RESUMO
EGFR exon 20 (EGFR Ex20) insertion mutations in non-small cell lung cancer (NSCLC) are insensitive to traditional EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is the only approved TKI specifically designed to target EGFR Ex20. We performed an international, real-world safety and efficacy analysis on patients with EGFR Ex20-positive NSCLC enrolled in a mobocertinib early access program. We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Data from 86 patients with a median age of 67 years and a median of two prior lines of treatment were analyzed. Treatment-related adverse events (TRAEs) occurred in 95% of patients. Grade ≥3 TRAEs were reported in 38% of patients and included diarrhea (22%) and rash (8%). In 17% of patients, therapy was permanently discontinued, and two patients died due to TRAEs. Women were seven times more likely to discontinue treatment than men. In the overall cohort, the objective response rate to mobocertinib was 34% (95% CI, 24-45). The response rate in treatment-naïve patients was 27% (95% CI, 8-58). The median progression-free and overall survival was 5 months (95% CI, 3.5-6.5) and 12 months (95% CI, 6.8-17.2), respectively. The intracranial response rate was limited (13%), and one-third of disease progression cases involved the brain. Mobocertinib also showed antitumor activity following EGFR Ex20-specific therapy and vice versa. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity.
Assuntos
Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas , Indóis , Neoplasias Pulmonares , Pirimidinas , Masculino , Humanos , Feminino , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Receptores ErbB/genética , ÉxonsRESUMO
As a result of advances in the treatment of lung cancer, the life expectancy of lung cancer patients has improved significantly, but it remains the leading cause of cancer death worldwide. For decades, most of the initial tumor biopsies have been obtained by bronchoscopy or computed tomography (CT)-guided transthoracic lung biopsy without concerning reports of cancer seeding following the latter. In this case report we discuss the patient history of a 56-year old women with low-differentiated squamous cell lung cancer who developed tumor seeding following a CT-guided transthoracic biopsy 11 months after the intervention. This is put into context reviewing former and current literature.
Assuntos
Neoplasias Pulmonares , Humanos , Feminino , Pessoa de Meia-Idade , Biópsia por Agulha/efeitos adversos , Biópsia por Agulha/métodos , Neoplasias Pulmonares/patologia , Pulmão/diagnóstico por imagem , Pulmão/patologia , Tórax/patologia , Biópsia Guiada por Imagem/efeitos adversos , Biópsia Guiada por Imagem/métodos , Inoculação de Neoplasia , Tomografia Computadorizada por Raios X/métodosRESUMO
PURPOSE OF REVIEW: The current review presents clinically relevant driver alterations in nonsmall cell lung cancer (NSCLC) and the targeted treatments currently available for clinical use as well as those in clinical trials and advanced stages of drug development. RECENT FINDINGS: Mesenchymal-epithelial transition factor, human epidermal growth factor receptor 2, proto-oncogene B-RAF (BRAF), proto-oncogene tyrosine-protein kinase ROS (ROS1), rearranged during transfection (RET) and neurotrophic tyrosine kinase are rare genetic driver alterations, each present in a small subset of patients with NSCLC. Treatments targeting BRAF, ROS1, RET and neurotrophic tyrosine kinase are approved in Europe, and promising treatments targeting mesenchymal-epithelial transition factor and human epidermal growth factor receptor 2 are available in clinical trials and compassionate use programs. The response rates, duration of response and tolerability observed in trials of targeted drugs in this setting are presented in detail here. SUMMARY: While rare driver alterations are, by definition, rare, their recognition can change the course of NSCLC for those patients affected. Targeted treatments for many rare driver alterations are well tolerated and effective. Screening for molecular changes in advanced NSCLC should include screening for rare drivers, and patients should be directed to clinical trials in setting where treatment of the driver alterations is not otherwise available.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
BACKGROUND: The novel coronavirus SARS-CoV-2 has caused a global COVID-19 pandemic, leading to worldwide changes in public health measures. In addition to changes in the public sector (lockdowns, contact restrictions), hospitals modified care to minimize risk of infection and to mobilize resources for COVID-19 patients. Our study aimed to assess the impact of these measures on access to care and behaviour of patients with thoracic malignancies. METHODS: Thoracic oncology patients were surveyed in October 2020 using paper-based questionnaires to assess access to ambulatory care services and tumor-directed therapy during the COVID-19 pandemic. Additionally, behaviour regarding social distancing and wearing of face masks were assessed, as well as COVID-19 exposure, testing and vaccination. Results are presented as absolute and relative frequencies for categorical variables and means with standard deviation for numerical variables. We used t-test, and ANOVA to compare differences in metric variables and Chi2-test to compare proportions between groups. RESULTS: 93 of 245 (38%) patients surveyed completed the questionnaire. Respiration therapy and physical therapy were unavailable for 57% to 70% of patients during March/April. Appointments for tumor-directed therapy, tumor imaging, and follow-up care were postponed or cancelled for 18.9%, 13.6%, and 14.8% of patients, respectively. Patients reported their general health as mostly unaffected. The majority of patients surveyed did not report reducing their contacts with family. The majority reduced contact with friends. Most patients wore community masks, although a significant proportion reported respiratory difficulties during prolonged mask-wearing. 74 patients (80%) reported willingness to be vaccinated against SARS-CoV-2. CONCLUSIONS: This survey provides insights into the patient experience during the second wave of the COVID-19 pandemic in Munich, Germany. Most patients reported no negative changes to cancer treatments or general health; however, allied health services were greatly impacted. Patients reported gaps in social distancing, but were prepared to wear community masks. The willingness to get vaccinated against SARS-CoV-2 was high. This information is not only of high relevance to policy makers, but also to health care providers.
Assuntos
Assistência Ambulatorial/tendências , COVID-19/terapia , Prestação Integrada de Cuidados de Saúde/tendências , Acessibilidade aos Serviços de Saúde/tendências , Neoplasias Pulmonares/terapia , Oncologia/tendências , Padrões de Prática Médica/tendências , Idoso , Agendamento de Consultas , COVID-19/diagnóstico , COVID-19/transmissão , Vacinas contra COVID-19/uso terapêutico , Estudos Transversais , Feminino , Alemanha , Pesquisas sobre Atenção à Saúde , Nível de Saúde , Humanos , Neoplasias Pulmonares/diagnóstico , Masculino , Máscaras/tendências , Pessoa de Meia-Idade , Modalidades de Fisioterapia/tendências , Terapia Respiratória/tendências , Comportamento Social , Fatores de Tempo , Tempo para o Tratamento/tendênciasRESUMO
Aim: To analyze immune cell populations in non-small-cell lung cancer (NSCLC) tumors and matched tumor-bearing and non-tumor-bearing lymph nodes (ntbLNs) to predict prognosis. Patients & methods: 71 patients with long-term disease-free survival and 80 patients with relapse within 3 years were included in this study. We used Cox regression to identify factors associated with overall survival (OS) and progression-free survival (PFS). Results: Sinus histiocytosis and tumor-infiltrating lymphocyte density in the tumor were positively associated with PFS and OS. CD4 expression in node 1 (hazard ratio = 0.72; p = 0.02) and node 2 (hazard ratio = 0.91; p = 0.04) ntbLNs were positively correlated with OS and PFS, respectively. Discussion: Immunological markers in ntbLNs could be used to predict survival in NSCLC.
Lay abstract Aim: We analyzed populations of immune cells in non-small-cell lung cancer (NSCLC). In addition, we also investigated lymph nodes from the same patient that contained or did not contain cancer cells. Patients & methods: We included 71 patients whose cancer did not return within 3 years and 80 patients whose cancer did return within 3 years after they underwent surgery to remove their tumors. We used various statistical methods to identify factors that can predict survival. Results: Sinus histiocytosis (a widening of ducts in the lymph nodes due to an increased number of certain cells) and the density of tumor-infiltrating lymphocytes (immune cells that enter the tumor to destroy it) can predict how long patients can survive after surgery or if their tumor will come back quickly. Discussion: Looking at immune cells can help physicians decide which patients need increased follow-up care due to an increased risk for their tumors to return.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/imunologia , Histiocitose Sinusal/imunologia , Neoplasias Pulmonares/imunologia , Linfonodos/imunologia , Linfócitos do Interstício Tumoral/imunologia , Idoso , Antígenos CD4/imunologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/cirurgia , Linfonodos/cirurgia , Masculino , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , RecidivaRESUMO
BACKGROUND: Lung emphysema is an important phenotype of chronic obstructive pulmonary disease (COPD), and CT scanning is strongly recommended to establish the diagnosis. This study aimed to identify criteria by which physicians with limited technical resources can improve the diagnosis of emphysema. METHODS: We studied 436 COPD patients with prospective CT scans from the COSYCONET cohort. All items of the COPD Assessment Test (CAT) and the St George's Respiratory Questionnaire (SGRQ), the modified Medical Research Council (mMRC) scale, as well as data from spirometry and CO diffusing capacity, were used to construct binary decision trees. The importance of parameters was checked by the Random Forest and AdaBoost machine learning algorithms. RESULTS: When relying on questionnaires only, items CAT 1 & 7 and SGRQ 8 & 12 sub-item 3 were most important for the emphysema- versus airway-dominated phenotype, and among the spirometric measures FEV1/FVC. The combination of CAT item 1 (≤ 2) with mMRC (> 1) and FEV1/FVC, could raise the odds for emphysema by factor 7.7. About 50% of patients showed combinations of values that did not markedly alter the likelihood for the phenotypes, and these could be easily identified in the trees. Inclusion of CO diffusing capacity revealed the transfer coefficient as dominant measure. The results of machine learning were consistent with those of the single trees. CONCLUSIONS: Selected items (cough, sleep, breathlessness, chest condition, slow walking) from comprehensive COPD questionnaires in combination with FEV1/FVC could raise or lower the likelihood for lung emphysema in patients with COPD. The simple, parsimonious approach proposed by us might help if diagnostic resources regarding respiratory diseases are limited. Trial registration ClinicalTrials.gov, Identifier: NCT01245933, registered 18 November 2010, https://clinicaltrials.gov/ct2/show/record/NCT01245933 .
Assuntos
Árvores de Decisões , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Enfisema Pulmonar/diagnóstico por imagem , Índice de Gravidade de Doença , Espirometria/métodos , Idoso , Estudos de Coortes , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Enfisema Pulmonar/epidemiologia , Tomografia Computadorizada por Raios X/métodosRESUMO
BACKGROUND: Patients with COPD-specific symptoms and history but FEV1/FVC ratio ≥0.7 are a heterogeneous group (former GOLD grade 0) with uncertainties regarding natural history. OBJECTIVE: We investigated which lung function measures and cutoff values are predictive for deterioration according to GOLD grades and all-cause mortality. METHODS: We used visit 1-4 data of the COSYCONET cohort. Logistic and Cox regression analyses were used to identify relevant parameters. GOLD 0 patients were categorized according to whether they maintained grade 0 over the following 2 visits or deteriorated persistently into grades 1 or 2. Their clinical characteristics were compared with those of GOLD 1 and 2 patients. RESULTS: Among 2,741 patients, 374 GOLD 0, 206 grade 1, and 962 grade 2 patients were identified. GOLD 0 patients were characterized by high symptom burden, comparable to grade 2, and a restrictive lung function pattern; those with FEV1/FVC above 0.75 were unlikely to deteriorate over time into grades 1 and 2, in contrast to those with values between 0.70 and 0.75. Regarding mortality risk in GOLD 0, FEV1%predicted and age were the relevant determinants, whereby a cutoff value of 65% was superior to that of 80% as proposed previously. CONCLUSIONS: Regarding patients of the former GOLD grade 0, we identified simple criteria for FEV1/FVC and FEV1% predicted that were relevant for the outcome in terms of deterioration over time and mortality. These criteria might help to identify patients with the typical risk profile of COPD among those not fulfilling spirometric COPD criteria.
Assuntos
Assistência ao Paciente , Seleção de Pacientes , Doença Pulmonar Obstrutiva Crônica , Espirometria/métodos , Fatores Etários , Idoso , Progressão da Doença , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Mortalidade , Avaliação de Processos e Resultados em Cuidados de Saúde , Assistência ao Paciente/métodos , Assistência ao Paciente/normas , Assistência ao Paciente/estatística & dados numéricos , Valor Preditivo dos Testes , Prognóstico , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/mortalidade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/terapia , Testes de Função Respiratória/métodos , Medição de Risco/métodos , Avaliação de Sintomas/métodosRESUMO
Alterations of cognitive functions have been described in COPD. Our study aimed to disentangle the relationship between the degree of cognitive function and COPD characteristics including quality of life (QoL).Data from 1969 COPD patients of the COSYCONET cohort (GOLD grades 1-4; 1216 male/ 753 female; mean (SD) age 64.9 ± 8.4 years) were analysed using regression and path analysis. The DemTect screening tool was used to measure cognitive function, and the St. George's respiratory questionnaire (SGRQ) to assess disease-specific QoL.DemTect scores were < 9 points in 1.6% of patients and < 13 points in 12% when using the original evaluation algorithm distinguishing between < 60 or > =60 years of age. For statistical reasons, we used the average of both algorithms independent of age in all subsequent analyses. The DemTect scores were associated with oxygen content, 6-min-walking distance (6-MWD), C-reactive protein (CRP), modified Medical Research Council dyspnoea scale (mMRC) and the SGRQ impact score. Conversely, the SGRQ impact score was independently associated with 6-MWD, FVC, mMRC and DemTect. These results were combined into a path analysis model to account for direct and indirect effects. The DemTect score had a small, but independent impact on QoL, irrespective of the inclusion of COPD-specific influencing factors or a diagnosis of cognitive impairment.We conclude that in patients with stable COPD lower oxygen content of blood as a measure of peripheral oxygen supply, lower exercise capacity in terms of 6-MWD, and higher CRP levels were associated with reduced cognitive capacity. Furthermore, a reduction in cognitive capacity was associated with reduced disease-specific quality of life. As a potential clinical implication of this work, we suggest to screen especially patients with low oxygen content and low 6-MWD for cognitive impairment.
Assuntos
Cognição/fisiologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/psicologia , Testes de Estado Mental e Demência , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/psicologia , Idoso , Disfunção Cognitiva/epidemiologia , Estudos de Coortes , Comorbidade , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Inquéritos e QuestionáriosAssuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/metabolismo , Radioisótopos de Gálio , Tomografia por Emissão de Pósitrons/métodosRESUMO
BACKGROUND: Generally, tyrosine kinase inhibitor (TKI) therapy is recommended in first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) harbouring a classic epidermal growth factor receptor (EGFR) mutation. However, the response of patients with rare or complex EGFR mutations to TKI treatment is not predictable, nor is the prognosis for such patients. OBJECTIVES: In cases of rare or complex EGFR mutations, the right approach to therapy remains challenging. That is why we sought to analyse the characteristics as well as the prognosis and the response to TKI treatment of patients with rare or complex EGFR mutations. PATIENTS AND METHODS: 343 NSCLC patients tested for EGFR mutation at a German lung cancer centre were analysed for age, gender, and smoking status as well as for the mutation status. For 12 patients with rare and complex mutations, response to TKI treatment was described. RESULTS: 282 of all patients had a wild-type EGFR, whereas 61 harboured an EGFR mutation. 32 of these were classic mutations, followed by 16 rare and 7 complex mutations. EGFR mutations were significantly more frequent in women. Patients with rare or complex mutations were significantly more often smokers compared to those with classic EGFR mutations. Furthermore, rare and complex mutations were less responsive to TKI therapy. CONCLUSION: Patients with rare or complex EGFR mutations differ from those with classic mutations in terms of smoking status and response to TKIs. As these mutations may not respond well to TKI therapy, first-line TKIs should not be automatically chosen based on the sole presence of an EGFR mutation.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Genes erbB-1 , Neoplasias Pulmonares/genética , Idoso , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Tirosina Quinases/antagonistas & inibidores , Estudos Retrospectivos , Fumar/efeitos adversosRESUMO
OBJECTIVE: The TNM 8 lung cancer staging system reclassifies patients with a solitary extrathoracic metastasis as M1b and two or more extrathoracic metastases as M1c. This study investigates the clinical relevance of this change. METHODS: Advanced lung cancer patients were retrospectively restaged according to the TNM8 M1b and M1c classifiers. Overall survival was compared in M1b and M1c patients staged with and without PET-CT. We then summarized the TNM 8 staging classification and the relevant literature on the treatment of oligometastatic lung cancer. RESULTS: In all, 82 patients with metastatic lung cancer were reclassified according to the TNM 8: 14 had M1b and 58 had M1c disease. Those with M1b disease lived significantly longer than those with M1c disease (15.2 vs. 7.3 months, p = 0.0029). Among those with M1b disease, survival was the highest when M1b status was confirmed by PET-CT (21.4 vs. 7 months). M1c patients with 4 or less distant metastases had a trend to longer survival vs. M1c patients with 5 or more metastases (9.4 vs. 7.3 months), especially when PET-CT staging was used (13.9 months). CONCLUSIONS: We confirmed the prognostic value of the M1b and M1c descriptors in a Western European tertiary care population. The use of PET-CT seems to increase the prognostic value of the M descriptor and may define an additional oligometastatic subgroup of M1c patients. Clinical trials investigating the treatment of patients with varying degrees of metastatic disease are needed and should be based on PET-CT staging.
Assuntos
Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Estadiamento de Neoplasias/normas , Guias de Prática Clínica como Assunto , Idoso , Idoso de 80 Anos ou mais , Alemanha/epidemiologia , Humanos , Incidência , Internacionalidade , Neoplasias Pulmonares/classificação , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Fatores de Risco , Taxa de SobrevidaAssuntos
COVID-19/prevenção & controle , Comportamentos Relacionados com a Saúde , Acessibilidade aos Serviços de Saúde , Neoplasias Pulmonares/terapia , Telemedicina , Exercício Físico , Feminino , Estado Funcional , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Distanciamento Físico , SARS-CoV-2 , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Small-cell lung cancer (SCLC) is a highly aggressive tumor, and overall survival (OS) remains poor despite intensive efforts to develop new treatment strategies. In second line, topotecan is the only approved drug, with a median OS of 5.9 months. However, real-world SCLC patients are often in worse condition and harbor more comorbidities than study populations. Therefore, the real-world performance of topotecan may differ from that seen in studies. Here, we analyzed outcomes of SCLC patients receiving topotecan and identified predictive and prognostic markers. PATIENTS AND METHODS: We retrospectively analyzed 44 consecutive SCLC patients receiving topotecan between 2015 and 2022. We analyzed baseline characteristics (age, ECOG-PS, topotecan cycles, and dosage) and pre-treatment blood values (LDH, CRP, sodium) as well as prognostic scores (neutrophil/lymphocyte ratio (NLR), thrombocyte/lymphocyte ratio (TLR), Glasgow Prognostic Score, prognostic nutritional score, systemic inflammation index (SII), and the prognostic index) extracted from electronic patients' charts to identify predictive and prognostic markers. RESULTS: In our cohort, mPFS and mOS were only 1.9 and 5.6 months, respectively. Gender, ECOG-PS, active brain metastases, NLR, GPS, PNI, and SII significantly influenced PFS and OS in univariate analysis. ECOG-PS (p > 0.001), active brain metastases (p = 0.001), and SII (p = 0.008) were significant independent prognostic variables in a multivariate COX regression model. Selecting patients by these three markers achieved an mPFS of 5.7 months and thus increased the mPFS three-fold. Patients not meeting all criteria had an mPFS of 1.8 months (p = 0.006). Patients identified by prognostic markers had an mOS of 9.1 months (p = 0.002). CONCLUSIONS: The efficacy of topotecan in SCLC real-world patients is poor, indicating that many patients were treated without any benefit. Easy-to-obtain markers can predict response and treatment efficacy and should therefore be validated in larger cohorts to identify patients who are more likely to benefit from topotecan.
RESUMO
Background: Despite many advances in molecular procedures many lung cancer patients do not receive full panel testing. This can limit the comprehensive understanding of their disease and potentially hinder personalized treatment options. Methods: In this retrospective analysis, we used results from next-generation sequencing (NGS) testing of 154 patients with adenocarcinoma (AC) or squamous cell carcinoma (SCC) of the lung treated at the University Hospital, Ludwig-Maximilians Universität (LMU) Munich between 2018 and 2021. We compared different clinicopathological features and patients' baseline characteristics with results of NGS testing. We used t-test and analysis of variance (ANOVA) to compare metric- and χ2-test and Fisher's exact test to compare categorical variables. Results: NGS testing found mutations in 107 (69.5%) patients; 44 patients (28.6%) had more than one mutation. The majority (79.2%) of patients had AC and 64.9% were metastasized at diagnosis. Patients with detected mutations had significantly higher PD-L1 expression than those without mutations (36.4% vs. 19.2%, P=0.005). Mean PD-L1 expression also differed between different mutations ranging from 24.0% in EGFR to 56.8% in patients with MET alterations, and increased with the number of different mutations (P=0.07). EGFR mutations were significantly more common in females compared to males (22.9% vs. 9.5%, P=0.04) and PIK3CA mutations significantly more common in SCC (21.9% vs. 2.5%, P=0.004). We found 23 different mutations in AC and 13 different gene mutations in SCC. Conclusions: Mutation profiles differed by histological type and metastases status and were significantly associated with PD-L1 expression. In the context of limited resources, our results may help prioritize patient for testing when tissue material and funding is limited.
RESUMO
Background: A debate persists on the prognostic value of the pre-therapeutic standardized uptake value (SUV) of non-tumorous lung tissue for the risk assessment of therapy-related pneumonitis, with most studies lacking significant correlation. However, the influence of patient comorbidities on the pre-therapeutic lung SUV has not yet been systematically evaluated. Thus, we aimed to elucidate the association between comorbidities, biological variables and lung SUVs in pre-therapeutic [18F]FDG-PET/CT. Methods: In this retrospective study, the pre-therapeutic SUV in [18F]FDG-PET/CT was measured in non-tumorous areas of both lobes of the lung. SUVMEAN, SUVMAX and SUV95 were compared to a multitude of patient characteristics and comorbidities with Spearman's correlation analysis, followed by a Bonferroni correction and multilinear regression. Results: In total, 240 patients with lung cancer were analyzed. An elevated BMI was significantly associated with increased SUVMAX (ß = 0.037, p < 0.001), SUVMEAN (ß = 0.017, p < 0.001) and SUV95 (ß = 0.028, p < 0.001). Patients with chronic obstructive pulmonary disease (COPD) showed a significantly decreased SUVMAX (ß = -0.156, p = 0.001), SUVMEAN (ß = -0.107, p < 0.001) and SUV95 (ß = -0.134, p < 0.001). Multiple other comorbidities did not show a significant correlation with the SUV of the non-tumorous lung. Conclusions: Failure to consider the influence of BMI and COPD on the pre-therapeutic SUV measurements may lead to an erroneous interpretation of the pre-therapeutic SUV and subsequent treatment decisions in patients with lung cancer.
RESUMO
BACKGROUND: This study provides comparative evidence of the selective MET inhibitor capmatinib versus standard of care (SOC) in first-line (1 L) and second-line (2 L) non-small cell lung cancer (NSCLC) patients with METex14 mutations in German routine care. METHODS: SOC data were collected from German routine care via retrospective chart review. Analyses were conducted as naive and propensity score adjusted (PSA) comparisons to capmatinib-treated patients within the GEOMETRY mono-1 trial. Effectiveness endpoints included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), time to CNS progression (CNSprog), and exploratory safety endpoints. RESULTS: The SOC arm included 119 patients in 1 L and 46 in 2 L versus 60 patients in 1 L and 81 in 2 L treated with capmatinib, with balanced baseline characteristics after PSA. In 1 L, the naive comparison showed a significant benefit of capmatinib versus SOC for OS (median: 25.49 vs 14.59 months; HR 0.58; 95 % CI 0.39-0.87; P = 0.011), PFS (median: 12.45 vs 5.03 months; HR: 0.44; 95 % CI: 0.31-0.63; P < 0.001), and ORR (event rate: 68.3 vs 26.9 %; RR 2.54; 95 % CI 1.80-3.58; P < 0.001). In 2 L, OS, PFS, and ORR showed positive trends favoring capmatinib over SOC. Capmatinib treatment in the 1 L and 2 L led to significant benefit in CNSprog. PSA analyses showed consistent results to naive analysis. Exploratory safety endpoints indicated a manageable safety profile for capmatinib. CONCLUSIONS: The present study demonstrates the important role of capmatinib in providing robust clinically meaningful benefit to patients with NSCLC harboring METex14 mutations and its significant role in preventing the development of brain metastases.
Assuntos
Benzamidas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Mutação , Proteínas Proto-Oncogênicas c-met , Triazinas , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Masculino , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Idoso , Benzamidas/uso terapêutico , Alemanha , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Triazinas/uso terapêutico , Triazinas/efeitos adversos , Estudos Retrospectivos , Adulto , Idoso de 80 Anos ou mais , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , ImidazóisRESUMO
BACKGROUND: The efficacy of checkpoint inhibitors for non-small cell lung cancer (NSCLC) with MET exon 14 skipping (METΔ14ex) remains controversial. MATERIALS AND METHODS: 110 consecutive METΔ14ex NSCLC patients receiving first-line chemotherapy (CHT) and/or immunotherapy (IO) in 10 German centers between 2016-2022 were analyzed. RESULTS: Combined CHT-IO was given to 35/110 (32%) patients, IO alone to 43/110 (39%), and CHT to 32/110 (29%) upfront. Compared to CHT, CHT-IO showed longer progression-free survival (median PFS 6 vs. 2.5 months, p = 0.004), more objective responses (ORR 49% vs. 28%, p = 0.086) and numerically longer overall survival (OS 16 vs. 10 months, p = 0.240). For IO monotherapy, OS (14 vs. 16 months) and duration of response (26 vs. 22 months) were comparable to those of CHT-IO. Primary progressive disease (PD) was more frequent with IO compared to CHT-IO (13/43 vs. 3/35, p = 0.018), particularly for never-smokers (p = 0.041). Higher PD-L1 TPS were not associated with better IO outcomes, but TP53 mutated tumors showed numerically improved ORR (56% vs. 32%, p = 0.088) and PFS (6 vs. 3 months, p = 0.160), as well as longer OS in multivariable analysis (HR=0.54, p = 0.034) compared to their wild-type counterparts. Any second-line treatment was administered to 35/75 (47%) patients, with longer survival for capmatinib or tepotinib compared to crizotinib (PFS 10 vs. 3 months, p = 0.013; OS 16 vs. 13 months, p = 0.270). CONCLUSION: CHT-IO is superior to CHT, and IO alone also effective for METΔ14ex NSCLC, especially in the presence of TP53 mutations and independent of PD-L1 expression, but never-smokers are at higher risk of primary PD.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Antígeno B7-H1 , Imunoterapia , Mutação , Éxons , Proteína Supressora de Tumor p53/genéticaRESUMO
PURPOSE: MET amplification is a common resistance mechanism to EGFR inhibition in EGFR-mutant non-small cell lung cancer (NSCLC). Several trials showed encouraging results with combined EGFR and MET inhibition (EGFRi/METi). However, MET amplification has been inconsistently defined and frequently included both polysomy and true amplification. METHODS: This is a multicenter, real-world analysis in patients with disease progression on EGFR inhibition and MET copy number gain (CNG), defined as either true amplification (MET to centromere of chromosome 7 ratio [MET-CEP7] ≥ 2) or polysomy (gene copy number ≥ 5, MET-CEP7 < 2). RESULTS: A total of 43 patients with MET CNG were included, 42 of whom were detected by FISH. Twenty-three, 7, and 14 received EGFRi/METi, METi, and SoC, respectively. Patients in the EGFRi/METi cohort exhibited a superior real-world clinical benefit rate, defined as stable disease or better, of 82% (95% confidence interval [CI], 60-95) compared to METi (29%, 4-71) and SoC (50%, 23-77). Median real-world progression-free survival was longer with EGFRi/METi with 9.8 vs. 4.3 months with METi (hazard ratio [HR], 0.19, 95% CI, 0.06-0.57) and 3.7 months with SoC (0.41, 0.18-0.91), respectively. Overall survival was numerically improved. Interaction analysis with treatment and type of CNG (amplification vs. polysomy) suggests that differences were exclusively driven by MET-amplified patients receiving EGFRi/METi (HR for OS, 0.09, 0.01-0.54). CONCLUSION: In this real-world study, EGFRi/METi showed clinical benefit over METi and SoC. Future studies should focus on the differential impact of the type of MET CNG with a focus on true MET amplification as predictor of response.
RESUMO
INTRODUCTION: Programmed death-ligand 1 expression currently represents the only validated predictive biomarker for immune checkpoint inhibition in metastatic NSCLC in the clinical routine, but it has limited value in distinguishing responses. Assessment of KRAS and TP53 mutations (mut) as surrogate for an immunosupportive tumor microenvironment (TME) might help to close this gap. METHODS: A total of 696 consecutive patients with programmed death-ligand 1-high (≥50%), nonsquamous NSCLC, having received molecular testing within the German National Network Genomic Medicine Lung Cancer between 2017 and 2020, with Eastern Cooperative Oncology Group performance status less than or equal to 1 and pembrolizumab as first-line palliative treatment, were included into this retrospective cohort analysis. Treatment efficacy and outcome according to KRAS/TP53 status were correlated with TME composition and gene expression analysis of The Cancer Genome Atlas lung adenocarcinoma cohort. RESULTS: Proportion of KRASmut and TP53mut was 53% (G12C 25%, non-G12C 28%) and 51%, respectively. In KRASmut patients, TP53 comutations increased response rates (G12C: 69.7% versus 46.5% [TP53mut versus wild-type (wt)], p = 0.004; non-G12C: 55.4% versus 39.5%, p = 0.03), progression-free survival (G12C: hazard ratio [HR] = 0.59, p = 0.009, non-G12C: HR = 0.7, p = 0.047), and overall survival (G12C: HR = 0.72, p = 0.16, non-G12C: HR = 0.56, p = 0.002), whereas no differences were observed in KRASwt patients. After a median follow-up of 41 months, G12C/TP53mut patients experienced the longest progression-free survival and overall survival (33.7 and 65.3 mo), which correlated with high tumor-infiltrating lymphocyte densities in the TME and up-regulation of interferon gamma target genes. Proinflammatory pathways according to TP53 status (mut versus wt) were less enhanced and not different in non-G12C and KRASwt, respectively. CONCLUSIONS: G12C/TP53 comutations identify a subset of patients with a very favorable long-term survival with immune checkpoint inhibitor monotherapy, mediated by highly active interferon gamma signaling in a proinflammatory TME.