Programmed Death Ligand 1 (PD1) inhibitors are indicated as monotherapy in first line in patients with stage IIIB/C and IV NSCLC with PD-L1 expression of 50% or above and no EGFR mutation or ALK translocation. Still, under 50% of these patients respond to Immune Checkpoint Inhibitor (ICI) treatment, and there is a need to increase the fraction of patients benefiting from ICI treatment. UV1 is a therapeutic peptide-based cancer vaccine targeting human telomerase (hTERT). hTERT is essential for tumor growth, expressed at high levels in 85% of human tumors, but only sparsely expressed in normal tissues. UV1 induces the expansion of CD4 T cells that recognize specific sequences in the UV1 peptides, and essentially initiates an anti-tumor immune response. UV1 is combined with ICI based on a presumed synergistic activity between the two modalities, as ICI blocks inhibitory signals for a vaccine-induced T cell expansion and anti-tumor effector activity. The LUNGVAC-study (NCT05344209) is a randomized phase II, open-label, multicenter study evaluating efficacy and safety of anti-PD-1 treatment with or without UV1 vaccination in treatment-naïve patients with advanced or metastatic NSCLC, with PD-L1 ≥ 50%. At least one measurable lesion according to Recist 1.1, adequate organ function, ECOG performance status 0-2 and no other active cancer are main eligibility criteria. Stratification factors are squamous versus non-squamous, and ECOG 2 versus 0+1. Primary endpoint is progression free survival. To test the PFS null hypothesis with 80% power and a 1-sided alpha level of 0.10, a total of 97 PFS events are required. Based on data published for pembrolizumab monotherapy in KEYNOTE-024, to generate the required 97 PFS events, 138 patients will be randomized 1:1 to PD-1-inhibitor for a maximum of 2 years, with or without 8 injections with UV1 vaccine during the first 2 months. Inclusion time is estimated to be 18 months and patients will be followed thereafter for a minimum of 18 months. 20 patients are included as of September 2023. NCT05344209, EudraCT 2021-005729-25. Drammen Hospital, Vestre Viken Health Trust. Ultimovacs.
e21198 Background: Despite revolutionizing cancer therapy, immune checkpoint inhibitors (ICI) still do not benefit a significant proportion of patients. The risks associated with ICI-related adverse events, mixed performance of PD-L1 staining in predicting treatment response and its high cost, present a clinical need for more precise methods to define disease states in the context of ICI treatment. ICI response is thought to depend on the phenotype of the tumor and the associated immune response, especially functional state of CD8+ T cells in the tumor microenvironment (TME). Methods: Here we show that the CD8+ T cell signatures from plasma cell-free DNA (cfDNA) could be used to predict response of patients to anti-PD-1 therapy, using samples collected before and shortly after start of treatment. Blood samples were drawn just before the first dose, 1 day to 1 week before the start of treatment and 45-60 days since start of treatment. The treatment duration varied depending on response. Response was evaluated by CT scans every 8-12 weeks. 11 of the samples are from patients with no or minor response ( < 6 months of treatment), and 12 are from patients with prolonged benefit of the medication ( > 1 year of treatment). Exhausted CD8+ T cells, one of the targets of immunotherapy treatment are epigenetically regulated. So, we utilized naïve and PD-1high CD8+ T cell ATAC-seq data to define the repertoire of accessible chromatin specific to these cell types. We found an enrichment of short cfDNA fragments at a significant fraction of these sites, enabling us to define responder-specific and non-responder-specific accessible PD-1high regions from cfDNA. Results: We used the enrichment of short- versus long-cfDNA fragments (reflecting transcription factor-nucleosome dynamics in tissue of origin of cfDNA) as a scoring function, and repeated-cross-validation as a classifier model to identify differentially enriched features between responders and non-responders. Our model accurately predicts the two classes of response both pre-treatment (mean test AUC = 0.86; SD = 0.14). Conclusions: Notably, in addition to generating an accurate classifier, our analysis enabled us to identify predominant transcription factor motifs from predictive ATAC-seq peaks that characterize both response and lack of response, paving the way for further understanding the mechanistic basis of patient-specific response to ICI. Our results suggest the possibility of personalized prediction of treatment response that is independent of specific tumor genotype.
Clinical studies have shown the efficacy of EGFR- and ALK-directed therapies in non-small cell lung cancer (NSCLC). Real-world data on, e.g., testing patterns, uptake, and duration of treatment are scarce. Reflex EGFR and ALK testing of non-squamous NSCLCs were implemented in Norwegian guidelines in 2010 and 2013, respectively. We present a complete national registry data on incidence, pathology procedures, and drug prescription in the period of 2013 to 2020. Test rates for both EGFR and ALK increased over time and were 85% and 89%, respectively, at the end of the study period, independent of age up to 85 years. The positivity rate for EGFR was higher among females and young patients, whereas no sex difference was observed for ALK. EGFR-treated patients were older than ALK-treated patients (71 vs. 63 years at start, p < 0.001). Male ALK-treated patients were significantly younger than females at the start of treatment (58 vs. 65 years, p = 0.019). The time from the first dispensation to the last dispensation of TKI (as a surrogate for progression-free survival) was shorter for EGFR- than for ALK-TKI, and survival for both EGFR- and ALK-positive patients was substantially longer than for non-mutated patients. We found a high adherence to molecular testing guidelines, good concordance of mutation positivity and treatment, and the real-world replication of findings in clinical trials, indicating that the relevant patients are provided substantially life-prolonging therapy.
Abstract Introduction: Approximately 50% of patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) develops brain metastases (BM), which is associated with a poor prognosis. Mutations in TP53 are associated with earlier development of resistance to EGFR tyrosine kinase inhibitors, but it is unclear whether patients who develops BM have a higher prevalence of TP53 mutations. Analyses of circulating tumor DNA (ctDNA) in blood have been established as a good alternative to tissue biopsies to assess the genomic landscape of NSCLC. In this study, we aim to analyze ctDNA from patients with advanced EGFR-mutated NSCLC to investigate the prevalence of TP53 mutations in patients with BM, and to explore whether patients with BM exhibit a distinct ctDNA profile compared to patients without. Materials and Methods: Plasma samples collected before treatment commenced from 97 of the 100 patients with EGFR-mutated advanced NSCLC enrolled in the First-line Treatment With Osimertinib in EGFR-mutated Non-small Cell Lung Cancer study (The FIOL study: NCT03804580) were analyzed. Patients were split into cohorts with (n=44) and without BM (n=53) at baseline. The cell-free DNA was isolated and sequenced with targeted next-generation sequencing with the AVENIO ctDNA Surveillance Panel (Roche) containing 197 lung cancer-related genes. Results: Mutations in ctDNA were found in 83 patients (85.6%), with 6 patients with BM having no ctDNA mutations and 8 patients without BM having no ctDNA mutations. Besides EGFR mutations, TP53 was the most frequently mutated gene, with 42 patients (43.3%) harboring TP53 mutations. There was no significant difference in the prevalence of TP53 mutations between the cohort with BM (n=23) and the cohort without (n=19), (p=0.15). There was no difference in the number of identified mutations in the two cohorts (BM: median: 2 (range: 0-6), without BM: median: 2 (range: 0-11), p=0.71). Patients with BM had a numerically lower ctDNA level (median: 45.5 mutant molecules/mL), than patients without BM (median: 75.9 mutant molecules/mL), though the difference was not statistically significant (p=0.68). Conclusion: Prevalence of TP53 mutations in plasma collected before osimertinib treatment initiation in advanced EGFR-mutated NSCLC was similar between patients with and without BM at baseline. Furthermore, there was no difference in the ctDNA profile between these two cohorts. Future experiments will clarify the impact of TP53 mutations in patients with or without BM. Citation Format: Simone Stensgaard, Inger Johanne Z. Eide, Elin Marie Stensland, Åslaug Helland, Simon Ekman, Karin H. Hansen, Saulius Cicenas, Bjørn Henning Grønberg, Peter Meldgaard, Boe S. Sørensen, Odd Terje Brustugun. Mutated TP53 prevalence in EGFR-mutated advanced non-small cell lung cancer patients with brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2413.
