The Society for Immunotherapy of Cancer (SITC) is pleased to present highlights of the latest advances in immunotherapy emerging from the ESMO Congress 2024. Below is a recap of highlighted research presented on Sunday, Sept. 15, 2024 and Monday, Sept.16, 2024.
2024 Scientific Highlights
Post-hoc analysis of pre-treatment samples from CheckMate 9ER to identify serum glycoproteomic predictive and prognostic biomarkers for advanced renal cell carcinoma
1694MO. Novel serum glycoproteomic biomarkers predict response to Nivolumab plus Cabozantinib (NIVO+CABO) versus Sunitinib (SUN) in advanced RCC (aRCC): analysis from CheckMate 9ER
David A. Braun (Yale University School of Medicine, New Haven, CT, United States of America) presented post-hoc exploratory predictive biomarker analysis of the CheckMate 9ER study, which indicated nivolumab plus cabozantinib (nivo + cabo) can maintain long-term clinical benefits over sunitinib for the treatment of advanced renal cell carcinoma (aRCC). This analysis focused on the association of site-specific glycopeptide modifications with response to nivo + cabo or suni using pre-treatment serum samples. Prior studies indicate that changes in protein glycosylation patterns are indicative of malignancy and are associated with tumor proliferation, resistance to cell death, angiogenesis and immune escape. CheckMate 9ER involved 951 patients with aRCC who were randomized 1:1 to receive nivo + cabo or suni. Analysis of 189 pre-treatment serum samples from patients treated with nivo + cabo or suni identified 24 serum glycopeptides associated with PFS or OS with nivo + cabo. Samples with high levels of sialylation and fucosylation of N-glycopeptides were associated with poor response to nivo + cabo and suni, reinforcing prior studies in melanoma. Glycoproteins involved in the complement system exhibited potential predictive power of response to nivo + cabo. For example, high levels of complement protein 3 (CO3) glycopeptide were associated with improved progression free survival (PFS) if treated with nivo + cabo compared to suni. Conversely, high levels of glycosylated complement factor H (CFAH), a negative regulator of the complement pathway correlated with lower PFS after treatment with nivo + cabo. Similar patterns were observed in analysis of glycoproteins involved in lipid metabolism. These preliminary data suggest fucosylation and sialyation of serum proteins may be associated with resistance to nivo + cabo or suni for aRCC. Furthermore, serum glycoproteins involved in complement signaling and lipid metabolism may be predictors of response to nivo + cabo compared to suni. More clinical studies are needed to confirm, validate, and further characterize the prognostic and predictive potential of these glycopeptide-based biomarkers.
ctDNA clearance as a predictive biomarker for pathologic response to perioperative durvalumab for resectable non-small cell lung cancer
LBA49. Associations of ctDNA clearance (CL) during neoadjuvant Tx with pathological response and event-free survival (EFS) in pts with resectable NSCLC (R-NSCLC): expanded analyses from AEGEAN
Martin Reck (German Center for Lung Research, Grosshansdorf, Germany) reported expanded analysis of AEGEAN, a phase 3 clinical trial that previously indicated perioperative durvalumab combined with neoadjuvant chemotherapy significantly improved event free survival and response rates in patients with resectable NSCLC. This study investigated the associations of circulating tumor DNA (ctDNA) clearance during neoadjuvant treatment with pathologic complete response (pCR), major pathologic response (MPR), EFS, and overall survival (OS). Prior analyses have indicated ctDNA clearance during neoadjuvant treatment was associated with pCR or MPR. ctDNA was evaluated from 1268 neoadjuvant samples (multiple time points) and 168 adjuvant samples representing 142 patients with resectable NSCLC who received perioperative durvalumab combined with 4 cycles of neoadjuvant chemotherapy (durvalumab arm) and 141 patients from the placebo arm who received 4 cycles of neoadjuvant chemotherapy. ctDNA clearance was associated with pathologic response. Among patients who were ctDNA-positive at baseline in both arms, all patients who had a pCR and over 93% of patients who had an MPR exhibited ctDNA clearance by cycle 4 of neoadjuvant treatment. Absence of early ctDNA clearance correlated with a low probability of a patient achieving a pCR (non-predictive value of 100% at cycle 4 of neoadjuvant therapy), while patients who achieved ctDNA clearance were more likely to have a pCR if treated with durvalumab compared to the placebo (positive predictive value 49% vs 11% at cycle 2). Early ctDNA clearance also identified patients with improved EFS, which was more pronounced in the durvalumab arm. Patients with ctDNA clearance pre-surgery had improved EFS outcomes in both treatment arms, and patients in the durvalumab arm exhibited longer periods of EFS, regardless of ctDNA clearance. Patients in the durvalumab arm with ctDNA clearance had longer EFS and OS compared to patients without ctDNA clearance and to patients in the placebo arm. In both treatment arms, patients with no ctDNA clearance and no pCR had the poorest outcomes, while patients with ctDNA clearance regardless of pCR status had longer EFS than patients with no ctDNA clearance and no pCR. Among patients who completed surgery, patients with detectable ctDNA had the poorest outcomes compared to ctDNA-negative patients in both treatment arms. These data indicate that lack of early ctDNA clearance may identify patients who are not likely to achieve a pCR. Pre-surgery ctDNA clearance and pCR have potential as surrogate endpoints of long-term clinical outcomes, and further study is needed to validate and further characterize these associations.
Safety and efficacy of CLDN6-targeting CAR T cells alone or in combination with a CLDN6-encoding mRNA vaccine for relapsed/refractory solid tumors
611O. Updated results from BNT211-01 (NCT04503278), an ongoing, first-in-human, Phase 1 study evaluating safety and efficacy of CLDN6 CAR T cells and a CLDN6-encoding mRNA vaccine in patients with relapsed/refractory CLDN6+ solid tumors
John B. A. G. Haanen (Netherlands Cancer Institute, Amsterdam, Netherlands) presented updated results from BNT211-01, an ongoing first in-human study of chimeric antigen receptor (CAR) T cells targeting the oncofetal antigen claudin 6 (CLDN6) in combination with a CLDN6-encoding RNA vaccine (CARVac) for relapsed/refractory (r/r) solid tumors. CLDN6 is expressed in many solid tumors but absent in healthy adult tissues, making it a potential target for cancer immunotherapies. Previous studies of CLDN6 CAR T cells that were manufactured by a manual process indicate the CAR T cells exhibit promising anti-tumor activity against CLDN6-expressing r/r tumors. In BNT211-01, 78 patients underwent lymphodepletion and received CAR T cells at five dose levels (DL) with or without repeat dosing of CARVac. 26 patients received CAR T cells alone, and 52 patients received CAR T cells in combination with CARVac. 30 patients in the study had testicular cancer, 31 patients had ovarian cancer, while the remainder had one of many solid tumor histologies. Toxicities were dependent on CAR T cell dosing, and CAR T cell associated adverse events were consistent with previous reports of CAR T cell therapies. Of the 52 cases of cytokine release syndrome, 50 were Grades 1 or 2, and all cases were manageable. 3 patients experienced neurotoxicity, and all were Grades 1 or 2. 74 patients were included in response analysis. Overall response rate (ORR) was 32.8%, with 3 patients (4.1%) achieving a complete response and 18 patients (24.3%) achieving a partial response. The disease control rate was 67.2%. Among patients who received 100% lymphodepletion and DL2 of CAR T cells(1 x 108 cells) or higher, ORR was 51.5%, and DCR was 84.8%. Treatment exhibited encouraging activity across all tumor types, including testicular tumors and ovarian tumors, with ORR of 41.7% and 58.3% among patients who received 100% lymphodepletion and DL2 or higher of CAR T cells. Addition of CARVac to treatment improved persistence of CAR T cells with CAR T cells persistence of over 100 days in 25% of patients who received CARVac in combination with CAR T cells. This level of CAR T cell persistence was not observed in patients who received CAR T cells alone. These preliminary results indicate that CLDN6-targeting CAR T cells alone or in combination with CARVac is well-tolerated and is associated with encouraging levels of anti-tumor activity across a variety of r/r tumors. Follow-up for BNT211-01 is ongoing, and the safety and efficacy of higher doses of CAR T cells + CARVac will be reported in the future.
Final overall survival data of KEYNOTE-522: Perioperative pembrolizumab for high-risk, early-stage triple negative breast cancer
LBA4. Neoadjuvant pembrolizumab or placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo for high-risk early-stage TNBC: Overall survival results from the phase 3 KEYNOTE-522 study
Peter Schmid (Barts Cancer Institute, Queen Mary University, London, United Kingdom) presented the final overall survival (OS) results of KEYNOTE-522, a phase 3 study investigating the addition of pembrolizumab (pembro) to chemotherapy (chemo – paclitaxel and carboplatin) for the neoadjuvant treatment of high-risk, early-stage triple negative breast cancer (TNBC). Prior reports indicated KEYNOTE-522 had met its primary endpoints with the addition of pembro to chemo followed by adjuvant pembro significantly improving pathologic complete response (pCR) rates and event-free survival (EFS). This regimen had subsequently been approved by the U.S. Food and Drug Association for high-risk, early-stage TNBC. Patients in the study received neoadjuvant pembro or placebo (pbo) with chemo. After surgery, patients received adjuvant pembro or pbo. 784 patients were in the pembro arm, and 390 patients were in the pbo arm. At a median follow-up of 75.1 months, 5-year EFS was 81.2% in the pembro arm and 72.2% in the pbo arm (HR 0.65). 14.7% of patients in pembro arm and 21.8% of patients in pbo arm had died (HR 0.66, p=0.0015), and 5-year OS rate was 86.6% in the pembro arm and 81.7% in the pbo arm. OS benefits associated with pembro were consistent across patient subgroups, regardless of PD-L1 status, tumor size, or disease stage. Pembro was associated with improvements in OS among patients who achieved a pCR (60-month OS 95.1% in pembro arm vs. 94.4% in pbo arm) and among patients who did not achieve a pCR (60-month OS 71.8% in pembro arm vs. 65.7% in pbo arm). No new safety signals were observed, and most toxicities were associated with chemotherapy. Results from this longer follow-up are consistent previous analyses that neoadjuvant pembro+ chemo followed by adjuvant pembro is tolerated and continues to show statistically and clinically significant survival benefits. These results provide further support for neoadjuvant pembro in combination with platinum-containing chemotherapy followed by adjuvant pembro after surgery as the standard-of-care treatment for patients with high-risk, early-stage TNBC.
NIAGARA: Perioperative durvalumab combined with neoadjuvant chemotherapy and subsequent surgery for patients with muscle-invasive bladder cancer
LBA5. A randomized phase 3 trial of neoadjuvant durvalumab plus chemotherapy followed by radical cystectomy and adjuvant durvalumab in muscle-invasive bladder cancer (NIAGARA)
Thomas B. Powles (Barts Cancer Institute, Queen Mary University of London, London, United Kingdom) presented results of the NIAGARA trial, a randomized phase 3 trial investigating durvalumab combined with neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) and adjuvant durvalumab for muscle-invasive bladder cancer (MIBC), a disease with a 50% rate of recurrence after surgery. Patients were randomized to receive neoadjuvant durvalumab + NAC followed by RC then adjuvant durvalumab (Durvalumab arm; 533 patients) or neoadjuvant NAC followed by RC and no adjuvant treatment (Comparator arm; n=530). Event free survival (EFS) and pathologic complete response (pCR) were dual primary endpoints, and overall survival (OS) was a key secondary endpoint. At a median follow-up of 42.3 months, EFS was significantly longer in the Durvalumab arm compared to the Comparator arm (HR 0.68, p<0.0001). Median EFS was not reached in the Durvalumab arm and 46.1 months in the Comparator arm, and 24-month EFS rates were 67.8% and 59.8%, respectively. When censoring patients who did not undergo RC, trends in EFS were similar (HR 0.69), with 24-month EFS rates of 73.5% and 67.9% for the Durvalumab and Comparator arms, respectively. The pathologic complete response (pCR) rates measured after completion of surgery were 37.3% for the Durvalumab arm and 27.5% for the Comparator arm, showing nominal statistical significance. Durvalumab was also associated with significant improvements in OS (HR 0.75, p=0.016), and 24-month OS rates were 82.2% vs 75.2% in the Durvalumab and Comparator arms, respectively. Perioperative durvalumab favored OS in all subgroups analyzed, and it did not delay or affect the completion of RC. 470 of the patients in the Durvalumab arm and 441 of patients in the Comparator arm underwent surgery. No new safety signals were reported, with 41% patients in each arm experiencing Grade 3 or 4 adverse events (AEs). 15% of patients in each arm discontinued neoadjuvant treatment and 8% of patients (Durvalumab arm) discontinued adjuvant durvalumab due to AEs. Perioperative durvalumab was tolerated in this patient population and resulted in statistically and clinically significant improvements in EFS and OS compared to NAC alone, supporting neoadjuvant durvalumab with NAC followed by adjuvant durvalumab after surgery as a potential new standard of care treatment for patients with MIBC.
Targeting PD-1 and TGF-beta for the treatment of HER2-negative gastric/gastroesophageal junction adenocarcinoma
LBA60. Phase 3 study of SHR-1701 versus placebo in combination with chemo as first-line (1L) therapy for HER2-negative gastric/gastroesophageal junction adenocarcinoma (G/GEJA)
Zhi Peng (Peking University Cancer Hospital & Institute, Beijing, China) presented a phase 3 study of SHR-1701 in combination with chemotherapy for HER2-negative gastric/gastroesophageal junction adenocarcinoma (G/GEJA). SHR-1701 is a bifunctional agent consisting of an anti-PD-1 monoclonal antibody fused with the extracellular domain of TGF-Beta receptor II. TGF-beta and PD-1 have non-redundant functions in immunosuppression, and it has been hypothesized that blockade of the TGF-beta pathway could enhance the therapeutic efficacy of PD-1 blockade. SHR-1701 monotherapy has previously been shown to exhibit anti-tumor activity against heavily pre-treated gastric cancer. 731 patients with unresectable locally advanced or metastatic G/GEJA were randomly assigned to treatment with SHR-1701 in combination with oxaliplatin and capecitabine (CAPOX; SHR-1701 + CAPOX; n=365) or placebo + CAPOX (n=366). At a median follow-up of 8.5 months, median OS was significantly higher with SHR-1701+CAPOX (15.8 months) compared to placebo + CAPOX (11.2 months; HR 0.66, p<0.0001). SHR-1701 + CAPOX compared to placebo + CAPOX significantly extended overall survival (OS), with median OS of 6.8 months vs. 10.4 months, respectively (HR 0.53, p<0.0001). Similar trends were observed in progression free survival, overall response rate (ORR), and duration of response for the ITT population and the patient subgroup. SHR-1701 improved the ORR by 20.6% in the ITT population and by 23.8% in the PD-L1 CPS >=5 subgroup. 62.6% of patients receiving SHR-1701 + CAPOX experienced a treatment-related adverse event of Grade 3 or higher, compared to 59.0% of patients who received placebo + CAPOX, and no new safety signals were observed. These findings support SHR-1701 in combination with CAPOX as a new treatment first-line treatment option for unresectable, locally advanced, or metastatic HER2-negative G/GEJA, especially for patients with PD-L1-positive tumors.
Clinical activity of a CD40 agonist in combination with pembrolizumab for metastatic melanoma
71MO. Clinical and biomarker analyses of intratumoral CD40 agonist sotigalimab in combination with pembrolizumab in metastatic melanoma: a phase 1/2 trial
Adi Diab (The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America) presented a phase 1/2 trial of intratumoral injection of sotagalimab (sotiga) with pembrolizumab in checkpoint inhibitor-naïve patients with metastatic melanoma (MM). Sotiga is a CD40 agonist antibody optimized for activation of CD40-expressing antigen presenting cells. 32 patients enrolled in the study and the overall response rate (ORR) was 47%. Among patients receiving the recommended phase 2 dose, the ORR was 50%, and the disease control rate was 91%. Patient samples from local (injected) lesions, distant (un-injected) lesions, and peripheral blood throughout the course of treatment were analyzed. Within 24 hours after intratumoral injection with sotiga, markers of activation of the CD40 pathway and dendritic cell infiltration and activation were upregulated at sites of injection. At week 6 of treatment with sotiga + pembrolizumab, upregulations in expression of genes involved in the innate and adaptive immune responses were observed at the local (injected) and distant (non-injected) lesions of responding patients. RNA-seq analyses indicated the CD40 pathway was preferentially activated in patients who responded to sogita + pembrolizumab combination therapy compared to patients who responded to anti-PD-1 monotherapy. Combination therapy with sogita + pembrolizumab also led to expansion of new T cell clones and sharing of these clones between local and distant lesions. Sotigalimab combined with pembrolizumab showed encouraging anti-tumor activity in this study, and this combination therapy activated both innate and adaptive immunity at local and distant lesions, corresponding with patient responses. A small, randomized trial combining sotagalimab with other immune checkpoint inhibitors for patients with recurrent/refractory melanoma is in planning stages.
Tertiary lymphoid structures as a predictor of response to immune checkpoint inhibition
75MO. Atlas of tertiary lymphoid structures in solid tumors: Genomic features and prediction of response to immunotherapy
Antoine Italiano (Institute Bergonié - Centre Régional de Lutte Contre le Cancer, Bordeaux, France, CEDEX) presented a study exploring the correlation between tertiary lymphoid structure (TLS) presence, defined by gene expression signatures, and patient outcomes in cancer treatment involving immune checkpoint inhibitors. Prior studies have indicated that the presence of mature TLS are predictors of response in patients with cancer who have been treated with anti-PD-(L)1 immune checkpoint inhibitors. DNA and RNA sequencing data from 204,231 patient samples representing over 50 cancer types that had been treated with immune checkpoint inhibitors were analyzed for the presence of TLS- and B cell-related gene signatures. TLS signatures correlated with tumor immune cell composition, and high TLS scores correlated with prolonged time on treatment and improved overall survival, specifically for non-small cell lung cancer, bladder cancer, breast cancer, renal cancer, and for cancers that are less responsive to immune checkpoint inhibition, like soft-tissue sarcoma and microsatellite stable colorectal cancer. High TLS gene expression scores did not predict outcomes for non-immunotherapy treatment regimens. Results from this study further support TLS as a biomarker for patient selection for treatment of solid tumors with immune checkpoint inhibitors.
Safety and efficacy of neoadjuvant immunotherapy without chemotherapy in patients with triple negative breast cancer with high levels of tumor-infiltrating lymphocytes
LBA11. Neoadjuvant nivolumab/relatlimab or nivolumab/ipilimumab in triple negative breast cancer with high tumor-infiltrating lymphocytes (TILs)
Iris Nederlof (Netherlands Cancer Institute, Amsterdam, Netherlands) presented results from cohorts C and D of the BELLINI trial, an adaptive phase 2 non-randomized basket trial exploring the value of neoadjuvant treatment with immune checkpoint inhibitors for early stage, triple negative breast cancer. The addition of PD-1 blockade to neoadjuvant chemotherapy is the new standard of care for patients with early triple negative breast cancer (TNBC), however, this treatment is associated with substantial toxicities. Previous observations from cohorts A and B of the BELLINI trial indicate that a short course of neoadjuvant treatment with immune checkpoint inhibitors in patients with TNBC resulted in immune activation in 58% of patients, and increased levels of tumor infiltrating lymphocytes (TILs) at diagnosis correlated with response. Cohort C was developed to examine pathologic complete response rates (pCR) in patients with TNBC treated with neoadjuvant immune checkpoint inhibitors and no chemotherapy. 15 patients with stage I-II high-TIL (50% or higher) TNBC were treated with a combination of nivolumab and ipilimumab for six weeks followed by surgery and then the standard of care. 5/15 patients experienced a pathologic complete response (pCR), and 8/15 (53%) of patients experienced a major pathologic response (MPR). No patients experienced a delay in surgery, but 6/15 (40%) of patients experienced a treatment-related adverse event (TRAE) of Grade 3 or 4. Due to the high rate of TRAEs and to provide neoadjuvant chemotherapy to patients who did not respond to neoadjuvant immunotherapy, the Cohort C study design was adapted for Cohort D, in which patients with stage I-II high-TIL (50% or higher) TNBC received neoadjuvant nivolumab in combination with relatlimab (anti LAG-3) for 8 weeks, followed by surgery and the standard of care. Patients underwent an MRI after 6 weeks of neoadjuvant immunotherapy, and if no response was detected, neoadjuvant therapy was changed to chemotherapy. Of the 15 patients in Cohort D, 3 patients underwent neoadjuvant chemotherapy, and 12 patients went on to resection. At a median follow-up of 5.1 months, 7/15 patients achieved a pCR, and 11/15 (73%) achieved an MPR. Although 5 patients had not yet met the 100-day follow-up for safety, one patient from Cohort D experienced Grade 3-4 TRAE. Although more work is needed to identify the mechanisms of resistance to immunotherapy in patients with TIL-high tumors, these exploratory results from Cohorts C and D indicate that neoadjuvant therapy with immune checkpoint inhibitors and no chemotherapy is associated with promising response rates in patients with TIL-high TNBC. Future research is needed to explore the efficacy and safety of chemotherapy-free immunotherapy for the treatment of TIL-high TNBC, specifically patients’ quality of life after immunotherapy, potential long-term IRAEs, and the durability of pCRs from immunotherapy compared to pCRs resulting from chemotherapy.
Phase 1 dose escalation study of IMA401, a next-generation T cell engaging receptor targeting MAGEA4/8 for recurrent or refractory solid tumors
1001MO. Initial safety, pharmacokinetics, and anti-tumor activity data of TCER IMA401, a MAGEA4/8-directed half-life extended TCR Bispecific, in Phase 1 dose escalation
Martin Wermke (Dresden University, Dresden, Germany) reported on a first-in-human phase 1 dose escalation trial of IMA401, a next-generation T cell engaging receptor combining a T cell receptor (TCR) domain against HLA-A*02:01-presented MAGEA4/8 peptide with a low affinity T cell recruiting antibody against CD3/TCR and an Fc domain for half-life extension. MAGEA4/8 is expressed at high density in a variety of tumors, making it an idea target for immunotherapy. The study included patients with recurrent or refractory solid tumors who were HLA-A*02:01 positive, MAGEA4/8 positive, and had exhausted all available indicated standard of care treatment options. 16 different types of cancer were represented in the patient population. Patients were dosed with IMA401 on a weekly basis until reaching target dose and then underwent biweekly dosing of the target dose. IMA401 exhibited a manageable tolerability profile. Among the patients in the safety population (n=35) 23% experienced Grade 1 cytokine release syndrome (CRS), 9% Grade 2, and no patients experienced CRS of Grade 3 or higher. The maximum tolerated dose of IMA401 has not been reached. In the efficacy evaluable population (n=29), the overall response rate (ORR) was 21%. Responses were durable, with one response lasting for over one year. Responses occurred in patients with head and neck squamous cell carcinoma, neuroendocrine tumors, and cutaneous and mucosal melanoma, and all responses occurred in patients who had received infusions of 1 mg or more. High expression levels of MAGEA4/A expression correlated with response: among patients expressing MAGE8/4 at high levels, ORR was 29% and confirmed ORR was 25%. This initial report indicates that the T cell engaging receptor IMA401 exhibits a tolerable safety profile and promising anti-tumor activity in a heavily pre-treated patient population. Dose escalation studies of IMA401 are ongoing.
Identification of a blood T cell fitness gene signature associated with increased response and survival to bispecific T cell engagers for metastatic uveal melanoma
66O. Association of a blood T cell fitness gene signature with clinical benefit from ImmTAC bispecific T cell engagers
Joseph J. Sacco (Clatterbridge Cancer Center, Wirral, United Kingdom) reported an exploratory study to identify factors related to baseline blood T cell fitness that are associated with clinical benefit from immune mobilizing monoclonal T cell receptors against cancer (ImmTAC) bispecific T cell engagers. ImmTAC bispecifics redirect T cells from the blood to the tumor, so it was hypothesized that specific T cell phenotypes may be associated with higher response rates and better clinical benefits with ImmTAC bispecifics. Tebentafusp, the first ImmTAC bispecific consists of an anti-CD3 antibody targeting the T cell, and an engineered T cell receptor (TCR) targeting the melanocytic protein gp100. Tebentafusp has been approved by the U.S. Food and Drug Association for the treatment of HLA-A*02:01-positive metastatic uveal melanoma (mUM). An investigational ImmTAC bispecific, brenetafusp, targets the PRAME protein on tumor cells and has shown anti-cancer activity against mUM, cutaneous melanoma, and ovarian cancer. Patient samples from a phase 1/2 trial of tebentafusp for mUM were used as a discovery set to identify potential gene signatures associated with overall survival (OS) benefit, tumor reduction, and association with monocyte-related adverse events (AEs) and cytokine release syndrome (CRS), and T cell signatures identified from the discovery set were then applied to the replication set, samples from a phase 1 study of brenetafusp for mUM. Bulk RNA sequencing of pre-treatment samples from patients with mUM identified a 3-gene T cell fitness (TCF) signature strongly associated with clinical benefit from tebentafusp. The TCF signature was defined by expression levels of TESPA, CD28, and GPR183 and was highly correlated with naïve and stem cell memory genes, indicating increased capacity to self-renew, proliferate, and differentiate into active T cells. Within the discovery set of tebentafusp for mUM, the TCF signature was strongly associated with longer OS (HR 0.42, p<0.001), longer median PFS, disease control rate, overall response rate, and tumor reduction. Patients with a median TCF signature or higher were also more likely to exhibit circulating tumor DNA clearance by week 9, which was associated with better outcomes. The TCF signature was also associated with significantly increased incidence of on-target, off-tumor melanocyte-related AEs but not CRS. Within the replication set, the TCF signature was also associated with brenetafusp-related clinical benefits, including increased OS (HR 0.21, p=0.052), increased PFS, DCR, ORR, and tumor reduction. This study has identified a novel T cell fitness gene expression signature highly correlated with expression of naïve/stem cell memory T cell genes that is associated with clinical and survival benefits for ImmTAC bispecifics for mUM. Similar associations have been observed with the ImmTAC brenetafusp for cutaneous melanoma, and ovarian carcinoma. The TCF signature provides new insights into the mechanisms of action of ImmTAC bispecifics, and more studies are needed to further investigate its potential as a prognostic and predictive biomarker.