Brene mono was administered intravenously weekly (QW) with 1-2 step-up doses to TD; TD 40 and 160 mcg were evaluated in expansion. Combo was 160 mcg brene QW + 400 mg pembrolizumab (pembro) Q6W. Molecular response: ≥ 0.5 log [68%] ctDNA reduction by week 9 (Hamid 2024). T cell fitness defined as 3-gene (TESPA1, CD28 and GPR183) signature in blood (Sacco 2024). Tumor PD-L1 measured by immunohistochemistry, beta2 microglobulin (B2m) by immunofluorescence. Results: As of Oct 2025, 66 pts with Mel (median 2.5 prior lines, 100% prior PD1, 30% PD1 refractory [progression <6 mo post start of first anti-PD1], 68% St IV-c/IV-d) received brene mono (TD 40, n=16; TD 160, n=24; other TD 10-320 mcg, n=26). The 40-mcg cohort had more favorable baseline prognostic factors (ECOG PS, tumor burden, ctDNA, prior treatment) and T cell fitness. Ten pts (median 2.5 prior lines, 90% prior PD1, 50% prior BRAF/MEKi, 70% St IV-c/IV-d) received brene + pembro. Safety was similar at TD 40 and 160 mcg with Gr1/2 CRS (56% vs 42%) and rash (44% vs 42%) initially. Gr3/4 events occurred in 25% vs 54%: mainly transient lymphocyte decrease, consistent with mechanism. Of 10 pts with prior ICI Gr3/4 irAE, none had recurrence. Combo profile resembled each agent alone. No new safety signals observed. Disease control, RECISTv1.1 response and ctDNA molecular response rates were numerically higher at 160 vs 40 mcg (Table), with similar rates across subgroups typically less responsive to anti-PD1. Overall survival was associated with baseline T cell fitness and tumor B2m, but not with PD-L1 status. Conclusions: Brene shows promising monotherapy activity in late-line Mel, including difficult to treat populations, without causing ICI-like irAEs, and can be safely combined with pembro. Ph1 results support 160 mcg as the selected dose in the Ph3 PRISM-MEL trial evaluating brene with nivolumab versus standard nivolumab regimens (NCT06112314). Clinical trial information: NCT04262466 . N DCR% (PR + SD) ORR% 6mo OS% ctDNA-evaluableN ctDNA response% Brene mono 66 52 12 83 50 38 40 mcg 16 56 6 81 10 20 160 mcg 24 67 17 79 15 33 PD1 refractory 20 55 10 70 15 53 Ac / Mu 7 57 14 86 5 40 Sum target lesions >10 cm 25 44 12 80 19 32 Brene + pembro 10 70 20 80 5 40 PD1 refractory 6 67 33 67 2 50

Peripheral Treg populations of interest by baseline Ruminococcaceae status prior to initiating anti-PD1 therapy

Abstract Introduction: IGSF8 (Immunoglobulin superfamily member 8) is a novel immune checkpoint that regulates both natural killer (NK) cell cytotoxicity and dendritic cell (DC)-mediated antigen presentation. GV20-0251, an artificial intelligence-designed antibody targeting IGSF8, is being evaluated in a Phase 1/2a clinical trial (NCT05669430) for metastatic solid tumors. Here, we report pharmacodynamic evaluation and potential predictive biomarkers from the monotherapy dose-escalation cohort. Methods: Target engagement and modulation were measured by flow cytometry on circulating CD3+ T cells. Pre- and on-treatment tumor tissues were assessed for IGSF8 expression and immune regulation by immunohistochemistry (IHC) and RNA-seq. IGSF8 expression in human tumors was examined using RNA-seq data from The Cancer Genome Atlas (TCGA) and IHC on tumor microarrays. Clinical response was evaluated per RECIST v1.1. Results: Forty-two participants were enrolled in this first-in-human monotherapy dose-escalation study. Among 16 evaluable cutaneous melanoma patients who had relapsed following prior anti-PD-1 treatment, three confirmed partial responses were observed. Target occupancy analysis demonstrated saturated IGSF8 binding by GV20-0251 on circulating T cells at doses ≥3 mg/kg. Treatment resulted in rapid reduction of IGSF8 cell surface expression on both circulating T cells and malignant cells within tumor tissues. IHC analysis of five paired tumor biopsies showed increased intratumoral infiltration of CD56+ NK cells and CD8+ T cells following treatment. RNA-seq of four paired melanoma tissues revealed immune cell infiltration, antigen presentation, and NK cytotoxicity as the top upregulated pathways post-treatment. Analysis of pretreatment tumors (n=10) revealed that patients achieving clinical benefit (partial response or stable disease) had higher IGSF8 RNA and membrane protein expression. In contrast, no objective response was observed in tumors with low or absent IGSF8 expression. TCGA database analysis demonstrated significant IGSF8 upregulation across multiple tumor types, including melanoma, hepatocellular carcinoma, and lung cancer. IHC examination of tissue microarrays further confirmed high IGSF8 positivity in these tumor types, all of which present high unmet medical needs. Conclusion: Pharmacodynamic analyses confirmed complete target occupancy at pharmacologically active doses with robust target modulation, leading to enhanced antigen presentation coupled with NK and CD8+ T cell infiltration. Preliminary data suggest a relationship between IGSF8 expression on cancer cells and clinical benefit, warranting further investigation. Collectively, these results provide proof-of-mechanism for GV20-0251 as a novel cancer immunotherapy and establish a potential biomarker strategy for further clinical development. Citation Format: Xingfeng Bao, Caibin Sheng, Inderjit Mehmi, Julio A. Peguero, Shivaani Kummar, Patricia LoRusso, Janice M. Mehnert, Aung Naing, Alexander I. Spira, Justin F. Gainor, Omid Hamid, Justin T. Moyers, Jin Wang, Xihao Wu, Hong Xiao, X. Shirley Liu, Tengfei Xiao, Kristopher Wentzel. Evaluation of pharmacodynamic and potential predictive biomarkers for GV20-0251, an anti-IGSF8 antibody, as monotherapy from ongoing Phase 1/2a study [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 CT001.

Abstract Background: Immune checkpoint blockade (ICB) has transformed cancer therapy, yet only a subset of patients benefit, underscoring the need for robust, generalizable biomarkers capable of identifying tumors with sufficient immune activation. Although numerous immune-related gene signatures and transcriptomic approaches have been proposed, most lack pan-cancer robustness and fail to generalize across independent cohorts. To address this gap, we derived TIME_ACT, an unsupervised 66-gene tumor immune activation (“hotness”) signature that integrates immune infiltration, inflammatory activity, and spatial TIL density. This signature accurately predicts tumor hotness across diverse cancer types, forming a robust pan-cancer measure of immune activation. Methods: TIME_ACT was evaluated across 22 publicly available pre-treatment ICB transcriptomic cohorts (n=1,416) spanning seven cancer types. To enable prediction from pathology, TIME_ACT scores were inferred from H&E slides using Path2Omics, a recently published deep-learning model trained on TCGA, and validated in nine new histopathology cohorts from different medical centers and populations (n=459). Results: TIME_ACT accurately identifies immune-hot tumors across eight TCGA cancer types (AUC 0.96-1.00) and two external datasets (AUC 0.96-0.98). TIME_ACT genes were consistently enriched in T cells, B cells, and dendritic cells at single-cell resolution. Spatial analyses shows that TIME_ACT-high regions co-localize with lymphocyte-dense niches adjacent to the tumor epithelium. Across 22 transcriptomic ICB cohorts, TIME_ACT robustly predicted response (mean AUC 0.74; mean OR 5.49). Importantly, histopathology-inferred TIME_ACT scores achieve strong performance across nine multi-centric cohorts (mean AUC 0.73; mean OR 5.07), matching transcriptomic-based prediction levels and importantly, outperforming direct slide-based models. Conclusions: TIME_ACT is a robust pan-cancer tumor immune activation signature that predicts ICB response directly from the readily available tumor pathology slides. Upon further prospective testing and validation, it offers an exciting new way for further democratizing precision immunotherapy. Citation Format: Danh-Tai Hoang, Sumit Mukherjee, Sumeet Patiyal, Lipika R. Pal, Tiangen Chang, Sumona Biswas, Saugato Rahman Dhruba, Amos Stemmer, Arashdeep Singh, Abbas Yousefi-Rad, Tien-Hua Chen, Binbin Wang, Denis Marino, Wonwoo Shon, Yuan Yuan, Mark Faries, Omid Hamid, Karen Reckamp, Barliz Waissengrin, Beatriz Ornelas, Keluo Yao, Pen-Yuan Chu, Lisa Ley, Dilara Akbulut, Nourhan El Ahmar, Sabina Signoretti, David Alexander Braun, Joo Sang Lee, Hyunjeong Joo, Hyungsoo Kim, Arsen Osipov, Robert A. Figlin, Jair Bar, Iris Barshack, Chi-Ping Day, Sridhar Hannenhalli, Karine Sargsyan, Andrea B. Apolo, Kenneth D. Aldape, Muh-Hwa Yang, Michael B. Atkins, Ze’ev A. Ronai, Eytan Ruppin. Pan-cancer prediction of response to immune checkpoint blockade from histopathology [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 3999.

TTFields have current FDA approval in GBM, NSCLC, and MPM that is refractory to frontline therapies. TTFields have also been shown to induce immunogenic cell death in vitro. Given the limited benefit of IpiNivo in mUM, we performed a signal seeking study of TTFields with IpiNivo in patients with refractory mUM. Patients with liver predominant mUM were treated with standard Ipi3Nivo1 dosing. After the first infusion, TTField arrays were placed for direct hepatic treatment with 200kHZ of alternating electric fields using the NovoTTF-200(O) device (>/= 18 hours daily); with imaging every 12 weeks for efficacy assessment. Fresh tissue and blood samples were collected for correlative work. 10 patients were enrolled. Patients were predominately Male (60%) with an ECOG of 0 (70%) and a median age of 60 and LDH of 575. The average number of prior lines of therapy was 1.5 with 70% of patients having prior checkpoint inhibitors (50% prior IpiNivo). Treatment was tolerated well with expected toxicity from IpiNivo. Rash due to TTFields was seen in 50% of patients with maximum severity of grade 2. A single partial response (10% ORR) was noted in one patient who had 5 prior lines of therapy, including IpiNivo without prior benefit. Four of five patients evaluable for ctDNA had at least a 0.5 log reduction with treatment, with one patient having full clearance of ctDNA. Median PFS and OS were 2.0 and 10 months for all patients. A PFS of 21 months was seen in one patient, who had previously progressed on two prior lines of therapy including immune checkpoint inhibitor and elected to come off study treatment after 1 cycle due to side effects from IpiNivo. Higher baseline peripheral interferon gamma levels were seen in patients who had PR or SD on imaging, while higher osteopontin levels were seen in patients who had PD. Following treatment, increases in macrophage and T-cell proportions were seen in two of the three patients with paired biopsy samples. Longer PFS was also seen in these patients. Additionally, increase in metabolic enzyme expression for mitochondrial metabolism and a corresponding decrease in glycolytic enzyme expression in macrophages and T-cells was seen after treatment. Overall, signs of clinical benefit from TTFields with IpiNivo were seen in this refractory and high disease burden patient population without signs of unexpected toxicity. Spatial transcriptomic data will be presented in the full presentation. Justin C. Moser, Joseph Lownik, Michael Gordon, Daniel Mocan, Chase Venable, Villamejor Anton, Ying Li, Sunil Sharma, Alexis Larsen, Justin Moyers, Omid Hamid, Akil Merchant, Inderjit Mehmi. Single Arm Pilot Study of Tumor Treating Fields (TTFields) with Nivolumab and Ipilimumab (IpiNivo) in Patients with Metastatic Uveal Melanoma (mUM) [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A026.

Primary analysis of KEYNOTE-942 (ClinicalTrials.gov identifier: NCT03897881 ) demonstrated prolonged recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) for the individualized neoantigen therapy intismeran autogene (intismeran; formerly mRNA-4157 or V940) with pembrolizumab versus pembrolizumab alone in high-risk resected melanoma. This update provides an additional year of follow-up to assess longer-term efficacy/safety. KEYNOTE-942 is a phase IIb study in patients with completely resected high-risk (stage IIIB to IV) cutaneous melanoma who were randomly assigned to receive either intismeran plus pembrolizumab or pembrolizumab alone. The primary end point was RFS; secondary end points included DMFS and safety/tolerability. Overall survival and biomarker data were exploratory. With a median follow-up of approximately 3 years, and a minimum of approximately 2 years (median [range] 34.9 [25.1-51.0] months), the combination continued to demonstrate improvement in RFS (hazard ratio [HR], 0.510 [80% CI, 0.351 to 0.743]) and DMFS (HR, 0.384 [80% CI, 0.227 to 0.650]) compared with pembrolizumab. The safety profile was consistent with earlier findings. Most adverse events (AEs) were low-grade, with serious AEs, immune-related AEs, and grade 3/4 events comparable between the arms and no grade 4/5 events related to intismeran. Intismeran plus pembrolizumab significantly prolongs RFS and DMFS compared with pembrolizumab alone for the adjuvant treatment of resected high-risk melanoma.

Assessment of gut microbiome networks by treatment arm and across timepoints

Tebentafusp (IMCgp100, Kimmtrak) is a first-in-class Immune mobilizing monoclonal T-cell receptors against cancer (ImmTAC). ImmTAC are fusion proteins comprising an affinity-enhanced soluble T-cell receptor (TCR) against a specific peptide-HLA complex and an anti-CD3 single-chain variable fragment (scFv). Tebentafusp binds gp100(280-288) peptide from the melanocyte lineage-specific protein Glycoprotein 100 presented by HLA-A*02:01; concurrently, it engages CD3 on polyclonal T-cells leading to T-cell activation, and melanoma cell lysis. In the phase III IMCgp100-202 trial, tebentafusp significantly improved overall-survival versus investigator's choice, establishing it as a first-line treatment for HLA-A*02:01-positive advanced uveal melanoma. The safety profile is characterized by predictable on-target effects, mainly cytokine release syndrome and skin reactions, both diminishing over time. Tebentafusp validated ImmTAC as a novel class of TCR-based biologics targeting intracellular antigens. Ongoing research explores tebentafusp in other settings, including cutaneous melanoma. Other ImmTACs, e.g. brenetefusp is being developed, underscoring the potential of this modality in cancer immunotherapy.

Progression-free survival in a retrospective melanoma immunotherapy cohort by baseline Ruminococcaceae status

Summary of clinical response by treatment arm and baseline Ruminococcaceae group

Disease control and objective response rates by Ruminococcaceae status