The Society for Immunotherapy of Cancer (SITC) is pleased to present highlights of the latest advances in cancer immunotherapy emerging from the 2025 ASCO Annual Meeting on June 1, 2025.
2025 Scientific Highlights
Making “cold” colorectal cancer tumors “hot”: A novel first-in-class PD-1/IL-2 bispecific antibody fusion protein for patients with advanced colorectal cancer
104. Efficacy and safety of IBI363 monotherapy or in combination with bevacizumab in patients with advanced colorectal cancer.
Zhenyu Lin (Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China) presented pooled analyses from two phase 1 studies of IBI363 for advanced colorectal cancer. IBI363 is a novel, first-in-class PD-1/IL-2alpha-bias bispecific antibody fusion protein that blocks PD-1 checkpoint and activates exhausted T cells by cis-activating alpha-bias IL-2, potentially turning immunologically “cold” tumors “hot.” IBI363 has potential to meet an unmet need for patients with microsatellite stable/mismatch repair proficient (MSS/pMMR) colorectal cancer (CRC), an immunologically “cold” tumor. 68 patients with advanced MSS/pMMR CRC were treated with IBI363 monotherapy at two dose levels, 0.6 mg/kg every two weeks (Q2W; n=26) or 1 mg/kg Q2W (n=22). The confirmed overall response rate (cORR) for patients treated with both dose levels was 10.3%. At a median follow-up of 20.1 months, the median overall survival (OS) was 16.1 months. Median OS was numerically longer in patients who received the 1 mg/kg dose than patients who received the 0.6 mg/kg dose, with median OS of 17.5 months and 12.0 months, respectively. In patients with liver metastases (LM), cORR was 7.1% and median OS was 14.4 months. In patients without LM, cORR was 15.4% and median OS was 17.0 months. Both patient subgroups had prolonged OS compared to the historical standard of care. Patients with a partial response or stable disease exhibited increased levels of CD8+ tumor-infiltrating T cells compared to baseline. In the 73 patients treated with IBI363 in combination with bevacizumab (IBI363 + beva), the cORR was 15.1%, the disease control rate (DCR) was 61.6%, and at a median follow-up of 9.9 months, median progression-free survival (PFS) was 4.7 months. In the subgroup of patients treated with the higher dose of IBI363 3 mg/kg every three weeks in combination with bevacizumab, cORR and DCR increased to 19.4% and 71.0%. Higher doses of IBI363 also increased median PFS to 5.6 months. Median PFS was also increased (7.4 months) in patients without liver metastases who were treated with IBI363 + beva (n=32). OS data for this patient subgroup is immature. The safety profiles of IBI363 as monotherapy and in combination with bevacizumab were manageable. 97% of patients who received IBI363 monotherapy and 100% of patients who received IBI363 + beva experienced treatment-emergent adverse events, and 35.3% and 41.1% of these were grade 3 or higher, respectively. IBI363 exhibits promising clinical activity as monotherapy and in combination with bevacizumab. Early data also indicate IBI363 is promoting recruitment of T cells to tumors, making typically “cold” CRC tumors immunologically “hot,” thus supporting further clinical development of IBI363 for patients with advanced CRC.
Exploratory analyses of the NIAGARA study: Circulating tumor DNA as a prognostic biomarker for patients receiving perioperative durvalumab for muscle-invasive bladder cancer
4503. Circulating tumor DNA (ctDNA) in patients with muscle-invasive bladder cancer (MIBC) who received perioperative durvalumab (D) in NIAGARA
Thomas Powles (Barts Cancer Centre, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, UK) reported exploratory analyses of circulating tumor DNA (ctDNA) and association with clinical outcomes in the NIAGARA trial. Previous reports ofNIAGARA, a phase 3 clinical trial, indicated that adding perioperative durvalumab to neoadjuvant chemotherapy significantly improved event-free survival (EFS) and overall survival (OS) compared to neoadjuvant chemotherapy alone in patients with muscle-invasive bladder cancer (MIBC). 237 patients from the durvalumab arm (perioperative durvaluamb + neoadjuvant chemotherapy) and 225 patients from the comparator arm (neoadjuvant chemotherapy) made up the biomarker evaluable population, and baseline characteristics of this population were similar to baseline characteristics of the intent to treat population. Plasma ctDNA was assessed with the Signatera personalized tumor-informed molecular residual disease assay. ctDNA was assessed at baseline, after neoadjuvant treatment prior to cystectomy, and after cystectomy, on the first day of adjuvant treatment. 57% of patients were ctDNA-positive at baseline, 22% were ctDNA-positive after neoadjuvant treatment, and 9% were ctDNA-positive after cystectomy. EFS was improved among patients who were ctDNA-negative at baseline (HR 0.42), and perioperative durvalumab was associated with improved EFS in patients who were ctDNA-positive or ctDNA-negative at baseline. Among patients who were ctDNA positive at baseline, ctDNA clearance after neoadjuvant treatment was higher in the durvalumab arm (70%) compared to the comparator arm (57%), and EFS was improved in patients who achieved ctDNA clearance compared those who were persistently ctDNA positive after neoadjuvant therapy (HR 0.32). ctDNA positivity after neoadjuvant therapy and before cystectomy was associated with a very low likelihood of a pathologic complete response (pCR). Disease-free survival (DFS) was improved in patients who were ctDNA-negative after cystectomy compared to those who were ctDNA-positive (HR 0.09), and perioperative durvalumab provided DFS benefit to patients who were ctDNA-negative (HR 0.49). Among the 91% of patients who were ctDNA-negative after cystectomy, pCR was associated with improved DFS (HR 0.41), and perioperative durvalumab was associated with DFS benefits, regardless of pCR status. In addition to further supporting the use of perioperative durvalumab and neoadjuvant chemotherapy for the treatment of MIBC, these results also underscore the potential for ctDNA as a prognostic biomarker for patients with MIBC.
Novel approaches to identify clinical features and liquid biomarkers associated with neurotoxicity after CAR T cellular therapy
2516. A novel application of deep learning (DL)-based MRI with liquid biomarkers for immune effector cell-associated neurotoxicity syndrome (ICANS) after chimeric antigen receptor (CAR) T cell therapy
Ankey Zhu (UC San Diego, La Jolla, CA, USA) reported a retrospective study to identify biomarkers and clinical features that serve as risk factors for immune effector cell-associated neurotoxicity syndrome (ICANS) after chimeric antigen receptor (CAR) T cell therapy. Samples were obtained from 163 patients who had received CAR T cellular therapy for non-Hodgkin lymphoma or acute lymphocytic leukemia at baseline, three days after CAR T cell infusion. In the 45% of patients with ICANS, samples were obtained during ICANS, and in patients without ICANS, samples were collected 7 days after CAR T cell infusion. Patients also underwent magnetic resonance imaging (MRI) for the year after infusion, and images were processed with deep-learning (DL) based 3D U-Net convolutional neural networks (CNNs), to quantify T2 FLAIR volumetrics. Baseline factors associated with ICANS included high-dose methotrexate and intrathecal methotrexate, and severity of cytokine release syndrome (CRS) was closely associated with severity of ICANS (p<0.001). Increased levels of inflammatory markers lactase dehydrogenase and C-reactive protein (CRP) 3- and 7-days post-infusion were also associated with ICANS. In the 93 post-infusion MRIs from 21 patients, FLAIR increased over time for all patients, and there was a trending association between higher ICANS grade and DL-derived FLAIR. More standardized MRI protocols and studies are needed to validate these potential clinical features and liquid biomarkers to better identify and characterize neurotoxicity after CAR T cellular therapy.
Addition of adjuvant atezolizumab to standard of care adjuvant chemotherapy for resected stage III mismatch repair deficient colon cancer significantly improves event-free survival compared to chemotherapy alone
LBA1. Randomized trial of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for patients with stage III deficient DNA mismatch repair (dMMR) colon cancer (Alliance A021502; ATOMIC)
Frank Sinicrope (Mayo Clinic Rochester, Rochester, MN, USA) presented results from the phase 3 ATOMIC trial investigating whether addition of the anti-PD-L1 immune checkpoint inhibitor (ICI) atezolizumab to adjuvant standard of care 5-fluorouracil, leucovorin plus oxaliplatin (mFOLFOX6) improved outcomes in patients with stage III mismatch repair defective (dMMR) colon cancer. mFOLFOX6 has been standard adjuvant therapy for stage III colon cancers, regardless of mismatch repair status. While ICIs have been approved for dMMR metastatic cancers, it is unclear if they will improve outcomes after surgical resection of dMMR stage III colon cancer. 712 patients with newly resected stage III dMMR colon cancer were randomized. Patients in Arm 1 (n = 355) were treated with adjuvant mFOLFOX6 and atezolizumab for 6 months, followed by 6 months of atezolizumab. Patients in Arm 2 (n = 357) received adjuvant mFOLFOX6 for 6 months. 46.2% of patients in Arm 1 and 59.7% of patients in Arm 2 completed treatment. At a median follow-up of 37.2 months, addition of atezolizumab to adjuvant mFOLFOX6 significantly improved disease-free survival (DFS), with 36-month DFS rates of 86.4% in Arm 1 and 76.6% in Arm 2 (HR 0.5 p<0.0001). Similar results were seen among patients with confirmed dMMR cancer. Atezolizumab was associated with DFS benefits in all predetermined patient subgroups. Overall survival data are not mature, and future may be confounded by future immunotherapy. The safety profile of atezolizumab and mFOLFOX6 aligned with the known profiles of each agent. 99.7% of patients in Arm 1 and 94.2% of patients in Arm 2 experienced treatment-related adverse events. Increased levels of non-febrile neutropenia were observed, but all cases were manageable. 2 deaths that occurred in Arm 1 may have been treatment related. Addition of atezolizumab to adjuvant mFOLFOX6 for dMMR stage III colon cancer reduced the risk of recurrence or death by 50% compared to mFOLFOX6 alone. Adjuvant atezolizumab in combination with mFOLFOX6 represents a new, practice-changing standard of treatment, meeting an unmet need for patients with resected stage III dMMR colon cancer.
First report of NIVOPSTOP: Adjuvant nivolumab combined with standard of care chemoradiotherapy vs. adjuvant chemoradiotherapy for resected locally advanced head and neck squamous cell carcinoma
LBA2. NIVOPOSTOP (GORTEC 2018-01): A phase III randomized trial of adjuvant nivolumab added to radiochemotherapy in patients with resected head and neck squamous cell carcinoma at high risk of relapse
Jean Bourhis, Sr (CHUV, Lausanne University Hospital Hospitalier, Lausanne, Switzerland) reported the first results of the NIVOPOSTOP study, a phase III trial comparing adjuvant nivolumab in combination with chemoradiotherapy to standard of care chemoradiotherapy in patients with resected locally advanced head and neck squamous cell carcinoma (LA-HNSCC) at high risk of relapse. For over 20 years, adjuvant cisplatin and radiotherapy have been the standard of care for LA-HNSCC with high risk of relapse, but the recurrence rate is 40 to 45%. PD-1 inhibitors are now the standard of care for HNSCC in the recurrent and metastatic settings, but it is less effective in the locally advanced setting. 680 patients with complete macroscopic surgical resection of LA-HNSCC and high-risk pathological features for recurrence were randomized to receive adjuvant nivolumab, followed by nivolumab + cisplatin and radiotherapy and subsequent nivolumab (NIVO + CRT, n=332) or adjuvant cisplatin and radiotherapy (CRT, n=334). At a median follow-up of 30.3 months, addition of adjuvant nivolumab to CRT significantly improved disease-free survival (DFS). 3-year DFS rates were 63.1% in the NIVO + CRT arm, compared to 52.5% in the CRT arm (HR 0.76, p=0.034). 13% of patients in the NIVO + CRT arm experienced a loco-regional relapse, compared to 20% of patients in the CRT arm (stratified sub-HR 0.63). Nivolumab was associated with DFS benefits improved in all patient subgroups, including patients with PD-L1 negative tumors (CPS < 1). Overall survival (OS) data are immature and could not be formally tested, but 3-year OS rates were 74.2% for NIVO + CRT and 67.8% for CRT. Adjuvant nivolumab + chemoradiotherapy was associated with an increase in grade 3 treatment-related adverse events, and 2 treatment-related deaths occurred in each arm. With statistically significant improvements in DFS and minimal increases in toxicity, these data provide strong support for adjuvant nivolumab to be added to the current standard of care adjuvant therapy of cisplatin and radiotherapy, providing the first new standard treatment for LA-HNSCC in over 20 years.
Event-free survival and safety analyses of MATTERHORN: A global study of perioperative durvalumab and chemotherapy for resectable gastric and gastroesophageal junction cancer
LBA 5. Event-free survival (EFS) in MATTERHORN: A randomized, phase 3 study of durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel chemotherapy (FLOT) in resectable gastric/gastroesophageal junction cancer (GE/GEJC)
Yelena Janjigian (Memorial Sloan Kettering Cancer Center, New York, NY, USA) presented results from MATTERHORN, a global phase 3 trial evaluating whether adding the anti-PD-L1 immune checkpoint inhibitor durvalumab to fluorouracil, leucovorin, oxaliplatin, and docetaxel chemotherapy (FLOT) improved outcomes in patients with resectable gastric or gastroesophageal junction cancer (GE/GEJC). 948 patients were randomized to receive 2 cycles of neoadjuvant durvalumab + FLOT or placebo + FLOT, then adjuvant durvalumab+FLOT or placebo + FLOT followed by durvalumab or placebo. 474 patients were assigned to the Durvalumab + FLOT arm, and 474 patients were assigned to the Placebo + FLOT arm. Addition of durvalumab did not compromise curative surgery, or completion of adjuvant therapy. Patient characteristics were balanced between the two arms. 19% of patients in the study were from Asia, 25% had T4 tumors, and 90% had PD-L1 positive tumors, determined by TAP. At median follow-ups of 31.6 months for the Durvalumab + FLOT arm and 31.4 months for the Placebo + FLOT arm, Addition of perioperative durvalumab to FLOT significantly increased event-free survival. Median EFS was not reached for the Durvalumab + FLOT arm and 32.8 months for the Placebo + FLOT arm (HR 0.71, p<0.001). 24-month EFS rates were 67% for the Durvalumab + FLOT arm and 59% for the Placebo + FLOT arm. EFS benefit was consistently associated with the addition of durvalumab across all patient subgroups, including patients over 65 years of age, patients from Asia, and patients with PD-L1 negative tumors. Overall survival (OS) was also improved, with median OS not reached in the Durvalumab + FLOT arm and 47.2 months in the Placebo + FLOT arm (HR 0.78, p=0.025). 19% of patients in the Durvalumab + FLOT arm and 7% of patients in the Placebo + FLOT arm achieved a pathologic complete response (pCR), and this increase was statistically significant (odds ratio 3.08, p<0.001). Among patients with R0 resection, median disease-free survival (DFS) was not reached in the Durvalumab + FLOT arm and 39.8 months in the Placebo + FLOT arm (HR 0.70). Two-year DFS rates were also higher in the Durvalumab + FLOT arm compared to the Placebo + FLOT arm, 755 and 66%, respectively. No new safety signals were detected, and adverse events aligned with known profiles of the individual agents. Although final OS analysis is pending, results from MATTERHORN supports the global adoption of perioperative durvalumab with FLOT as a new standard of care for gastric and gastroesophageal adenocarcinoma.
Exploratory analyses of MRD status, ctDNA dynamics, genomic mutations, and clinical outcomes in patients from the AEGEAN trial: perioperative durvalumab and neoadjuvant chemotherapy for resectable non-small cell lung cancer
8009. Association of post-surgical MRD status with neoadjuvant ctDNA dynamics, genomic mutations, and clinical outcomes in patients with resectable NSCLC (R-NSCLC) from the phase 3 AEGEAN trial.
Martin Reck (German Center for Lung Research, Grosshansdorf, Germany) presented exploratory analyses from the phase 3 AEGEAN trial, which indicated perioperative durvalumab combined with neoadjuvant chemotherapy improved event-free survival (EFS) and pathologic complete response (pCR) compared to neoadjuvant chemotherapy for resectable non-small cell lung cancer (R-NSCLC). Previous exploratory analyses of AEGEAN indicated that circulating tumor DNA (ctDNA clearance) was associated with improved pCR, EFS, and overall survival (OS). In addition, patients with molecular residual disease (MRD; i.e. ctDNA-positive) after surgery had worse disease-free survival outcomes compared patients without MRD. The goal of these analyses were to identify associations of post-surgical MRD status with patient characteristics, pathological response, neoadjuvant ctDNA dynamics, genomic mutations, and outcomes. ctDNA was evaluable in 168 patients, and MRD landmark analysis was evaluable in 168 patients. ctDNA analysis was performed using patient-specific tumor derived MRD assays. 10.1% of all patients at the post-surgery landmark were MRD-positive. When comparing MRD-positive and MRD-negative patient populations, most patient characteristics were similar, but a higher proportion of MRD-positive patients had stage III or N2 disease at baseline, compared to MRD-negative patients. Among patients who received perioperative durvalumab, no patients with a pCR or major pathologic response (MPR) were MRD-positive at the post-surgery landmark. 76.5% of patients who were MRD-positive at the post-surgery landmark relapsed or died within 12 months of surgery, compared to 11.9% of patients who were MRD-negative. All MRD-positive and 87.8% of MRD-negative patients had ctDNA detected at baseline, and 70.6% of MRD-positive patients and 31.9% of MRD-negative patients had ctDNA detected after neoadjuvant therapy and before surgery. 58.8% of all MRD-positive patients had persistent ctDNA detection throughout neoadjuvant therapy, compared to 21.2% of MRD-negative patients. Exome-wide sequencing indicated that within the Durvalumab arm, mutations in the KMT2C and KEAP1 genes were associated with MRD positivity. Patients with these mutations who received durvalumab had a higher likelihood of worse DFS outcomes, compared to patients with wild type KMT2C or KEAP1, but patient numbers for these subgroups were small. Although patient subgroups were small, and further investigation is needed these preliminary results may identify patients who are at higher risk for reduced benefit from immunotherapy and indicate potential roles for KMT2C and KEAP1 in molecular residual disease.