Background/AimImmune checkpoint inhibitors (ICIs) have improved survival in metastatic renal cell carcinoma (mRCC), with nivolumab (NIVO) plus ipilimumab (IPI) showing benefits in intermediate- and poor-risk patients. Despite first-line efficacy, progression is common, requiring second-line therapies. Tyrosine kinase inhibitors (TKIs) are commonly administered after ICIs; however, the relationship between progression-free survival (PFS) in first- and second-line settings is not well defined. This study examined the correlation of PFS in patients with mRCC treated with ICIs followed by TKIs.Patients and MethodsThis retrospective multicenter study analyzed 66 patients with mRCC who received NIVO + IPI as first-line therapy and subsequent TKIs between September 2018 and February 2023. Patients were stratified according to the International Metastatic RCC Database Consortium (IMDC) risk classification.ResultsMedian PFS for second-line TKIs was 6.9 months, and overall survival was 17.7 months. While no significant correlation was observed between first- and second-line PFS in the overall cohort or the IMDC intermediate-risk subgroup, a significant positive correlation was found in the poor-risk group (Spearman’s rho=0.677, p=0.002).ConclusionTreatment outcomes in poor-risk patients may exhibit a predictable response pattern across therapy lines, potentially informing personalized treatment strategies.

1703eTiP Phase I/IIa dose-finding study of triplet regimen of relatlimab (R) ipilimumab (IPI) and nivolumab (N) in first-line therapy of metastatic melanoma (MM) (TRINITY)

1471MO Adding ipilimumab (IPI) to atezolizumab (ATEZO) plus bevacizumab (BEV) in patients (pts) with unresectable hepatocellular carcinoma (uHCC) in first-line systemic therapy (1L): PRODIGE 81/FFCD 2101 - TRIPLET HCC

2106P Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) vs chemo as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): 5-year follow-up from CheckMate 648

Despite the clear therapeutic benefits of neoadjuvant treatment (NT) with immune checkpoint inhibitors (ICIs) in clinical trials, the efficacy of NT ICIs (NT-ICI) and the optimal regimen for patients (pts) with resectable metastatic melanoma (RMM) remain to be confirmed in real life. To assess the efficacy and safety of NT-ICI among pts with RMM in real life. NEOMEL is a French retrospective multicentric cohort study. Dermato-oncologists from the French group of skin cancers included pts treated with NT-ICI for RMM (AJCC 8th stage III or IV) between July 2016 and April 2024.Pts were treated either with NT anti-programmed cell death protein-1 (anti-PD-1) monotherapy or with the combination of anti-cytotoxic T lymphocyte-associated protein-4 (anti-CTLA-4) plus anti-PD-1 (1-mg/kg ipilimumab (IPI) and 3-mg/kg nivolumab (NIVO); or 3-mg/kg IPI and 1-mg/kg NIVO).The primary endpoint was the pathological complete response (pCR) rate. The secondary endpoints were pathological response according to the International Neoadjuvant Melanoma Consortium criteria, radiological response, the occurrence of immune-related adverse events (irAEs) including those of ≥ grade 3 and outcomes with recurrence-free survivals (RFS) and event-free survivals (EFS). Among the 174 included pts, 149 (86%) underwent surgery. NT-ICI achieved a high pCR rate of 43% (95% CI, 34.9-51.3), including 44.7% (95% CI, 35.4-54.3) with NT-anti-PD-1 and 37.1% (95% CI, 21.5-55.1) with NT-IPI-NIVO (p=0.427). The major (complete + near-complete) pathological response rate was 53.2%. Radiological responses were observed in 49.9% of pts, including 12 complete responses (12.1%), of which 91.7% (n=11) corresponded to pCR. Severe immune-related adverse events (irAEs) occurred more frequently with NT-IPI-NIVO (24.4%) compared to NT-anti-PD-1 (3.1%) (p<0.001). The median RFS was 29.61 months (95% CI, 27.70-not reached [NR]) with significantly higher RFS in pts with pCR than no-pCR (HR, 0.218 [95% CI, 0.082-0.583], p=0.0009). The median EFS was 35.7 months 2 (95% CI, 28-NR). In this retrospective real-life study, NT-ICI confirms its efficacy in RMM pts, achieving high pathological response rates. However, dual checkpoint inhibition with IPI-NIVO was associated with a higher risk of severe irAEs. These findings underscore the relevance of NT-ICI for RMM in clinical practice and required further confirmation.

1O Nivolumab (NIVO) plus ipilimumab (IPI) vs NIVO monotherapy for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Health-related quality of life (HRQoL) analyses from CheckMate 8HW

157P Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line (1L) treatment in Chinese patients with unresectable/advanced hepatocellular carcinoma (HCC): CheckMate 9DW expanded analyses

ABSTRACTMyositis is a rare (<1%) but potentially severe immune‐related adverse event (irAE) of immune checkpoint inhibitors (ICIs), with a 40%–50% fatality rate. Its incidence and pathology in curative, neoadjuvant settings, particularly with chemoradiotherapy (CRT), remain poorly defined. Given the severity, stringent diagnostic and therapeutic approaches may be warranted in curative patients. In the CHINOREC trial, 50 rectal cancer (RC) patients receiving neoadjuvant CRT with ipilimumab (IPI) and nivolumab (NIVO) were prospectively monitored for myotoxicity biomarkers, including creatine kinase (CK) and cardiac troponins (cTnT, cTnI). Patients with CK and cTnT levels above the upper limit normal with or without overt clinical symptoms underwent muscle biopsy and guideline‐adapted treatment (glucocorticoids, immunoglobulin, infliximab, plasma exchange). Six patients (12%) developed biopsy‐confirmed myositis. Elevated cTnT, but not cTnI, distinguished skeletal from cardiac involvement, aligning with normal cardiac magnetic resonance imaging (CMR) findings. Immunohistochemistry showed a predominant CD8+ T cell infiltrate and patchy human leukocyte antigen (HLA) Class I upregulation. Despite myositis, all patients underwent successful tumor resection with normalized CK levels and no residual cardiac dysfunction. ICI‐induced myositis may be more frequent in neoadjuvant‐treated RC patients receiving CRT+ICI than in palliative settings. Comprehensive biomarker monitoring and early T cell‐directed intervention are essential for mitigating life‐threatening irAEs while preserving oncologic outcomes.

3501 Background: In the phase 3 CheckMate 8HW study (NCT04008030), both dual primary endpoints of progression-free survival (PFS) for first-line (1L) NIVO + IPI vs chemo (HR 0.21; P &lt; 0.0001) and NIVO + IPI vs NIVO across all lines (HR 0.62; P = 0.0003) in patients (pts) with centrally confirmed MSI-H/dMMR mCRC were met. We report expanded analyses of NIVO + IPI vs NIVO (all lines) and longer follow-up results for NIVO + IPI vs chemo (1L). Methods: The study design was described previously. Pts with MSI-H/dMMR per local testing were enrolled. After randomization, IHC and PCR based tests were used for central confirmation. PFS2 (time from randomization to progression after subsequent systemic therapy, start of second subsequent systemic therapy, or death) was a key exploratory endpoint. Results: In all randomized pts (all lines), 296 of 354 (84%) in the NIVO + IPI arm, 286 of 353 (81%) in the NIVO arm, and 113 of 132 (86%) in the chemo arm had centrally confirmed MSI-H/dMMR. In all randomized 1L pts, 171 of 202 (85%) in the NIVO + IPI arm and 84 of 101 (83%) in the chemo arm had centrally confirmed MSI-H/dMMR. Median follow-up was 47.0 mo (range 16.7–60.5). 1L NIVO + IPI continued to show PFS benefit vs chemo (Table). Subsequent systemic therapy was received by 27 (16%) and 61 (73%) pts after 1L NIVO + IPI and chemo, respectively; 10 (6%) and 21 (25%) received subsequent non-study immunotherapy. In the 1L chemo arm, 39 (46%) pts crossed over to NIVO + IPI on study. PFS2 continued to favor 1L NIVO + IPI vs chemo (Table). Across all lines, NIVO + IPI demonstrated superior PFS vs NIVO (Table). Subsequent systemic therapy was received by 54 (18%) pts in the NIVO + IPI arm and 83 (29%) in the NIVO arm; 20 (7%) and 31 (11%) received subsequent non-study immunotherapy. PFS2 favored NIVO + IPI vs NIVO across all lines of therapy (Table). In all treated pts, grade 3/4 treatment-related adverse events occurred in 78 (22%) and 50 (14%) pts in the NIVO + IPI and NIVO arms, respectively. Additional analyses will be presented. Conclusions: NIVO + IPI demonstrated sustained clinical benefit vs chemo (1L) and NIVO (all lines) despite use of subsequent therapy, as shown by improved PFS2 in pts with centrally confirmed MSI-H/dMMR mCRC. No new safety signals were observed. These results support NIVO + IPI as a standard of care treatment for MSI-H/dMMR mCRC. Clinical trial information: NCT04008030 . Centrally confirmed MSI-H/dMMR (1L) NIVO + IPI(n = 171) Chemo(n = 84) Median PFS (95% CI), mo 54.1 (54.1–NE) 5.9 (4.4–7.8) HR (95% CI) 0.21 (0.14–0.31) Median PFS2 (95% CI), mo NR (NE–NE) 30.3 (15.2–NE) HR (95% CI) 0.28 (0.18–0.44) Centrally confirmed MSI-H/dMMR (all lines) NIVO + IPI (n = 296) NIVO (n = 286) Median PFS (95% CI), mo NR (53.8–NE) 39.3 (22.1–NE) HR (95% CI) 0.62 (0.48-0.81); P = 0.0003 Median PFS2 (95% CI), mo NR (NE–NE) NR (NE–NE) HR (95% CI) 0.57 (0.42–0.78) NE, not evaluable; NR, not reached.

9527 Background: An indirect-treatment (Tx)-comparison (ITC) suggested first-line (1L) NIVO + RELA may have similar efficacy vs NIVO + IPI in clinical trial patients (pts) with untreated advanced melanoma. However, there is no real-world study comparing these Tx. This study compared survival outcomes among pts with advanced melanoma treated with 1L NIVO + RELA or NIVO + IPI in the Flatiron Health EHR-derived de-identified database, which includes ≥ 280 oncology clinics across the US. Methods: Data were extracted for pts aged ≥ 18 yrs who received 1L NIVO + RELA or NIVO + IPI between March 18, 2022 (date of NIVO + RELA FDA approval) and March 31, 2024. Pts who received adjuvant Tx, including anti–PD-1, were included, while pts with other primary cancers or treated in any clinical trial were excluded. Endpoints were OS and real-world PFS from start of 1L Tx. Outcomes were summarized using Kaplan–Meier methods, and Tx were compared using Cox models adjusted for age, sex, practice type, BRAF, brain metastases (mets), liver mets, prior adjuvant anti–PD-1 monotherapy, time from advanced melanoma diagnosis to start of 1L Tx, ECOG PS, stage, and LDH. Missing data for ECOG PS, BRAF, stage, and LDH were imputed. Results: Median (m) follow-up was 7.4 mo for NIVO + RELA (N = 408) and 7.7 mo for NIVO + IPI (N = 600). The NIVO + RELA group was older (m [IQR], 74.1 [65.9–81.5] yrs) than the NIVO + IPI group (66.2 [57.3–74.5] yrs), but generally had better prognostic factors (Table). Prior anti–PD-1 adjuvant Tx was 12% in both groups, while time from end of adjuvant Tx to 1L Tx and time from advanced melanoma diagnosis to 1L Tx trended longer with NIVO + RELA vs NIVO + IPI (Table). 74% of the NIVO + RELA group and 70% of the NIVO + IPI group were missing PD-L1 status, while 16% vs 20%, respectively, had PD-L1 &gt; 1% (P = 0.61). mOS was not reached (NR) for both groups, with 95% CIs of 20.1–NR mo for NIVO + RELA vs 21.5–NR mo for NIVO + IPI (adjusted HR, 0.91 [95% CI, 0.70–1.18]). Median rwPFS was longer with NIVO + RELA (11.5 [8.9–18.7] mo) vs NIVO + IPI (4.8 [3.7–6.3] mo; adjusted HR, 0.75 [0.61–0.91]). Conclusions: This real-world study supports the ITC observation that NIVO + RELA and NIVO + IPI convey similar OS benefits for pts with advanced melanoma. The longer rwPFS for NIVO + RELA vs NIVO + IPI warrants additional research with longer follow-up and further evaluation of baseline characteristics, as the NIVO + IPI group had poorer prognostic factors. Important limitations included short follow-up, covariate missingness, and potential unmeasured confounding. NIVO + RELA(N = 408) NIVO + IPI(N = 600) Community practice, a % 62 77 Brain mets, a % 9 21 Liver mets, a % 7 11 LDH ≤ ULN, a,b % 76 61 BRAF mutant, a,b % 40 50 ECOG PS, b %0–1≥ 2 8911 8911 Time from advanced diagnosis to 1L Tx (mo) a , m (IQR) 1.4 (0.8–3.0) 1.1 (0.7–2.1) Time from end of adjuvant therapy to 1L Tx (mo), m (IQR) 13.0 (3.4–30.0) 8.3 (0.1–20.3) a Between-Tx difference P &lt; 0.05. b Includes imputed values.

TPS9593 Background: NIVO (anti-PD1) alone or in combination with IPI (anti-CTLA-4) or RELA (anti-LAG3) are approved immune checkpoint blockade (ICB) agents for the treatment (tx) of patients (pts) with advanced, unresectable metastatic melanoma. Doublet combinations induce higher rates of durable disease control vs single agent, translating into nominal improvements in survival. While there is no established dose-response relationship for NIVO alone or with RELA, IPI at higher doses induces higher objective response rate (ORR) but increased grade ≥3 immune-related adverse events. Deeper mechanistic understanding points towards potential synergy given IPI’s role in expanding the TCR repertoire and modulating suppressive T cell populations while NIVO+RELA regulate the exhaustion signatures of activated T cells and allow for improved effector function. Recently, results from RELATIVITY-048 combining all three ICB agents (NIVO 480 mg Q4W + RELA 160 mg Q4W + IPI 1 mg/kg Q8W) demonstrated impressive efficacy with high response rates (59% ORR) and seemingly improved progression free and overall survival (PFS, OS) over previously reported doublet regimens. This study evaluated a markedly lower IPI dose than the approved regimen and did not include a dose escalation component to optimize the IPI dosing strategy. Our team seeks to optimize the dose and schedule of IPI to combine with NIVO+RELA in order to determine the recommended phase II dose (RP2D) for triplet ICB and maximize clinical benefit while maintaining a toxicity profile comparable to approved regimens. Methods: In this single center, investigator initiated, phase I/IIa study evaluating triplet ICB (NCT06683755), all pts will receive FDA approved regimen of NIVO 480mg + RELA 160mg IV Q4W along with escalating doses of IPI . Dose escalation (DE) with IPI will begin at 0.5mg/kg Q4W 4 induction doses and will incrementally escalate up to 2mg/kg Q4W. Maintenance tx will consist of NIVO+RELA Q4W. Bayesian optimal interval (BOIN) design will be used to identify the maximum tolerated dose (MTD) and RP2D (primary objective) in the DE portion, accruing an estimated 12-18 pts. The PhIIa portion will accrue an additional 12-18 pts at the RP2D to better characterize safety, and determine the ORR, (primary objective) by RECIST 1.1. Secondary objectives include PFS, OS, and tumor and immunological correlatives obtained on pre and post tx blood and tumor samples. Pts must be previously untreated, unresectable, or advanced melanoma. Non IPI containing prior adjuvant or neo-adjuvant tx will be permitted if the last dose has been &gt;6 months. Pts with asymptomatic brain metastasis are allowed, provided no immunesuppressive doses of corticosteroids are required. Safely biopsiable lesions are required for pts enrolled in the PhII portion. This study is open for accrual at MD Anderson Cancer Center in Houston, Texas. Clinical trial information: NCT06683755 .

Background:Selinexor (SEL) is an oral inhibitor of nuclear export protein Exportin 1 (XPO1) previously shown to upregulate programmed cell death protein 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression.Objective:To investigate the safety and antitumor activity of SEL, nivolumab (NIVO), and ipilimumab (IPI) in Asian patients with treatment-refractory solid organ cancers.Design:Phase I study of escalating doses of SEL in combination with NIVO + IPI. Patients were enrolled in a 3 + 3 design.Methods:NIVO and IPI were dosed at 240 mg Q2W and 1 mg/kg Q6W, respectively. SEL was dosed with a 2-week monotherapy run-in prior to triplet therapy, at dose levels (DL) 1 (40 mg once/week) and DL2 (60 mg once/week). Dose-limiting toxicity (DLT) was assessed over the first 6 weeks.Results:Twelve patients were enrolled; 11 were evaluable for response, and 6 were evaluable for DLT (1 had a non-treatment-related stroke and 5 had progressive disease (PD) prior to completion of the DLT period). The median age was 64.5 (range 39–78) years. The median line of prior therapy was 3 (range 2–5). Dose escalation proceeded through DL1 (n = 7, 3 evaluable for DLT) and DL2 (n = 5, 3 evaluable for DLT). No DLTs were observed among evaluable patients. No patients required dose reduction of SEL. Most frequent treatment-related AEs were fatigue (5/12; G ⩾ 3 = 1), nausea (5/12; G ⩾ 3 = 0), anorexia (4/12; G ⩾ 3 = 0), transaminitis (2/12; G ⩾ 3 = 0), and hypomagnesemia (2/12; G ⩾ 3 = 0). The recommended phase II dose was SEL 60 mg once/week combined with NIVO + IPI. One patient had a partial response (PR; progression-free survival (PFS) of 61 days), 3 had prolonged stable disease (SD; PFS of 141, 344, and 442 days, respectively), and 7 had PD. All patients with SD or PR had previously progressed on immunotherapy but experienced prolonged disease control on SEL in combination with NIVO + IPI.Conclusion:SEL in combination with NIVO + IPI was well tolerated without any new safety signals. The combination showed promising and durable antitumor activity in Asian patients with advanced malignancies who had failed prior immunotherapy and merits further investigation.Trial registration:NCT04850755 (https://clinicaltrials.gov/study/NCT04850755).

Health-related quality of life of patients with metastatic melanoma treated with tumor-infiltrating lymphocytes compared with ipilimumab in a randomized phase III trial.

2049 Background: Intravenous (IV) administration of ipilimumab (IPI) and nivolumab (NIVO) has shown limited activity in recurrent glioblastoma (rGBM). Intracerebral (iCer; within the brain tissue lining the resection cavity) and intracavitary (iCav; through an Ommaya reservoir) administration (admin) of IPI and NIVO was proven to be safe and resulted in promising survival outcomes (Duerinck et al. Neuro-Oncol 2024). Adding a neoadjuvant (NEOADJ) treatment phase to iCer/iCav IPI/NIVO may further improve outcome. Methods: In the Neo-Glitipni trial (NCT06097975), a single center, phase I clinical trial, patients (pts) with resectable rGBM (WHO grade 4, IDH wild type) who progressed after radiotherapy and temozolomide, with a baseline ECOG performance status of 0-2 and ≤8 mg methylprednisolone daily, received 2 NEOADJ cycles of IV IPI 1 mg/kg + NIVO 3 mg/kg followed by maximal safe resection (MSR) in week 5 with iCer admin of IPI 5 mg + NIVO 10 mg and iCav admin of IPI 1 mg + NIVO 10 mg. The adjuvant phase consists of biweekly postoperative iCav admin of IPI 1 mg + NIVO 10 mg and IV NIVO 240 mg for 12 cycles, followed by monthly NIVO 480 mg IV maintenance for up to two years. Results: 5 pts (4 male, median age 57 years (44-65); 1st recurrence in 3 pts) were enrolled. All pts received the 1 st and 4 pts also the 2 nd NEOADJ dose of IV IPI/NIVO. Out of the 5 pts, 3 were not amenable to MSR with iCer/iCav IPI/NIVO admin according to the protocol because of disease progression during the NEOADJ treatment phase and required corticosteroids (1 pt in week 2, 2 pts in week 4). Two pts successfully underwent MSR with iCer/iCav admin of IPI/NIVO per protocol. One pt initiated adjuvant treatment with iCav IPI/NIVO and IV NIVO. There were no unexpected adverse events (AE). Two pts experienced an immune-related AE that required corticosteroids and interruption of study treatment (grade 4 hepatitis in 1 pt, onset 8 days after MSR and grade 2 colitis in 1 pt, onset 28 days after MSR). One pt developed a thyroiditis during the NEOADJ treatment phase and 2 pts experienced a grade 3 treatment related AE that was not immune-related (seizure and Ommaya reservoir infection). None of the rGBM were characterized by a high tumor mutational burden on next generation sequencing. Gene expression profiling, and pharmacokinetic analysis of NIVO and IPI in the cerebrospinal fluid and blood are ongoing. After a median follow-up of 15 weeks (9-35w) all pts are alive, one pt remains free of progression (median progression free survival: 4.3 weeks). Conclusions: Four weeks of NEOADJ IV IPI/NIVO (comprising 2 admin) is safe, but symptomatic disease progression was observed in 3 out of 5 rGBM pts prior to the planned MSR with iCer/iCav IPI/NIVO admin in week 5. Therefore, the trial is being amended by shortening the NEOADJ treatment phase to 2 weeks (1 admin) and planned MSR with iCer/iCav IPI/NIVO admin in week 3. Clinical trial information: NCT06097975 .

e16051 Background: Nivolumab (NIVO) is an IgG4 anti-PD-1 monoclonal antibody, approved against advanced esophageal carcinoma (EC). Our study aimed to analyze NIVO efficacy against advanced EC [esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC)] in phase III randomized clinical trials (RCTs). Methods: We collected data through a systemic search of major databases, using MeSH terms for esophageal carcinoma and nivolumab, through December 2024. Initial search yielded 387 articles. After excluding irrelevant articles, we included four phase III RCTs, reporting NIVO efficacy in EC. Results: A total of 2062 (EAC: 539, ESCC: 1533) patients were evaluated in 4 phase III RCTs: 1270 in NIVO and 792 in chemotherapy group (Table 1). Checkmate 649 evaluated NIVO + chemotherapy vs chemotherapy alone in advanced EAC [median follow-up:13.1 months (mo)]. NIVO + chemotherapy exhibited improved efficacy vs chemotherapy: objective response rate (ORR): 60% vs 40%, median overall survival (mOS): 12.3 vs 11.6 mo [hazard ratio (HR):0.84, 0.63-1.12], and median progression-free survival (mPFS): not achieved . Checkmate 648 evaluated 3 groups; NIVO + chemotherapy, NIVO + ipilimumab (IPI) and chemotherapy in untreated and unresected advanced ESCC (median follow-up: 13 mo). NIVO + chemotherapy showed favorable efficacy vs chemotherapy: ORR: 47% vs 27%, mOS: 13.2 vs 10.7 mo (HR: 0.74, 0.58-0.96), mPFS (HR: 0.81 (0.64-1.04). NIVO + IPI vs chemotherapy exhibited ORR: 28% vs 27%, mOS: 12.7 vs 10.7 mo (HR: 0.78, 0.62-0.98). ATTRACTION-3 analyzed NIVO vs chemotherapy in refractory ESCC (median follow-up of 36 mo). NIVO vs chemotherapy revealed; ORR: 19% vs 22%, mOS: 10.9 vs 8.5 (HR: 0.79, 0.62-0.96), and mPFS: not achieved. Checkmate 577 evaluated NIVO alone vs placebo in resected advanced EC, with a median disease-free survival of 22.4 vs. 11 months, HR: 0.69,0.56-0.96. On average, grade ≥3 treatment-related adverse events, mainly gastrointestinal and hematological were more prevalent in NIVO group. Conclusions: NIVO + chemotherapy compared with chemotherapy and NIVO alone, showed superior antitumor efficacy in advanced EC (EAC, ESCC) in terms of ORR and OS with a manageable toxicity profile, providing a benchmark for future studies. Trial ID/phase Regimen Patient number Histology Median age (year) Median follow-up (mo) Overall response rate (%) Overall survival (mo) Progression-free survival (mo) Adverse events, grade ≥3 (%) Checkmate 649/III NIVO + chemotherapy, chemotherapy 103, 108 EAC 63, 62 13.1 60, 40 12.3, 11.6 NA 59.2, 45.37 Checkmate 648/III NIVO + chemotherapy, chemotherapy 321, 324 ESCC 64, 64 13 47, 27 13.2, 10.7 5.8, 5.6 47, 36 NIVO plus Ipilimumab, chemotherapy 325, 324 ESCC 64, 63 13 28, 27 12.7, 10.7 NA 32, 36 Checkmate 577/III NIVO, placebo 311, 151 ESCC, EAC 62, 61 38.5 34, 32 Attraction/III NIVO, chemotherapy 210, 209 ESCC 64, 67 36 19, 22 10.9, 8.5 1.7, 3.4 18, 63 NA: not achieved, mo: months.

2071 Background: Innovative treatments are needed for recurrent high-grade glioma (rHGG) patients (pts) as current salvage therapies fail to improve overall survival (OS). Immune checkpoint inhibitors lack efficacy in rHGG when administered IV. This single center, multicohort phase I trial (Glitipni, NCT03233152) investigated intracerebral (iCer) administration of ipilimumab (IPI) +/- nivolumab (NIVO) +/- myDC after maximal safe resection (MSR), followed by adjuvant intracavitary (iCav) IPI/NIVO through an Ommaya reservoir. Methods: Eligible pts (ECOG ≤ 2, ≤ 8mg/day methylprednisolone) with rHGG (WHO 2021 grade 3/4, IDH-1/2 wild type (wt) or mutant) after standard postoperative radiotherapy (RT) and temozolomide (TMZ) were included. Pts underwent MSR or stereotactic biopsy (if unresectable) &lt; 24h after receiving NIVO IV (10mg), followed by iCer injection of varying doses of IPI +/- NIVO +/- myDC and Ommaya catheter placement depending on the cohort (C). NIVO was administered IV (all cohorts) +/- iCav (C3-7) bi-weekly up to 12 cycles. Baseline tumor microenvironment characteristics were assessed by immunohistochemical (IHC) analysis and gene expression profiling (GEP). Results: Between 2016 and 2023, 110 pts (68% male, median age 57, 92% ECOG 0/1) were enrolled. At primary diagnosis, the majority (85%) were glioblastoma pts (WHO grade 4, IDH-wt), treated with the standard of care (MSR + RT + TMZ) (71%). All pts received 10mg NIVO IV preoperatively. Ninety percent of the pts who underwent the neurosurgical procedure started the postoperative treatment. Early discontinuation of study treatment occurred in 76% of pts, mainly due to tumor progression (86%). Treatment-related adverse events (TRAE) were mild (CTCAE grade 1/2), no grade 5 TRAE occurred. Most frequent TRAE were fatigue, headache and fever. At database lock (Jan 1st, ‘25), 9 pts remained progression-free. When including durable benefit from bevacizumab at first progression (13 pts), PFS and OS were significantly higher in C5/6 (+myDC) compared to other cohorts (-myDC) of our trial with resectable rHGG, and to a historical control group treated with VEGF(R)-inhibitors (descriptive p &lt; 0.05 for each pairwise comparison). Absence of B7H3 on resected tumor tissues as demonstrated by IHC (C4, 5, 7) showed longer median OS, which was consistent with GEP. PD-L1 expression and density of CD8, Granzyme B or FOXP3 positive cells/mm 2 did not correlate with survival. A proliferative gene signature on GEP was significantly correlated with shorter PFS and OS. Conclusions: Intracranial administration of IPI/NIVO co-administered with myDC was feasible and safe, resulting in encouraging survival in pts with resectable rHGG. Baseline B7H3 levels and a proliferative gene signature correlated with survival. Clinical trial information: NCT03233152 .

Immune checkpoint inhibitor (ICI) therapy, although effective in treating patients with a variety of advanced malignancies, can result in potentially severe or even fatal immune-related adverse events (irAEs). This study aimed to generate real-world evidence on irAE characteristics, clinical management and clinical outcomes among patients with advanced (unresectable or metastatic) malignant melanoma (a/mMM) or advanced renal cell carcinoma (aRCC) treated with nivolumab (NIVO) and/or ipilimumab (IPI) in the UK. This was a multi-centre, retrospective cohort study of adult patients with a/mMM or aRCC, who received NIVO and/or IPI at one of five specialist treatment centres in the UK between 1 January 2016 and 31 March 2020. The incidence and grading of irAEs were described, as well as time to irAE onset, the management of irAEs and overall survival (OS). In total, 199 patients were included in the study: 162 with a/mMM and 37 with aRCC. The majority of patients in both a/mMM (75.3%) and aRCC (62.2%) cohorts reported any irAE, while 45.9% and 30.4% in the a/mMM and aRCC cohorts reported grade 3 or 4 irAEs, respectively. Colitis/diarrhoea, skin reactions and hepatitis were most frequently reported, and the predominant treatment prescribed for any irAE was corticosteroids only. Analysis indicated a positive association between the development of an irAE and longer OS. Findings from this study support current literature, provide further insights into the characteristics and clinical management of irAEs and support an association between the development of an irAE and improved OS in these patient groups.

Ipilimumab (IPI) improved outcomes for patients with high-risk melanoma compared with IFN-α2b in E1609, a phase III adjuvant trial. We hypothesized that combining candidate immune biomarkers in both tumor and circulating blood could generate a superior predictive biomarker signature. We conducted gene expression profiling on baseline tumors of patients treated with IPI and IFN. We also performed multicolor flow cytometry to compare cellular marker expression on thawed peripheral blood mononuclear cells and Luminex multiplex assay to measure serum biomarkers. We tested the expression levels of 31 genes and 40 circulating biomarkers in relation to survival outcomes. We then developed two separate multivariate Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression models followed by integrative modeling of risk prediction using the prioritized biomarkers. In blood, enriched populations of CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, CTLA4+IFN-γ+CD8+ T cells, and higher levels of CCL3 and CXCL11 were associated with significantly improved overall survival and relapse-free survival, whereas high levels of CTLA4+ regulatory T cells (CD3+CD4+CD25hi+CD152+) and monocytic myeloid-derived suppressor cells (Lin-CD33+HLA-DrloCD14+CD15+) correlated with worse overall survival and relapse-free survival. In tumor, CXCL9, CD8A, CXCL10, and inositol polyphosphate-5-phosphatase D were identified as tier-1 (P < 0.05) and indoleamine 2, 3-dioxygenase 1, Igκ constant, and IL2RB as tier-2 (P < 0.1) biomarkers of survival. Multivariate survival analysis identified that ∼50% of the risk groups were defined by circulating and tumor biomarker models, indicating complementary features of defining risk groups in IPI-treated but not in IFN-treated patients. Integrating candidate blood and tumor immune-related biomarkers generated a baseline signature that maximizes the prediction of immunotherapeutic benefits in reference to the compartmental biomarker signatures.

Association of Immune-Related Adverse Events With Efficacy in Consolidation Nivolumab Plus Ipilimumab or Nivolumab Alone After Chemoradiation in Patients With Unresectable Stage III Nonsmall Cell Lung Cancer: An Exploratory Analysis From the Big 10 Cancer Research Consortium Study BTCRC LUN 16-081.

Abstract Background: The composition of the tumor microenvironment (TME) can regulate T cell infiltration and potentially immunotherapy efficacy. Versican (VCAN), an extracellular matrix proteoglycan, regulates the presence of tumor infiltrating lymphocytes (TILs) and their activation, while its proteolytic byproduct, versikine (Vkine), can stimulate an immune response. Here we aim to validate our prior findings that VCAN status correlates with CD8+ T cell infiltration in intestinal cancers and evaluate the predictive role of VCAN/Vkine for patients undergoing immunotherapy for microsatellite instability high (MSI-H) cancers. Methods: A total of 28 consented subjects were identified with intestinal cancers that were MSI-H, high tumor mutation burden, or with alterations in mismatch repair genes as part of an IRB-approved protocol. Baseline characteristics, immunotherapy response, and survival data were collected. Cancer samples were obtained and stained for VCAN, Vkine, and CD8+ TILs. An intensity binning system was used to score VCAN and Vkine, ranging from 0-3. TILs were averaged across high power fields (HPF). Cancers with high VCAN (2-3) and any Vkine were categorized as VCAN proteolytic weak (VPW), cancers with low VCAN (0-1) and high Vkine (2-3) as VCAN proteolytic predominant (VPP), and cancers with both low VCAN (0-1) and low Vkine (0-1) as VCAN/Vkine low (VVL). Results: Clinical characteristics of the 28 subjects studied: median age 62.5 years (32-90); 17 females; 19 colon cancers; six rectal cancers; one rectosigmoid cancer and two small intestinal cancers. Further, nineteen were stage 3, nine were stage 4 and 71% were MSI-H. Six were VVL, one was VPP and 21 were VPW. The VVL and VPP cancers had a median of 27 CD8+ TILs/HPF, while the VPW cohort had a median of 15.7 (p=0015). CD8+ TILs in the MSI-H VPW subset trended higher than the microsatellite stable VPW cancers (21.7 versus 8.5; p=0.35). Thirteen subjects with MSI-H cancers received immunotherapy (10 pembrolizumab (PEMBRO), three ipilimumab (IPI) and nivolumab (NIVO)). Of these cancers, six were VPW and completed PEMBRO. None of the VPW cancers achieved a complete response to PEMBRO alone with most developing progressive disease. An additional VPW subject is still receiving therapy with a partial response to PEMBRO to date. Two patients with VPW cancers received IPI and NIVO and had complete responses. The four subjects with VVL or VPP cancers have all achieved a complete response and are alive without cancer recurrence. Three were treated with PEMBRO and one with IPI and NIVO. Conclusion: The VCAN status in the TME of intestinal cancers shows promise as a biomarker for T cell infiltration and response to immune checkpoint blockade. The ability of VCAN status to identify patients who are more likely to benefit from dual immune checkpoint blockade deserves further investigation. Citation Format: Elizabeth L. Field, Sean Kraus, Madeleine Buratti, Heidi Koehnke, Cheri A. Pasch, Fotis Asimakopoulos, Dustin A. Deming. Versican abundance/proteolysis as a biomarker for immunotherapy efficacy in intestinal cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3282.