Purpose: Transcriptomic subtyping holds promise for personalized therapy in extensive-stage small cell lung cancer (ES-SCLC). In this study, we aimed to assess intratumoral transcriptomic subtype diversity and to identify biomarkers of long-term chemoimmunotherapy benefit in human ES-SCLC.Experimental Design: We analyzed tumor samples from 58 patients with ES-SCLC enrolled in two multicenter single-arm phase IIIb studies evaluating frontline chemoimmunotherapy in Spain: n = 32 from the IMfirst trial and n = 26 from the CANTABRICO trial. We used the GeoMx Digital Spatial Profiler system to perform multi-region transcriptomic analysis. For subtype classification, we performed hierarchical clustering using the relative expression of ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1 (SCLC-Y).Results: Subtype distribution was found to be similar between bothcohorts, except for SCLC-P, which was not identified in the CANTABRICO_DSP cohort. A total of 44% of the patients in both cohorts had tumors with multiple coexisting transcriptional subtypes. Transcriptional subtypes or subtype heterogeneity was not associated with outcomes. Most potential targets did not show subtype-specific expression. Consistently in both cohorts, tumors from patients with long-term benefit (time to progression ≥12 months) contained an IFNγ-dominated mRNA profile, including enhanced capacity for antigen presentation. Hypoxia and glycolytic pathways were associated with resistance to chemoimmunotherapy.Conclusions: This work suggests that intratumoral heterogeneity, inconsistent association with outcome, and unclear subtype-specific target expression might be significant challenges for subtype-based precision oncology in SCLC. Preexisting IFNγ-driven immunity and mitochondrial metabolism seem to be correlates of long-term efficacy in this study, although the absence of a chemotherapy control arm precludes concluding that these are predictive features specific for immunotherapy.

Although the benefit of first-line epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs) over chemotherapy has been demonstrated in several clinical trials, data from clinical practice is lacking and the optimal EGFR TKI to be used remains unclear. This study aims to assess the real-life diagnostic and clinical management and outcome of patients with advanced non-small-cell lung cancer (NSCLC) carrying EGFR mutations in Spain. All consecutive patients recently diagnosed with advanced or metastatic NSCLC from April 2010 to December 2011 in 18 Spanish hospitals and carrying EGFR mutations were retrospectively evaluated. Between March and November 2013, a total of 187 patients were enrolled (98.3% Caucasian, 61.9% female, 54.9% never-smokers, 89.0% adenocarcinoma). Mutation testing was mainly performed on biopsy tumour tissue specimens (69.0%) using a qPCR-based test (90%) (47.0% Therascreen EGFR PCR Kit). Common sensitising mutations were detected in 79.8% of patients: 57.1% had exon 19 deletions and 22.6% exon 21 L858R point mutations. The vast majority of patients received first-line therapy (n = 168; 92.8%). EGFR TKIs were the most commonly used first-line treatment (81.5%), while chemotherapy was more frequently administered as a second- and third-line option (51.9% and 56.0%, respectively). Of 141 patients who experienced disease progression, 79 (56.0%) received second-line treatment. After disease progression on first-line TKIs (n = 112), 33.9% received chemotherapy, 8.9% chemotherapy and a TKI, and 9.8% continued TKI therapy. Most patients received first-line gefitinib (83.0%), while erlotinib was more frequently used in the second-line setting (83.0%). Progression-free survival (PFS) and overall survival (OS) in patients harbouring common mutations were 11.1 months and 20.1 months respectively (exon 19 deletions: 12.4 and 21.4 months; L858R: 8.3 and 14.5 months), and 3.9 months and 11.1 months respectively for those with rare mutations. EGFR TKIs (gefitinib and erlotinib) are used as the preferred first-line treatment while chemotherapy is more frequently administered as a second- and third-line option in routine clinical practice in Spain. In addition, efficacy data obtained in the real-life setting seem to concur with data from EGFR TKI phase III pivotal studies in NSCLC.

Oral squamous cell carcinoma (OSCC) constitutes approximately 25% of all head and neck cancer, for which the consumption of tobacco and alcohol are the main associated risk factors. The field cancerization effect of OSCC is one of the main reasons for the poor survival rates associated with this disease. Despite some advances, its ccharacterization and early diagnosis continue to challenge modern oncology, and the goal of improving the prognosis remains to be achieved. Among new early diagnostic tools for OSCC that have been proposed, liquid biopsy appears to be an ideal candidate, as studies have shown that the analysis of blood and saliva provides promising data for the early detection of relapses or second tumours.

Background/Objectives: Immune checkpoint inhibitors (ICIs) have transformed the treatment of patients with non-small cell lung cancer (NSCLC). Numerous studies have suggested that immune-related adverse events (irAEs) are associated with ICI efficacy and can affect any organ system. This study aims to evaluate the prognostic significance of cutaneous IrAEs (cirAEs) and their impact on the effectiveness of PD-1/PD-L1 inhibitors in real-world NSCLC data. Methods: We retrospectively collected NSCLC patients treated with ICI as first- or second-line therapy between 2015 and 2022 at a single institution. We evaluated the association between cirAEs and treatment efficacy, measured by objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Kaplan–Meier survival curves were generated, and log-rank tests were used for significance testing. Multivariable analysis was performed using Cox proportional hazards regression models. Results: A total of 510 patients were included in the analysis, with a median age of 62 years (range 34–85), and 75% of patients were males. CirAEs of any grade were observed in 139 patients (27.3%). Among patients assessed for efficacy, the ORR was significantly higher in those with cirAEs compared to those without (54.3% vs. 29.9%, p = 0.0001). At a median follow-up of 48 months, PFS (14.6 vs. 4.7 months, p = 0.0001) and OS (29 vs. 9.2 months, p = 0.0001) were significantly improved in patients with cirAEs. Patients with grade 1–2 cirAEs showed even greater survival benefits (PFS: median 14.9 months, p = 0.003; OS: median 30 months, p = 0.001). Multivariable analysis confirmed that the development of any cirAE was independently associated with significantly improved OS (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.44–0.80, p = 0.0001). The presence of multisystem ≥ 2 SOC irAEs, including cirAE, was strongly correlated with the greatest benefit from ICIs HR:0.51 (95% CI 0.35–0.74), p = 0.001. Conclusions: This study supports that cirAEs could be used as a potential marker of ICI efficacy in NSCLC. The development of multisystem cirAEs may prognose the greatest benefit of treatment.

Immunotherapy trials involving patients with extensive-stage small cell lung cancer (ES-SCLC) from real-world clinical practice are needed. We aimed to evaluate the safety and effectiveness of durvalumab plus platinum-etoposide as a first-line treatment in a real-world population of patients with ES-SCLC. A prospective, single-arm study was conducted in adult patients who had histologically or cytologically confirmed ES-SCLC and a WHO/ECOG PS of 0-2 (a maximum of 30 % of patients with a PS of 2 were allowed). Patients received durvalumab plus platinum-etoposide for up to 6 cycles, followed by durvalumab every 4 weeks as a single agent. The primary outcomes included the incidence of grade ≥ 3 adverse events (AEs) and immune-mediated AEs (imAEs). Between December 2020 and April 2021, 101 patients were included in this trial. Grade 3 or higher AEs occurred in 77 patients (76.2 %) and were considered treatment-related in 58 patients (57.4 %). Thirty-eight patients (37.6 %) reported at least one imAE, all of which were considered treatment related. Among the 82 imAEs reported during the study, 68 (82.9 %) were grade 1-2. The median overall survival was 9.6 months (95 % CI, 7.8 to 11.3), and the 12-month and 24-month overall survival rates were 40.7 % (31.1 % to 50.3 %) and 25.4 % (95 % CI, 16.8 % to 34.0 %), respectively. This phase 3B trial suggests that first-line treatment of patients with ES-SCLC with an initial regimen of up to six cycles of durvalumab plus platinum-etoposide followed by maintenance with durvalumab is feasible providing more options in daily clinical practice for the management of these patients depending on their characteristics.. NCT04712903.

Supplementary Data 2 from Spatially Preserved Multi-Region Transcriptomic Subtyping and Biomarkers of Chemoimmunotherapy Outcome in Extensive-Stage Small Cell Lung Cancer