The advent of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represented the most important innovation in NSCLC treatment over the last years. However, despite a great ...initial activity, secondary mutations in the same target, or different alterations in other molecular pathways, inevitably occur, leading to the emergence of acquired resistance, in median within the first year of treatment. In this scenario, the mesenchymal-epidermal transition (cMET) tyrosine kinase receptor and its natural ligand, the hepatocyte growth factor (HGF), seem to play an important role. Indeed either the overexpression or the amplification of cMET, as well as the overexpression of the HGF, have been reported in a substantial subgroup of NSCLC patients resistant to EGFR-TKIs. Several cMET-inhibitors have been developed as potential therapeutic candidates, and are currently under investigation in clinical trials. These compounds include both monoclonal antibodies and TKIs, and most of them have been investigated as dual combinations including an anti-EGFR TKI, to improve the efficacy of the available treatments, and ultimately overcome acquired resistance to EGFR-inhibitors.
The rapid fatality of pancreatic cancer is, in large part, the result of diagnosis at an advanced stage in the majority of patients. Identification of individuals at risk of developing pancreatic ...adenocarcinoma would be useful to improve the prognosis of this disease. There is presently no biological or genetic indicator allowing the detection of patients at risk. Our main goal was to identify copy number variants (CNVs) common to all patients with sporadic pancreatic cancer.
We analyzed gene CNVs in leukocyte DNA from 31 patients with sporadic pancreatic adenocarcinoma and from 93 matched controls. Genotyping was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix).
We identified 431 single nucleotide polymorphism (SNP) probes with abnormal hybridization signal present in the DNA of all 31 patients. Of these SNP probes, 284 corresponded to 3 or more copies and 147 corresponded to 1 or 0 copies. Several cancer-associated genes were amplified in all patients. Conversely, several genes supposed to oppose cancer development were present as single copy.
These data suggest that a set of 431 CNVs could be associated with the disease. This set could be useful for early diagnosis.
Use of anti-epidermal growth factor receptor (anti-EGFR) agents has yielded significant advances in the treatment of patients with metastatic colorectal cancer. In fact these drugs, which include the ...monoclonal antibodies cetuximab and panitumumab, can be delivered both as a single agent and in combination with chemotherapy, achieving better survival and quality of life and in some cases also resectability of metastases. However, these agents can result in the development of toxicities that are usually different from those observed with chemotherapy alone. For the management of these adverse effects, proper knowledge is mandatory. Skin toxicity is the most frequent adverse effect. Other toxicities can be observed, such as hypomagnesemia, gastrointestinal toxicity, and thromboembolic events. Severe infusion reactions can be life-threatening. For these reasons a review of anti-EGFR-drug-related toxicity is useful for clinical practice.
The improved understanding of tumor biology associated with the recent technological advancement has revealed a growing number of potential tumor biomarkers as candidate for clinical use, providing ...new opportunities for improving the management of cancer patients in all phases of care. Biomarkers have several clinical applications in oncology, including risk assessment for disease recurrence or early diagnosis in healthy population. After the advent of targeted therapies, a growing interest has been focused on their potential role as prognostic, predictive, and surrogate endpoints, in order to promote personalized strategies. The introduction of molecular biomarkers in clinical practice has radically changed the natural history of some tumors, including gastrointestinal stromal tumor (GIST), colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and melanoma, allowing many patients to receive an individualized treatment. Liquid biopsies and the use of circulating biomarker represent the new perspective of the oncological scientific community, with very promising implications in the clinical management of cancer patients.
The discovery of new oncogenic driver mutations and the clinical development of targeted therapies have completely changed the paradigm treatment of non-small cell lung cancer (NSCLC). Epidermal ...growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs), erlotinib, gefitinib, afatinib, ALK-inhibitors, crizotinib, and ceritinib, have been already approved for clinical use, benefiting many patients whose tumors harbor, respectively, EGFR or EML4-ALK molecular alterations. However, despite an initial benefit, tumor progression inevitably occurs, due to the development of acquired resistance to the targeted treatments. Several mechanisms of resistance have been identified, such as the secondary mutation of EGFR/EML4-ALK genes, or the activation of other oncogenic drivers. Several new compounds have been developed in order to overcome acquired resistance to first-generation TKIs, showing promising results in early phase I/II clinical trials, but further studies are needed to define their optimal role in the treatment algorithm of molecular selected NSCLC.
MET exon 14 skipping mutation (METex14) is a rare alteration in non-small cell lung cancer (NSCLC), occurring in about 3-4% of cases. Here we report disease and patients characteristics, efficacy and ...tolerability of MET inhibitors among advanced METex14 NSCLC patients from the Italian real-world registry ATLAS.
Clinical-pathological and molecular data, treatment efficacy/tolerability outcomes were retrospectively collected from the ATLAS registry.
From July 2020 to July 2023 a total of 146 METex14 advanced NSCLC patients were included across 27 Italian centers. Median age was 74 years old, most patients were male (52%), with ECOG- PS <2 (72%) and adenocarcinoma subtype (83%). 125 out of 146 (86%) patients received at least one line of systemic anticancer therapy. 56 (38%) were treated with capmatinib and 34 (23%) with tepotinib. 29% and 52% of them received targeted treatment in 1st and 2nd line, respectively. In the cohort of patients treated with MET inhibitors, response rate (RR) was 37% (33% in previously treated patients and 46% in treatment-naïve) with a disease control rate of 62%. With a median follow up of 10.8 months, progression free survival was 6.6 months (95% CI: 4.3-8.3) and overall survival 10.7 (95% CI: 7.2-19.3). In patients with measurable brain metastases (17 cases), the intracranial RR was 41%. Grade>3 treatment-related adverse events (TRAEs) occurred in 12% of patients with grade 3 peripheral edema in 7% of cases. A fatal adverse reaction occurred in one patient due to pneumonitis. TRAEs-related dose reduction and discontinuation were reported in 6% and 8% of cases.
Capmatinib and tepotinib represent an effective treatment option in NSCLC patients with METex14. Real-world efficacy outcomes are worse than those reported in prospective clinical trials. Their activity is more pronounced in the treatment-naïve population, suggesting that this is the right setting in METex14 patient’s management.
•This study reports real-world data of METex14 NSCLC patients treated with MET inhibitors (capmatinib or tepotinib)•Safety profile, potentially driven by the retrospective nature of data, is better than expected (12% of grade >3 AEs)•Antitumour activity is more pronounced in the treatment-naïve setting (RR 46% as 1st line and 33% in later lines)•Progression free survival was 6.6 months and overall survival 10.7 months.•Intracranial RR was of 41%, brain radiotherapy was previously performed in 71% of cases.
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