Abstract Background the duration of tumor persistence within the host–defined as Tumor Longevity (TL) – may capture cumulative biological and immunologic interactions, shaping immunotherapy treatment response. However, the impact of TL on outcomes with immune checkpoint inhibitors (ICI) remains unexplored. We hypothesized that TL may reflect integrated tumor-host dynamics influencing ICI efficacy and investigated this association in patients with head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), renal and urothelial cancer (R/UC). Materials and methods we conducted a retrospective, observational study including adult patients with advanced HNSCC, NSCLC, R/UC receiving ICI (≥first line) across 2 Italian cancer centers. TL, defined as the time from first histological diagnosis to ICI initiation, was analyzed as a continuous variable using 3-knot restricted cubic spline models. Multivariable logistic and Cox regression analyses assessed associations between TL and disease control rate (DCR), grade (G)≥3 immune-related adverse events (irAEs), and overall survival (OS). Results 304 patients, diagnosed from 2002 to 2022, started ICI from 2014 to 2022. Median TL was 15.30 months (IQR 5.52-33.05). Overall DCR was 56.25% [95% CI 50.47; 61.91]; CTCAE G ≥ 3 irAEs occurred in 16 (5.2%) patients; 231 (76.0%) patients died. In multivariable analyses, longer TL was associated with higher DCR (OR Q3 vs. Q1 = 3.26; 95%CI 1.24; 8.59, p = 0.004), while no significant associations for G ≥ 3 irAEs (OR = 1.27; 95% CI 0.39–4.12) and OS (HR = 0.79; 95% CI 0.49–1.28; p = 0.407) were observed. Conclusions These real-world, hypothesis-raising results suggest that TL may capture clinically relevant information associated with ICI outcomes. TL may represent a pragmatic, time-dependent biomarker integrating tumor behavior and host factors. Prospective and translational studies incorporating TL with molecular and immune profiling are warranted to elucidate whether this association reflects tumor biology, host factors, treatment history, or their combination.
Abstract Background Despite improved outcomes with immune checkpoint inhibitor (ICI) combinations in metastatic renal cell carcinoma (mRCC), reliable biologically-driven prognostic markers remain needed. The CHOMET study evaluated tumor ABCA1/ABCG1 expression and their association with systemic lipid parameters, nutritional status, nephrectomy status and survival outcomes. Methods CHOMET was a retrospective observational biomarker study including mRCC patients undergoing first-line ICI-combinations. Tumor ABCA1 and ABCG1 expressions were assessed by immunohistochemistry (IHC). Serum total cholesterol (TC), triglycerides (TG), and the Controlling Nutritional Status score (CONUT) were collected. Publicly available transcriptomic datasets were used for exploratory bulk RNA-seq, immune deconvolution, and single-cell analyses. Results Among 86 patients (46 with IHC), high ABCA1 and ABCG1 expression was associated with shorter overall survival (OS, p = 0.003 and p = 0.01) and progression-free survival (PFS, p = 0.05 and p = 0.08). A composite nephrectomy-cholesterol score and a lower CONUT score were both significantly associated with improved PFS and OS. Exploratory bulk RNA-seq analyses suggested that high ABCA1 expression correlated with features of an immunosuppressive microenvironment enriched in M2 macrophages and depleted of CD8+ T cells, whereas high ABCG1 expression correlated with increased regulatory T cells. Exploratory single-cell analyses from four patients showed ABCA1 and ABCG1 expression across tumor-associated macrophages and tumor cells, with donor-specific pathway enrichment patterns involving immune signaling and cholesterol metabolism-related transcriptional programs. Conclusions ABCA1 and ABCG1 expression levels were associated with poorer outcomes in mRCC treated with ICI combinations and support a link between cholesterol transport programs and an immunosuppressive, metabolically reprogrammed tumor microenvironment.
Abstract Background Appendiceal cancers (AC) are rare, heterogenous tumors with unique diagnostic and management challenges requiring highly specialized multidisciplinary management. Access to multidisciplinary care varies widely, particularly across community and rural settings. Further, at the time of this study, limited evidence-based guidelines existed for the management of AC, presenting a challenge for gastrointestinal (GI) oncologists. Methods We conducted a two-part study. First, we established and evaluated the impact of a regional virtual AC-dedicated multidisciplinary care conference (MCC) at a high-volume tertiary care center. Second, we performed a national cross-sectional survey of GI oncologists to assess perceived gaps in knowledge, confidence, and standardization of care for AC. Results The regional AC-dedicated MCC reviewed 614 unique cases between May 2020 and June 2022 with multidisciplinary participation across medical oncology, surgical oncology, pathology, and radiology. Among MCC participants, 88.5% reported improved knowledge, 94% reported perceived improved quality of care, and 100% reported increased confidence in managing AC. Most participants reported that MCC discussions influenced treatment decisions in ≥ 30% of cases. A total of 114 gastrointestinal oncologists completed the national survey. Most practiced in academic centers (86.1%) and reported low clinical exposure to AC, with 72.0% managing fewer than 10 cases annually. Only 17.5% believed sufficient evidence exists to guide systemic therapy, and two-thirds reported that AC treatment is not or only somewhat standardized. Confidence in managing AC was moderate in most respondents (44.7%), with only 37.7% reporting high confidence. Educational resources were rated as fair or poor by 83.5% of respondents. Conclusions Significant national gaps remain in evidence, standardization, provider confidence, and educational resources for AC management. In parallel, implementation of a regional virtual AC-dedicated MCC was feasible and was associated with participant-reported improvements in knowledge, confidence, and perceived quality of care. This model may offer valuable expert guidance, improve clinician education and confidence, and facilitate decision-making in the management of a rare disease for which high-quality evidence remains limited.
Abstract Purpose We report the results of a Phase 1 study of TAVO412, an anti-EGFR, cMET, and VEGF-A multi-specific antibody. Patients and Methods Patients of age ≥18 years with advanced solid tumors refractory to standard therapies were enrolled (TAVO412-CN001, NCT06761651). The study used a standard 3 + 3 design for dose-escalation from 150 to 1500 mg every two weeks in a 28-day cycle. Patients were backfilled for further assessment of safety and preliminary anti-tumor activities. Results The study included 67 patients, with 6 tumor types. Serum drug exposures increased with the dose. TAVO412 had low immunogenicity (5.9%). No DLTs were reported and the MTD was not reached up to 1500 mg. The most common treatment-related (TR) AEs (≥30%) across all doses were rash, hypoalbuminemia, stomatitis, infusion related reaction, increased ALT, and hypokalemia. Preliminary anti-tumor activities were observed in NSCLC patients (n = 27) with 5 PRs (3 of 9 EGFR Exon20ins and 2 of 12 Exon21 L858R) and 13 SDs, in ESCC (n = 11) with 1 PR and 8 SDs, and in CRC (n = 15) with 4 PRs and 7 SDs, in the dose range from 750 to 1500 mg. All PRs were confirmed except 1. The longest treatment duration was approximately 39 weeks. Baseline soluble VEGF-A levels correlated with treatment responses. Conclusions TAVO412 was tolerated up to 1500 mg, with mostly target-related AEs. Preliminary activities of TAVO412 were observed in CRC, ESCC, and NSCLC patients who had been heavily treated. Further evaluation of TAVO412 in patients with these tumor types is warranted.
Abstract Background Early integration of specialist palliative care (PC) improves outcomes for patients with advanced cancer, yet implementation of needs-based referral remains inconsistent in routine oncology practice. The Palliative Care Referral System (PCRS) is a digital clinical decision-support tool designed to support referral using patient-reported symptoms, prognostic indicators, and clinical complexity. We evaluated the impact of PCRS implementation on referral patterns, patient-centered outcomes, healthcare utilization, and end-of-life (EoL) care. Patients and Methods In this single-center prospective quasi-experimental pre–post implementation study, 380 patients with advanced solid tumors were enrolled before (pre-PCRS, n = 190) and after (post-PCRS, n = 190) PCRS implementation. During the post-PCRS phase, oncologists completed the PCRS at each outpatient visit. Patient and caregiver satisfaction, quality of life, healthcare utilization, and EoL indicators were assessed monthly for 6 months. Time to first PC referral was analyzed using competing-risk methods. Results Overall 24-week referral rates were similar in the post-PCRS and pre-PCRS cohorts (21% vs 20%). However, referral timing and patterns changed across tumor types, with earlier referrals in breast and prostate cancer after PCRS implementation. The proportion of patients with at least 1 hospitalization was numerically lower after implementation (16% vs 27%; odds ratio, 0.53; 95% CI, 0.32-0.88; P = .017), but the difference was not significant after correction for multiple comparisons (P = .085). No significant differences were observed in patient or caregiver satisfaction, quality of life, emergency department visits, oncology visits, or PC visits. Indicators of aggressive EoL care were not significantly different between cohorts. Conclusions PCRS implementation did not increase the overall referral rate but was associated with changes in referral timing and patterns across tumor types. Whether these changes reflect more appropriate, needs-based care and translate into lower healthcare utilization requires confirmation in larger studies.
