This study aimed at investigating feasibility of programmed death ligand-1 (PD-L1) testing in plasma samples of advanced NSCLC patients receiving first-line treatment, assessing whether circulating ...(c)PD-L1 levels were modified by the therapy and whether baseline cPD-L1 levels were associated with patients' clinical responses and survival outcome.
Peripheral blood samples were collected from 16 healthy volunteers and 56 newly diagnosed NSCLC patients before and at 12th week during the course of first-line therapy. The level of PD-L1 was measured in plasma samples using the human (PD-L1/CD274) ELISA kit (CUSABIO, MD, USA). The Mann Whitney test or Fisher's test were used for comparisons. Survival analysis was performed using Kaplan Meyer method, providing median and
-value.
Baseline median cPD-L1 was 42.21 pg/ml (range 12.00-143.49) in NSCLC patients and 37.81 pg/ml (range 9.73-90.21) in healthy control cohort (
= 0.78). Median cPD-L1 increased in patients treated with first-line chemotherapy (63.20 pg/ml vs 39.34 pg/ml;
= 0.002), with no changes in patients exposed to non-chemotherapy drugs (42.39 pg/ml vs 50.67 pg/ml;
= 0.398). Time to progression and overall survival were 4.4 vs 6.9 months (
= 0.062) and 8.8 vs 9.3 months (
= 0.216) in cPD-L1 positive vs cPD-L1 negative patients. Baseline cPD-L1 levels increased with the ascending number of metastatic sites, even if the association was not statistically significant (
= 0.063).
This study showed that cPD-L1 testing is feasible, with chemotherapy influencing PD-L1 plasma levels. The possibility of using such test for predicting or monitoring the effect of immunotherapy or combination of chemotherapy and immunotherapy warrant further investigations.
•The EGFR ex20ins has become a “druggable target” in NSCLC.•Amivantamab and Mobocertinib have been approved in pre-treated EGFR ex20ins NSCLC patients.•Novel selective EGFRex20ins inhibitors are ...being investigated in clinical trials.•NGS is the standard approach for the molecular detection of EGFRex20ins.
The Epidermal growth factor receptor (EGFR) exon (ex) 20 insertions (ins) has been considered as an “undruggable target” for a long time, with platinum-pemetrexed combination recommended as upfront standard treatment for newly diagnosed advanced non-small cell lung cancer (NSCLC) patients. Recent preliminary data from early phase clinical trials have demonstrated that pharmacological inhibition of EGFRex20ins is possible, offering new treatment opportunities to 1–2% of advanced NSCLC patients harboring such hard-to-treat molecular alteration. Among the different drugs under clinical investigation, both amivantamab and mobocertinib have received regulatory approval in the United States, by the Food and Drugs Administration (FDA), while amivantamab has been recently approved also in Europe, for the clinical treatment of advanced NSCLC patients harboring EGFRex20ins who failed at least one prior line of systemic therapy, representing a major breakthrough in lung cancer treatment over the last year. With novel effective targeted options on the horizon, there is a renewed interest on optimizing the molecular screening of advanced NSCLC, and next-generation sequencing (NGS)-based genotyping is currently considered the gold standard approach to profile advanced NSCLC patients, as recommended by international guidelines. Herein we provide an updated overview of the most recent findings and upcoming challenges regarding both molecular detection and therapeutic management of EGFR ex20ins mutant advanced NSCLC patients.
Despite the high prevalence of Kirsten rat sarcoma (KRAS) mutations in non-small cell lung cancer (NSCLC), for a long time it has been defined as an ‘undruggable target’, with precision medicine not ...considered as an adequate approach to treat this subgroup of patients. After several years of efforts, preliminary data from early clinical trials have recently demonstrated that direct pharmacological inhibition of KRAS p.G12C mutation is possible, emerging as an effective targeted treatment for about 10–12% of patients with advanced NSCLC, with potential relevant impact on their long-term survival and quality of life.
This review reports the current status of KRAS mutations detection in the Italian real-word scenario, summarises the biological basis of KRAS inhibition in NSCLC and provides an updated overview of therapeutic strategies, discussing the potential reasons for past failures and analysing the upcoming challenges related to the advent of new targeted agents in clinical practice.
•Kirsten rat sarcoma (KRAS) p.G12C mutations characterise about 10–12% of lung adenocarcinoma.•KRAS p.G12C mutation is now considered as a druggable target in non–small cell lung cancer.•KRAS p.G12C small-molecule inhibitors are emerging as an effective treatment option for metastatic disease.•Combinations with the Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) or immunotherapy represent promising therapeutic strategies.•Molecular and biological heterogeneity represent major challenges for clinical lung cancer research.
Many new drugs have appeared in last years in the oncological treatment scenario. Each drug carries an important set of adverse events, not less, cardiovascular adverse events. This aspect is even ...more important considering the increasing use of combination therapies with two drugs, or three drugs as in some ongoing clinical trials. Besides it represents a growing problem for Cardiologists, that face it in every day clinical practice and that will face it probably more and more in the coming years. This work reviews the mechanism of action of BRAF-inhibitors and MEK-inhibitors used together, the pathophysiological mechanisms that lead to cardiovascular toxicity. Particularly, it focuses on hypertension and ejection fraction reduction development. Then, it follows the examination of published data for each combination therapy. A Literature research was carried out using Pubmed selecting review articles, original studies and clinical trials, but mainly focusing on phase 3 studies. This work aims to summarize the knowledge about BRAF-inhibitor and MEK-inhibitor treatment and its cardiovascular toxicity to make it usable and give the basic tools to Cardiologists and Oncologists for a better management of cancer patient undergoing this treatment. Besides a deeper knowledge of the cardiovascular adverse events linked to this treatment and the magnitude of their expression and frequency can lead to a targeted cardiological treatment.
Abstract
Increasingly, health authorities and the medical community are investing resources into evaluating real-world data (RWD) on precision biomarker-based treatments. Neurotrophic tyrosine ...receptor kinase (NTRK) gene fusions are oncogenic drivers in various cancers. Larotrectinib is a highly selective, central nervous system (CNS)-active TRK inhibitor approved for tumor-agnostic use in pediatric and adult patients with various cancers. ON-TRK (NCT04142437) is an ongoing non-interventional post-approval study that is critical in gaining RWD on the treatment of patients with TRK fusion cancer and will contribute to the broader understanding of personalized therapy. This open-label, global, multi-cohort, prospective study will enroll up to 300 pediatric and adult patients with TRK fusion cancer scheduled to receive larotrectinib, including ≥ 30 pediatric patients. Patients with cancer harboring NTRK gene fusions, detected locally, are eligible. Patients who have had prior TRK inhibitor therapy and patients with NTRK genomic alterations other than functional gene fusions are excluded. Decisions on the dose and duration of treatment are at the discretion of the treating physician. The primary endpoint is safety, including specific long-term parameters in pediatric patients. Secondary endpoints include: efficacy (objective response rate, disease control rate, time to response, duration of response, progression-free survival, and overall survival), dosing patterns and long-term effects of larotrectinib in pediatric patients. The effects of larotrectinib on growth and developmental milestones in pediatric patients will be reported, including change in height and weight from baseline, age at adrenarche for males and menarche for females, number and percentage of patients with abnormal Tanner stages, and abnormal neurological assessments. All variables will be analyzed using descriptive statistics. Pediatric and adult patients will be followed for ≥ 5 years and ≥ 2 years, respectively, unless lost to follow-up, withdrawal, or death. Enrollment is ongoing worldwide; 24 patients with primary CNS cancer have been enrolled to date.
Clinical trials of immune checkpoints modulators, including both programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors, have recently shown promising activity and ...tolerable toxicity in pre-treated NSCLC patients. However the predictive role of PD-L1 expression is still controversial. This pooled analysis aims to clarify the association of clinical objective responses to anti PD-1/PD-L1 monoclonal antibodies (MoAbs) and tumor PD-L1 expression in pre-treated NSCLC patients.
Data from published studies, that evaluated efficacy and safety of PD-1/PD-L1 inhibitors in pre-treated NSCLC patients, stratified by tumor PD-L1 expression status (immunohistochemistry, cut-off point 1%), were collected by searching in PubMed, Cochrane Library, American Society of Clinical Oncology, European Society of Medical Oncology and World Conference of Lung Cancer, meeting proceedings. Pooled Odds ratio (OR) and 95% confidence intervals (95% CIs) were calculated for the Overall Response Rate (ORR) (as evaluated by Response Evaluation Criteria in Solid Tumors, version 1.1), according to PD-L1 expression status.
A total of seven studies, with 914 patients, were eligible. Pooled analysis showed that patients with PD-L1 positive tumors (PD-L1 tumor cell staining ≥1%), had a significantly higher ORR, compared to patients with PD-L1 negative tumors (OR: 2.44; 95% CIs: 1.61-3.68).
PD-L1 tumor over-expression seems to be associated with higher clinical activity of anti PD-1/PD-L1 MoAbs, in pre-treated NSCLC patients, suggesting a potential role of PD-L1 expression, IHC cut-off point 1%, as predictive biomarker for the selection of patients to treat with immune-checkpoint inhibitors.
In this review, we report a complete and updated summary of the most recent treatment advances in the fields of oncogene-addicted disease and provide expert perspectives on the evolving paradigm of ...precision medicine in lung cancer patients.
The advent of innovative genome sequencing technologies is rapidly increasing the number of targetable molecular alterations in advanced nonsmall cell lung cancer (NSCLC), leading to the introduction of novel selective inhibitors into the clinical arena, showing unprecedent tumor responses against rare and elusive NSCLC targets. The results of the ADAURA trial suggested that targeting EGFR pathway in the adjuvant setting is a feasible and effective strategy. The routine use of next-generation sequencing (NGS) is currently recommended as new standard approach to profile advanced NSCLC samples while recent findings suggest the potential application of a plasma-based first approach for tumor genotyping. Innovative umbrella trials provide the right infrastructure to investigate the role of precision medicine in advanced NSCLC, but failed to show clinical benefit.
Implementing NGS-based molecular screening, increasing patients' access to biomarker driven-clinical trials, ensuring equal access to molecular testing and innovative treatments, overcoming disparities and preserve health systems' financial sustainability represents the main challenges of precision medicine worldwide.
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