Nivolumab Research Articles

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.

CA209-7AL is a randomized, multicenter, phase 2 trial evaluating the efficacy and safety of consolidative nivolumab (NIVO) versus observation following neoadjuvant NIVO plus chemotherapy and concurrent chemoradiotherapy (CCRT) for unresectable stage III NSCLC. Patients received 2 cycles of neoadjuvant chemo-NIVO therapy (docetaxel + cisplatin + NIVO) and CCRT (total dose 54–64 Gy). Post-CCRT, eligible patients were randomized 1:1 to receive consolidative NIVO (360 mg every 3 weeks for up to 12 months) or observation. The primary endpoint was progression-free survival (PFS) from randomization. Between December 3rd, 2019, and August 18th, 2023, 264 patients were enrolled, and 172 were randomized to NIVO consolidation (n = 86) or observation (n = 86). With a median follow-up of 22·8 months, NIVO consolidation resulted in significantly longer PFS than did observation (median not reached vs. 12.2 months [95% CI 10.2–20.8]; stratified hazard ratio 0·49 [95% CI 0.30–0.79], p = 0.003). NIVO consolidation also demonstrated superior PFS compared with a parallel real-world study, where patients received CCRT followed by consolidative immunotherapy (median PFS: 15.7 months [95% CI 11.9-NA]). Grade 3 or 4 toxicities occurred in 9.3% of patients in the consolidation group versus 4·6% in the observation group, with similar rates of pneumonitis (2.3% each) and proximal bronchial tree toxicity (3.5% vs. 2.3%). Treatment-related death occurred in 1 (1.2%) patient in the consolidation group because of pneumonitis. Patients with a high TMB had a longer PFS with consolidation (NR vs. 15.2 months, p = 0.042). Consolidative NIVO following neoadjuvant NIVO plus chemotherapy and CCRT demonstrated effectiveness and tolerability for patients with unresectable stage III NSCLC (ClinicalTrials.gov NCT04085250).

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.

Purpose:Administration of the lymphocyte activation gene 3 (LAG-3) inhibitor relatlimab (RELA) and the PD-1 inhibitor nivolumab (NIVO) significantly prolonged progression-free survival (PFS) versus NIVO alone in patients with advanced melanoma treated in RELATIVITY-047. This report describes correlative analyses of biospecimens collected within that trial to better understand the mechanisms of action and identify patients who could benefit from treatment with NIVO + RELA.Patients and Methods:Pre- and on-treatment peripheral blood samples from 563 patients were analyzed using flow cytometry for changes in 77 prespecified immune cell populations and using immunoassay for peripheral IFNγ. Pretreatment tumor biopsies were evaluated using IHC and RNA sequencing.Results:On-treatment expansion of 25 peripheral immune cell populations was significantly greater with NIVO + RELA versus NIVO alone. Responders to NIVO + RELA had greater on-treatment increases in LAG-3+CD4+ T cells than nonresponders. Significantly greater increases in peripheral IFNγ occurred after treatment with NIVO + RELA versus NIVO alone. A longer PFS was observed in patients treated with NIVO + RELA whose tumors had low CD8 expression compared with the NIVO arm. When evaluating the co-expression of CD8 and LAG-3, patients whose tumors had high CD8+LAG-3+ also showed a PFS benefit with NIVO + RELA versus NIVO. RNA sequencing revealed several distinct gene signatures associated with response to NIVO + RELA.Conclusions:These results highlight the unique biological effects of RELA in combination with NIVO and provide further understanding of the patient characteristics associated with increased benefit from NIVO + RELA.

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.

453P Real-world (RW) evidence in gastric and esophageal cancer: First results of patients (pts) treated with nivolumab (NIVO) plus chemotherapy (chemo) from the noninterventional INGA study in Germany

LBA8010 Background: The phase 3 CheckMate 77T study demonstrated statistically significant and clinically meaningful improvement in EFS with perioperative NIVO vs PBO in pts with resectable NSCLC. pCR rates were also improved. Here, we report updated EFS, OS from the first prespecified interim analysis, and exploratory biomarker analyses. Methods: Pts with resectable stage IIA–IIIB (N2; AJCC v8) NSCLC were randomized 1:1 to neoadjuvant (neoadj) NIVO + chemotherapy (chemo) Q3W (up to 4 cycles [cyc]) followed by adjuvant (adj) NIVO Q4W (up to 13 cyc) or neoadj PBO + chemo Q3W (up to 4 cyc) followed by adj PBO Q4W (up to 13 cyc). The primary endpoint was EFS per BICR. Secondary endpoints included pCR, OS, and safety. Exploratory analyses included efficacy by pCR status, presurgery ctDNA clearance (CL), and tumor genomic alterations. Results: At a median follow-up of 41.0 mo (database lock, 16 Dec 2024), NIVO continued to provide EFS benefit vs PBO (HR [95% CI], 0.61 [0.46–0.80]; 30-mo EFS rates, 61% vs 43%) in all randomized pts and regardless of disease stage, tumor histology, or PD-L1 expression (Table). EFS from surgery (HR [95% CI]) continued to favor NIVO vs PBO in pts with pCR (0.90 [0.19–4.15]) or without (w/o; 0.72 [0.50–1.05]). In biomarker-evaluable pts (NIVO, 98; PBO, 92), pts with ctDNA CL had greater EFS benefit (assessed from randomization) vs pts w/o (HR [95% CI]: NIVO, 0.41 [0.20–0.86]; PBO, 0.62 [0.31–1.22]); pts with ctDNA CL with or w/o pCR had improved EFS vs pts w/o ctDNA CL and pCR (data to be presented). EFS (HR [95% CI]) favored NIVO vs PBO in pts with tumor genomic alterations ( KRAS , and/or STK11 , and/or KEAP1 mutations; 0.63 [0.32–1.23]) or w/o (0.65 [0.39–1.10]). Higher ctDNA CL and pCR rates were seen with NIVO vs PBO regardless of mutation status; additional efficacy and ctDNA outcomes will be presented. At the first prespecified interim OS analysis, NIVO showed a trend of OS improvement vs PBO in all randomized pts (HR [97.63% CI], 0.85 [0.58–1.25]; median OS, not reached in both tx arms; 30-mo OS rates, 78% vs 72%). Safety outcomes were consistent with previous reports. Conclusions: In this update, perioperative NIVO continued to show long-term EFS benefit and a favorable OS trend vs PBO in pts with resectable NSCLC; no new safety signals were observed. In exploratory analyses, presurgery ctDNA CL was associated with EFS benefit. EFS favored NIVO vs PBO regardless of KRAS , STK11 , and KEAP1 mutation status. Clinical trial information: NCT04025879 . All pts Stage II Stage III Squamous Non-squamous PD-L1 &lt; 1% PD-L1 ≥ 1% NIVO (N = 229) vs PBO(N = 232) NIVO (n = 80) vs PBO(n = 81) NIVO (n = 149) vs PBO(n = 149) NIVO (n = 116) vs PBO(n = 118) NIVO (n = 113) vs PBO(n = 114) NIVO (n = 93) vs PBO(n = 93) NIVO (n = 128) vs PBO(n = 128) Median EFS, mo 46.6 vs 16.9 NR vs NR 42.1 vs 13.4 NR vs 16.4 40.1 vs 16.9 40.1 vs 19.8 46.6 vs 15.1 HR (95% CI) 0.61(0.46–0.80) 0.77(0.46–1.30) 0.54(0.39–0.74) 0.53(0.35–0.80) 0.69 (0.48–1.00) 0.79(0.52–1.21) 0.53(0.36–0.76)

LBA2 Background: The standard of care (SOC) over the past two decades for resected locally advanced SCCHN (LA-SCCHN) with high-risk of relapse is adjuvant cisplatin-radiotherapy (CRT). Despite these definitive treatments, many patients develop recurrence, indicating that more effective treatments are needed. This study evaluated the addition of nivolumab (NIVO) to SOC CRT compared to SOC CRT alone after surgery. Methods: NIVOPOSTOP is an international randomized, open-label Phase 3 trial (NCT03576417). Main inclusion criteria were patients &lt; 75 years, ECOG PS 0-1, with resected LA-SCCHN of the oral cavity, oropharynx (OPC), hypopharynx or larynx at high-risk of relapse defined by presence of nodal extra capsular extension and/or positive tumor margins, ≥4 nodal involvements, multiple peri-neural invasion. The primary endpoint was Disease Free Survival (DFS); key secondary endpoints include overall survival (OS) and safety. Patients were randomized 1:1 after surgery to receive Arm A SOC 66 Gy RT and cisplatin (100 mg/m2 every 3 weeks (Q3W) for three cycles) or Arm B NIVO 240 mg, followed by SOC CRT with 3 cycles of NIVO 360 mg Q3W, and followed by 6 cycles of NIVO 480 mg Q4W. Treatment allocation was done by minimization for centers and p16 status. To detect a HR of events of 0.65 at 2-sided alpha error 0.05 and power 90%, 230 events were required. Analysis was performed when this required number of events was reached (cutoff date April 30, 2024). Results: A total of 680 patients were randomized. DFS analysis was based on 666 patients randomized before the cutoff date (334 in Arm A vs 332 in Arm B; intent-to-treat analysis) and 252 events at a median follow-up of 30.3 months (IQR 16.0; 44.9). Baseline characteristics were balanced between both arms. DFS was significantly improved across PD-L1 all-comers with adjuvant NIVO + CRT vs. CRT alone (HR 0.76 (95% CI, 0.60-0.98); stratified log rank test p value = 0.034). The 3-year DFS was 52.5% (95% CI, 46.2-58.4%) with CRT vs. 63.1% (57-68.7%) with NIVO + CRT. The analysis of OS will occur when the required number of deaths will be reached (currently 158 and required 283 deaths). The compliance with CRT was similar in both arms. Safety analysis up to 9 months after CRT was based on patients who received at least one administration of treatment. Patients experiencing grade 4 adverse events were less frequent in patients receiving CRT vs. NIVO + CRT (5.6% vs. 13.1% until 100 days after CRT and then 0% vs. 1.2% up to 9 months), and treatment related deaths occurred in 0.7% and 0.6% of patients, respectively. Conclusions: Adjuvant NIVO added to CRT after surgery provided a statistically and clinically meaningful DFS improvement in PD-L1 all-comers patients. This is the first time in over 2 decades that a therapy demonstrated superiority over SOC CRT in patients with resected LA-SCCHN at high-risk of relapse. Clinical trial information: NCT03576417 .

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.

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.

8527 Background: The addition of RELA HD, a lymphocyte activation gene-3 (LAG-3) inhibitor, to NIVO + PDCT has improved clinical benefits vs NIVO + PDCT for pts with PD-L1 expression ≥1% and NSQ histology in RELATIVITY-104 study. We report exploratory biomarker analyses from this study to elucidate mechanisms underlying NIVO + RELA HD + PDCT activity. Methods: Baseline and on-treatment blood samples were analyzed by flow cytometry for pharmacodynamic (PD) changes in immune cell populations including proliferating LAG-3-expressing CD4+ and CD8+ effector memory (EM) and central memory (CM) T cells. Baseline tumor samples were analyzed by monoplex immunohistochemistry (IHC) for tumor cell PD-L1, LAG-3, and CD8 expression. Associations between biomarkers and overall response rate (ORR) and progression free survival (PFS) were assessed. Results: NIVO + RELA HD + PDCT significantly modulated levels of proliferating LAG-3 expressing EM and CM T cells in the periphery on-treatment; no such PD change was observed with NIVO + PDCT. Among pts with NSQ histology, baseline tumor LAG-3 expression ≥1% showed improved ORR and median PFS in both treatment arms compared with LAG-3 &lt;1%. Further, the benefit of RELA HD addition to NIVO + PDCT was also seen in patients with LAG-3 &lt;1%, suggesting that baseline LAG-3 expression at 1%, unlike PD-L1 expression, would not help identify patients who can benefit from LAG-3 inhibition (Table). In contrast to NSQ, the same association trend of PD-L1 and LAG-3 expression with efficacy was not observed in pts with SQ histology, which could be partly attributable to the limited sample size in some SQ subgroups. Interestingly, PD-L1 ≥1% is more strongly correlated with CD8 T cells in NSQ as compared to SQ. Conclusions: These data represent the first in-depth biomarker analyses from a randomized phase 2 study to reveal that RELA can expand proliferating LAG-3 expressing T cells in NSCLC. NIVO + RELA HD + PDCT activity might be particularly robust in pts with NSQ histology and PD-L1 expression ≥1%, where CD8 T cells are enriched. The ongoing phase 3 RELATIVITY-1093 study is evaluating 1L NIVO + RELA HD + PDCT vs standard-of-care pembrolizumab + PDCT in mNSCLC. Clinical trial information: NCT04623775 . Efficacy of NIVO + RELA HD + PDCT vs NIVO + PDCT in pts with NSCLC by baseline histology, PD-L1 and LAG-3 expression. NIVO + RELA HD + PDCTvsNIVO + PDCT NSQ, PD-L1 ≥1%(n = 50 vs 48) NSQ, PD-L1 &lt;1%(n = 48 vs 46) NSQ,LAG-3 ≥1%(n = 56 vs 42) NSQ,LAG-3 &lt;1%(n = 38 vs 42) SQ,PD-L1 ≥1%(n = 29 vs 23) SQ,PD-L1 &lt;1%(n = 22 vs 21) SQ,LAG-3 ≥1%(n = 38 vs 34) SQ,LAG-3 &lt;1%(n = 13 vs 10) PFS HR(90% CI) 0.55(0.36–0.85) 1.24(0.84, 1.83) 0.81(0.54, 1.22) 0.79(0.51, 1.23) 0.78(0.46, 1.34) 1.25(0.7, 2.23) 0.97(0.61, 1.52) 0.98(0.45, 2.15) ORR, % 58% vs 39.6% 35.4% vs 34.8% 57.1% vs 45.2% 34.2% vs 26.2% 44.8% vs 43.5% 81.8% vs 66.7% 52.6% vs 55.9% 84.6% vs 50%

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 .

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).

11514 Background: It was hypothesized that anthracycline-based chemotherapy plus anti-PD1 (nivolumab) could enhance the activity of upfront chemotherapy in advanced UPS, based on a double-hit in the immunogenic cell death circuit. This peculiar tumor cell death eventually activates an adaptive immune response through particular molecular changes in dying tumor cells and microenvironment, triggered by specific drugs such as anthracyclines. We previously reported a phase Ib trial in leiomyosarcoma patients with the combination of doxorubicin, dacarbazine, and nivolumab, obtaining 56.5% of ORR. We present here the phase Ib, cohort 7a, of the ImmunoSarc2 trial. Methods: Adult patients (pts), with ECOG 0-1, naïve of previous anthracycline-containing treatments, and with a centrally confirmed diagnosis of advanced/metastatic UPS were eligible. Initial dose level 0 (L0) was defined as epirubicin 60 mg/m 2 /d 20 min on D1 and D2 followed by ifosfamide 3 g/m 2 /d 3-h on D1-3, plus nivolumab (NIV) 360 mg on D3 after chemotherapy. Cycles were given Q3W with GCSF and MESNA support. This combo would be given up to 6 courses of 21-day cycles, followed by 1-year NIV maintenance. A -1 dose level (L-1) was defined with the same regimen but with NIV 240 mg. A classic 3+3 phase 1 design was used to determine the MTD based on DLTs (main endpoint) observed during the first 21-day cycle. The cohort was foreseen to be extended with the RP2D to include up to a maximum of 20 evaluable patients. Secondary endpoints included ORR and safety profile among others. Results: Between January 2022 and June 2024, 16 patients M/F (9/7), ECOG 0/1 (15/1), with median age 56 years (29-77) were enrolled. All patients were treated with the initial L0 scheme and no DLTs were observed, being L0 the RP2D. Grade 3-4 toxicities were neutropenia 62.5%, febrile neutropenia 18.8%, anemia 31.3%, and thrombocytopenia 25%. A patient died following a subarachnoid hemorrhage in the context of grade 4 thrombocytopenia and an accidental fall. Of 16 patients, RECIST ORR according to local clinical site assessment was 68.8% distributed as 1 CR (6%), 10 PR (63 %), 4 SD (25%), and 1 PD (6%). With a median follow-up of 16.3 months (95% CI, 7.2-25.4), the median of PFS was 9.9 months (95% CI 7-12.7), while the median OS was not reached, and the 1-year OS rate was 81% (95% CI 62-100). Conclusions: Epirubicin 60 mg/m 2 /d d1-2 plus Ifosfamide 3 g/m 2 /d d1-3 plus NIV 360 mg on d3 Q3W, followed by 1 year of NIV is a feasible and manageable scheme that exhibits relevant activity as an upfront line in advanced UPS patients. A phase II/III trial is designed aiming to confirm the advantage of chemo-immunotherapy over chemotherapy alone in this context. Clinical trial information: NCT03277924 .

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 .

Estimating the Impact of Adjuvant Treatment With Nivolumab on Long-Term Survivorship Rates Compared With Surveillance in Muscle Invasive Urothelial Carcinoma: Mixture Cure Modeling Analyses of Disease-Free Survival From the Phase 3 CheckMate 274 Trial.

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 .