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 2, 2025.
2025 Scientific Highlights
Dose finding and dose expansion reports of LINKER-MM2, linvoseltiamab, a BCMAxCD3 bispecific antibody, in combination with protease inhibitor bortezomib for patients with heavily pretreated multiple myeloma
7510. Linvoseltamab (LINVO) + bortezomib (BTZ) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): First results from the LINKER-MM2 trial.
Xavier Leleu (Hospital La Mileterie, Poitiers, France) presented preliminary safety and efficacy data from the dose-finding and expansion portions of LINKER-MM2, a phase 1b, open-label trial of linvoseltamab, a BCMA x CD3 bispecific antibody, in combination with the protease inhibitor bortezomib (BTZ) for relapsed/refractory multiple myeloma (RRMM). Linvoseltamab has been approved in the European Union for RRMM after three or more prior therapies, and combinations of linvoseltamab with other standard-of-care agents, like bortezomib, are being investigated for additive or synergistic activity. 12 patients were treated in the dose finding portion of the study, and 12 patients were treated in the dose expansion portion. Patients were pretreated with a median of 3 prior lines of therapy, all had been exposed to at least one protease inhibitor, and 87.5% had prior exposure to bortezomib. 62.5% of patients had disease that was refractory to a protease inhibitor. Of the 11 evaluable patients, one patient experienced a dose-limiting toxicity. The safety profile of linvoseltamab + bortezomib was generally consistent with the known profiles of the individual agents. 58.3% of patients experienced cytokine release syndrome, 17% of patients experienced immune effector cell-associated neurotoxicity syndrome (ICANS), and all cases were grade 1 or 2. At a median follow-up of 9.3 months, the overall response rate for the total patient population was 85%, with 50% of patients achieving a complete response or stringent complete response. The 6-month duration of response rate was 88%, and the 6-month progression-free survival rate was 78%. 5 of 5 evaluable patients (100%) were negative for minimal residual disease. With its high clinical efficacy and manageable safety profile, combination therapy of linvoseltamab with bortezomib shows promising for patients with RRMM, which will be evaluated in earlier lines of therapy.
Cafelkibart, an anti-CCR8 monoclonal antibody, in combination with anti-PD-1 therapy in patients with pancreatic cancer
4010. Efficacy and safety of cafelkibart (LM-108), an anti-CCR8 monoclonal antibody, in combination with anti-PD-1 therapy in patients with pancreatic cancer: Results from phase 1/2 studies.
Jifang Gong (Peking University Cancer Hospital and Institute, Beijing, China) presented pooled analysis of phase 1/2 studies of cafelkibart, an anti-CCR8 monoclonal antibody, in combination with anti-PD-1 therapy in patients with pancreatic cancer. Previous studies have shown cafelkibart selectively depletes tumor infiltrating regulatory T cells (Tregs), disrupting the immunosuppressive intratumoral environment. Cafelkibart has exhibited promising anti-tumor activity alone or with pembrolizumab in advanced solid tumors. Patients with pancreatic cancer who progressed on or after one or more prior line of systemic therapies received cafelkibart and the anti-PD-1 antibody toripalimab (n=74) or cafelkibart and anti-PD-1 antibody pembrolizumab (n=6). 60% of patients had received one prior line of treatment, and 40% had received two or more prior lines. 17.5% had received prior anti-PD-1 therapy. In the evaluable patient population (n=74), the confirmed objective response rate (cORR) was 17.6%, with all responders (n=13) achieving a confirmed partial response (cPR). The disease control rate (DCR) was 62.2%, and median duration of response (DoR) was 5.5 months. Median progression-free survival (mPFS) was 3.1 months, and while overall survival (OS) data were immature, median OS was 10.0 months, and 12-month OS rate was 41.2%. Among the evaluable patients who received cafelkibart and anti-PD-1 therapy in the second-line (2L) setting (n=45), the cORR was 22.2%, with all responders (n=10) achieving a cPR. The DCR was 71.1%, and the median DoR was 6.9 months. mPFS was 4.9 months, median OS was not reached, and 12-month OS rate was 51.6%. CCR8 expression levels were determined in the tumors of the 2L patient population, and the overall response rate (ORR) was highest among patients with CCR8-positive cells >=2% of total cells (n=9, ORR 33.3%), compared to an ORR of 13.3% among patients with CCR8-positive cells < 1% of total cells (n=15). Larger patient populations are needed to validate this trend. Over 95% of the total patient population experienced a treatment-related adverse event, and 52.5% were grade 3 or higher. With its encouraging anti-tumor activity and manageable safety profile, cafelkibart in combination with anti-PD-1 therapy represents a promising new alternative for treating patients with pancreatic cancer that progressed after one or more prior systemic therapy, and these results support further investigation of this combination therapy.
Identifying characteristics of TIL infusion products that predict response to TIL therapy for melanoma
9516. Infusion product characteristics to predict response to tumor-infiltrating lymphocyte (TIL) therapy in metastatic melanoma (MM).
Lilit Karapetyan (H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA) presented a study of tumor infusion lymphocyte product (TILp) characteristics that were associated with clinical outcomes in patients with metastatic melanoma. Tumor infiltrating lymphocytes (TIL) therapy has been approved for the management of metastatic melanoma in 2024, but only a subset of patients derive durable benefit from TIL therapy. The purpose of this study was to identify TILp characteristics associated with response to improve TIL therapy and patient outcomes. The study involved treatment and outcomes data from 50 patients who were treated at the H. Lee Moffitt Cancer Center from 2009-2018. 19 patients had received TIL therapy only, 13 received TIL therapy with ipilimumab, 11 received TIL therapy with nivolumab, and 17 received TIL therapy with the BRAF inhibitor vemurafenib. 36% of patients in this population experienced a response that lasted one year or more, and at a median follow-up time of 102 months, median progression-free survival (PFS) was 8.2 months, and median overall survival (OS) was 52 months. Higher number of infused TIL was associated with response. The median PFS of patients who received more than 42.7 x 109 cells was 11.0 months, compared to 2.9 months for patients who received 42.7 x 109 cells or lower (p<0.001). Higher TIL persistence was associated with response (p=0.008), but TIL clonality and diversity were not. Higher fraction and number of CD8+ TIL were also associated with response. The median PFS of patients who received more than 39 x 109 infused CD8+ TIL was not reached, and 5 months among patients who received 39 x 109 infused CD8+ TIL or fewer (p<0.001). Similar associations were observed with stem cell-like memory CD8+ T cells (CD8+ TSCM). The median PFS of patients who received more than 1.2 x 109 infused CD8+ TSCM was not reached, and 5 months among patients who received 1.2 x 109 infused CD8+ TSCM or fewer (p=0.015). Surface expression of LAG3+, specifically on CD3+ T cells was also associated with response. Patients who received more than 22.3 x 109 cells had not yet reached a median PFS, and patients who received 22.3 x 109 LAG3+ CD3+ T cells or fewer had a median PFS of 2.9 months (p=0.001). Although this study involved a relatively small sample size of patients who were treated in the single institution, these results provide insights into future strategies to modulate the ex vivo TIL expansion process, optimizing TILp efficacy, increasing patient response rates, and improving patient survival.
OBX-115, an engineered tumor-infiltrating lymphocyte cell therapy that abrogates the need for high-dose IL-2, in patients with advanced, immune checkpoint inhibitor-resistant melanoma
9517. OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy with regulatable membrane-bound IL15 (mbIL15) in patients (pts) with immune checkpoint inhibitor (ICI)–resistant advanced melanoma: Phase 1 results of the Agni-01 multicenter study.
Jason Chesney (University of Louisville Brown Cancer Center, Louisville, KY, USA) reported the first data from the phase 1/2 Agni-01 study of OBX-115, an engineered tumor-infiltrating lymphocyte (TIL) therapy expressing regulatable membrane-bound IL-15 (mblIL-15), in patients with advanced melanoma that is resistant to immune checkpoint inhibitors (ICI). TIL therapy has been approved for advanced ICI-resistant melanoma, but it requires lymphodepletion and high-dose IL-2, which are often associated with adverse events and toxicity and can limit patient eligibility. OBX-115 TILs are engineered to express mbIL-15 regulated by the FDA-approved small molecule drug acetazolamide (ACZ), abrogating the need for high-dose IL-2 after TIL infusion. 11 patients with advanced melanoma that relapsed and/or was refractory to ICIs participated in the study. 10 patients received low-dose lymphodepletion, with one patient in the outpatient setting. 3 patients received dose level (DL) 1 of OBX-115 and ACZ (30 x 109 cells and 250 mg ACZ/day for 13 days), 2 patients received DL2 (100 x 109 cells and 250 mg ACZ/day for 13 days), and 6 patients received the recommended phase 2 dose (RP2D) of 100 x 109 cells and 500 mg ACZ/day for 13 days. ACZ redosing occurred in the outpatient setting every 6 weeks to increase or decrease TIL levels. Because treatment with OBX-115 uses low dose lymphodepletion and does not require high-dose IL-2, Agni-01 did not have an upper age limit, and patient ages ranged from 27 to 78 years. At a median follow-up of 34 weeks, most non-hematological treatment-related adverse events (TRAEs) were grade 1 or 2. No dose-limiting toxicities were observed, all cases of cytokine release syndrome were grade 1 or 2, and no cases of immune effector cell-associated neurotoxicity syndrome (ICANS) were reported. The objective response rate (ORR) of the entire patient population was 36%, and the disease control rate (DCR) was 82%. Among patients who received the recommended phase 2 dose (RP2D), the ORR was 67%, with 1 CR, and the DCR was 100%. Tumor burden reduction occurred in 73% of all patients and in 83% of patients who received RP2D. The median duration of response has not been reached. In addition to its promising clinical efficacy, OBX-115 TIL therapy with ACZ-driven regulatable expression of mbIL-15 represents a potentially safer option for TIL therapy and may broaden the eligible population of patients with advanced ICI-resistant melanoma. The RP2D of OBX-115 is being explored in phase 2 of the Agni-01trials, and a phase 1/2 multicenter trial of OBX-115 is currently enrolling patients with advanced melanoma and advanced non-small cell lung cancer
PD-L1 inhibitor benmelstobart in combination with small molecule antiangiogenesis agent anlotinib as consolidation therapy for locally advanced unresectable non-small cell lung cancer that has not progressed on chemoradiotherapy
LBA8004. R-ALPS: A randomized, double-blind, placebo-controlled, multicenter phase III clinical trial of TQB2450 with or without anlotinib as maintenance treatment in patients with locally advanced and unresectable (stage III) NSCLC without progression following concurrent or sequential chemoradiotherapy
Ming Chen (Sun Yat-sen University Cancer Center, Guangzhou, China) presented results from the phase 3 R-ALPS trial investigating the safety and efficacy of the novel humanized PD-L1 inhibitor benmelstobart as monotherapy and in combination with the small molecule antiangiogenesis agent anlotinib in patients with unresectable stage III non-small cell lung cancer (NSCLC) that did not progress after concurrent or sequential radiotherapy. The anti–programmed death ligand 1 (PD-L1) antibody durvalumab as consolidation therapy after concurrent chemoradiation have been the standard of care for unresectable NSCLC since 2017, but PD-L1 inhibitors were not available until 2019 in China, when study was initiated. 553 patients with locally advanced, unresectable stage 3 NSCLC that did not progress after concurrent/sequential chemoradiotherapy were randomized to three arms. The trial used a two-phase design in which patients in the first phase were randomized 1:1:1 to compare monotherapy and combination therapy with placebo, and in the second phase patients were randomized 1:1 between the monotherapy arm and the combination arm. Patients in the combination arm were treated with benmelstobart and anlotinib (n=209), patients in the monotherapy arm were treated with benmelstobart and received anlotinib placebo (n=212), and patients in the placebo arm received placebos for both benmelstobart and anlotinib (n=132). At the data cutoff point of the first phase of the trial, the median progress-free survival (mPFS) for the combination arm was 15.1 months, 9.7 months for the monotherapy arm, and 4.2 months for the placebo. mPFS was significantly improved for the combination arm compared to the placebo (HR 0.49 p<0.0001) and in the monotherapy arm compared to the placebo (HR 0.53, p<0.0001). PFS benefits were associated with combination and monotherapy compared to placebo in all patient subgroups analyzed. Objective response rates for the combination, monotherapy, and placebo arms were 25.6%, 23.3%, and 12.9%, respectively, and disease control rates were 84.5%, 86.1%, and 70.5%. In the second phase of the trial comparing combination therapy to monotherapy, at data cutoff, mPFS in the combination arm was 17.38 months vs 11.20 months for monotherapy (HR 0.82, p=0.1218). Survival data are immature and will be reported at a later time. Incidences of treatment-related adverse events (TRAEs) were increased in the combination arm (97.1%) and the monotherapy arm (99.1%) compared to the placebo arm (91.7%). Treatment-related serious TRAEs occurred in 38.3% of patients in the combination arm, 33.2% of patients in the monotherapy arm, and 26.5% of patients in the placebo arm. Although the general incidence of TRAEs increased in the combination arm, the safety profile was manageable. These data suggest benmelstobart with and without anlotinib provides effective consolidation therapy for patients with unresectable stage III NSCLC, providing significantly improved PFS benefits with a manageable safety profile. Long term follow-up of R-ALPS is ongoing.
The phase III DELII trial: Ultra-low does nivolumab vs. physician’s choice chemotherapy for patients in India with recurrent or refractory solid tumors
2509. Phase III randomized study comparing ultra-low dose immunotherapy to standard cytotoxic chemotherapy for solid tumors in second line and beyond setting (DELII: Development of Low dose Immunotherapy in India)
Vanita Noronha (Tata Memorial Hospital, Mumbai, India) presented results from an open label phase 3 trial of ultra-low dose nivolumab for patients with solid tumors that progressed on at least one line of systemic treatment. This study occurred in India, costs of immunotherapy limit its accessibility. A recent study of patients in India with head and neck cancer suggest that less than 3% of patients who have an indication for cancer immunotherapy do have access to immunotherapy. Other studies have shown that lower doses of nivolumab have achieved adequate target occupancy, and response rates over a dose range of 0.1 – 10 mg/kg for patients with melanoma are similar. The DELII study investigated whether low-dose nivolumab (one-twelfth of the standard dose) would be superior to physician’s choice of chemotherapy across a wide range of recurrent or relapsed solid tumors. 500 patients with relapsed or refractory solid tumors in the second-line setting were enrolled. 250 patients received ultra-low dose nivolumab (20 mg/kg), and 250 patients received physician’s choice chemotherapy. Tumors included in the study were lung, head urothelial, esophageal, and any tumor with microsatellite instability-high or mismatch repair-deficient status. Patients had received a median of 1 prior line of therapy, and 28.8% of patients were beyond the second line of therapy. Ultra-low dose nivolumab prolonged overall survival (OS) compared to chemotherapy, with median OS of 5.88 months for the nivolumab arm and 4.70 months for the chemotherapy arm (HR 0.80, p=0.022). Ultra-low dose nivolumab improved OS for all patient subgroups analyzed. Radiologic response rates for the two arms were similarly low (7.7% in the nivolumab arm and 8.1% in the chemotherapy arm), and a similar pattern was observed for progression-free survival (PFS). Median PFS was 2.04 months in the nivolumab arm and 2.09 months in the chemotherapy arm. Disease stabilization rates were 37.7% and 39.3% for the nivolumab and chemotherapy arms, respectively. Incidence of grade 3 or higher treatment related adverse events were significantly higher in the chemotherapy arm (60.3%) compared to the nivolumab arm (42.0%; p<0.001), and patient-reported quality of life was numerically higher in the nivolumab arm compared to the chemotherapy arm. Given its statistically significant improvements in overall survival and safety, these results indicate the potential of ultra-low dose immunotherapy as a new treatment option if full-dose immunotherapy is unaffordable or inaccessible. These results also support further investigations of ultra-low dose immunotherapy for specific tumor types and in curative settings.