Gilberto Lopes

TPS650 Background: High-grade neuroendocrine neoplasms (NENs), including poorly differentiated neuroendocrine carcinomas (NECs) and well-differentiated grade 3 neuroendocrine tumors (NETs), are aggressive malignancies with limited effective treatment options. Immune checkpoint inhibitors (ICIs) have demonstrated limited clinical activity in these tumors. Seneca Valley Virus (SVV-001) is a novel oncolytic RNA virus that has shown synergistic activity with ICIs in preclinical models. Additionally, SVV-001 has been observed to reverse checkpoint inhibitor resistance in vivo, supporting its evaluation in combination with nivolumab and ipilimumab. Methods: This is an investigator-initiated, phase 1, dose-escalation and cohort-expansion study evaluating intratumoral SVV-001 in combination with nivolumab and ipilimumab in patients with histologically confirmed poorly differentiated NEC or well-differentiated grade 3 NET. The trial was activated in March 2025, with patient enrollment currently ongoing and a target of up to 36 patients. A standard 3+3 dose-escalation design is being employed to determine the recommended phase 2 dose (RP2D). Following dose escalation, an expansion cohort will further evaluate safety and preliminary signals of activity. Tumor endothelial marker 8 (TEM8), a potential biomarker of SVV-001 sensitivity, will be assessed as part of correlative studies. Clinical trial information: NCT06889493 .

Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide, with higher death rates in Asia than in Europe and North America. Programmed cell death protein-(ligand) 1 [PD-(L)1] inhibitors are effective in NSCLC treatment, but their comparative effectiveness in Asian . non-Asian populations is unclear. The aim of this systematic literature review (SLR) and meta-analysis was to assess the efficacy of PD-(L)1 inhibitor monotherapy or combination therapy (with platinum-based chemotherapy or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors as first-line (1L), second-line (2L), and later (2L+) treatment for locally advanced or metastatic NSCLC in Asian . non-Asian patients. Multiregional randomized, controlled studies that included subgroup analyses for Asian patients by ethnicity or region were selected. Studies were excluded if the control arm was not platinum-based chemotherapy or if the primary population did not meet the criteria. Literature searches were undertaken from January 1, 2010, to October 25, 2024 and were performed using the Ovid SP platform. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were extracted using random-effects models. Quality and bias were evaluated using the Cochrane Risk of Bias tool and funnel plot and Begg's test. 1,431 records were screened, and 1L (n=21) and 2L/2L+ (n=10) studies in 10,233 patients with locally advanced or metastatic squamous/non-squamous NSCLC were identified. OS favored 1L PD-(L)1 inhibitor monotherapy or combination therapy (plus platinum-based chemotherapy and/or CTLA-4 inhibitors) in both Asian [HR =0.70; 95% confidence interval (CI): 0.64-0.76] and non-Asian (HR =0.71; 95% CI: 0.65-0.77) patients. Similar findings were observed with PFS in Asian (HR =0.53; 95% CI: 0.47-0.59) and non-Asian (HR =0.58; 95% CI: 0.53-0.64) patients. 1L PD-(L)1 inhibitor monotherapy or combination therapy was extremely effective at improving OS in Asian (HR =0.50; 95% CI: 0.39-0.64) and non-Asian (HR =0.64; 95% CI: 0.55-0.76) patients with tumor cell PD-L1 expression ≥50%, and there was also a greater magnitude of effect on PFS in Asian (HR =0.38; 95% CI: 0.32-0.44) than non-Asian (HR =0.46; 95% CI: 0.37-0.56) patients with tumor cell PD-L1 expression ≥50%. These data support the global use of PD-(L)1 inhibitors for Asian and non-Asian patients with 1L or 2L/2L+ locally advanced or metastatic NSCLC. However, it was not possible to assess outcomes in all subgroups due to lack of data (e.g., wider PD-L1 subgroups, genetic profiles), warranting further studies by ethnicity.

Background Immunologically mediated clearance of senescent cells has been demonstrated in several model systems. Given increasing evidence for these cells promoting tumor pathology and immune escape, we sought to examine whether a vaccine against senescent cells can lead to tumor regression. Materials and Methods A senolytic dendritic cell (DC) immunotherapy ("SenoVax (TM)") was created by pulsing DCs with lysate from in vitro generated syngeneic senescent fibroblasts. Prophylactic and therapeutic activity of SenoVax on tumor growth and metastasis was assessed in the Lewis Lung Carcinoma (LLC) model. The immunogenicity of SenoVax (TM) was measured using cytotoxicity, proliferation, and cytokine assays. Adoptive transfer of lymphocytes from vaccinated mice into na & iuml;ve mice was performed in a prophylactic tumor challenge model. Assessment of plasma senescence associated biomarkers IL-11, IL-6, IL-23 receptor, and YLK-40 was performed by ELISA. Synergy of SenoVax (TM) with immune checkpoint inhibitors and the universality of the vaccine's effects against other tumors was assessed. Furthermore, induction of autoimmunity was assessed by complement activation and autoantibody formation. Results SenoVax (TM) was created by pulsing DC with cell lysate from senescent fibroblasts, producing DCs that expressed co-stimulatory molecules, stimulated T cell proliferation, and expressed the senescence antigen p16. SenoVax (TM) induced prophylactic and therapeutic tumor regression in LLC primary and metastatic murine tumor models. T cell proliferative and cytokine recall responses towards senescent cells but not to control stromal cell pulsed DCs were detected in vaccinated mice. Additionally, reduction in senescence associated biomarkers IL-11, IL-6, IL-23 receptor, and YLK-40 were observed. Adoptive transfer experiments revealed a role for CD8+ T cells in transplanting protection. When SenoVax (TM) was administered in combination with anti-PD-L1 or anti-CTLA-4 antibodies, the data showed synergistic effects in reducing tumor growth. SenoVax (TM) also demonstrated reduction of GL281 glioma, Pan01 pancreatic cancer, and 4T1 breast cancer cell growth. No significant activation of complement or induction of autoantibodies was observed. Conclusion Vaccination with DC pulsed senescent cells resulted in reduction of tumor growth in a CD8+ T cell and interferon gamma-associated manner in lung cancer as well as other tumor models. The data provide mechanistic support for advancement of senolytic immunotherapy as a novel form of cancer therapy.

PURPOSELung cancer remains a leading cause of cancer mortality in Brazil, with non-small cell lung cancer (NSCLC) accounting for 85% of cases, with 1.6% carrying epidermal growth factor receptor (EGFR) exon 20 mutations. In the phase I CHRYSALIS trial (ClinicalTrials.gov identifier: NCT02609776), amivantamab demonstrated a median overall survival (OS) of 22.8 months versus 8.3 months with docetaxel, the standard second-line Brazil's Unified Health System (SUS) therapy. Although the Brazilian Health Regulatory Agency approved amivantamab, the National Commission for the Incorporation of Technologies' cost-effectiveness reviews result in an average 10-year delay before SUS incorporation. We aimed to estimate premature deaths and life-years lost attributable to this access gap.METHODSUsing National Institute of Cancer (INCA) data, we estimated SUS-eligible patients, NSCLC prevalence, and EGFR exon 20 frequency. Stage distribution and 5-year recurrence rates identify candidates for amivantamab. A hazard ratio (HR) was derived from the inverse exponential method (ln(2)/OS ratio). Preventable deaths were calculated as: eligible patients × (1 - HR). Life-years gained per patient were estimated as OS difference.RESULTSOf the 26,548 new patients with lung cancer, 18,973 are SUS-eligible, 16,127 have NSCLC, and 258 have EGFR exon 20 mutations. Metastatic disease accounts for 114, whereas recurrences occur in 60 (stage III), eight (II), and four (I), totaling 186 candidates annually. With an HR of 0.364, the annual preventable death in the base-case scenario is equal to 186 × (1 - 0.364) × 95% = 112 patients. Over 10 years, 1,120 premature deaths and 1,353 life-years could be avoided.CONCLUSIONDelayed SUS incorporation of amivantamab may result in over a 1,000 preventable deaths and life-years lost among Brazilian EGFR exon 20-mutated NSCLC. Urgent real-world studies and cost-effectiveness analyses are needed.