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INTRODUCTION: Current research in EGFR-mutated NSCLC focuses on the management of drug resistance and uncommon mutations, as well as on the opportunity to extend targeted therapies' field of action to earlier stages of disease. AREAS COVERED: We conducted a review analyzing literature from the PubMed database with the aim to describe the current state of art in the management of EGFR-mutated NSCLC, but also to explore new strategies under investigation. To this purpose, we collected recruiting phase II-III trials registered on Clinicaltrials.govand conducted on EGFR-mutated NSCLC both in early and advanced stage. EXPERT OPINION: With this review, we want to provide an exhaustive overview of current and new potential treatments in EGFR-mutated NSCLC, with emphasis on the most promising newly investigated strategies, such as association therapies in the first-line setting involving EGFR-TKIs and chemotherapy (FLAURA2) or drugs targeting different driver pathways (MARIPOSA). We also aimed at unearthing challenges to achieve in this field, specifically the need to fully exploit already available compounds while developing new ones, the management of new emerging toxicities and the necessity to improve our biological understanding of the disease to design trials with a solid scientific rationale and to allow treatment personalization such in case of uncommon mutations.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Resistencia a Antineoplásicos , Receptores ErbB , Neoplasias Pulmonares , Terapia Molecular Dirigida , Inhibidores de Proteínas Quinasas , Animales , Humanos , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Desarrollo de Medicamentos , Receptores ErbB/genética , Receptores ErbB/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Mutación , Estadificación de Neoplasias , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/administración & dosificaciónRESUMEN
PURPOSE OF REVIEW: Although the recent development of direct KRASG12C inhibitors (G12Ci) has improved outcomes in KRAS mutant cancers, responses occur only in a fraction of patients, and among responders acquired resistance invariably develops over time. Therefore, the characterization of the determinants of acquired resistance is crucial to inform treatment strategies and to identify novel therapeutic vulnerabilities that can be exploited for drug development. RECENT FINDINGS: Mechanisms of acquired resistance to G12Ci are heterogenous including both on-target and off-target resistance. On-target acquired resistance includes secondary codon 12 KRAS mutations, but also acquired codon 13 and codon 61 alterations, and mutations at drug binding sites. Off-target acquired resistance can derive from activating mutations in KRAS downstream pathway (e.g., MEK1), acquired oncogenic fusions (EML4-ALK, CCDC176-RET), gene level copy gain (e.g., MET amplification), or oncogenic alterations in other pro-proliferative and antiapoptotic pathways (e.g., FGFR3, PTEN, NRAS). In a fraction of patients, histologic transformation can also contribute to the development of acquire resistance. We provided a comprehensive overview of the mechanisms that limit the efficacy of this G12i and reviewed potential strategies to overcome and possibly delay the development of resistance in patients receiving KRAS directed targeted therapies.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Desarrollo de Medicamentos , MutaciónRESUMEN
Despite the positive results obtained by first-line chemoimmunotherapy in patients with metastatic non-small-cell lung cancer (NSCLC), only a few second-line options are available after disease progression. Combi-TED is a phase II international study that will assess the efficacy of Tedopi®, a cancer vaccine, combined with either docetaxel or nivolumab and compared with docetaxel monotherapy in patients with metastatic NSCLC after chemoimmunotherapy. The study, currently in the recruitment phase, will assess 1-year overall survival (primary end point), patient's progression-free survival and overall response rate, as well as the correlation of efficacy with several tumor or blood biomarkers. The results will hopefully provide more information on Tedopi combinational treatment compared with current standard of care in NSCLC patients who fail first-line chemoimmunotherapy. Clinical Trial Registration: NCT04884282 (ClinicalTrials.gov).
Patients with lung cancer that has spread to other parts of the body are usually treated with a combination of chemotherapy and drugs that stimulate the immune system to kill cancer cells, which is referred to as immunotherapy. If after receiving these drugs the cancer still gets worse, patients have only a few treatment options left and are usually treated with chemotherapy only. Researchers will study if a new medicine called Tedopi®, a vaccine that specifically attacks cancer cells, used together with chemotherapy or immunotherapy, will work better then chemotherapy alone for these patients. The study will monitor how long patients will live after treatment, for how long they will live without their disease getting worse and how many patients will improve after treatment. Moreover, researchers will study if patients present specific features, such as certain molecules in their tumor cells or blood cells, that may indicate that they respond better to certain treatments.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Docetaxel/uso terapéutico , Nivolumab , Neoplasias Pulmonares/patología , Supervivencia sin Progresión , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Treatment with immune checkpoint inhibitors (ICIs) can be complicated by cardiovascular toxicity, including pericardial disease. To date, no prospective studies specifically investigated the optimal treatment of ICI-associated pericardial disease, and the available evidence is based on case reports and series only. We performed a systematic review of case reports and series including 20 publications for a total of 28 cases of ICI-associated pericardial disease. In this review, pericardial disease was reversible in the majority of cases (75%), although 2 deaths were reported. The majority of cases were life-threatening (G4, 53.6%) or severe (G3, 21.4%), requiring pericardiocentesis. Higher rates of improvement were associated with administration of corticosteroids (86.7% vs 61.5%), presence of other immune-related adverse events (90.9% vs. 64.7%), and non-malignant effusions (86.7% vs 42.8%). ICIs were discontinued in the majority of cases and then restarted in 7 patients with no recurrence of pericardial disease. Based on these results, ICI-associated G3-G4 pericardial disease as well as G2 pericardial disease with moderate-severe effusion should be treated with ICIs discontinuation and high-dose steroids, also performing pericardiocentesis, pericardial drainage or pericardial window in case of cardiac tamponade. For G2 with small effusion or G1 pericardial disease, ICIs might be continued and colchicine or NSAIDs could be considered. For patients requiring ICIs discontinuation, a rechallenge with ICIs seems to be feasible after resolution or meaningful improvement of pericardial disease.
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Inhibidores de Puntos de Control Inmunológico/efectos adversos , Derrame Pericárdico/complicaciones , HumanosRESUMEN
Objectives: We retrospectively analysed patients with advanced non-small-cell lung cancer (NSCLC) harbouring high PD-L1 expression (>50%) and treated with front-line pembrolizumab, comparing outcomes of patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 to those with PS 0-1.Methods: Data were collected by 16 participating centres. All patients with NSCLC and high PD-L1, treated with first-line pembrolizumab were included. We collected medical data from patient files, pathology and laboratory reports. Patient characteristics, comorbidities, PS, and tumour characteristics were reported. Overall survival (OS), progression-free survival (PFS) and response rate (RR) were calculated.Results: 302 patients were included, 246 with PS 0-1, 56 with PS 2. RR was 72% among patients with PS 0-1 compared to 45% with PS2 (odds ratio (OR) 0.31 (95% CI: 0.17-0.57), p < .001). Median PFS was 2.6 months (95% CI: 1.9-5.1) among patients with PS2 and 11.3 months (95% CI: 8.5-14.4) among those with PS 0-1. Median OS was 7.8 months (95% CI: 2.5-10.7) in the PS2 group, not reached in the PS 0-1 group. PS 2 remained predictive of poor outcomes in multivariate analysis.Conclusion: PS 2 is a strong independent predictor of poor response and survival in NSCLC patients with high PD-L1, treated with front-line pembrolizumab. Prospective randomised trials comparing immunotherapy to chemotherapy in this population would be welcome.
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Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos Inmunológicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/análisis , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Resistencia a Antineoplásicos , Europa (Continente)/epidemiología , Femenino , Humanos , Pulmón/patología , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Supervivencia sin Progresión , Estudios Retrospectivos , Adulto JovenRESUMEN
In the original article, the names of authors Mariantonia Carosi and Tatiana Koudriavtseva were incorrectly captured, and author Francesco Cognetti's affiliation was incorrect. The information is correctly shown here.
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PURPOSE: Patients with relapse of recurrent glioma have a poor outcome and limited treatment options. The aim of this study is to investigate the clinical benefit and tolerability of weekly intravenous administration of carboplatin-based monotherapy in adult glioma patients who had progressed from previous chemotherapy lines based on temozolomide and nitrosoureas. METHODS: This was a single-arm, phase II study. Eligibility criteria included progressive or recurrent glioma after radiotherapy and chemotherapy-based treatments and Karnofsky performance status (KPS) > 60. RESULTS: Thirty-two patients (median age 43.5 years) were enrolled to receive weekly carboplatin monotherapy in an intravenous method of administration. The median duration of response was 7.3 months with an overall disease control rate of 31.3%. Median progression-free survival was 2.3 months while overall survival was 5.5 months. Pre-treatment with corticosteroids (i.e. dexamethasone) was associated to clinical benefit in 43.8% of patients. Patients achieving clinical benefit exhibited a longer progression-free survival (4.6 vs. 1.5 months; p > 0.001) and overall survival (7.9 vs. 3.2 months; p = 0.041) compared with those not achieving clinical benefit. CONCLUSIONS: Our findings show that single agent, weekly, intravenous administration of carboplatin may have a role in patients with recurrent glioma and suggest that pre-treatment with corticosteroids may confer survival benefit.
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Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Carboplatino/uso terapéutico , Glioma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Terapia Recuperativa , Adulto , Anciano , Neoplasias Encefálicas/patología , Femenino , Estudios de Seguimiento , Glioma/patología , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Pronóstico , Tasa de Supervivencia , Adulto JovenRESUMEN
Aim: Osimertinib is a third-generation, irreversible, oral EGFR tyrosine kinase inhibitor. We report real-world effectiveness and safety data. Patients & methods: EGFR T790M positive advanced non-small-cell lung cancer adults, who received ≥1 prior EGFR tyrosine kinase inhibitor, received osimertinib 80 mg daily. Primary effectiveness outcome: overall survival. Secondary effectiveness outcomes included: investigator-assessed clinical response, progression-free survival, time-to-treatment discontinuation. Results: At data cutoff, 3015 patients had enrolled: 57.1% had investigator-assessed response (95% CI: 55.2-58.9). Median progression-free survival: 11.1 months (95% CI: 11.0-12.0) and median time-to-treatment discontinuation: 13.5 months (95% CI: 12.6-13.9). Interstitial lung disease/pneumonitis-like events reported in 28 (1%) patients. Conclusion: Osimertinib demonstrated clinical effectiveness similar to efficacy observed in the clinical trial program with no new safety signals.
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Acrilamidas/uso terapéutico , Compuestos de Anilina/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Acrilamidas/administración & dosificación , Acrilamidas/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Sustitución de Aminoácidos , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/efectos adversos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Receptores ErbB/genética , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Resultado del TratamientoRESUMEN
Epidermal growth factor receptor (EGFR)-mutated (exons 18-21) advanced non-small cell lung cancers (NSCLCs) are generally characterized by exquisite sensitivity to treatment with an EGFR-tyrosine kinase inhibitor (-TKI). First-generation or reversible EGFR-TKIs include gefitinib and erlotinib, while, more recently, second-generation or irreversible EGFR-TKIs have been developed, namely afatinib and dacomitinib, with the aim of overcoming/delaying acquired resistance to treatment. Nevertheless, clinical trials have shown that resistance eventually emerges after a median time of slightly less than one year, regardless of whether first- or second-generation EGFR-TKIs are used. In this context, a secondary EGFR mutation in exon 20, namely T790M, has been found to be responsible for approximately 60% of cases of acquired resistance. Alternatively, T790M resistance mutation can be found de novo, in which case it limits the antitumor activity of both first- or second-generation EGFR-TKIs. Osimertinb is an orally bioavailable, third-generation EGFR-TKI that acts by irreversibly binding both EGFR activating mutations and T790M, while sparing wild-type EGFR. On this basis, osimertinib has proven more efficacious than platinum-based chemotherapy in the setting of EGFR T790M-positive NSCLCs pretreated with a first- or second-generation EGFR-TKI. More recently, in another phase 3 trial, osimertinib outperformed gefitinib or erlotinib as first-line treatment of EGFR-mutated (ex19del or L858R) advanced NSCLCs, thus emerging as a new standard of care in this setting. In the present review, we will discuss the preclinical and clinical development of osimertinib, briefly touching upon its activity in special populations and biomarkers of sensitivity to treatment.
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Antineoplásicos/farmacología , Carbazoles/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Animales , Receptores ErbB/antagonistas & inhibidores , HumanosRESUMEN
AIM: Ceritinib was evaluated within a compassionate use program of Italian patients. PATIENTS & METHODS: 70 patients with anaplastic lymphoma kinase-positive crizotinib-refractory advanced non-small-cell lung cancer received ceritinib. RESULTS: Overall response was 40.6%, median progression-free survival was 8.2 months and median survival was 15.5 months. Dose reduction due to treatment-related adverse events occurred in 50.8% of patients starting at 750 mg/day. No significantly different progression-free survival was observed between patients who underwent any time dose reduction (n = 38) versus those who remained on the recommended dose of 750 mg/day (n = 32; p = 0.07). CONCLUSION: The efficacy of ceritinib compassionate use program resembled that of clinical trials. Dose reductions and adjustments did not appear to negatively affect clinical outcome.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/administración & dosificación , Proteínas Tirosina Quinasas Receptoras/genética , Sulfonas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Quinasa de Linfoma Anaplásico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Ensayos de Uso Compasivo , Crizotinib , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Reordenamiento Génico , Humanos , Masculino , Persona de Mediana Edad , Mutación , Inhibidores de Proteínas Quinasas/efectos adversos , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Piridinas/administración & dosificación , Piridinas/efectos adversos , Pirimidinas/efectos adversos , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Sulfonas/efectos adversosRESUMEN
In the present study we assessed the activity of the next-generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (-TKI) alectinib, in patients with ALK-postive, advanced non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases. NSCLCs with ALK-positive disease, as assessed by fluorescence in situ hybridization, and CNS metastases were treated with alectinib 600 mg BID. Included patients were followed prospectively in order to evaluate the efficacy of the drug, with particular emphasis on activity in the CNS. Eleven consecutive patients were enrolled. The majority of them were pretreated with crizotinib (n = 10, 90.9 %), and cranial radiotherapy (n = 8, 72.7 %). Six of the seven patients with measurable CNS disease experienced a CNS response, including three patients who were naïve for cranial radiation. Median duration of response was 8 months. For the whole population, median CNS-progression-free survival (-PFS), systemic-PFS, overall-PFS, overall survival, and 1-year survival were 8, 11, 8, 13 months, and 31.1 %, respectively. Two patients experiencing a CNS response were assessed for alectinib's concentrations in serum and cerebro-spinal fluid (CSF), and showed a CSF-to-serum ratio ranging from 0.001 to 0.003 ng/mL. Alectinib is highly active against CNS metastases from ALK-positive NSCLCs, irrespective of prior treatment(s) with ALK-TKI(s) and/or cranial radiotherapy. The low CSF-to-serum ratio of alectinib suggests that measuring the concentrations of the drug in the CSF may not be a reliable surrogate of its distribution into the CNS.
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Carbazoles/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/secundario , Neoplasias Pulmonares/patología , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Quinasa de Linfoma Anaplásico , Encéfalo/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Neoplasias del Sistema Nervioso Central/diagnóstico por imagen , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Proteínas Tirosina Quinasas Receptoras/sangre , Proteínas Tirosina Quinasas Receptoras/líquido cefalorraquídeo , Estudios RetrospectivosRESUMEN
Management of stage II-III non-small cell lung cancer (NSCLC) has been dramatically revolutionized by studies testing the addition of immunotherapy (IO) to chemotherapy in the pre- or perioperative setting. That is because the integration of chemoimmunotherapy (chemo-IO) with surgery has consistently shown a significant improvement in pathological complete response (path CR) rate, event-free survival, and, more recently, overall survival, versus preoperative chemotherapy alone. Particularly, resectable stage III NSCLCs represent a disease entity with a high risk of distant recurrence after radical surgery, for whom pre- or perioperative chemo-IO should be considered as the preferential treatment option. However, owing to the heterogeneity of stage III NSCLC, a standard definition of resectability is not established yet, being often subjective according to the expertise and clinical background of the thoracic surgeon. In addition, careful patient selection on the basis of tumor biomarkers, meticulous staging of the disease, and accurate monitoring of treatment-related adverse events are critical factors that could prevent the ineligibility for surgery of patients treated with pre- or perioperative chemo-IO. Finally, the impact of downstaging for initially borderline resectable tumors, as well as the exact number of preoperative chemo-IO cycles needed and the indications for adjuvant IO, still need to be fully elucidated. In this podcast, we will touch upon the above-mentioned topics from the perspectives of the thoracic surgeon and the oncologist, and suggest a shared agreement between two of the main actors involved in the treatment of resectable stage III NSCLCs.Podcast audio available for this publication.
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The PAPILLON trial showed that adding amivantamab to carboplatin-pemetrexed for advanced non-small cell lung cancer (NSCLC) patients with EGFR exon 20 insertion mutations is more effective than chemotherapy. Although safety concerns may arise, this study highlights the need for alternative therapeutic strategies beyond chemotherapy for this subtype of NSCLC.
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Anticuerpos Biespecíficos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Pemetrexed/uso terapéutico , Carboplatino/uso terapéutico , Receptores ErbB/genética , Receptores ErbB/uso terapéutico , Exones/genéticaRESUMEN
Current non-small cell lung cancer (NSCLC) management relies on genome-driven precision oncology thus shifting treatment paradigm towards biomarker-guided tumor-agnostic approaches. Recently, rearranged during transfection (RET) has been endorsed as tissue-agnostic target with sensitivity to RET inhibition. There are currently two selective RET tyrosine kinase inhibitors, pralsetinib and selpercatinib. The recent introduction of pralsetinib in the treatment algorithm of RET-rearranged tumor along with the mounting clinical evidence of pralsetinib durable activity from both randomized and observational studies holds the potential to disclose new avenues in the management of RET fusion positive NSCLC patients. Our narrative review aims to discuss the available clinical evidence on pralsetinib efficacy, particularly on brain metastases, and tolerability profile. In addition, our work explores the relevance of detecting RET fusions upfront in the disease history of patients with NSCLC.
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Neoplasias Encefálicas , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Pirazoles , Piridinas , Pirimidinas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Medicina de Precisión , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Proto-Oncogénicas c-ret/genéticaRESUMEN
In this work, we report on a clinically significant response of meningeal carcinomatosis to repotrectinib in a woman with a heavily pretreated ROS1-rearranged non-small cell lung cancer (NSCLC) that harbored the concomitant solvent front G2032R mutation. Meningeal carcinomatosis has a higher incidence in oncogene addicted NSCLC due to increased life expectancy, yet no report has ever documented the activity of repotrectinib in this context. In line with its activity, we documented the presence of the drug at potentially active concentrations in the cerebrospinal fluid. Nevertheless, the short-lived response reported by our patient highlights the importance for novel ROS1-tyrosine kinase inhibitors (TKIs) to be specifically developed to be able to penetrate the blood-brain barrier.
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INTRODUCTION: Dysregulated MET is an established oncogenic driver in non-small cell lung cancer (NSCLC). MET signaling may also suppress anticancer immune responses. Concomitant MET inhibition with capmatinib (a MET inhibitor) synergistically enhanced the efficacy of immunotherapies in murine cancer models, regardless of tumor dependency to MET signaling. Here, we report results of a multicenter, open-label, phase 2 study of capmatinib plus nivolumab (a PD-1 inhibitor) in patients with EGFR wild-type advanced NSCLC, previously treated with platinum-based chemotherapy. METHODS: Patients were allocated into high-MET or low-MET groups according to MET expression determined by immunohistochemistry, MET gene copy number as assessed by fluorescence in-situ hybridization, and presence of MET exon 14 skipping mutation, then received capmatinib 400 mg, oral, twice daily in combination with nivolumab 3 mg/kg intravenously every 2 weeks. The primary endpoint was investigator-assessed 6-month progression-free survival (PFS) rate per RECIST v1.1. RESULTS: The primary endpoint was met in both the high-MET (N = 16) and low-MET (N = 30) groups. In the high-MET and low-MET groups, respectively, the estimated mean 6-month PFS rate (95 % credible interval) by Bayesian analysis was 68.9 % (48.5-85.7) and 50.9 % (35.6-66.4). The Kaplan-Meier median PFS (95 % CI) was 6.2 months (3.5-19.2) and 4.2 months (1.8-7.4). The overall response rate (95 % CI) was 25.0 % (7.3-52.4) and 16.7 % (5.6-34.7). Most frequent treatment-related adverse events (≥30 % any grade, N = 46) were nausea (52.2 %), peripheral edema (34.8 %), and increased blood creatinine (30.4 %). CONCLUSIONS: Capmatinib plus nivolumab showed clinical activity and manageable safety in pretreated patients with advanced EGFR wild-type NSCLC, independent of MET status. TRIAL REGISTRATION: ClinicalTrials.gov NCT02323126.
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Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Neoplasias Pulmonares , Nivolumab , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Nivolumab/administración & dosificación , Nivolumab/uso terapéutico , Femenino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Receptores ErbB/genética , Receptores ErbB/antagonistas & inhibidores , Benzamidas/uso terapéutico , Benzamidas/administración & dosificación , Adulto , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/metabolismo , Anciano de 80 o más Años , Acrilamidas/uso terapéutico , Acrilamidas/administración & dosificación , Imidazoles , TriazinasRESUMEN
PURPOSE: This phase 1b/2 trial evaluated the efficacy and safety of capmatinib plus nazartinib in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). METHODS: In phase 1b, patients with progression on first-/second-generation EGFR-TKIs received escalating doses of capmatinib 200-400 mg bid plus nazartinib 50-150 mg qd. Once the MTD/RP2D was declared, phase 2 commenced with patient enrollment into groups according to mutation status and prior lines of treatment: group 1 (fasted; EGFR-TKI resistant; 1-3 prior lines; EGFRL858R/ex19del; any T790M/MET); group 2 (fasted; EGFR-TKI naïve; 0-2 prior lines; de novo T790M+; any MET); group 3 (fasted; treatment-naïve; EGFRL858R/ex19del; T790M-; any MET); group 4 (with food; 0-2 prior lines; EGFRL858R/ex19del; any T790M/MET). Primary endpoints in phase 2 were investigator-assessed overall response rate (ORR) per RECIST v1.1 (groups 1-3), safety, and tolerability of the combination with food (group 4). Efficacy was assessed by T790M and MET status for a subgroup of patients. RESULTS: The RP2D was capmatinib 400 mg bid plus nazartinib 100 mg qd. In phase 2 (n = 144), the ORR was 28.8 %, 33.3 %, 61.7 %, and 42.9 % in groups 1 (n = 52), 2 (n = 3), 3 (n = 47), and 4 (n = 42), respectively. In group 1 +phase 1b RP2D, the ORR was 45.8 %, 26.2 %, 37.9 %, and 32.4 % in MET+ (n = 24), MET- (n = 42), T790M+ (n = 29), and T790M- (n = 34) patients. Most common any-grade treatment-related adverse events (≥25 %; n = 144) were peripheral edema (54.9 %), nausea (41.7 %), diarrhea (34.0 %), and maculopapular rash (25.0 %). CONCLUSION: Capmatinib plus nazartinib showed antitumor activity in patients with EGFR-TKI-resistant, EGFR-mutated NSCLC. The overall safety profile was acceptable. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02335944.
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Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Neoplasias Pulmonares , Mutación , Triazinas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Masculino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Femenino , Receptores ErbB/genética , Receptores ErbB/antagonistas & inhibidores , Persona de Mediana Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Triazinas/administración & dosificación , Triazinas/uso terapéutico , Triazinas/efectos adversos , Adulto , Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Benzamidas/uso terapéutico , Anciano de 80 o más Años , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , ImidazolesRESUMEN
Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced non-small cell lung cancer (NSCLC), although patient survival is still unsatisfactory. Accurate predictive markers capable of personalizing the treatment of patients with NSCLC are still lacking. Circulating extracellular vesicles involved in cell-to-cell communications through miRNAs (EV-miRs) transfer are promising markers. Plasma from 245 patients with advanced NSCLC who received nivolumab as second-line therapy was collected and analyzed. EV-miRnome was profiled on 174/245 patients by microarray platform, and selected EV-miRs were validated by qPCR. A prognostic model combining EV-miR and clinical variables was built using stepwise Cox regression analysis and tested on an independent patient cohort (71/245). EV-PD-L1 gene copy number was assessed by digital PCR. For 54 patients with disease control, EV-miR changes at best response versus baseline were investigated by microarray and validated by qPCR. EV-miRNome profiling at baseline identified two EV-miRs (miR-181a-5p and miR-574-5p) that, combined with performance status, are capable of discriminating patients unlikely from those that are likely to benefit from immunotherapy (median overall survival of 4 months or higher than 9 months, respectively). EV-PD-L1 digital evaluation reported higher baseline copy number in patients at increased risk of mortality, without improving the prognostic score. Best response EV-miRNome profiling selected six deregulated EV-miRs (miR19a-3p, miR-20a-5p, miR-142-3p, miR-1260a, miR-1260b, and miR-5100) in responding patients. Their longitudinal monitoring highlighted a significant downmodulation already in the first treatment cycles, which lasted more than 6 months. Our results demonstrate that EV-miRs are promising prognostic markers for NSCLC patients treated with nivolumab.
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Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas , Vesículas Extracelulares , Neoplasias Pulmonares , MicroARNs , Nivolumab , Humanos , MicroARNs/genética , MicroARNs/sangre , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Masculino , Femenino , Persona de Mediana Edad , Pronóstico , Anciano , Nivolumab/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Biomarcadores de Tumor/genética , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Anciano de 80 o más Años , Adulto , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéuticoRESUMEN
BACKGROUND: Sotorasib showed a significant improvement of progression free survival (PFS), safety and quality of life over docetaxel in patients with KRASp.G12C-mutated advanced non-small-cell lung cancer (NSCLC) within the CodeBreak-200 study. Here we report real-world efficacy and tolerability data from NSCLC patients who received sotorasib within the Italian expanded access program (EAP). METHODS: Sotorasib (960 mg, orally, once daily) was available on physician request for KRASp.G12C mutant advanced NSCLC patients. Clinical-pathological and molecular data were collected from the Italian ATLAS real-world registry. Patients underwent CT-scan and responses were evaluated by RECIST criteria. Efficacy and tolerability outcomes have been assessed. RESULTS: A total of 196 advanced NSCLC patients were treated across 30 Italian centers. Median age was 69 years old (range 33-86). Most patients were male (61 %), former (49 %) or current smokers (43 %), with ECOG-PS 0/1 (84 %) and adenocarcinoma subtype (90 %). 45 % and 32 % of patients received sotorasib in 2nd and 3rd line, respectively. Overall, response rate was 26 % and the median duration of response was 5.7 months (95 % CI: 4.4-7.0). Median PFS and OS were 5.8 months (95 % CI: 5 - 6.5) and 8.2 months (95 % CI: 6.3 - 9.9). Grade 3-4 TRAEs occurred in 16.5 % of patients, with Grade ≥ 3 liver enzyme increase and TRAEs-related discontinuation reported in 12 % and 4.6 % of cases. CONCLUSION: Real-world data from the Italian EAP confirm the tolerability and effectiveness of sotorasib in patients with KRASp.G12C-mutated advanced NSCLC and highlight the value of the national ATLAS network as source of real-world evidence driving the clinical management of NSCLC patients.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Masculino , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Femenino , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Calidad de Vida , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Italia/epidemiología , Proteínas Proto-Oncogénicas p21(ras)/genética , MutaciónRESUMEN
INTRODUCTION: Despite several therapeutic efforts, lung cancer remains a highly lethal disease. Novel therapeutic approaches encompass immune-checkpoint inhibitors, targeted therapeutics and antibody-drug conjugates, with different results. Several studies have been aimed at identifying biomarkers able to predict benefit from these therapies and create a prediction model of response, despite this there is a lack of information to help clinicians in the choice of therapy for lung cancer patients with advanced disease. This is primarily due to the complexity of lung cancer biology, where a single or few biomarkers are not sufficient to provide enough predictive capability to explain biologic differences; other reasons include the paucity of data collected by single studies performed in heterogeneous unmatched cohorts and the methodology of analysis. In fact, classical statistical methods are unable to analyze and integrate the magnitude of information from multiple biological and clinical sources (eg, genomics, transcriptomics, and radiomics). METHODS AND OBJECTIVES: APOLLO11 is an Italian multicentre, observational study involving patients with a diagnosis of advanced lung cancer (NSCLC and SCLC) treated with innovative therapies. Retrospective and prospective collection of multiomic data, such as tissue- (eg, for genomic, transcriptomic analysis) and blood-based biologic material (eg, ctDNA, PBMC), in addition to clinical and radiological data (eg, for radiomic analysis) will be collected. The overall aim of the project is to build a consortium integrating different datasets and a virtual biobank from participating Italian lung cancer centers. To face with the large amount of data provided, AI and ML techniques will be applied will be applied to manage this large dataset in an effort to build an R-Model, integrating retrospective and prospective population-based data. The ultimate goal is to create a tool able to help physicians and patients to make treatment decisions. CONCLUSION: APOLLO11 aims to propose a breakthrough approach in lung cancer research, replacing the old, monocentric viewpoint towards a multicomprehensive, multiomic, multicenter model. Multicenter cancer datasets incorporating common virtual biobank and new methodologic approaches including artificial intelligence, machine learning up to deep learning is the road to the future in oncology launched by this project.