The Society for Immunotherapy of Cancer (SITC) is pleased to present highlights of the latest advances in cancer immunotherapy emerging from the 2025 ESMO Annual Meeting on Oct. 19 and 20, 2025.
2025 Scientific Highlights
Bexmarilimab, a macrophage reprogramming monoclonal antibody, in combination with azacitidine for high-risk myelodysplastic syndrome
1249MO. Macrophage reprogrammer bexmarilimab plus azacitidine in myelodysplastic syndrome: PK/PD and biomarker results from the phase I/II BEXMAB study
Mika Kontro (University of Helsinki, Helsinki, Finland) reported safety and efficacy data from the phase 1/2 BEXMAB study of bexmarilimab and azacitidine in myelodysplastic syndrome (MDS). Bexmarilimab interacts with and inhibits the novel macrophage immune checkpoint Clever-1, reprogramming immunosuppressive macrophages to a pro-inflammatory state and activating the T cell response. Bexmarilimab also contributes to anti-cancer activity by inhibiting energy production of malignant blast cells. 53 patients with MDS at intermediate, high, or very high risk of progressing to acute myeloid leukemia were treated with bexmarilimab combined with standard of care chemotherapy azacitidine. 21 patients had treatment-naïve MDS, and 32 patients had MDS that was recurrent or refractory to hypomethylating agents (r/r MDS). The combination therapy was well-tolerated, with 36% of patients experiencing bexmarilimab-related adverse events (AEs). The most common bexmarilimab-related AEs included decreased white blood cell count (11.3%), fatigue (7.6%), and decreased neutrophil count (7.6%). No grade 5 bexmarilimab-related AEs were observed. Among patients with treatment-naïve MDS, 9 patients achieved a complete response, and the overall response rate (ORR) was 85% (17/20). Among the patients with r/r MDS, 2 patients achieved a complete response, and the ORR was 63% (20/32). In the patient subgroups with mutated TP53, the ORR was 78% among patients with treatment-naïve MDS patients and 46% among patients with r/r MDS. 55% of patients with treatment-naïve MDS showed full clearance of bone marrow blasts. 23% of all trial participants were bridged to allogeneic hematopoietic stem cell transplantation. Median overall survival in patients with r/r MDS was 13.4 months, which was encouraging compared to past studies. The pharmacokinetic profile of bexmarilimab was typical for a monoclonal antibody, and all dose levels of bexmarilimab engaged with targets in the bone marrow. Responding patients exhibited significantly better target engagement in the bone marrow, compared to non-responding patients, especially among patients with less than 5% baseline blast counts. With its manageable safety profile and promising response rates for both treatment-naïve and r/r MDS, bexmarilimab plus azacitidine shows promising efficacy in treating and managing high-risk MDS, supporting its further clinical development.
IMbrave152/SKYSCRAPER-14: Addition of anti-TIGIT tiragolumab to standard of care atezolizumab and bevacizumab for advanced hepatocellular carcinoma
LBA50. IMbrave152/SKYSCRAPER-14: A phase III study of first-line tiragolumab (tira) + atezolizumab (atezo) + bevacizumab (bev) vs placebo (pbo) + atezo + bev for patients (pts) with untreated locally advanced or metastatic hepatocellular carcinoma (HCC)
Richard S. Finn (University of California Los Angeles, Los Angeles, California, United States of America) presented results from IMbrave152/SKYSCRAPER-14, a double-blind, placebo-controlled, phase 3 study evaluating the addition of the anti-TIGIT checkpoint inhibitor (ICI) tiragolumab to atezolizumab (anti-PD-L1) and bevacizumab (anti-VEGF) for first-line treatment of locally advanced or metastatic hepatocellular carcinoma (HCC). The combination of atezolizumab and bevacizumab has been approved as the standard of care for first-line treatment of unresectable HCC. However, unresectable HCC is a highly heterogeneous and challenging disease to treat, and there is an unmet need for new treatment regimens. The co-inhibitory receptor TIGIT has been implicated in several cancers, including HCC, and prior clinical studies have suggested that addition of tiragolumab to the standard of care combination of atezolizumab and bevacizumab may be more clinically active against HCC than the standard of care alone. 669 patients with unresectable locally advanced or metastatic HCC and no prior systemic therapy for advanced disease participated in the study. Patients randomized to receive tiragolumab with atezolizumab and bevacizumab (tira+atezo+bev; n=331) or placebo with atezolizumab and bevacizumab (pbo+atezo+bev; n=338) until loss of clinical benefit or unacceptable toxicity. At a median follow-up of 7.5 months, addition of tiragolumab to standard of care atezolizumab and bevacizumab did not affect progression free survival (PFS), with median PFS of 8.3 months with tira+atezo+bev and 8.2 months with pbo+atezo+bev (HR 0.97), and this was consistent across all patient subgroups analyzed. At a median follow-up of approximately 12.5 months, the overall response rate was 29.9% with tira+atezo+bev and 26.0% with tira+atezo+bev, and the disease control rate was 77.9% with the addition of tiragolumab, compared to 74.9% with the standard of care atezolizumab and bevacizumab. Median duration of response was slightly longer with tira+atezo+bev (15.0 months), compared to pbo+atezo+bev (13.2 months). Safety signals were similar between the two arms, but more adverse events were observed in the tira+atezo+bev arm (98.8%) compared to the pbo+atezo+bev arm (97.6%). Addition of tiragolumab was associated with increased incidences of immune-mediated adverse events, specifically immune-mediated rash and infusion-related reactions. Based on these data, IMbrave/SKYSCRAPER-14 did not meet its primary endpoint of improving PFS. Overall survival data are immature and not expected to reach statistical significance (HR 0.94). The study has been unblinded, and long-term survival follow-up is ongoing, but these current data reinforce the use of atezolizumab and bevacizumab as the standard of care for first-line treatment of advanced HCC.
Efficacy and safety data from HARMONi-6: Bispecific ivonescimab combined with chemotherapy for first-line treatment of advanced squamous non-small cell lung cancer
LBA4. Phase III study of ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy as first-line treatment for advanced squamous non-small cell lung cancer (HARMONi-6)
Shun Lu (Shanghai Chest Hospital, Shanghai, China) presented results from HARMONi-6, a phase 3 clinical trial comparing the PD-1 x VEGF bispecific ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy in squamous non-small cell lung cancer (NSCLC) regardless of PD-L1 expression. Results from the HARMONi-2 indicated that ivonescimab significantly improved progression-free survival (PFS) compared to pembrolizumab as first-line therapy for advanced NSCLC in patients with PD-L1-positive (TPS >=1%) tumors. Ivonescimab has been approved for treatment of non-squamous NSCLC and for first-line treatment of PD-L1-positive advanced NSCLC in China. 532 patients with squamous NSCLC and no prior systemic therapy were randomized. Patients in the ivonescimab + chemo arm (n=266) received up to four cycles of ivonescimab with chemotherapy (carboplatin and paclitaxel) followed by maintenance therapy with ivonescimab for up to 24 months or until unacceptable toxicity. Patients in the tislelizumab + chemo arm (n=266) received up to four cycles of tislelizumab with chemotherapy (carboplatin and paclitaxel) followed by maintenance therapy with tislelizumab for up to 24 months or until unacceptable toxicity. As of the time of data cutoff, treatment was ongoing in 162 patients in the ivonescimab + chemo arm and 134 patients in the tislelizumab + chemo arm. Ivonescimab and chemotherapy was associated with significant improvement in progression free survival (PFS) compared to tislelizumab and chemotherapy. At a median follow-up of 10.3 months, the median PFS for the ivonescimab + chemo arm was 11.14 months, compared to 6.90 months for the tislelizumab + chemo arm (HR 0.60, p<0.0001). PFS benefit favored ivonescimab across all key subgroups, and ivonescimab was associated with meaningful PFS improvements regardless of PD-L1 expression (HR 0.55 in patients with PD-L1 negative (TPS<1%) tumors and HR 0.66 in PD-L1 positive tumors). The overall response rate in the ivonescimab + chemo arm was 75.9% with one complete response, compared to 66.5% and no complete responses in the tislelizumab + chemo arm. Responses in the ivonescimab + chemo arm were more durable than in the tislelizumab + chemo arm with median duration of response of 11.20 months and 8.38 months, respectively (p=0.0219). Ivonescimab and chemotherapy was associated with a manageable safety profile, and safety signals were consistent with previous studies. Treatment-related adverse events leading to ivonescimab or tislelizumab discontinuation (3.4% vs. 4.2%, respectively) and death (3.0% in the ivonescimab + chemo arm vs. 3.8% in the tislelizumab + chemo arm) were similar. Ivonescimab exhibited similar immune-related adverse events to tislelizumab. As expected, more possible VEGF-related adverse events occurred in the ivonescimab + chemo arm, and over 80% of these events were grade 1 or 2. The manageable safety profile and significant improvements in PFS support ivonescimab and chemotherapy as a new standard of care for first-line treatment of advanced squamous NSCLC. Overall survival data for the HARMONi-6 study are maturing and will be reported later.
HER2-targeting antibody drug conjugate disitamab vedotin combined with toripalimab as first-line treatment of HER2-expressing locally advanced or metastatic urothelial carcinoma
LBA7. Disitamab vedotin (DV) plus toripalimab (T) versus chemotherapy (C) in first-line (1L) locally advanced or metastatic urothelial carcinoma (la/mUC) with HER2-expression
Jun Guo (Peking University Cancer Hospital and Institute, Beijing, China) reported results from RC48-C016, a multicenter, randomized phase 3 trial, comparing disitamab vedotin (DV), a HER2-targeting antibody drug conjugate, combined with the immune checkpoint inhibitor toripalimab (T) versus chemotherapy (gemcitabine and cisplatin or carboplatin) for first-line treatment of locally advanced or metastatic urothelial carcinoma (la/mUC) expressing HER2. HER2 expression is highly prevalent in urothelial carcinoma (UC), representing approximately 70% of all cases. Antibody drug conjugates targeting HER2 for the treatment of UC have been approved in China and the United States, and prior phase 1/2 trials of the combination of DV with toripalimab has shown promising clinical activity against la/mUC. 484 patients with no prior systemic treatment for unresectable la/mUC that was confirmed to express HER2 were randomized. Patients in the DV+T arm (n=243) received DV and toripalimab until disease progression or death, and patients in the chemo arm (n=241) received a maximum of six cycles of gemcitabine with cisplatin or carboplatin. At the time of the data cutoff, 91 patients in the DV+T arm and no patients in the chemo arm remained on treatment. At a median follow-up of 18.2 months, DV and toripalimab were associated with a significant improvement in progression free survival (PFS) compared to chemotherapy, reducing the risk of disease progression or death by 64%. Median progression free survival was 13.1 months in the DV+T arm and 6.5 months in the chemo arm (HR 0.36, p<0.0001). PFS benefits were associated with DV and toripalimab across all patient subgroups examined. DV + toripalimab was also associated with significant improvements in overall survival (OS) compared to chemotherapy, with median OS of 31.5 months and 16.9 months, respectively (HR 0.54, p<0.0001). OS benefits favored DV and toripalimab across all patient subgroups examined. The overall response rate in the DV+T arm was 76.1%, compared to 50.2% in the chemo arm, and significantly longer responses were associated with DV + toripalimab compared to chemotherapy (median duration of response 14.6 months and 5.6 months, respectively).64.7% of patients in the chemo arm received subsequent systemic therapy, compared to 27.2% of patients in the DV + T arm. Among patients in the chemo arm who received subsequent systemic therapy, 40.2% chose anti-HER2 therapy, and 50.2% chose PD(L)-1-targeting therapy. The safety profile of DV and toripalimab was manageable, and 55.1% of treatment-related adverse events in the DV+T arm were grade 3 or higher, compared to 86.9% of adverse events in the chemo arm. The RC48-C016 clinical trial is the first study to demonstrate improved clinical efficacy of a HER2-targeting antibody-drug conjugate in combination with an anti-PD1 inhibitor in a patient population selected for HER2-expressing la/mUC. With its favorable safety profile and statistically significant survival benefits, disitamab vedotin combined with toripalimab represents a new option and a potential standard of care for the treatment of HER2-expressing la/mUC.
Bispecific armored CAR T cells targeting CD44 and CD133 for recurrent high-grade glioma
1511O. Locoregional bispecific CAR-T cells targeting CD44 and CD133 show safety and efficacy in recurrent high-grade glioma in a first-in-human investigator-initiated trial
You Zhai (Beijing Tiantan Hospital, Beijing, China) reported final results from an early-phase exploratory first in-human study of bispecific CAR T cells targeting CD44 and CD133 armored with a truncated version of the IL7Ra intracellular domain for recurrent grade IV glioma. CD44 and CD133 are tumor-associated antigens expressed on stem cells of glioma and other cancers, and IL7Ra promotes development and survival of CAR T cells. 10 patients with recurrent grade 4 glioma who had completed chemotherapy and radiotherapy were included in the study. CAR T cells were administered by intrathecal injection, and patients received a maximum of 8 doses of cells. Adverse events (AEs) were manageable; the most common AE was cytokine release syndrome, experienced by 7 patients, and all cases were grade 1. Only 1 patient experienced a grade 3 AEs (lymphophenia). No AEs higher than grade 3 were observed. Due to the intrathecal delivery of the CAR T cells CAR molecules were detected in cerebral spinal fluid (CSF) but not in peripheral blood. Elevated levels of IL6 were detected in the CSF, but most other cytokine levels remained stable. Three patients experienced a partial response, and four patients experienced stable disease. Median overall survival was 465 days after first CAR T cell injection, and median progression-free survival was 45 days after first CAR T cell injection. Patients who did not respond to treatment exhibited elevated baseline levels of chemokines in the CSF, such as VEGFA and CXCL8, suggesting chronic inflammation may be associated with a poor response. Patients who responded to treatment often had low baseline levels of these chemokines that increased chemokines after CAR T cell injection. Single-cell analyses of responders and non-responders indicated that pre-treatment macrophages in the CSF of responders exhibited increased activity in antigen presentation and processing, while pre-treatment macrophages of non-responders exhibited higher levels of migration and chemotaxis activities. Macrophages from non-responders also showed stronger lipid metabolism and weaker interaction with T cells, also indicating chronic inflammation. Results from this study reflect the feasibility of dual-targeted CAR T cells against glioma stem cells and the locoregional administration of these cells. These results also highlight the roles of macrophage immune phenotype and chronic inflammation in promoting clinical responses.
Clinical activity and safety of NW-301V, a TCR T cell therapy targeting KRAS G12V in advanced tumors
1514O. First-in-human phase I study of TCR-T therapy targeting KRAS G12V in metastatic solid tumors
Xueli Bai (The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China)
First in-human phase 1 study of NW-301V, a novel TCR T cell therapy with a TCR specific for the KRAS G12V neoantigen presented by HLA-A*11:01. KRAS G12V is a known driver mutation for pancreatic cancer (PC), colorectal cancer (CRC), and non-squamous non-small cell lung cancer (nsq NSCLC), and it is associated with poor prognosis. NW-301V also expresses the CD8αβ co-receptor to enhance T cell functionality. Preclinical studies have indicated NW-301V exhibits strong avidity against KRAS G12V-derived peptides and anti-tumor activity in vivo and in vitro. 14 patients with unresectable advanced solid tumors that tested positive for HLA-A*11:01 and KRAS G12V underwent lymphodepletion and received infusions of NW-301V at three different dose levels, 300 million cells (DL1; n=4), 1.6 billion cells (DL2; n=4), or 7.5 billion cells (DL3; n=6). 8 patients had PC and 6 patients had CRC. No dose limiting toxicities, immune effector cell-associated neurotoxicity syndrome (ICANS), or grade 5 adverse events (AEs) were observed. The most common AEs of grade 3 or higher were hematological toxicities associated with lymphodepletion. Cytokine release syndrome occurred in 6 patients, and all cases were grade 1 or 2. The objective response rate (ORR) was 42.9%, with 6 patients achieving a partial response. The disease control rate (DCR) was 78.6%. Among patients who received DL2 and DL3, the ORR was 50%, and the DCR was 100%. Median progression-free survival was 4.2 months for the total patient population and 5.8 months for patients who received DL2 and DL3. NW-301V reached peak expansion in peripheral blood one week after infusion, and peak expansion levels correlated with dose levels. Responding patients included those who were heavily pre-treated, and some responses have been ongoing for 12 months or longer. NW-310V exhibits encouraging efficacy and a manageable safety profile in patients with advanced pancreatic and colorectal cancers with the KRAS G12V mutation. Further dose expansion and follow-up is ongoing, and an Investigational New Drug phase 1 clinical trial is being planned.
Safety and clinical activity of NI-1801, a bispecific antibody targeting mesothelin and CD47 as monotherapy and in combination with pembrolizumab for platinum-resistant ovarian cancer
1512O. NI-1801, a mesothelin x CD47 bispecific antibody: Safety and activity as single agent and in combination with pembrolizumab, in heavily pretreated (>= 4 prior lines) mesothelin expressing platinum-resistant epithelial ovarian cancer patients
Thibault De La Motte Rouge (Centre Eugéne Marquis-Rennes, Rennes, France) presented safety and clinical efficacy data from a first in-human study of NI-1801, a human mesothelin (MSLN) x CD47 bispecific antibody in patients with platinum-resistant epithelial ovarian cancer (PROC). MSLN is a well-characterized tumor-associated antigen that is minimally expressed on non-cancerous cells. The high-affinity anti-MSLN arm of NI-1801 allows for the specific targeting of tumors and minimizing on-target, off-tumor toxicities. The low-affinity anti-CD47 arm of NI-1801 interacts with the “don’t eat me” signal CD47 on MSLN-expressing tumor cells, blocking CD47-SIRPa interactions and promoting phagocyte-mediated destruction of cancer cells. It has been hypothesized that by promoting phagocytosis of cancer cells, NI-1801 will enhance anti-cancer immunity and the activity of the PD-1 inhibitor pembrolizumab. 56 patients with epithelial ovarian cancer, non-squamous non-small cell lung cancer, and pancreatic ductal adenocarcinoma participated in the study. Patients in cohort 1 received NI-1801 monotherapy with doses ranging from 15 mg to 600 mg weekly or 900 mg to 2000 mg every two weeks (n=30). Patients in cohort 2 received NI-1801 (doses ranging from 300 mg to 600 mg weekly or 900 mg every two weeks) in combination with 400 mg pembrolizumab every six weeks (n=26). All 56 patients were included in the safety analysis. NI-1801 was well-tolerated as monotherapy and in combination with pembrolizumab. At the recommended phase 2 dose (RP2D) of 900 mg every two weeks, all reported adverse events (AEs) with NI-1801 monotherapy were grade 1 or 2; common AEs included anemia (27%), fatigue (30%), lymphopenia (20%), and infusion-related reactions (30%). Combination therapy with the RP2D dose of NI-1801 and pembrolizumab was associated with two grade 3 AEs, lipase elevation and capillary leak syndrome. Across the entire patient cohort, all adverse events were transient and manageable, and no dose-limiting toxicities were observed. The clinical efficacy analysis was limited to 42 patients with PROC. 21 patients in this subgroup received NI-1801 monotherapy at 600 mg or 900 mg doses, and 21 patients received NI-1801 at doses of 600 mg or 900 mg combined with pembrolizumab. The objective response rate (ORR) with NI-1801 monotherapy was 5%, and the clinical benefit rate (responses and stable disease) was 38%. The ORR with NI-1801 in combination with pembrolizumab was 28.5%, and the clinical benefit rate was 48%. Long-lasting responses were achieved with NI-1801 monotherapy and in combination with pembrolizumab, and the median duration of response with the NI-1801 and pembrolizumab combination has not been reached. Progression-free survival (PFS) data are maturing; the 9-month PFS rate for NI-1801 in combination with pembrolizumab was 32.7%, and the 20-month PFS rate was 20.4%. Overall survival (OS) data are also immature; the 12-month OS rate was 35.3% with NI-1801 monotherapy and 75.2% with NI-1801 and pembrolizumab. NI-1801 was safe and well-tolerated as monotherapy and in combination with pembrolizumab. These early clinical results are encouraging, and preliminary PFS and OS rates associated with NI-1801 and pembrolizumab in patients with PROC are especially promising, given the limited treatment options for this disease. NI-1801 may be beneficial for a wide range of solid tumors expressing mesothelin, and these results support further clinical development and testing.
Long-term follow-up of GDFATHER-01: Anti-GDF-15 visugromab in combination with nivolumab for relapsed/refractory anti-PD-(L)1 tumors
1513O. Long-term follow-up GDFATHER-01 trial: GDF-15 neutralization combined with nivolumab can enable deep, long-term remission in heavily pretreated, anti-PD1/-L1 relapsed/refractory non-squamous non-small cell lung cancer (NSCLC), urothelial cancer (UC) and hepatocellular cancer (HCC)
Ignacio Melero (Pamplona, Spain) reported the long-term results of the GDFATHER-01, a phase 1/2a trial investigating visugromab in combination with nivolumab in patients with anti-PD(L)-1-relapsed/refractory locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC), urothelial cancer (UC), or hepatocellular cancer (HCC). Visugromab is a monoclonal antibody targeting Growth and Differentiation Factor 15 (GDF-15), a cytokine that is a critical resistance factor to anti-PD(L)-1 immune checkpoint inhibitors. GDF-15 is the most overexpressed cytokine in cancer, and it is associated with reduced survival. The phase 1 dose escalation and phase 2a dose expansion cohorts of GDFATHER-01 included 77 patients with NSCLC (n=22), UC (n=27), and HCC (n=28) that relapsed or were refractory to anti-PD-(L)1 treatment and were treated with visugromab and nivolumab. Previous reports of GDFATHER-01 indicate that combination therapy with visugromab and nivolumab was associated with increased T cell infiltration and proliferation in the tumor microenvironment and an objective response rate of 14% to 18.5%. No new safety signals were reported, and the safety profile is consistent with previous studies of retreatment with nivolumab monotherapy. The ORR for the entire patient population was 16.9%, with five patients achieving a complete response (CR) and 3 patients achieving a complete metabolic response (CMR): 3 patients with non-squamous NSCLC, 2 patients with UC, and 3 patients with HCC achieved a CR/CMR. The median duration of response was 28.8 months, and 53.8% of responses are ongoing, including 75% of patients with non-squamous NSCLC. 61.5% of responders experienced a deeper or more durable response with nivolumab and visugromab than with their initial anti-PD-(L)1 treatment, and 76.9% of responders experienced a longer response with nivolumab and visugromab. In addition to promoting resistance to immunotherapy, GDF-15 also plays a role in promoting nausea and cachexia, and the small subgroup of patients who were cachectic at baseline achieved significant weight gain on treatment with visugromab and nivolumab. These results have contributed to the development of a positive feedback loop model of GDF-15 and tumor progression. GDF-15 is secreted by tumors, inducing immunosuppression and immunotherapy resistance in the tumor microenvironment. Cancer therapies stress tumor cells, further inducing GDF-15 secretion. GDF-15 secretion also induces patient nausea and cachexia, reducing their tolerance for therapy, thereby promoting tumor growth and GDF-15 secretion. These data identify GDF-15 as an emerging target for immuno-oncology drug development and support the use of visugromab in combination with PD-(L)1 blockade to treat tumors that are relapsed or refractory to anti-PD-(L)1 therapies. Phase 2b studies of visugromab and nivolumab for first-line and second-line treatment of non-squamous NSCLC are ongoing, and other phase 2b trials of visugromab and nivolumab for second-line treatment of HCC and visugromab for cachexia will begin recruiting in the near future.
Using serial ctDNA monitoring to identify patients with muscle-invasive bladder cancer who will benefit from adjuvant immunotherapy
LBA8. IMvigor011: A phase III trial of circulating tumour (ct)DNA-guided adjuvant atezolizumab vs placebo in muscle-invasive bladder cancer
Thomas B. Powles (Queen Mary University of London, London, United Kingdom) presented the primary analysis of the phase 3 IMvigor011 trial studying circulating tumor DNA- (ctDNA-) guided atezolizumab vs. placebo in the adjuvant setting for patients with high-risk muscle-invasive bladder cancer (MIBC). Radical cystectomy can be curative for many patients with MIBC, but approximately 50% of patients experience disease recurrence after surgery, which is associated with poor outcomes. The IMvigor011 study investigated whether serial testing for ctDNA can identify patients with molecular residual disease (MRD) who could potentially benefit from adjuvant immunotherapy. The IMvigor011 study builds upon exploratory analyses from the IMvigor010 study, which demonstrated that patients who tested ctDNA positive did experience overall survival benefits from adjuvant atezolizumab, while patients who were ctDNA negative did not benefit. Patients MIBC who had had no evidence of radiographic disease after cystectomy underwent ctDNA testing every six weeks and radiographic imaging every 12 weeks until one year after cystectomy. Of the 379 patients who tested positive for ctDNA at any time, 250 ctDNA-positive patients who had no evidence of radiographic disease were randomized to receive atezolizumab (n=167) or placebo (n=83) every four weeks for up to one year. 377 patients consistently tested negative for ctDNA, and 310 of those patients have completed or are in ongoing surveillance. At a median follow-up of 16.1 months, adjuvant atezolizumab was associated with significant improvements in disease free survival (DFS) compared to placebo in patients who tested positive for ctDNA. Median DFS was 9.9 months and 4.8 months, respectively (HR 0.64, p=0.0047). Adjuvant atezolizumab in ctDNA-positive patients was also associated with significant gains in overall survival (OS) compared to placebo, with median OS of 32.8 months and 21.1 months, respectively (HR 0.59, p=0.0131). PFS benefits or OS benefits were generally observed across patient subgroups, including patients who tested ctDNA-positive at their initial test (n=148, 59.2% of ctDNA-positive patients) and patients who converted to ctDNA positivity throughout the testing period (n=102, 40.8% of ctDNA-positive patients). Among patients who consistently texted ctDNA-negative, the 24-month DFS rate was 88.4%, and the 24-month OS rate was 97.1%, indicating that patients who are consistently ctDNA-negative are at low risk of recurrence. 51.5% of patients who received adjuvant atezolizumab and 54.2% of patients who received adjuvant placebo are currently receiving follow-up systemic anti-cancer therapy. The safety signals were similar to prior studies of adjuvant atezolizumab. 7.3% of patients in the atezolizumab arm experienced a grade 3 or 4 treatment-related adverse event (AE), compared to 3.6% of patients in the placebo arm. 1.8% of patients in the atezolizumab arm died of a treatment-related AE. These results indicate that for patients with MIBC who are ctDNA-positive, adjuvant atezolizumab is associated with a manageable safety profile and statistically significant survival benefits compared to placebo. These findings also underscore the potential of serial ctDNA monitoring to detect MRD and early metastatic disease, thus identifying ctDNA-positive patients who will likely benefit from adjuvant immunotherapy and sparing patients who are consistently ctDNA-negative from unnecessary treatment.
Safety and clinical efficacy of anzutresgene autoleucel, a PRAME-targeting TCR T cell therapy, for uveal melanoma
1600O. Efficacy and safety of IMA203, a PRAME-directed T-cell receptor (TCR) T-cell therapy, in patients with previously treated advanced or metastatic uveal melanoma from a phase I trial
Sapna P. Patel (University of Colorado, Aurora, CO, United States of America) presented results from an ongoing phase 1a/b trial of anzutresgene autoleucel (IMA203; anzu-cel), a PRAME-directed TCR T cell therapy in patients with previously treated advanced or metastatic uveal melanoma (UM). UM, the most common tumor in the adult eye, is an immunologically “cold” tumor, with few therapeutic options. PRAME is an intracellular protein expressed at high levels in a number of cancers, including in approximately 90% of cases of UM, making it an ideal target for TCR T cell therapy. Anzu-cel is engineered to recognize and destroy tumor cells presenting intracellular PRAME-derived by HLA-A*02:01. Patients who were HLA-A*02:01-positive with PRAME-expressing tumors underwent lymphodepletion and received a one-time azu-cel infusion followed by low-dose IL2. In the efficacy population with UM (n=16), patients received a median of 3.94 x 10^9 cells. 13 of the 16 patients in the study had liver and extrahepatic lesions and patients had received a median of 2 prior systemic therapies. The most common treatment-emergent adverse events were cytopenias from lymphodepletion, observed in 15 patients. All patients experienced cytokine release syndrome (CRS) and all but three cases were grade 1 or 2. Most CRS cases were resolved by day 14, and no patients experienced long term CRS or grade 5 adverse events. All 16 patients experienced some degree of target lesion shrinkage. The objective response rate was 67%, and the disease control rate was 88%. At a minimum follow-up of 4.6 months, the median duration of response was 11.0 months, and four responses are ongoing. The median progression-free survival was 8.5 months (median follow-up 10.4 months), and the median overall survival was not reached (median follow-up 14.3 months). Responses occurred in patients with prior TCR-based or PRAME-targeted therapies. These early results support the hypotheses that TCR-T cell therapy targeting a highly expressed intracellular antigen, like PRAME, can result in clinical activity in immunologically cold tumors. Although the initial patient population is small, these preliminary efficacy and safety data support further clinical development of anzu-cel, and a phase 2 study of an extension cohort to verify these results is ongoing.