Biomedical subjects
Publications and source records attributed to Laura Mezquita.
A recent article provides the largest characterization to date of KRAS Q61-mutant NSCLC. The findings reveal clinically relevant differences between Q61 alleles and highlight the importance of interpreting KRAS mutations within their genomic context. As RAS-directed therapies evolve, understanding this heterogeneity becomes increasingly relevant for patient stratification and therapeutic development.
BACKGROUND: Immune checkpoint inhibitor (ICI) monotherapy is the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with PD-L1 ≥ 50%; however, up to 30% of patients experience early progression or death, including cases of hyperprogressive disease (HPD). High baseline levels (≥ 30.5%) of circulating CD10- low-density neutrophils (LDNs) have been associated with increased HPD occurrence. Emerging evidence suggests that combining ICI with platinum-based chemotherapy (PCT) may mitigate the risk of HPD. Currently, no prospective studies have addressed HPD prevention in this context. PATIENTS AND METHODS: HYPERBOLIC (NCT07274384) is a phase 2, randomized, open-label, multicenter, international trial evaluating whether adding 3 cycles of PCT to first-line cemiplimab reduces HPD rate in stage IV NSCLC with PD-L1 ≥ 50% and CD10- LDNs (identified by flow cytometry as CD15⁺CD11b⁺ within the PBMC fraction, with immature cells defined by loss of CD10) ≥ 30.5%. Seventy-four patients will be randomized (1:1 ratio) to receive cemiplimab alone or cemiplimab plus 3 PCT cycles, followed by cemiplimab maintenance. Randomization will be stratified by Lung Immune Prognostic Index. The first computed tomography scan at week 7 after treatment start will assess HPD occurrence, defined as RECIST v 1.1. disease progression with a delta tumor growth rate (ΔTGR) ≥ 50% and/or TGR ratio ≥ 2. The primary endpoint will be the combined rate of HPD and early death (death within 12 weeks with no radiological evaluation). Secondary endpoints will be HPD rate according to alternative definitions, overall survival, progression free survival, objective response rate, and safety. An extensive translational research platform will include spatial transcriptomics of tumor tissue, single-cell RNA sequencing of PBMCs, circulating-free DNA and plasma factors profiling, and saliva/stool microbiome genomics and metabolomics, to longitudinally explore tumor-host dynamic interactions during treatment. CONCLUSION: to our knowledge, HYPERBOLIC is the first prospective, biomarker-driven trial investigating early treatment escalation based on HPD risk in PD-L1-high NSCLC.
BACKGROUND: The Lung Immune Prognostic Index (LIPI) is an inflammation-based biomarker associated with outcomes to immunotherapy across several tumor types. Its prognostic value in extensive-stage small-cell lung cancer (ES-SCLC), however, remains insufficiently validated. We aimed to validate the prognostic impact of LIPI in ES-SCLC using data from two phase III trials. METHODS: Patients enrolled in the CASPIAN (NCT03043872) and IMpower133 (NCT02763579) trials were included. LIPI groups were defined as good (dNLR<3 and LDH<ULN), intermediate (dNLR≥3 or LDH≥ULN) and poor (dNLR≥3 and LDH≥ULN). Overall survival (OS) and progression-free survival (PFS) were assessed across LIPI categories and treatment arms. RESULTS: LIPI was available for 1140 patients (Good: 34%, Intermediate: 49%, Poor: 17%), including 708 treated with chemotherapy-immunotherapy and 432 with chemotherapy alone. Poor LIPI was associated with unfavorable characteristics, including lower albumin levels and higher rate of liver metastases. Median OS was 14.6 months (95%CI: 12.4-15.9) for LIPI Good, 10.9 (10.1-11.5) for Intermediate, and 8.4 (7.1-9.3) for Poor (p < 0.0001). In multivariate models adjusted on gender, age, ECOG, treatment arm and metastatic sites, LIPI remained an independent prognostic factor for OS (HR Poor vs. Good: 1.76, 95%CI: 1.45-2.15, p < 0.001) and PFS (HR: 1.59, 95%CI: 1.33-1.90, p < 0.001). Although patients with poor LIPI derived limited benefit from immunotherapy, no significant treatment-LIPI interaction was observed. CONCLUSION: This large post hoc analysis confirms LIPI as a robust and clinically applicable prognostic biomarker in ES-SCLC. Patients with poor LIPI have substantially worse outcomes and limited benefit from immunotherapy, highlighting the need for novel therapeutic strategies in this subgroup.