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BACKGROUND: Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population. METHODS: This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete). FINDINGS: Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea. INTERPRETATION: Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated. FUNDING: Merck (CrossRef Funder ID: 10.13039/100009945).
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Acrilamidas , Compuestos de Anilina , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Amplificación de Genes , Neoplasias Pulmonares , Mutación , Proteínas Proto-Oncogénicas c-met , Humanos , Acrilamidas/uso terapéutico , Femenino , Masculino , 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 , Proteínas Proto-Oncogénicas c-met/genética , Persona de Mediana Edad , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Anciano , Receptores ErbB/genética , Receptores ErbB/antagonistas & inhibidores , Compuestos de Anilina/uso terapéutico , Compuestos de Anilina/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Pirimidinas/efectos adversos , Pirimidinas/uso terapéutico , Pirimidinas/administración & dosificación , Progresión de la Enfermedad , Anciano de 80 o más Años , Indoles , Piperidinas , PiridazinasRESUMEN
Selective rearranged during transfection (RET) tyrosine kinase inhibitor, pralsetinib, demonstrated clinical efficacy and was well tolerated in lung and thyroid cancers with RET gene mutations or fusions in clinical trials. While the latter focused on the risk of pneumonitis, there is a lack of data regarding other types of infectious risks associated with pralsetinib. Herein, we report the case of a 53-year-old patient with a CCDC6-RET fusion neuroendocrine tumor, who achieved a partial response with pralsetinib as the fifth-line therapy. Of particular note, during pralsetinib therapy, the clinical course was complicated by five severe infectious events, namely, two oxygen-requiring pneumonias, two distinct spondylodiscitis, and one pneumocystis. Our study highlights the increased risk of any type of opportunistic infectious event with pralsetinib, but not selpercatinib, which is probably caused by off-target JAK1/2 inhibition.
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The gut microbiota influences the clinical responses of cancer patients to immunecheckpoint inhibitors (ICIs). However, there is no consensus definition of detrimental dysbiosis. Based on metagenomics (MG) sequencing of 245 non-small cell lung cancer (NSCLC) patient feces, we constructed species-level co-abundance networks that were clustered into species-interacting groups (SIGs) correlating with overall survival. Thirty-seven and forty-five MG species (MGSs) were associated with resistance (SIG1) and response (SIG2) to ICIs, respectively. When combined with the quantification of Akkermansia species, this procedure allowed a person-based calculation of a topological score (TOPOSCORE) that was validated in an additional 254 NSCLC patients and in 216 genitourinary cancer patients. Finally, this TOPOSCORE was translated into a 21-bacterial probe set-based qPCR scoring that was validated in a prospective cohort of NSCLC patients as well as in colorectal and melanoma patients. This approach could represent a dynamic diagnosis tool for intestinal dysbiosis to guide personalized microbiota-centered interventions.
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Carcinoma de Pulmón de Células no Pequeñas , Microbioma Gastrointestinal , Inmunoterapia , Neoplasias Pulmonares , Neoplasias , Femenino , Humanos , Masculino , Akkermansia , Carcinoma de Pulmón de Células no Pequeñas/microbiología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Disbiosis/microbiología , Heces/microbiología , Microbioma Gastrointestinal/efectos de los fármacos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunoterapia/métodos , Neoplasias Pulmonares/microbiología , Neoplasias Pulmonares/tratamiento farmacológico , Metagenómica/métodos , Neoplasias/microbiología , Resultado del TratamientoRESUMEN
INTRODUCTION: Myocarditis is the most lethal cardiovascular immune related adverse events with a low incidence, depending on the studies. We prospectively studied the potential interest of a systematic screening to early detect immune related myocarditis and confirm the incidence of immune-induced myocarditis in advanced lung cancer and the impact of troponin systematic screening in early detection of other major cardiovascular events (MACE). MATERIAL AND METHODS: This prospective bicentric study includes adults who received at least one dose of immune checkpoint inhibitor (ICI) for advanced lung cancer. Cardiac biomarkers dosage, ECG and transthoracic echography (TTE) were done at baseline. Diagnosis of myocarditis was based on European Society of Cardiology recommendations. MACEs were reported during the observation period. RESULTS: Among 298 patients, 5 (1.68 %) immune-induced myocarditis occurred, all being asymptomatic with at first troponin elevation, treated by corticosteroids and ICI's discontinuation. No attributable death occurred, and no specific clinical characteristics were identified with myocarditis onset. Three patients were rechallenged with ICI after troponin normalization in the absence of other therapeutic options. Recurrence occurred in 2 patients, with a re-increase of troponin and a de novo modification of the ECG. Systematic cardiovascular screening also led to 14 cardiovascular diseases detection and 11 MACEs during ICI. CONCLUSION: Systematic cardiovascular screening has uncovered slightly more immuno-induced myocarditis cases than reported previously, but without altering treatment strategies due to their subclinical nature. Additionally, it helps detecting other cardiovascular diseases in this comorbid population.
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Inhibidores de Puntos de Control Inmunológico , Miocarditis , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Masculino , Estudios Prospectivos , Femenino , Anciano , Persona de Mediana Edad , Miocarditis/inducido químicamente , Miocarditis/epidemiología , Miocarditis/diagnóstico , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/etiología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/complicaciones , Adulto , Anciano de 80 o más Años , Incidencia , Neoplasias Torácicas/tratamiento farmacológico , Troponina/sangreRESUMEN
Drug-tolerance has emerged as one of the major non-genetic adaptive processes driving resistance to targeted therapy (TT) in non-small cell lung cancer (NSCLC). However, the kinetics and sequence of molecular events governing this adaptive response remain poorly understood. Here, we combine real-time monitoring of the cell-cycle dynamics and single-cell RNA sequencing in a broad panel of oncogenic addiction such as EGFR-, ALK-, BRAF- and KRAS-mutant NSCLC, treated with their corresponding TT. We identify a common path of drug adaptation, which invariably involves alveolar type 1 (AT1) differentiation and Rho-associated protein kinase (ROCK)-mediated cytoskeletal remodeling. We also isolate and characterize a rare population of early escapers, which represent the earliest resistance-initiating cells that emerge in the first hours of treatment from the AT1-like population. A phenotypic drug screen identify farnesyltransferase inhibitors (FTI) such as tipifarnib as the most effective drugs in preventing relapse to TT in vitro and in vivo in several models of oncogenic addiction, which is confirmed by genetic depletion of the farnesyltransferase. These findings pave the way for the development of treatments combining TT and FTI to effectively prevent tumor relapse in oncogene-addicted NSCLC patients.
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Carcinoma de Pulmón de Células no Pequeñas , Resistencia a Antineoplásicos , Farnesiltransferasa , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Farnesiltransferasa/antagonistas & inhibidores , Farnesiltransferasa/metabolismo , Farnesiltransferasa/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Resistencia a Antineoplásicos/genética , Línea Celular Tumoral , Animales , Ratones , Dependencia del Oncogén/genética , Terapia Molecular Dirigida , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Femenino , Ensayos Antitumor por Modelo de Xenoinjerto , Oncogenes/genética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , QuinolonasRESUMEN
Purpose: Immune checkpoint inhibitors (ICIs) are now one of the standards of care for patients with lung cancer and have greatly improved both progression-free and overall survival, although <20% of the patients respond to the treatment, and some face acute adverse events. Although a few predictive biomarkers have integrated the clinical workflow, they require additional modalities on top of whole-slide images and lack efficiency or robustness. In this work, we propose a biomarker of immunotherapy outcome derived solely from the analysis of histology slides. Approach: We develop a three-step framework, combining contrastive learning and nonparametric clustering to distinguish tissue patterns within the slides, before exploiting the adjacencies of previously defined regions to derive features and train a proportional hazards model for survival analysis. We test our approach on an in-house dataset of 193 patients from 5 medical centers and compare it with the gold standard tumor proportion score (TPS) biomarker. Results: On a fivefold cross-validation (CV) of the entire dataset, the whole-slide image-based survival analysis for patients treated with immunotherapy (WhARIO) features are able to separate a low- and a high-risk group of patients with a hazard ratio (HR) of 2.29 (CI95=1.48 to 3.56), whereas the TPS 1% reference threshold only reaches a HR of 1.81 (CI95=1.21 to 2.69). Combining the two yields a higher HR of 2.60 (CI95=1.72 to 3.94). Additional experiments on the same dataset, where one out of five centers is excluded from the CV and used as a test set, confirm these trends. Conclusions: Our uniquely designed WhARIO features are an efficient predictor of survival for lung cancer patients who received ICI treatment. We achieve similar performance to the current gold standard biomarker, without the need to access other imaging modalities, and show that both can be used together to reach even better results.
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PURPOSE: Lorlatinib improved progression-free survival (PFS) and intracranial activity versus crizotinib in patients with previously untreated, advanced, ALK-positive non-small cell lung cancer (NSCLC) in the phase III CROWN study. Here, we report long-term outcomes from CROWN after 5 years of follow-up. METHODS: Two hundred ninety-six patients with ALK-positive NSCLC were randomly assigned 1:1 to receive lorlatinib 100 mg once daily (n = 149) or crizotinib 250 mg twice daily (n = 147). This post hoc analysis presents updated investigator-assessed efficacy outcomes, safety, and biomarker analyses. RESULTS: With a median follow-up for PFS of 60.2 and 55.1 months, respectively, median PFS was not reached (NR [95% CI, 64.3 to NR]) with lorlatinib and 9.1 months (95% CI, 7.4 to 10.9) with crizotinib (hazard ratio [HR], 0.19 [95% CI, 0.13 to 0.27]); 5-year PFS was 60% (95% CI, 51 to 68) and 8% (95% CI, 3 to 14), respectively. Median time to intracranial progression was NR (95% CI, NR to NR) with lorlatinib and 16.4 months (95% CI, 12.7 to 21.9) with crizotinib (HR, 0.06 [95% CI, 0.03 to 0.12]). Safety profile was consistent with that in prior analyses. Emerging new ALK resistance mutations were not detected in circulating tumor DNA collected at the end of lorlatinib treatment. CONCLUSION: After 5 years of follow-up, median PFS has yet to be reached in the lorlatinib group, corresponding to the longest PFS ever reported with any single-agent molecular targeted treatment in advanced NSCLC and across all metastatic solid tumors. These results coupled with prolonged intracranial efficacy and absence of new safety signals represent an unprecedented outcome for patients with advanced ALK-positive NSCLC and set a new benchmark for targeted therapies in cancer.
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Fenómenos Electromagnéticos , Humanos , Masculino , Femenino , Persona de Mediana Edad , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/diagnóstico , Anciano , Nódulo Pulmonar Solitario/diagnóstico por imagen , Nódulo Pulmonar Solitario/patología , Pueblo EuropeoRESUMEN
BACKGROUND AND OBJECTIVE: Little is known about malignant central airway obstruction (MCAO) complicating the metastatic spread of non-bronchogenic solid cancers (NBC) and their bronchoscopic management. This study aimed to describe the epidemiology of this population and determine prognostic factors before therapeutic bronchoscopy (TB). METHODS: In this multicenter study using the EpiGETIF registry, we analysed patients treated with TB for MCAO caused by NBC between January 2019 and December 2022. RESULTS: From a database of 2389 patients, 436 patients (18%) with MCAO and NBC were identified. After excluding patients with direct local invasion, 214 patients (8.9%) were analysed. The main primaries involved were kidney (17.8%), colon (16.4%), sarcoma (15.4%), thyroid (8.9%) and head and neck (7.9%) cancers. Most patients (63.8%) had already received one or more lines of systemic treatment. Obstructions were purely intrinsic in 58.2%, extrinsic in 11.1% and mixed in 30.8%. Mechanical debulking was used in 73.4% of cases, combined with thermal techniques in 25.6% of cases. Airway stenting was required in 38.4% of patients. Median survival after TB was 11.2 months, influenced by histology (p = 0.002), performance status (p = 0.019), initial hypoxia (HR 1.45 [1.01-2.18]), prior oncologic treatment received (HR 1.82 [1.28-2.56], p < 0.001) and assessment of success at the end of the procedure (HR 0.66 [0.44-0.99], p < 0.001). Complications rate was 8.8%, mostly mild, with no procedure-related mortality. CONCLUSION: TB for MCAO caused by a NBC metastasis provides rapid improvement of symptoms and prolonged survival. Patients should be promptly referred by medical oncologists for bronchoscopic management based on the prognostic factors identified.
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Obstrucción de las Vías Aéreas , Broncoscopía , Sistema de Registros , Humanos , Broncoscopía/métodos , Masculino , Femenino , Obstrucción de las Vías Aéreas/etiología , Obstrucción de las Vías Aéreas/epidemiología , Persona de Mediana Edad , Anciano , Pronóstico , Neoplasias de Cabeza y Cuello/complicaciones , Neoplasias de Cabeza y Cuello/epidemiología , Neoplasias de Cabeza y Cuello/patologíaRESUMEN
INTRODUCTION: Previous studies have identified an interaction between protein kinase inhibitors (PKIs) and proton pump inhibitors (PPIs) in patients with lung cancer. This type of interaction may reduce the efficacy of PKIs. However, the effect of PKI-PPI interaction on patient mortality remains controversial. This study set out to determine the impact of PKI-PPI interaction on overall survival for lung cancer patients. MATERIALS AND METHODS: This study was conducted using data from the French National Health Care Database from January 1, 2011 to December 31, 2021. We identified patients with: (i) an age equal to or greater than 18 years; (ii) lung cancer; and (iii) at least one reimbursement for one of the following drugs: erlotinib, gefitinib, afatinib and osimertinib. Patients were followed-up between the first date of PKI reimbursement and either December 31, 2021 or if they died, the date on which death occurred. The cumulative exposure to PPI duration during PKI treatment was calculated as the ratio between the number of concomitant exposure days to PKI and PPI and the number of exposure days to PKI. A survival analysis using a Cox proportional hazards model was then performed to assess the risk of death following exposure to a PKI-PPI interaction. RESULTS: 34,048 patients received at least one reimbursement for PKIs of interest in our study: 26,133 (76.8 %) were exposed to erlotinib; 3,142 (9.2 %) to gefitinib; 1,417 (4.2 %) to afatinib; and 3,356 (9.9 %) to osimertinib. Patients with concomitant exposure to PKI-PPI interaction during 20 % or more of the PKI treatment period demonstrated an increased risk of death (HR, 1.60 [95 % CI, 1.57-1.64]) compared to other patients. When this cut-off varied from 10 % to 80 %, the estimated HR ranged from 1.46 [95 % CI, 1.43-1.50] to 2.19 [95 % CI, 2.12-2.25]. DISCUSSION/CONCLUSION: In our study, an elevated risk of death was observed in patients exposed to PKI-PPI interaction. Finally, we were able to identify a dose-dependent effect for this interaction. This deleterious effect of osimertinib and PPI was revealed for the first time in real life conditions.
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Neoplasias Pulmonares , Inhibidores de Proteínas Quinasas , Inhibidores de la Bomba de Protones , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Inhibidores de la Bomba de Protones/uso terapéutico , Inhibidores de la Bomba de Protones/efectos adversos , Inhibidores de la Bomba de Protones/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/efectos adversos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Estudios de Cohortes , Afatinib/uso terapéutico , Afatinib/farmacología , Compuestos de Anilina/uso terapéutico , Compuestos de Anilina/farmacología , Compuestos de Anilina/efectos adversos , Acrilamidas/uso terapéutico , Acrilamidas/farmacología , Anciano de 80 o más Años , Interacciones Farmacológicas , Francia/epidemiología , Adulto , Gefitinib/uso terapéutico , Gefitinib/farmacología , Estudios RetrospectivosRESUMEN
BACKGROUND: STK11/LKB1 mutations have been associated with primary resistance to PD-1 axis inhibitors and poor prognosis in advanced KRAS-mutant lung adenocarcinoma. This study aimed to assess the prognostic significance of STK11/LKB1 alterations in localized non-squamous non-small cell lung carcinoma (non-sq NSCLC). PATIENTS AND METHODS: Surgical samples from patients undergoing complete resection for stage IIa, IIb, or IIIa (N2 excluded) non-sq NSCLC in the randomized adjuvant phase II trial (NCT00775385 IFCT-1801 TASTE trial) were examined. Patients received either standard chemotherapy (Pemetrexed Cisplatin) or personalized treatment based on EGFR mutation (Erlotinib) and ERCC1 expression. Tumor molecular profiles were analyzed using targeted NGS and correlated with overall survival (OS) and disease-free survival (DFS), adjusting for relevant clinical variables. Additionally, interactions between treatment groups and molecular alterations on OS, PD-L1 expression, and tumor-circulating DNA in post-operative plasma samples were evaluated. RESULTS: Among 134 patients (predominantly male smokers with adenocarcinoma), KRAS mutations were associated with shorter DFS (HR: 1.95, 95 % CI: 1.1-3.4, p = 0.02) and OS (HR: 2.32, 95 % CI: 1.2-4.6, p = 0.014). Isolated STK11/LKB1 mutations (n = 18) did not significantly impact DFS or OS. However, within KRAS-mutated samples (n = 53), patients with concurrent STK11/LKB1 mutations (n = 10) exhibited significantly shorter DFS (HR: 3.85, CI: 1.5-10.2, p = 0.006) and a trend towards shorter OS (HR: 1.80, CI: 0.6-5.3, p = 0.28). No associations were found between PD-L1 expression, other gene mutations, progression-free survival (PFS), or OS. CONCLUSION: This analysis reinforces KRAS mutations as predictive factors for relapse and poor survival in localized non-sq NSCLC. Furthermore, the presence of concomitant STK11/LKB1 mutations exacerbated the prognosis within the KRAS-mutated subset. These findings emphasize the clinical relevance of these molecular markers and their potential impact on treatment strategies in non-sq NSCLC.
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Adenocarcinoma del Pulmón , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Femenino , Humanos , Masculino , Adenocarcinoma del Pulmón/genética , Quinasas de la Proteína-Quinasa Activada por el AMP , Antígeno B7-H1/metabolismo , 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 , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Recurrencia Local de Neoplasia , Pronóstico , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismoRESUMEN
Lorlatinib is a brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) indicated for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC). In clinical trials, lorlatinib has shown durable efficacy and a manageable safety profile in treatment-naive patients and in those who have experienced progression while receiving first- and/or second-generation ALK TKIs. Lorlatinib has a distinct safety profile from other ALK TKIs, including hyperlipidemia and central nervous system effects. Clinical trial data showed that most adverse events (AEs) can be managed effectively or reversed with dose modifications (such as dose interruptions or reductions) or with concomitant medications without compromising clinical efficacy or quality of life for patients. A pragmatic approach to managing AEs related to lorlatinib is required. We present patient-focused recommendations for the evaluation and management of select AEs associated with lorlatinib developed by clinicians and nurses with extensive lorlatinib expertise in routine clinical practice. The recommendations follow the general framework of "prepare, monitor, manage, reassess" to streamline AE management and assist in practical, actionable, and personalized patient care.
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Aminopiridinas , Carcinoma de Pulmón de Células no Pequeñas , Lactamas Macrocíclicas , Lactamas , Neoplasias Pulmonares , Inhibidores de Proteínas Quinasas , Pirazoles , Humanos , Lactamas/efectos adversos , Aminopiridinas/efectos adversos , Aminopiridinas/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Pirazoles/efectos adversos , Pirazoles/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Lactamas Macrocíclicas/uso terapéutico , Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Manejo de la EnfermedadRESUMEN
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Osimertinib has been established as a standard of care for patients with common sensitizing EGFR-mutant advanced non-small-cell lung cancer (NSCLC) although the sequential approach (first-generation inhibitor gefitinib followed by osimertinib) has not been formally compared. The phase II APPLE trial (ClinicalTrials.gov identifier: NCT02856893) enrolled 156 treatment-naïve patients, and two treatment strategies were evaluated: osimertinib up front or the sequential treatment approach with gefitinib up front followed by osimertinib at the time of progression, either molecular progression (detection of plasma T790M resistance mutation) regardless of the radiologic status or just at the time of radiologic progression. Patients' characteristics were well balanced, except for the higher proportion of baseline brain metastases in the sequential approach (29% v 19%). Per protocol, 73% of patients switched to osimertinib in the sequential arm. Up-front treatment with osimertinib was associated with a lower risk of brain progression versus the sequential approach (hazard ratio [HR], 0.54 [90% CI, 0.34 to 0.86]), but a comparable overall survival was observed between both strategies (HR, 1.01 [90% CI, 0.61 to 1.68]), with the 18-month survival probability of 84% and 82.3%, respectively. The APPLE trial suggests that a sequential treatment approach is associated with more frequent progression in the brain but a similar survival in advanced EGFR-mutant NSCLC.
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Acrilamidas , Carcinoma de Pulmón de Células no Pequeñas , Indoles , Neoplasias Pulmonares , Pirimidinas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Gefitinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Receptores ErbB/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Mutación , Compuestos de Anilina/uso terapéuticoRESUMEN
WHAT IS THIS SUMMARY ABOUT?: This is a summary of a research study called ARROW, which tested a medicine called pralsetinib in patients with non-small cell lung cancer (NSCLC), thyroid cancer, and other advanced solid tumours caused by a change in a gene called RET. For the purposes of this summary, only patients with NSCLC with a change in RET called fusion (RET fusion+) are highlighted. WHAT WERE THE RESULTS?: In total, 281 patients with RET fusion+ NSCLC had taken part in this study across the USA, Europe, and Asia. Patients were asked to take four pills (adding up to 400 mg) of pralsetinib each day and were checked for any changes in their tumours, as well as for any side effects. After an average of 8 months of treatment with pralsetinib, 72% of previously untreated patients and 59% of patients who had previously received chemotherapy had considerable shrinkage of their tumours. Among 10 patients with tumours which had spread to the brain (all of whom had received previous treatments), 70% had their tumours shrink greatly in the brain after treatment with pralsetinib. On average, patients lived with little to no tumour growth for 16 months. In previously untreated patients, the most common severe side effects that were considered related to pralsetinib treatment were decreased white blood cells (neutrophils and lymphocytes), increased blood pressure, and an increase in a blood protein called creatine phosphokinase. In previously treated patients, the severe side effects were decreased white blood cells (neutrophils, lymphocytes, and leukocytes), increased blood pressure, and low levels of red blood cells. In both untreated and previously treated patients, the most common severe side effects that required hospital attention were lung inflammation/swelling causing shortness of breath (pneumonitis) and lung infection (pneumonia). WHAT DO THE RESULTS MEAN?: Overall, the ARROW study showed that pralsetinib was effective in shrinking tumours in patients with RET fusion+ NSCLC regardless of previous treatment history. The recorded side effects were expected in patients receiving this type of medicine. Clinical Trial Registration: NCT03037385 (ARROW) (ClinicalTrials.gov).
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , 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 , Pirazoles , Piridinas , Proteínas Proto-Oncogénicas c-ret/genéticaRESUMEN
Background: While much progress has been accomplished in the understanding of radiation-induced immune effects in tumors, little is known regarding the mechanisms involved at the tumor draining lymph node (TDLN) level. The objective of this retrospective study was to assess the immune and biological changes arising in non-involved TDLNs upon node sparing concurrent chemoradiotherapy (CRT) of non-small cell lung cancer (NSCLC) tumors. Methods: Patients with proven localized (cN0M0) NSCLC, treated by radical surgery plus lymph node dissection with (CRT+) or without (CRT-) neoadjuvant chemoradiotherapy, whereby radiotherapy was targeted on the primary tumor with no significant incidental irradiation of the non-involved TDLN station (stations XI), were identified. Bulk RNA sequencing of TDLNs was performed and data were analyzed based on differential gene expression (DGE) and gene sets enrichment. Results: Sixteen patients were included and 25 TDLNs were analyzed: 6 patients in the CRT+ group (12 samples) and 10 patients in the CRT- group (13 samples). Overall, 1001 genes were differentially expressed between the two groups (CRT+ and CRT-). Analysis with g-profiler revealed that gene sets associated with antitumor immune response, inflammatory response, hypoxia, angiogenesis, epithelial mesenchymal transition and extra-cellular matrix remodeling were enriched in the CRT+ group, whereas only gene sets associated with B cells and B-cell receptor signaling were enriched in the CRT- group. Unsupervised dimensionality reduction identified two clusters of TDLNs from CRT+ patients, of which one cluster (cluster 1) exhibited higher expression of pathways identified as enriched in the overall CRT+ group in comparison to the CRT- group. In CRT+ cluster 1, 3 out of 3 patients had pathological complete response (pCR) or major pathological response (MPR) to neoadjuvant CRT, whereas only 1 out of 3 patients in the other CRT+ cluster (cluster 2) experienced MPR and none exhibited pCR. Conclusion: Neoadjuvant node sparing concurrent CRT of NSCLC patients is associated with distinct microenvironment and immunological patterns in non-involved TDLNs as compared to non-involved TDLNs from patients with non-irradiated tumors. Our data are in line with studies showing superiority of lymph node sparing irradiation of the primary tumor in the induction of antitumor immunity.
RESUMEN
Introduction: In the phase 3 KEYNOTE-604 study (NCT03066778), pembrolizumab plus etoposide and platinum chemotherapy (EP) significantly (p = 0.0023) improved progression-free survival versus placebo plus EP in previously untreated extensive-stage SCLC (ES-SCLC). We present health-related quality of life (HRQoL) results from KEYNOTE-604. Methods: Patients with stage IV SCLC were randomized 1:1 to pembrolizumab 200 mg or placebo every 3 weeks for 35 cycles plus four cycles of EP. Secondary end points included mean change from baseline to week 18 in the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (QLQ-C30) global health status/quality of life (GHS/QoL) scale and time to deterioration in the composite outcome of cough, chest pain, or dyspnea from QLQ-C30 and QLQ-Lung Cancer Module 13. Two-sided, nominal p values are reported. Results: A total of 439 patients completed at least one QLQ-C30 and QLQ-Lung Cancer Module 13 assessment (pembrolizumab + EP, n = 221; placebo + EP, n = 218). GHS/QoL scores improved from baseline to week 18: least squares mean (95% confidence interval [CI]) changes were 8.7 (5.3-12.1) for pembrolizumab plus EP and 4.2 (0.9-7.5) for placebo plus EP. Between-group differences in least squares mean scores were improved for pembrolizumab plus EP (4.4 [95% CI: 0.2-8.7], p = 0.040]). Median time to deterioration for the composite end point was not reached and 8.7 (95% CI: 5.9-not reached) months, respectively (hazard ratio = 0.80 [95% CI: 0.56-1.14], p = 0.208). Conclusions: First-line pembrolizumab plus EP therapy maintained HRQoL in patients with ES-SCLC and may be associated with greater improvement than placebo plus EP. Together with the efficacy and safety findings in KEYNOTE-604, HRQoL data support the benefit of pembrolizumab in ES-SCLC.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Polinesia/epidemiología , Adenocarcinoma del Pulmón/diagnóstico , Adenocarcinoma del Pulmón/epidemiología , Adenocarcinoma del Pulmón/genética , Pacientes , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/genéticaRESUMEN
BACKGROUND: NRAS mutations are observed in less than 1% of non-small cell lung cancer (NSCLC). Clinical data regarding this rare subset of lung cancer are scarce and response to systemic treatment such as chemotherapy or immune checkpoint inhibitors (ICI) has never been reported. METHODS: All consecutive patients with an NRAS mutated NSCLC, diagnosed between August 2014 and November 2020 in 14 French centers, were included. Clinical and molecular data were collected and reviewed from medical records. RESULTS: Out of the 164 included patients, 106 (64.6%) were men, 150 (91.5%) were current or former smokers, and 104 (63.4%) had stage IV NSCLC at diagnosis. The median age was 62 years, and the most frequent histology was adenocarcinoma (81.7%). NRAS activating mutations were mostly found in codon 61 (70%), while codon 12 and 13 alterations were observed in 16.5% and 4.9% of patients, respectively. Programmed death ligand-1 expression level <1%/1-49%/≥50% were respectively found in 30.8%/27.1%/42.1% of tumors. With a median follow-up of 12.5 months, median overall survival (OS) of stage IV patients was 15.3 months (95% CI 9.9-27.6). No significant difference in OS was found according to the type of mutation (codon 61 vs. other), HR = 1.12 (95% CI 0.65-1.95). Among stage IV patients treated with platinum-based doublet (n = 66), ICI (n = 48), or combination of both (n = 10), objective response rate, and median progression free survival were respectively 45% and 5.8 months, 35% and 6.9 months, 70% and 8.6 months. CONCLUSION: NRAS mutated NSCLC are characterized by a high frequency of smoking history and codon 61 mutations. Further studies are needed to confirm the encouraging outcome of immunotherapy in combination with chemotherapy.
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Adenocarcinoma , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Masculino , Humanos , Persona de Mediana Edad , Femenino , 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 , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Adenocarcinoma/genética , Codón , Estudios Retrospectivos , Proteínas de la Membrana/genética , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/uso terapéuticoRESUMEN
Neoadjuvant chemoimmunotherapy improves pathologic complete response rate and event-free survival in patients with resectable non-small cell lung cancer (NSCLC) versus chemotherapy alone. NeoCOAST was the first randomized, multidrug platform trial to examine novel neoadjuvant immuno-oncology combinations for patients with resectable NSCLC, using major pathologic response (MPR) rate as the primary endpoint. Eighty-three patients received a single cycle of treatment: 26 received durvalumab (anti-PD-L1) monotherapy, 21 received durvalumab plus oleclumab (anti-CD73), 20 received durvalumab plus monalizumab (anti-NKG2A), and 16 received durvalumab plus danvatirsen (anti-STAT3 antisense oligonucleotide). MPR rates were higher for patients in the combination arms versus durvalumab alone. Safety profiles for the combinations were similar to those of durvalumab alone. Multiplatform immune profiling suggested that improved MPR rates in the durvalumab plus oleclumab and durvalumab plus monalizumab arms were associated with enhanced effector immune infiltration of tumors, interferon responses and markers of tertiary lymphoid structure formation, and systemic functional immune cell activation. SIGNIFICANCE: A neoadjuvant platform trial can rapidly generate clinical and translational data using candidate surrogate endpoints like MPR. In NeoCOAST, patients with resectable NSCLC had improved MPR rates after durvalumab plus oleclumab or monalizumab versus durvalumab alone and tumoral transcriptomic signatures indicative of augmented immune cell activation and function. See related commentary by Cooper and Yu, p. 2306. This article is featured in Selected Articles from This Issue, p. 2293.