Adjuvant Immunotherapy Research Articles

Persistently Elevated Expression of Systemic, Soluble Co-Inhibitory Immune Checkpoint Molecules in People Living with HIV before and One Year after Antiretroviral Therapy.

Increasing drug resistance and the absence of a cure necessitates exploration of novel treatment strategies for people living with HIV (PLWH). Targeting of soluble co-inhibitory immune checkpoint molecules (sICMs) represents a novel, potentially effective strategy in the management of HIV. In this retrospective, longitudinal, observational study, the plasma levels of five prominent co-inhibitory sICMs-CTLA-4, LAG-3, PD-1 and its ligand PD-L1, as well as TIM-3-were quantified in 68 PLWH-before and one year after antiretroviral therapy (ART)-and compared with those of 15 healthy control participants. Relative to control participants, PLWH had substantially elevated pre-treatment levels of all five co-inhibitory sICMs (p < 0.0001-p < 0.0657), which, over the 12-month period of ART, remained significantly higher than those of controls (p < 0.0367-p < 0.0001). PLWH with advanced disease, reflected by a CD4+ T cell count <200 cells/mm3 before ART, had the lowest levels of CTLA-4 and LAG-3, while participants with pre-treatment HIV viral loads ≥100,000 copies/mL had higher pre-treatment levels of TIM-3, which also persisted at 12 months. Plasma levels of CTLA-4, LAG-3, PD-1, PD-L1 and TIM-3 were significantly elevated in treatment-naïve PLWH and remained so following one year of virally-suppressive ART, possibly identifying LAG-3 and TIM-3 in particular as potential targets for adjuvant immunotherapy.

Histological predictors of aggressive recurrence of hepatocellular carcinoma after liver resection

Assessment of recurrence risk after liver resection (LR) is critical in hepatocellular carcinoma (HCC), particularly with the advent of effective adjuvant therapy. The aim of this study was to analyze the clinical and pathological factors associated with recurrence, aggressive recurrence, and survival after LR. We performed a retrospective study in which all single HCC (BCLC-0/A) patients treated with LR between February 2000 and November 2020 were included. The main clinical variables were recorded. Histological features were blindly evaluated by two independent pathologists. Aggressive recurrence was defined as those that exceeded the Milan criteria at 1st recurrence. A total of 218 patients were included (30% BCLC 0 and 70% BCLC A), median (IQR) tumor size of 28 (19-42mm). The prevalence of microvascular invasion and/or satellitosis (mVI/S) was 39%, with a kappa-index between both pathologists of 0.8. After a median follow-up of 49 (23-85) months, 61/218 (28%) patients died, 32/218 (15%) underwent liver transplantation, 127 (58%) developed HCC recurrence. The prevalence of aggressive recurrence was 35% (44/127 Milan-out, with 20 cases at advanced stage), and the 5-year survival rate was 81%. The presence of mVI/S was the only independent predictor of recurrence (hazard ratio [HR] 1.83, 95% CI 1.28-2.61, p <0.001), aggressive recurrence (HR 3.31, 95% CI 1.74-6.29, p <0.001) and mortality (HR 2.23, 95% CI 1.27-3.91, p= 0.005). The macrotrabecular-massive subtype was significantly associated with a higher prevalence of mVI/S, Edmonson Steiner grade III-IV, AFP values and vessels that encapsulate tumor clusters, but not with recurrence, aggressive recurrence, or overall survival. The presence of mVI/S was the only independent risk factor for aggressive recurrence and mortality. This has important implications for early-stage patient management, especially in the setting of adjuvant immunotherapy or ab initio LT. Assessment of recurrence risk after liver resection is crucial in patients with hepatocellular carcinoma. Patients with a high risk of recurrence are candidates for liver transplantation as an ab initio indication or for the potential use of adjuvant therapy. Aggressive recurrences, defined as those exceeding the Milan criteria at first recurrence, have a significant impact on overall survival (OS). Fifty-eight percent of patients experienced hepatocellular carcinoma recurrence, with a prevalence of aggressive recurrence at the first occurrence standing at 35%. After a median follow-up of 49 (23-85) months, 61 (28%) patients died, and 32 (15%) underwent liver transplantation, resulting in a 5-year OS rate of 81%. Microvascular invasion and/or satellitosis was present in 39% of our cohort and was the only independent predictor of recurrence, aggressive recurrence, and OS on multivariate analysis. This is important as it could be used to guide therapeutic management.

Drug Delivery Opportunities in Esophageal Cancer: Current Treatments and Future Prospects.

With one of the highest mortality rates of all malignancies, the 5-year survival rate for esophageal cancer is under 20%. Depending on the stage and extent of the disease, the current standard of care treatment paradigm includes chemotherapy or chemoradiotherapy followed by surgical esophagogastrectomy, with consideration for adjuvant immunotherapy for residual disease. This regimen has high morbidity, due to anatomic changes inherent in surgery, the acuity of surgical complications, and off-target effects of systemic chemotherapy and immunotherapy. We begin with a review of current treatments, then discuss new and emerging targets for therapies and advanced drug delivery systems. Recent and ongoing preclinical and early clinical studies are evaluating traditional tumor targets (e.g., human epidermal growth factor receptor 2), as well as promising new targets such as Yes-associated protein 1 or mammalian target of rapamycin to develop new treatments for this disease. Due the function and location of the esophagus, opportunities also exist to pair these treatments with a drug delivery strategy to increase tumor targeting, bioavailability, and intratumor concentrations, with the two most common delivery platforms being stents and nanoparticles. Finally, early results with antibody drug conjugates and chimeric antigenic receptor T cells show promise as upcoming therapies. This review discusses these innovations in therapeutics and drug delivery in the context of their successes and failures, with the goal of identifying those solutions that demonstrate the most promise to shift the paradigm in treating this deadly disease.

Digital assessment of tertiary lymphoid structures and therapeutic responses in gastric cancer: A multi-centric retrospective study.

Tertiary lymphoid structures (TLSs) are associated with favorable prognosis and enhanced response to anti-cancer therapy. A digital assessment of TLSs could provide an objective alternative that mitigates variability inherent in manual evaluation. This study aimed to develop and validate a digital gene panel based on biological prior knowledge for assessment of TLSs, and further investigate its associations with survival and multiple anti-cancer therapies. The present study involved 1,704 patients with gastric cancer from seven cancer centers. TLSs were identified morphologically through hematoxylin-and-eosin staining. We further developed a digital score based on targeted gene expression profiling to assess TLSs status, recorded as gene signature of tertiary lymphoid structures (gsTLS). For enhanced interpretability, we employed the SHapley Additive exPlanation (SHAP) analysis to elucidate its contribution to the prediction. We next evaluated the signature's associations with prognosis, and investigated its predictive accuracy for multiple anti-cancer therapies, including adjuvant chemotherapy and immunotherapy. The gsTLS panel with nine gene features achieved high accuracies in predicting TLSs status in the training, internal and external validation cohorts (area under the curve, range: 0.729-0.791). In multivariable analysis, gsTLS remained an independent predictor of disease-free and overall survival (hazard ratio, range: 0.346-0.743, all P < 0.05) after adjusting for other clinicopathological variables. SHAP analysis highlighted gsTLS as the strongest predictor of TLSs status compared with clinical features. Importantly, patients with high gsTLS (but not those with low gsTLS) exhibited substantial benefits from adjuvant chemotherapy (P < 0.05). Furthermore, we found that the objective response rate to anti-programmed cell death protein 1 (anti-PD-1) immunotherapy was significantly higher in the high-gsTLS group (40.7%) versus the low-gsTLS group (5.6%, P = 0.036), and the diagnosis was independent from Epstein-Barr virus (EBV), tumor mutation burden (TMB), and programmed cell death-ligand 1 (PD-L1) expression. The gsTLS digital panel enables accurate assessment of TLSs status, and provides information regarding prognosis and responses to multiple therapies for gastric cancer.

Differential predictive value of tissue-specific PD-L1 expression scores in adjuvant immunotherapy of melanoma.

Adjuvant treatment of stage II-IV melanoma with PD-1-based immune checkpoint inhibitors (ICI) has improved relapse-free survival (RFS) and has therefore become a standard-of-care treatment option. Approximately 25%-30% of patients still recur within 1 year. Predictive biomarkers reflecting real-world data are desired. The predictive relevance of tumour tissue PD-L1 expression in the adjuvant setting remains inconclusive. This retrospective, observational study was conducted to evaluate the value of PD-L1 expression scores in different tumour tissue locations in predicting response towards adjuvant immunotherapeutic treatment. Tumour tissue taken prior to anti-PD-1 adjuvant ICI in 243 stage II-IV melanoma patients was collected at University Skin Cancer Center Hamburg. PD-L1 expression was evaluated on immune cells (ICS), tumour cells (TPS) and combined (CPS). Scores were determined by independent pathological physician quantification and correlated with therapy outcome at different cut-off (CO) levels (relapse-free survival, RFS) for different tumour tissue locations (primary tumour, metastases). A total of 104 patients were eligible for analysis. Positivity of ICS, TPS and CPS showed no predictive RFS outcome association at different CO levels when analysed irrespective of tissue origin. In primary tumours, ICS at CO 1% showed a significantly improved RFS upon positivity (HR 0.22). In contrast, positivity to TPS (CO 1%) correlated significantly and independently with improved RFS when evaluated in metastatic tumour tissue specimens (HR 0.37). PD-L1 tumour tissue expression may serve as a predictive biomarker for adjuvant ICI treatment response stratification in melanoma, but caution should be spent on the origin of tumour tissue analysed. The cell-type relevant for the predictive value of PD-L1 expression is tissue-specific with immune cells being important in primary tumours while tumour cells are key in metastases. The present results should be validated in a multicentre cohort.

Recurrence patterns following nephrectomy for renal cell carcinoma in a Danish nationwide cohort.

This study aimed to characterize the demographic and clinical features of patients with renal cell carcinoma (RCC) post-surgery for localized or locally advanced disease in a national Danish cohort, with a specific focus on describing recurrence patterns in a subgroup aligned with the adjuvant KEYNOTE-564 trial classification. This was a retrospective analysis of the Danish Renal Cancer (DaRenCa) database. Eligible subjects were individuals with an RCC diagnosis between January 2014 and December 2017 who subsequently underwent radical or partial nephrectomy. Variables of interest were demographic and clinical characteristics, rates and sites of recurrence. Recurrence rates were also assessed in a subpopulation stratified using the risk classifications of the KEYNOTE-564 trial. A total of 2164 RCC patients were identified. Most patients (84.8%) had non-metastatic RCC (stage M0). A recurrence was observed in 250 of the M0 patients (13.6%). Patients with a recurrence were older, male, had a higher tumour stage, had undergone radical nephrectomy and had a higher Leibovich score. The majority (74.8%) of M0 patients had recurrence at distant metastatic sites. A total of 392 patients were stratified by the KEYNOTE-564 risk classification: 335 intermediate-high risk, 17 high risk and 40 M1 NED (metastatic with no evidence of disease). Recurrence was observed in 37.0%, 88.2% and 27.5% of these risk groups, respectively. This study elucidates the rates and determinants of post-surgical RCC recurrence in Denmark, underscoring the potential of adjuvant immunotherapy in refining therapeutic strategies, identifying suitable beneficiaries and minimizing overtreatment risks in RCC care.

TNIK Inhibition Sensitizes TNIK-Overexpressing Lung Squamous Cell Carcinoma to Radiotherapy.

Most patients with lung squamous cell carcinoma (LSCC) undergo chemotherapy, radiotherapy, and adjuvant immunotherapy for locally advanced disease. The efficacy of these treatments is still limited because of dose-limiting toxicity or locoregional recurrence. New combination approaches and targets such as actionable oncogenic drivers are needed to advance treatment options for patients with LSCC. Moreover, other options for chemotherapy-ineligible patients are limited. As such, there is a critical need for the development of selective and potent chemoradiosensitizers for locally advanced LSCC. In this study, we investigated inhibiting TRAF2- and NCK-interacting protein kinase (TNIK), which is amplified in 40% of patients with LSCC, as a strategy to sensitize LSCC tumors to chemotherapy and radiotherapy. Employing a range of human LSCC cell lines and the TNIK inhibitor NCB-0846, we investigated the potential of TNIK as a chemo- and radiosensitizing target with in vitro and in vivo preclinical models. The combination of NCB-0846 with cisplatin or etoposide was at best additive. Interestingly, pre-treating LSCC cells with NCB-0846 prior to ionizing radiation (IR) potentiated the cytotoxicity of IR in a TNIK-specific fashion. Characterization of the radiosensitization mechanism suggested that TNIK inhibition may impair the DNA damage response and promote mitotic catastrophe in irradiated cells. In a subcutaneous xenograft in vivo model, pretreatment with NCB-0846 significantly enhanced the efficacy of IR and caused elevated necrosis in TNIKhigh LK2 tumors but not TNIKlow KNS62 tumors. Overall, these results indicate that TNIK inhibition may be a promising strategy to increase the efficacy of radiotherapy in patients with LSCC with high TNIK expression.

Efficacy and safety of perioperative, neoadjuvant or adjuvant immunotherapy alone or in combination chemotherapy in early-stage non-small cell lung cancer: A systematic review and meta-analysis of randomized clinical trials.

8025 Background: Adjuvant (AD), neoadjuvant(NE), or perioperative(PE) immunotherapy in early-stage non-small cell lung cancer (eNSCLC) has been validated in multiple clinical trials in recent years. However, the comparations of efficacy and safety among three treatment modalities remain unclear. Methods: The PubMed, Embase, and Cochrane databases were searched for randomized controlled trials (RCTs) of immune checkpoint inhibitors (ICI) plus chemotherapy (CT) for eNSCLC. We calculated hazard ratios (HRs) or advantage ratios (ORs) for binary endpoints with 95% confidence intervals (CIs). Network meta-analysis was performed using a Bayesian framework to indirectly compare the three treatment modalities. Results: A total of 11 RCTs (2 NE, 6 PE, and 3 AD) including 6951 NSCLC patients were included. Among the three treatment modalities, indirect comparisons revealed that efficacy differed between PE and AD immunotherapy was only observed in the EFS/DFS (HR=0.68, 95%CI: 0.49-0.89). Compared with the control group, NE/PE immunotherapies significantly improved pathologic complete response (pCR) (OR=7.56, 95%CI: 5.24-10.92), major pathologic response(MPR) (OR=5.46, 95%CI: 3.97-7.51), EFS(HR=0.58, 95% CI: 0.50-0.67), and AD immunotherapy significantly improved DFS (HR=0.83, 95% CI: 0.73-0.94). No significant OS difference was observed in NE and AD setting (HR=0.62, 95% CI: 0.36-1.05; HR=0.90, 95% CI: 0.76-1.06, respectively), and only PE immunotherapy showed OS benefits(HR=0.67, 95%CI: 0.54-0.84). In addition, EFS was significantly improved in the PE treatment subgroup regardless of stage, pathologic response, histology, PD-L1 expression, and gender (Table), but no significant benefit in the EGFRm NSCLC subgroup(HR=0.54, 95% CI: 0.21-1.43). AD (OR 1.52, 95% CI: 1.01-2.30) and PE (OR 1.29, 95% CI: 1.08-1.54) immunotherapies were significantly associated with higher grade ≥3 adverse events (AEs) compared with controls. Rash was the most common grade ≥3 irAEs. Conclusions: PE immunotherapy seems to be more effective than NE and AD immunotherapy in three treatment modes. NE and PE immunotherapy significantly improved pCR, MPR, EFS, and AD immunotherapy significantly improved DFS in eNSCLC patients in comparison with the control group, but only PE immunotherapy significantly improved OS. [Table: see text]

Survival outcomes with adjuvant immunotherapy after hepatic resection in patients with intermediate/advanced (BCLC stage B/C) hepatocellular carcinoma: Insights from a propensity-matched multicenter study.

4096 Background: With the growing interest in adjuvant immunotherapy for reducing recurrence and improving prognosis after hepatic resection in hepatocellular carcinoma (HCC), particularly in high-risk patients, this study aims to evaluate the impact of adjuvant immunotherapy on long-term recurrence and survival in patients with intermediate/advanced HCC. Methods: A prospective multicenter database was utilized to identify patients who underwent curative-intent resection for Barcelona Clinic Liver Cancer (BCLC) stage B/C HCC. Propensity score matching (PSM) was employed to equate recurrence-free survival (RFS) and overall survival (OS) between patients receiving adjuvant immune checkpoint inhibitors (ICIs) and those who did not. Multivariate Cox-regression analysis was used to identify independent predictors of RFS and OS. Results: Out of 627 patients, 109 (23.3%) received adjuvant immunotherapy, with most ICI-related adverse reactions being grade I-II. The ICI agents used among these 109 patients were tislelizumab (51.4%, n=56), sintilimab (29.3%, n=32), camrelizumab (9.2%, n=10), pembrolizumab (6.4%, n=7), and toripalimab (3.7%, n=4). All patients receiving adjuvant immunotherapy completed at least 3 months of ICI treatment, with no patients discontinuing the treatment due to irAEs. PSM resulted in 99 matched pairs with comparable baseline characteristics. In this cohort, patients receiving adjuvant immunotherapy showed significantly improved median RFS (29.6 vs. 19.3 months, P=0.031) and OS (35.1 vs. 27.8 months, P=0.036) compared to those who did not. Multivariable analyses confirmed adjuvant immunotherapy as an independent factor for better RFS (HR: 0.630; 95% CI: 0.435-0.914; P=0.015) and OS (HR: 0.601; 95% CI: 0.401-0.898; P=0.013). Subgroup analyses suggested prognostic benefits of adjuvant immunotherapy in both intermediate and advanced-stage HCC. Conclusions: This real-world observational study indicates that adjuvant immunotherapy is associated with improved RFS and OS in patients undergoing curative-intent resection for intermediate/advanced HCC. These findings support the need for future randomized controlled trials to establish definitive evidence for this high-risk population.

WDR4 as a potential indicator of clinical prognosis and immunotherapy in hepatocellular carcinoma.

e16275 Background: Immunotherapy has garnered increasing attention in hepatocellular carcinoma (HCC) treatment. However, there remains a pressing need for effective immunological predictive biomarkers. In our previous study, utilizing data extracted from The Cancer Genome Atlas (TCGA) database, we identified a positive correlation between WDR4 expression levels in hepatocellular carcinoma and various clinical parameters, encompassing Stage, T-stage, pathological grade, AFP level, and vascular invasion. Additionally, higher WDR4 expression was linked to poorer prognosis. Leveraging The TIMER and GEPIA databases, we further elucidated a significant association between WDR4 expression levels and the extent of immune cell infiltration, particularly macrophages, B lymphocytes, and myeloid suppressor cells, in hepatocellular carcinoma. These findings propose the potential utility of WDR4 as a biomarker for immune infiltration in hepatocellular carcinoma. As noted in the trial NCT03867084, which hypothesized that adjuvant pembrolizumab might surpass placebo efficacy, there still exists a gap in identifying the specific population benefiting from adjuvant immunotherapy. Methods: Clinical and pathological data from patients who underwent single-agent immunotherapy for HCC were additionally collected from Hunan Provincial People's Hospital between January 1, 2019, and January 31, 2024. These patients participated in the clinical trial (NCT03867084) with informed consent. The relationship between WDR4 expression levels, clinical pathological data, and patient prognosis was assessed using the Kruskal-Wallis test and Kaplan-Meier survival curve analysis. Results: WDR4 displayed significant upregulation in HCC tissues compared to para-carcinoma tissues (P &lt; 0.001) and exhibited robust diagnostic potential. WDR4 expression showed significant associations with various immune cells, including macrophages (r = 0.278, P &lt; 0.001). Kaplan-Meier survival analysis indicated that patients with high WDR4 expression had shorter postoperative progression-free survival in the context of immunotherapy. Data from 37 patients who underwent postoperative single-agent immunotherapy for hepatocellular carcinoma (NCT03867084) revealed a significant correlation between WDR4 expression levels and Disease-Free Survival (DFS), with notable statistical significance (Log-rank P &lt; 0.001). Conclusions: WDR4 demonstrates elevated expression levels within HCC tissues and is associated with immune infiltration, establishing it as a prognostic biomarker in HCC. Furthermore, the positive correlation observed between WDR4 and CD68 as well as PD-L1 underscores its potential as a guiding factor in immunotherapeutic approaches for HCC.

Cutaneous melanoma during pregnancy: Management and real-world outcomes.

e21554 Background: Pregnancy associated melanoma (PAM) occurs in 1% of female patients with melanoma and affects 1 in 2200 pregnancies. Antepartum evaluation of melanoma must incorporate both maternal and fetal factors, and currently there is lack of standardization. Our study aimed to review the incidence of antepartum melanoma at our institution and highlight patterns in management and treatment during this high-risk scenario. Methods: After IRB approval, the Mayo Clinic electronic medical record was searched with key words “melanoma” and “pregnancy”. 25 patients with melanoma during pregnancy were identified from 1987-2023. 6 patients were excluded as skin changes noted during pregnancy were not formally diagnosed as melanoma until after delivery. Abstracted data included demographic information, disease characteristics, staging (per AJCC guidelines at time of diagnosis), and clinical outcomes. Survival data were calculated. Results: 19 patients were included. Diagnosis occurred at an average maternal age of 30 years (range 24-38 years) and a mean gestational age of 20 weeks (range 6-35 weeks). All patients had a term delivery. 4 patients underwent labor induction at 37 weeks for staging/treatment. 60% of patients had a delay in imaging or treatment attributed to pregnancy, including 1 patient who was upstaged with metastatic disease based on postpartum imaging. 82% of stage I-III patients underwent wide local excision during pregnancy; however, 35% of sentinel lymph node sampling was delayed until postpartum. 3 stage II/III patients received adjuvant therapy (interferon or sargramostim) after delivery. Adjuvant immunotherapy was discussed with 2 patients in the postpartum period but ultimately not given due to the time lapse between surgery and delivery. 1 patient with stage IV disease diagnosed at a gestational age of 20 weeks was evaluated with MRI PET scan then treated with vemurafenib monotherapy during pregnancy. Workup and outcomes were reviewed by stage (Table 1). 7 of 19 patients had subsequent pregnancies, and 1 had recurrence of melanoma during a second pregnancy (stage II followed by stage IV). Due to a low number of censoring events, median progression free survival and overall survival were not reached. Conclusions: Melanoma diagnosed during pregnancy can be safely and effectively staged with sentinel lymph node surgery, MRI imaging (PET-MRI vs standard), and CT imaging with shielding without a need for early induction of labor nor a delay in cancer care. Furthermore, we report a patient with stage IV disease treated with vemurafenib during and immunotherapy after pregnancy, indicating that treating stage IV PAM with systemic therapy is a consideration. [Table: see text]

Stratified absolute benefit with adjuvant immunotherapy (aIO) in muscle-invasive bladder cancer (MIBC): A meta-analysis.

Stratified absolute benefit with adjuvant immunotherapy (aIO) in muscle-invasive bladder cancer (MIBC): A meta-analysis.

Association between circulating tumor DNA (ctDNA) and recurrence-free survival (RFS) in patients (pts) with resected stage III melanoma: An exploratory analysis of SWOG S1404.

9564 Background: Our exploratory study aimed to understand the association between the presence of ctDNA after definitive surgical resection and RFS in pts with stage III melanoma treated with adjuvant immunotherapy. Methods: This study included 92 pts with resected stage III melanoma enrolled in a phase 3 trial (NCT02506153) that evaluated the efficacy of adjuvant pembrolizumab compared to interferon alfa-2b or ipilimumab in pts with stage IIIA(N2a)-IV resected melanoma. Personalized, tumor-informed ctDNA assays (Signatera) were run on banked plasma samples (median: 3.8 mL) collected at up to 5 time points after resection: pre-adjuvant treatment (pre-Tx), 1, 3, 6, or 12 months after Tx initiation and at recurrence. RFS was measured from randomization (pre-Tx) to first recurrence or death. A case-control design was used: 50% with recurrence within 2 yrs of randomization and 50% alive without recurrence for &gt; 2 yrs. Conditional logistic regression compared the presence of ctDNA at pre-Tx between case-control groups. Results: Of the 92 pts, samples from 10 did not pass quality control. This study analyzed a total of 245 plasma samples from 82 pts. No significant differences in demographics, including stage, number of + lymph nodes, and BRAF status, existed between pts who were ctDNA+ or ctDNA- pre-Tx. 7 of 10 pts (70.0%) who were ctDNA+ pre-Tx had disease recurrence within 2 yrs compared to 33 of 72 pts (45.8%) who were ctDNA- (p = 0.19). 2-yr RFS was 30% in pts who were ctDNA+ pre-Tx and 54% in pts who were ctDNA- (HR 1.75; 95% CI: 0.78, 3.94; p = 0.18). Of the 7 pts who were ctDNA+ pre-Tx and had disease recurrence within 2 yrs, 5 were ctDNA+ at all time points assessed. The other 2 pts transiently cleared ctDNA during Tx, turning back ctDNA+ prior to recurrence. Of the 3 pts who were ctDNA+ pre-Tx and did not recur within 2 yrs, 2 cleared ctDNA during immunotherapy and remained ctDNA- at later time points. All 39 pts who were ctDNA- pre-Tx and did not recur within 2 yrs remained ctDNA- at later time points. Among 29 pts having ctDNA timepoints available for analysis near the time of recurrence (end-of-Tx or on-progression timepoints), 22 (75.9%) were ctDNA+. Conclusions: In this study, pre-Tx incidence of ctDNA+ after surgical resection was low, potentially related to limited plasma yield. However, the ctDNA positivity rate increased in subsequent serial testing. ctDNA might help identify early disease recurrence in patients with melanoma in the adjuvant setting, but further studies of larger cohorts accounting for treatment effect with more uniform pre-analytic collection are needed.

Adjuvant immunotherapy and targeted therapy in early and locally advanced resectable lung cancer: expanding treatment tentacles?

Adjuvant platinum-based chemotherapy has been the main treatment following surgical resection with curative intent in early and locally advanced nonsmall cell lung cancer (NSCLC) albeit with a 5% improvement in 5-year survival rates. Recent advances in biomarkers pave the way for targeted treatments and immunotherapy in a broader spectrum of patients with subsequently improved clinical outcomes. Targeted treatments and immunotherapy have established their place in the adjuvant setting of resected NSCLC.

First-line systemic therapy following adjuvant immunotherapy in renal cell carcinoma (RCC): An international multi-center study.

First-line systemic therapy following adjuvant immunotherapy in renal cell carcinoma (RCC): An international multi-center study.

Sex as a predictor of progression-free survival in sentinel node-negative stage II melanoma.

e21560 Background: Adjuvant immunotherapy can improve outcomes for resected stage IIB/C melanoma patients, but also poses challenges. Many patients are cured by surgery alone, making them susceptible to unnecessary treatment risks. Additionally, current staging may overlook some high-risk stage IIA patients who could benefit from immunotherapy. Accurate risk assessment is therefore critical to balance benefits and risks of early immunotherapy and optimise patient selection. This study sought to identify clinicopathologic predictors to refine risk stratification for sentinel lymph node-negative (SLN(-)) stage II melanoma patients, with a focus on the role of sex in prognostic accuracy and treatment personalisation. Methods: We retrospectively analysed 565 stage II melanoma patients with negative sentinel lymph node biopsies at four UK hospitals between 2004-2017. The primary outcome was progression-free survival (PFS). Analysed clinicopathologic factors included Breslow thickness, ulceration sex and tumour-infiltrating lymphocytes (TILs). Univariate and multivariate analyses were conducted. Results: Median follow-up was 9.5 years. Melanoma progression occurred in 24% of patients. Sex emerged as a significant PFS predictor. Specifically, stage IIA and IIB males had higher progression risks than females at the same stages. We also observed disparities across stages; for instance, PFS was significantly worse in stage IIA males than stage IIB females (PFS difference: χ2 = 5.629, p = 0.018), revealing gaps in the prognostic accuracy of current staging systems. Stage IIB females—identified as at risk by current standards—had 5-year PFS of 91%. This highlights potential overestimation of their treatment needs and subsequent risk of undue exposure to treatment toxicity. The sex-based discrepancies observed may be partially explained by differences in antitumor immune function, evidenced by the discovery that Non-brisk TILs-an independent predictor of high progression risk in SLN(-) stage II melanoma- were associated with a 20% reduction in PFS in males vs females (p &lt; 0.001). Conclusions: Significant sex-based PFS disparities exist among sentinel lymph node-negative stage II melanoma patients, with implications for treatment decisions. Incorporating sex enables more refined risk assessment than current substaging alone. Specifically, stage IIA males may be under-recognised for progression risks, while many stage IIB females could face overtreatment. Our findings advocate for nuanced, sex-specific approaches to enhance prognostic accuracy and optimise patient care.

Use of gene expression patterns to identify unique molecular subtypes in muscle invasive bladder cancer: GUSTO.

TPS4621 Background: Muscle invasive bladder cancer (MIBC) is an aggressive disease with poor survival rates that are not improving. Curative treatment includes systemic neoadjuvant chemotherapy prior to radical cystectomy and adjuvant immunotherapy. However, many patients do not respond to chemotherapy or immunotherapy. Histologically similar MIBCs can be classified using gene expression patterns into unique molecular subtypes. Retrospective studies have shown that molecular subtypes each have unique biology and consequently respond differently to treatment. The GUSTO trial tests the hypothesis that outcomes can be optimized through subtype-guided allocation. Methods: Eligible participants are those with confirmed non-metastatic MIBC, an ECOG performance status 0-1, being considered for cisplatin-based neoadjuvant chemotherapy and radical cystectomy. Formalin-fixed diagnostic (TURBT) tumor samples undergo gene expression microarray analysis and characterization using the GUSTO Classifier (consisting of the Veracyte Decipher assay and TCGA_2017 classification system) to determine the molecular subtype: basal, neuronal, luminal infiltrated, luminal or luminal papillary. A total of 320 eligible patients (T2-4a N0 M0 or T(any) N1 M0 MIBC) will be randomized 1:1 to either standard of care treatment (neoadjuvant cisplatin and gemcitabine) or subtype-guided treatment (basal and neuronal subtypes - neoadjuvant cisplatin, gemcitabine, durvalumab and tremelimumab and adjuvant durvalumab; luminal infiltrated - neoadjuvant durvalumab and tremelimumab and adjuvant durvalumab; luminal and luminal papillary - proceeding directly to radical cystectomy). Sites are notified when a patient has been assigned a molecular subtype. Patients and sites in the standard of care arm remain blind to the genomic subtype. The trial has three stages: Stage 1 (after 6 months of recruitment) will assess feasibility of recruitment and molecular subtyping in clinical timelines. Outcomes include recruitment rate, time to, and success of subtype allocation. Stage 2 (after 24 months of recruitment) will confirm recruitment feasibility and assess sample size assumptions. Outcomes are recruitment numbers, distributions of subtypes, and pathological complete response (pCR) in the standard of care arm. A re-estimation of the sample size for stage 3 will be considered. Stage 3 (after 12 months post-cystectomy for the last participant randomized) will assess treatment outcomes using this stratified approach. The primary outcome for Stage 3 is the rate of pCR in each molecular subtype within the experimental arm. Progression between trial stages will be dependent upon achieving pre-defined criteria. Recruitment began in September 2023. The study will open the first 20 sites ready to proceed and is accepting expressions of interest. Clinical trial information: 17378733.

Neoadjuvant dual checkpoint inhibition followed by immune-chemoradiation in patients with resectable gastric adenocarcinoma.

4067 Background: Localized gastric cancer is a potentially curable condition and long-term outcomes depend on YP staging. Currently, preferred adjunctive therapy depends on geographic location. Preliminary data from NCT01928394 have shown promising clinical activity of immunotherapy (IO) agents nivolumab (nivo) +/- ipilimumab (ipi) in the metastatic setting. We conducted a single-arm study using IO + chemotherapy followed by immune-chemoradiation prior to surgery, followed by adjuvant IO, in patients with localized gastric adenocarcinoma. Our primary objective was to determine safety and toxicity with this approach. Secondary objectives included efficacy by YP staging and R0 resection rate. Methods: Patients with localized gastric adenocarcinoma were enrolled into NCT03776487 (n=30). Participants received the following: (1) biweekly chemotherapy with 4 doses of 5-Fluorouracil (5-FU)/Oxaliplatin, (2) nivo 240mg q2weeks (x3) and ipi 1mg/kg q6weeks (x1), (3) immune-chemoradiation (biweekly nivo + 5FU Mon-Fri concurrently with a total of 45 Gy given in 25 fractions), and (4) surgical resection. Those with residual disease received adjuvant nivolumab monthly for 6 doses. Correlative studies are planned. To assess preliminary efficacy, the clinical and pathologic complete response rates (pCR) were estimated along with the corresponding exact 95% confidence interval. Adverse events and toxicities were summarized using descriptive statistics. Results: Median follow-up was 27.4 months at the time of data cutoff. Of 30 enrolled, 23 patients completed surgery and seven did not due to progression of disease(n=5) and worsening co-morbidities(n=2). The side effect profile was similar to prior IO studies, with no grade 5 events observed. Three patients (10%) experienced grade 4 events (acute kidney injury, myocarditis, and neutropenia). The most frequent grade 3 toxicity was nausea and vomiting (10%). From the 23 participants that underwent resection, 22 had pathologic data at the time of analysis, with 9 achieving ypT0ypN0 (40.9%, 95% CI: 20.7%, 63.7%). There was an 86% R0 resection rate. Conclusions: Our results are encouraging and support further development of this strategy for localized gastric adenocarcinomas. The regimen is safe and potentially generalizable. Clinical trial information: NCT03776487 .

Screening for ocular toxicities of immunotherapy in a real-world population.

e24125 Background: Nivolumab, Pembrolizumab, and Ipilimumab have revolutionized the treatment of melanoma. However, patients receiving these treatments risk immunotherapy-related adverse events (IRAEs). IRAEs can occur in any organ system, are treated with steroids or immunosuppressive medications, and may require treatment delay or discontinuation. Ocular IRAEs, which are caused by off-target reactions with ocular immune mechanisms, are often identified after significant damage to the eye. Ocular IRAEs are rare in the literature with an approximate prevalence of 3.3%. After observing intraocular inflammation (uveitis) with uveal depigmentation (pigment release) in some patients receiving immunotherapy, we hypothesized that the rate of such events in a real-world population may be higher than previously reported. We predict ophthalmic screening and early intervention may prevent severe and potentially permanent ocular IRAEs. Methods: Patients starting immunotherapy for melanoma were referred to an ocular screening clinic at the Cancer Centre of Southeastern Ontario (Queen’s University, Kingston, Canada) for baseline ocular assessments. Repeat assessments occurred every three months (single agent) or at every cycle (dual immunotherapy). Intake visits included examination by an attending ophthalmologist, including examination for uveitis and anterior chamber free pigment under high-powered field. Intraocular inflammation (IOI) was defined as the presence of endothelial deposits and/or anterior chamber cell and/or pigment that was not present at baseline. Ocular findings were monitored alongside other IRAEs during treatment. Results: 28 patients (17 male, 11 female) receiving adjuvant (46.4%) or palliative (53.6%) immunotherapy for melanoma were evaluated. 9 of these patients received dual immunotherapy (Ipilimumab/Nivolumab) and 19 received single agent immunotherapy. IOI was identified in 11 patients (39.2%), while only 4 presented with symptoms. None of the patients had overt signs of anterior segment inflammation such as erythema, conjunctival injection, and chemosis. IOI developed in 54.5% of dual immunotherapy-treated patients. Patients with ocular IRAEs were treated with topical/systemic steroids or other immunosuppressive medications. None required discontinuation of immunotherapy. The development of IOI was more common in metastatic patients whose cancer was responding to immunotherapy, and many of these patients sustained IRAEs in other organ systems. Conclusions: Our findings suggest IOI related to ocular IRAEs are quite common and develop in a third of patients receiving immunotherapy for melanoma. Ocular screening for IOI identified early, often asymptomatic toxicities that could progress to permanent visual disability. Further evaluation of dedicated ocular screening is indicated in patients receiving immunotherapy.

The preliminary efficacy and safety results of neoadjuvant phase 2 study of penpulimab combined with taxanes and carboplatin in triple-negative breast cancer (neoTAPPL).

e12617 Background: The KEYNOTE-522 trial demonstrated the addition of pembrolizumab to anthracycline-taxane-platinum chemotherapy improves pathologic complete response (pCR) and event free survival (EFS) in triple-negative breast cancer (TNBC). Penpulimab is a newly developed PD-1 monoclonal antibody with complete elimination of FcgR binding and ADCC/ADCP. This study aims to assess the efficacy of the anthracycline free neoadjuvant regimen of penpulimab plus carboplatin and taxanes in TNBC. Methods: In this open-label, phase 2 study, patients with untreated, histologically confirmed TNBC in stage II-III were enrolled. Patients received 6 cycles of neoadjuvant therapy with penpulimab (200 mg, d1, q3w) plus taxanes (docetaxel 75 mg/m2 or nab-paclitaxel 260 mg/m2, d1, q3w) and carboplatin (AUC=6, d1, q3w). Patients who either completed or discontinued the neoadjuvant treatment would undergo breast surgery. Adjuvant chemotherapy and immunotherapy were at the discretion of the treating physician, and radiation therapy was per standard of care. The primary endpoint was the rate of pCR based on the definition of ypT0/Tis ypN0. Secondary endpoints included residual cancer burden (RCB), EFS, overall survival (OS), adverse events (AE), and immune response biomarkers. Based on the Simon’s Two-Stage design, if &gt;7 of 16 patients achieved pCR, the enrollment would proceed to full accrual of 46 patients as planned. If &gt;23 of 46 patients achieved pCR, we would deem the study to have met the primary endpoint. Results: Nine out of 16 pts achieved pCR in the first stage, reaching the threshold for the second stage. From Nov 2022 to Jan 2024, 22 patients were enrolled, among which 17 patients received neoadjuvant treatment and underwent breast surgery. The median age was 51 years (range, 32-69). 13 (76.5%) patients had stage II breast cancer at diagnosis. 10 of the 17 patients achieved pCR (58.8%; 95% CI, 32.9-81.6), and 12 patients achieved RCB 0-I (70.6%; 95% CI, 44.0%-89.7%). Subgroup analysis showed the pCR rate of patients who were diagnosed initially to be lymph node negative was 75.0% (6/8), higher than that of patients who were lymph node positive (44.4%; 4/9). The ORR and DCR were 82.4% (95% CI, 56.6%-96.2%) and 88.2% (95% CI, 63.6%-98.5%), respectively. Treatment-emergent adverse events (TEAEs) of any grade occurred in all 17 pts, in which 10 (58.8%) were grade ≥3. The most common grade ≥3 TEAEs were neutropenia (47.1%), leukopenia (41.2%), anemia (23.5%), and thrombocytopenia (17.6%). 6 patients (35.3%) experienced immune related adverse events (irAEs), all of which were grade 1 hypothyroidism. Conclusions: The preliminary results demonstrated that penpulimab plus carboplatin and taxanes as neoadjuvant therapy for early-stage TNBC showed promising antitumor efficacy and manageable safety profile. The study is still ongoing. Clinical trial information: ChiCTR2300071925.