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INTRODUCTION: The observational multicenter prospective FLOWER study (NCT04965701) confirmed effectiveness and safety of osimertinib in the real-world (RW) management of untreated EGFR-mutant advanced non-small cell lung cancer (aNSCLC) patients. METHODS: Herein, we report updated survival data, post-progression management, cost/effectiveness and budget impact (BI) of osimertinib compared with a RW population receiving gefitinib or erlotinib. RESULTS: Overall, 189 Caucasian patients receiving first-line osimertinib were included. After a follow-up of 20.7 months, 74(39.2%) patients discontinued osimertinib, median time-to-treatment discontinuation (mTTD) was 27.9 months, overall survival 36.8 months. At progression, tissue biopsy was performed in 29 (56.9%), liquid biopsy in 15 (29.4%) and both in 7 (13.7%) cases. The most frequent resistant mechanism was MET amplification (Nâ =â 14, 29.8%). At data cutoff, 13 (6.9%) patients were continuing osimertinib beyond progression; 52 (67.5%) received second-line treatment; no further treatments were administered in 25 (32.5%) cases. Thirty-three (63.4%) patients received chemotherapy, 12(23.1%) TKIs combination. Cost-effectiveness analysis showed a total cost per patient based on RW mTTD of 98,957.34, 21,726.28 and 19,637.83 for osimertinib, erlotinib and gefitinib, respectively. The incremental cost-effectiveness ratio (ICER)/month for osimertinib was 359,806.0/life-year-gained (LYG) and 197,789.77/LYG compared to erlotinib and gefitinib. For osimertinib, the BI-gap between RW-TTD and theoretical-TTD was 16,501.0 per patient. CONCLUSIONS: This updated analysis confirms the effectiveness of osimertinib in RW. Although the ICER of osimertinib seems not cost-effective, additional costs for the management of disease progression to old generation TKIs were not considered in this study. The BI-gap suggests RW mTTD as a more reliable measure for expense estimation.
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Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/economia , Compostos de Anilina/uso terapêutico , Compostos de Anilina/economia , Acrilamidas/uso terapêutico , Acrilamidas/economia , Acrilamidas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/economia , Masculino , Feminino , Receptores ErbB/genética , Idoso , Pessoa de Meia-Idade , Estudos Prospectivos , Mutação , Adulto , Idoso de 80 Anos ou mais , Progressão da Doença , Análise Custo-Benefício , Cloridrato de Erlotinib/uso terapêutico , Cloridrato de Erlotinib/economia , Gefitinibe/uso terapêutico , Gefitinibe/economia , Antineoplásicos/uso terapêutico , Antineoplásicos/economia , Indóis , PirimidinasRESUMO
Lung cancer (LC) is one of the most prevalent cancers in both men and women and today is still characterized by high mortality and lethality. Several biomarkers have been identified for evaluating the prognosis of non-small cell lung cancer (NSCLC) patients and selecting the most effective therapeutic strategy for these patients. The introduction of innovative targeted therapies and immunotherapy with immune checkpoint inhibitors (ICIs) for the treatment of NSCLC both in advanced stages and, more recently, also in early stages, has revolutionized and significantly improved the therapeutic scenario for these patients. Promising evidence has also been shown by analyzing both micro-RNAs (miRNAs) and the lung/gut microbiota. MiRNAs belong to the large family of non-coding RNAs and play a role in the modulation of several key mechanisms in cells such as proliferation, differentiation, inflammation, and apoptosis. On the other hand, the microbiota (a group of several microorganisms found in human orgasms such as the gut and lungs and mainly composed by bacteria) plays a key role in the modulation of inflammation and, in particular, in the immune response. Some data have shown that the microbiota and the related microbiome can modulate miRNAs expression and vice versa by regulating several intracellular signaling pathways that are known to play a role in the pathogenesis of lung cancer. This evidence suggests that this axis is key to predicting the prognosis and effectiveness of ICIs in NSCLC treatment and could represent a new target in the treatment of NSCLC. In this review, we highlight the most recent evidence and data regarding the role of both miRNAs and the lung/gut microbiome in the prediction of prognosis and response to ICI treatment, focusing on the link between miRNAs and the microbiome. A new potential interaction based on the underlying modulated intracellular signaling pathways is also shown.
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Carcinoma Pulmonar de Células não Pequenas , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , MicroRNAs , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/microbiologia , Carcinoma Pulmonar de Células não Pequenas/genética , MicroRNAs/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/microbiologia , Neoplasias Pulmonares/patologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Microbiota , Microbioma Gastrointestinal/efeitos dos fármacos , Prognóstico , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , AnimaisRESUMO
The majority of epidermal growth factor receptor (EGFR) mutations (85-90%) are exon 19 deletions and L858R point mutations of exon 21, characterized by high sensitivity to EGFR-tyrosine kinase inhibitors (TKIs). Less is known about uncommon mutations (10-15% of EGFR mutations). The predominant mutation types in this category include exon 18 point mutations, exon 21 L861X, exon 20 insertions, and exon 20 S768I. This group shows a heterogeneous prevalence, partly due to different testing methods and to the presence of compound mutations, which in some cases can lead to shorter overall survival and different sensitivity to different TKIs compared to simple mutations. Additionally, EGFR-TKI sensitivity may also vary depending on the specific mutation and the tertiary structure of the protein. The best strategy remains uncertain, and the data of EGFR-TKIs efficacy are based on few prospective and some retrospective series. Newer investigational agents are still under study, and there are no other approved specific treatments targeting uncommon EGFR mutations. Defining the best treatment option for this patient population remains an unmet medical need. The objective of this review is to evaluate existing data on the outcomes, epidemiology, and clinical characteristics of lung cancer patients with rare EGFR mutations, with a focus on intracranial activity and response to immunotherapy.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Estudos Retrospectivos , Estudos Prospectivos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Receptores ErbB/metabolismo , MutaçãoRESUMO
In recent years, we have seen the development and approval for clinical use of an increasing number of therapeutic agents against actionable oncogenic drivers in metastatic non-small cell lung cancer (NSCLC). Among them, selective inhibitors, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies targeting the mesenchymal-epithelial transition (MET) receptor, have been studied in patients with advanced NSCLC with MET deregulation, primarily due to exon 14 skipping mutations or MET amplification. Some MET TKIs, including capmatinib and tepotinib, have proven to be highly effective in this molecularly defined subgroup of patients and are already approved for clinical use. Other similar agents are being tested in early-stage clinical trials with promising antitumor activity. The purpose of this review is to provide an overview of MET signaling pathways, MET oncogenic alterations primarily focusing on exon 14 skipping mutations, and the laboratory techniques used to detect MET alterations. Furthermore, we will summarize the currently available clinical data and ongoing studies on MET inhibitors, as well as the mechanisms of resistance to MET TKIs and new potential strategies, including combinatorial approaches, to improve the clinical outcomes of MET exon 14-altered NSCLC patients.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Mutação , Inibidores de Proteínas Quinases/farmacologiaRESUMO
BACKGROUND: Osimertinib became the standard treatment for patients with untreated EGFR-mutant advanced non-small cell lung cancer (aNSCLC) following results reported in the phase III randomized FLAURA trial. Because of strict exclusion criteria, patient populations included in pivotal trials are only partially representative of real-world patients. METHODS: We designed an observational, prospective, multicenter study enrolling patients with EGFR-mutant aNSCLC receiving first-line osimertinib to evaluate effectiveness, safety, and progression patterns in the real-world. RESULTS: At data cutoff, 126 White patients from nine oncology centers were included. At diagnosis, 16 patients (12.7%) had a performance status (PS) ≥2 and 38 (30.2%) had brain metastases. Overall response rate (ORR) was 73%, disease control rate (DCR) 96.0%. After a median follow-up of 12.3 months, median time to treatment discontinuation (mTTD) was 25.3 months, median progression-free-survival (mPFS) was 18.9 months and median overall survival (mOS) was not reached (NR). One hundred and ten patients (87%) experienced adverse events (AEs), 42 (33%) of grade 3-4, with venous thromboembolism (VTE) as the most common (n = 10, 7.9%). No difference in rates of VTE was reported according to age, PS, comorbidity, and tumor load. We observed longer mTTD in patients without symptoms (NR vs. 18.8 months) and with fewer than three metastatic sites at diagnosis (NR vs. 21.4 months). Patients without brain metastases experienced longer mPFS (NR vs. 13.3 months). No difference in survival outcome was observed according to age, comorbidity, and type of EGFR mutation. Isolated progression and progression in fewer than three sites were associated with longer time to treatment discontinuation (TTD). CONCLUSION: Osimertinib confirmed effectiveness and safety in the real world, although thromboembolism was more frequent than previously reported.
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Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Estudos Prospectivos , Inibidores de Proteínas Quinases/uso terapêutico , Tromboembolia VenosaRESUMO
Epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma are a frequent class of driver mutations. Single EGFR tyrosine kinase inhibitor (TKI) provides substantial clinical benefit, but almost nil radiographic complete responses. Patients invariably progress, although survival can reach several years with post-treatment therapies, including EGFR TKIs, chemotherapy or other procedures. Endeavours have been clinically oriented to manage the acquisition of EGFR TKI-resistant mutations; however, basic principles on cancer evolution have not been considered in clinical trials. For years, evidence has displayed rapidly adaptive mechanisms of resistance to selective monotherapy, posing several dilemmas for the practitioner. Strict adherence to non-small cell lung cancer (NSCLC) guidelines is not always practical for addressing the clinical progression that EGFR-mutant lung adenocarcinoma patients suffer. The purpose of this review is to highlight regulatory mechanisms and signalling pathways that cause therapy-induced resistance to EGFR TKIs. It suggests combinatorial therapies that target EGFR, as well as potential mechanisms underlying EGFR-mutant NSCLC, alerting the reader to clinical opportunities that may lead to a deeper and more durable response. Molecular reprogramming contributes to EGFR TKI resistance, and the compiled information is relevant in understanding the development of new combined targeted strategies in EGFR-mutant NSCLC.
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Neoplasias Pulmonares/terapia , Receptores ErbB/metabolismo , Humanos , MutaçãoRESUMO
AIMS: To provide an overview of immune checkpoint inhibitors (ICIs) safety profile using the Italian spontaneous adverse drug reaction (ADR) reporting system. METHODS: We selected all ADR reports attributed to ipilimumab (CTLA-4 inhibitor), nivolumab, pembrolizumab, atezolizumab (PD-1/PD-L1 inhibitors) from the Italian spontaneous reporting system (2011-2018). Descriptive analyses of reports for ICIs have been conducted. Time to onset of adverse effects was stratified by system organ class. Reporting odds ratio was used as measure of ADR reporting disproportionality. ICI-related ADR reports were compared with 2 reference groups, i.e. all other suspected drugs or all other antineoplastic agents. RESULTS: Overall, 2217 (0.7%) reports were related to ICIs (nivolumab: 72.2% of those reports; ipilimumab: 14.3%; pembrolizumab: 10.3%; and atezolizumab: 3.5%). ICI-related ADR reports mostly involved males (65%) and median age was 67 (interquartile range 59-73) years. Serious reports accounted for 48.8%. Frequencies of endocrine, general, hepatobiliary, metabolism, musculoskeletal, respiratory disorders, infections and neoplasms were significantly higher for ICIs than for all other drugs (P < .001). Except for infections, similar results emerged through comparison with other anticancer drugs. Colitis, hypophysitis and skin disorders were more frequently reported for anti-CTLA-4 drugs than PD-1/PD-L1 ICIs, and the opposite for musculoskeletal effects, pneumonia, and thyroid dysfunctions. ICIs were disproportionally associated also with less known risks, e.g. ischaemic heart disease, cardiac failure and optic nerve disorders. CONCLUSION: The most frequently reported safety issues were probably immune-related adverse events including general, gastrointestinal and respiratory disorders. Potentially emerging safety signals, such as ischaemic heart disease and cardiac failure, requiring further investigation were detected.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Inibidores de Checkpoint Imunológico , Idoso , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Nivolumabe , FarmacovigilânciaRESUMO
KRAS is the most frequently mutated oncogene in non-small cell lung cancer (NSCLC). However, the prognostic role of KRAS mutation status in NSCLC still remains controversial. We hypothesize that the expression changes of genes affected by KRAS mutation status will have the most prominent effect and could be used as a prognostic signature in lung cancer. We divided NSCLC patients with mutation and RNA-seq data into KRAS mutated and wild type groups. Mann-Whitney test was used to identify genes showing altered expression between these cohorts. Mean expression of the top five genes was designated as a "transcriptomic fingerprint" of the mutation. We evaluated the effect of this signature on clinical outcome in 2,437 NSCLC patients using univariate and multivariate Cox regression analysis. Mutation of KRAS was most common in adenocarcinoma. Mutation status and KRAS expression were not correlated to prognosis. The transcriptomic fingerprint of KRAS include FOXRED2, KRAS, TOP1, PEX3 and ABL2. The KRAS signature had a high prognostic power. Similar results were achieved when using the second and third set of strongest genes. Moreover, all cutoff values delivered significant prognostic power (p < 0.01). The KRAS signature also remained significant (p < 0.01) in a multivariate analysis including age, gender, smoking history and tumor stage. We generated a "surrogate signature" of KRAS mutation status in NSCLC patients by computationally linking genotype and gene expression. We show that secondary effects of a mutation can have a higher prognostic relevance than the primary genetic alteration itself.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Regulação Neoplásica da Expressão Gênica , Genes ras , Neoplasias Pulmonares/genética , Transcriptoma , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Genótipo , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Prognóstico , Modelos de Riscos Proporcionais , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Resultado do TratamentoRESUMO
Lung cancer is the leader malignancy worldwide accounting 1.5 millions of deaths every year. In the United States the 5 year-overall survival is less than 20% for all the newly diagnosed patients. Cisplatin-based cytotoxic chemotherapy for unresectable or metastatic NSCLC patients in the first line of treatment, and docetaxel in the second line, have achieved positive results but with limited benefit in overall survival. Targeted therapies for EGFR and ALK mutant patients have showed better results when compared with chemotherapy, nevertheless most of patients will fail and need to be treated with chemotherapy if they still have a good performance status.Immunotherapy recently has become the most revolutionary treatment in solid tumors patients. First results in unresectable and metastatic melanoma patients treated with an anti CTLA-4 monoclonal antibody showed an unexpected 3-year overall survival of at least 25%.Lung cancer cells have multiple immunosuppressive mechanisms that allow to escape of the immune system and survive, however blocking CTLA-4 pathway with antibodies as monotherapy treatment have not achieved same results than in melanoma patients. PD-1 expression has been demonstrated in different tumor types, suggesting than PD-1 / PD-L1 pathway is a common mechanism used by tumors to avoid immune surveillance and favoring tumor growth. Anti PD-1 and anti PD-L1 antibodies have showed activity in non-small cell lung cancer patients with significant benefit in overall survival, long lasting responses and good safety profile, including naïve and pretreated patients regardless of the histological subtype. Even more, PD-1 negative expression patients achieve similar results in overall survival when compared with patients treated with chemotherapy. In the other side high PD-1 expression patients that undergo immunotherapy treatment achieve better results in terms of survival with lesser toxicity. Combining different immunotherapy treatments, combination of immunotherapy with chemotherapy or with targeted treatment are under research with some promising PRELIMINARY results in non-small cell lung cancer patients.This chapter attempts to summarize the development of immunotherapy treatment in non-small cell lung cancer patients and explain the results that have leaded immunotherapy as a new standard of treatment in selected NSCLC patients.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Imunoterapia/métodos , Neoplasias Pulmonares/tratamento farmacológico , Animais , Anticorpos Monoclonais/efeitos adversos , Especificidade de Anticorpos , Antineoplásicos/efeitos adversos , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Imunoterapia/efeitos adversos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacosRESUMO
Adjuvant cisplatin-based chemotherapy significantly improves outcomes of completely resected early-stage non-small-cell lung cancer (NSCLC) patients. However, its effect on overall survival is limited and may be unsuitable for many patients due to toxicity. Targeted therapies and individualization of adjuvant treatment offer the potential to improve curability and extend survival of these patients while decreasing toxicity. Here we review Phase II and III studies examining the role of EGF receptor inhibitors, including tyrosine kinase inhibitors and the monoclonal antibody cetuximab, as adjuvant therapy in resected patients or as part of multimodality treatment for stage III NSCLC. Recent results from genotype-directed adjuvant tyrosine kinase inhibitors trials including early-stage NSCLC patients with EGFR mutations are promising, but more data are needed to support their use in this setting.
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Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Medicina de Precisão , Inibidores de Proteínas Quinases/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Cetuximab/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Terapia Combinada , Humanos , Terapia de Alvo Molecular , Estadiamento de NeoplasiasAssuntos
Antineoplásicos Imunológicos , Carcinoma de Células Escamosas , Neoplasias Cutâneas , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Humanos , Neoplasias Cutâneas/tratamento farmacológicoRESUMO
BACKGROUND: Molecular alterations of the PI3K and Ras pathways often occur in human cancer. In this trial, the pharmacokinetics, toxicity, and activity of two drugs inhibiting these pathways-everolimus and sorafenib-were investigated. METHODS: Thirteen patients with progressing solid tumors were treated with everolimus and sorafenib, according to a 3+3 scheme. Patients were selected on the basis of immunohistochemical expression of tumor molecular targets, including phospho-AKT, -p70S6K, and -ERK1/2. RESULTS: The daily recommended dose identified was 2.5 mg of everolimus and 600 mg of sorafenib. Dose-limiting toxicities included grade 3 asthenia and hand-foot skin reaction. No grade 4 adverse events were observed. The most frequent grade 3 toxicities were hypophosphatemia (30.8%), alanine aminotransferase level increase, asthenia, and anorexia (14%). No pharmacokinetic interactions were identified between everolimus and sorafenib. Of 12 evaluable patients, we observed 2 partial responses, with greater than 10% shrinkage in an additional 5 patients. Objective responses were observed in one patient with a thymoma and in one patient with a lung adenocarcinoma. Tumor shrinkage that did not qualify as a partial response was seen in an abdominal leiomyosarcoma and in adenoid cystic carcinomas. CONCLUSION: The combination of everolimus and sorafenib is safe. The tumor activity observed in different tumor types could be the result of the combined action of these drugs as well as the molecular selection of the treated population. Further research is warranted to better investigate drugs simultaneously blocking the PI3K and the Ras pathways and to refine patient selection.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Sirolimo/análogos & derivados , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Everolimo , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Humanos , Niacinamida/efeitos adversos , Niacinamida/farmacocinética , Niacinamida/uso terapêutico , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacocinética , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Sirolimo/efeitos adversos , Sirolimo/farmacocinética , Sirolimo/uso terapêutico , Sorafenibe , Proteínas ras/antagonistas & inibidoresRESUMO
Background: Somatic mutations in epidermal growth factor receptor (EGFR) exon 18 are classified as uncommon or rare mutations in non-small cell lung cancer (NSCLC), in this context, other than G719X or E709X exon 18 mutations are even more rare and heterogeneous. In such scenario, first line treatment options are still debated. The aim of this study was to investigate the response of NSCLC patients harboring very rare exon 18 mutations to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Methods: This retrospective descriptive study included 105 patients with NSCLC harboring mutations in EGFR exon 18 diagnosed at West China Hospital. The clinical response to EGFR-TKIs was evaluated according to different classifications of mutations in 45 NSCLC patients: 39 harboring G719X or E709X mutations and 6 harboring very rare mutations in EGFR exon 18. Results: Among 105 patients, 84% (88/105) harbored rare mutations in EGFR exon 18, including G719X and E709X mutations. The remaining 16% (17/105) had very rare mutations in EGFR exon 18, including E709_710delinsX and G724S. For the subsequent efficacy analysis of EGFR-TKI in 45 NSCLC patients, patients harboring very rare mutations achieved a favorable disease control rate (DCR) of 100% and had a median progression-free survival (PFS) of 17.2 months, which was not significantly different compared to patients harboring G719X or E709X (P=0.59). Conclusions: EGFR-TKIs showed great efficacy in terms of responses and survival in patients harboring exon 18 EGFR rare mutations. This may justify the use of targeted therapies as a potential treatment strategy for these patients.
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Immune checkpoints inhibitors (ICIs) have markedly improved the therapeutic management of advanced NSCLC and, more recently, they have demonstrated efficacy also in the early-stage disease. Despite better survival outcomes with ICIs compared to standard chemotherapy, a large proportion of patients can derive limited clinical benefit from these agents. So far, few predictive biomarkers, including the programmed death-ligand 1 (PD-L1), have been introduced in clinical practice. Therefore, there is an urgent need to identify novel biomarkers to select patients for immunotherapy, to improve efficacy and avoid unnecessary toxicity. A deeper understanding of the mechanisms involved in antitumor immunity and advances in the field of liquid biopsy have led to the identification of a wide range of circulating biomarkers that could potentially predict response to immunotherapy. Herein, we provide an updated overview of these circulating biomarkers, focusing on emerging data from clinical studies and describing modern technologies used for their detection.
Assuntos
Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Biomarcadores Tumorais/sangue , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Imunoterapia/métodos , Prognóstico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/sangueRESUMO
BACKGROUND: Immune checkpoint inhibitors have revolutionized the therapeutic approach to several solid tumors, becoming the standard of care for cancer treatment in different disease settings. Despite the fact that these agents are better tolerated than conventional chemotherapy, their use is associated with a specific toxicity profile, so-called immune-related adverse events (irAEs), that can involve several organs. Endocrine irAEs are among the most frequent toxicities (around 10 to 16%) and include hypophysitis, thyroid disorders, adrenalitis, and diabetes mellitus. Some of them may be life-threatening if not promptly recognized (such as diabetic ketoacidosis and acute adrenal crisis). CASE PRESENTATION: A 55-year-old woman with a personal history of euthyroid Hashimoto's thyroiditis was diagnosed with a metastatic melanoma, BRAF wild type. Under treatment with anti-PD-1 pembrolizumab, she developed thyrotoxicosis followed by hypothyroidism due to destructive thyroiditis and concurrent primary adrenal insufficiency due to adrenalitis. CONCLUSIONS: The simultaneous occurrence of adrenal and thyroid autoimmune diseases, resembling autoimmune polyendocrine syndrome type 2, may occur as a rare but serious side effect of ICI treatment. It often presents with abrupt onset and rapid evolution towards polyglandular insufficiency. Physicians should be aware of the potential association of two or more endocrine disorders and careful monitoring of endocrine function is needed during ICI therapy.
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KRAS G12C mutations in non-small cell lung cancer (NSCLC) partially respond to KRAS G12C covalent inhibitors. However, early adaptive resistance occurs due to rewiring of signaling pathways, activating receptor tyrosine kinases, primarily EGFR, but also MET and ligands. Evidence indicates that treatment with KRAS G12C inhibitors (sotorasib) triggers the MRAS:SHOC2:PP1C trimeric complex. Activation of MRAS occurs from alterations in the Scribble and Hippo-dependent pathways, leading to YAP activation. Other mechanisms that involve STAT3 signaling are intertwined with the activation of MRAS. The high-resolution MRAS:SHOC2:PP1C crystallization structure allows in silico analysis for drug development. Activation of MRAS:SHOC2:PP1C is primarily Scribble-driven and downregulated by HUWE1. The reactivation of the MRAS complex is carried out by valosin containing protein (VCP). Exploring these pathways as therapeutic targets and their impact on different chemotherapeutic agents (carboplatin, paclitaxel) is crucial. Comutations in STK11/LKB1 often co-occur with KRAS G12C, jeopardizing the effect of immune checkpoint (anti-PD1/PDL1) inhibitors.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Paclitaxel , Carboplatina , Mutação , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína LigasesRESUMO
INTRODUCTION: Although immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, the consequential over activation of the immune system is often complicated by adverse events that can affect several organs and systems, including the nervous system. The precise pathophysiology underlying neurological irAEs (n-irAEs) is not completely known. Around 3.8% of patients receiving anti-CTLA-4 agents, 6.1% of patients receiving anti-PD-1/PD-L1, and 12% of patients receiving combination therapies have n-irAEs. Most n-irAEs are low-grade, while severe toxicities have rarely been reported. in this article, we performed an updated literature search on immuno-related neurotoxicity on main medical research database, from February 2017 to December 2023. AREAS COVERED: We have also compared the latest national and international guidelines on n-irAEs management with each other in order to better define patient management. EXPERT OPINION: A multidisciplinary approach appears necessary in the management of oncological patients during immunotherapy. Therefore, in order to better manage these toxicities, we believe that it is essential to collaborate with neurologists specialized in the diagnosis and treatment of n-irAEs, and that a global neurological assessment, both central and peripheral, is necessary before starting immunotherapy, with regular reassessment during treatment.
RESUMO
Erlotinib is an orally administered small-molecule inhibitor of EGF receptor (EGFR) tyrosine kinase that is approved for the treatment of non-small-cell lung cancer (NSCLC) and pancreatic cancer. Erlotinib was first approved for the treatment of unselected NSCLC patients with advanced disease after failure of at least one prior chemotherapy regimen, and it was subsequently demonstrated to also confer a significant clinical benefit as maintenance therapy after first-line platinum-based chemotherapy. In all clinical studies, erlotinib treatment was associated with a good safety profile. Activating mutations in the EGFR gene have emerged as the strongest predictive marker of response to tyrosine kinase inhibitors, erlotinib and gefitinib, independently of other clinical and molecular features. Results from recently published, randomized Phase III trials showed that first-line erlotinib significantly prolongs progression-free survival in patients with advanced EGFR mutation-positive NSCLC with favorable tolerability, compared with standard chemotherapy. EGFR mutation testing is a crucial factor in the decision-making process regarding the most appropriate initial treatment option for patients. Specific molecular alterations in crucial genes have been discovered and associated with resistance to erlotinib, limiting its efficacy. New targeted agents and combined-treatment strategies are now under evaluation in clinical trials of NSCLC patients following progression to tyrosine kinase inhibitors.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/uso terapêutico , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ensaios Clínicos como Assunto , Sinergismo Farmacológico , Receptores ErbB/genética , Cloridrato de Erlotinib , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Terapia de Alvo Molecular , Mutação , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Resultado do TratamentoRESUMO
Metastatic urothelial bladder cancer is associated with high mortality rates. The advent of immunocheckpoint inhibitors (ICIs), with the approval of pembrolizumab in second line treatment, has changed the treatment landscape and improved clinical outcomes of patients. Until recently, subsequent lines of therapy have been limited to single-agents chemotherapy, poor efficacy and relevant toxicities. Recent studies in pretreated urothelial bladder cancer have led to the approval in clinical practice of enfortumab vedotin, demonstrating better clinical efficacy compared with the standard of care. Herein we report a case of a 57-year-old male patient with metastatic bladder cancer, who had unsatisfactory responses to first-line chemotherapy and subsequent second-line immunotherapy. Based on robust data of efficacy and safety from clinical trials, we treated the patient with enfortumab vedotin as third-line therapy. An initial adverse event, probably not strictly related to the drug, led to temporarily discontinuation of enfortumab vedotin and subsequent administration with a dose reduction. Despite this, the drug induced a first partial response on most of the metastatic sites and a complete response on lung and pelvic metastases was subsequently observed. Of note, responses were durable, with good tolerability and improvement in cancer-associated symptoms, such as pain.
Assuntos
Neoplasias da Bexiga Urinária , Masculino , Humanos , Pessoa de Meia-Idade , Neoplasias da Bexiga Urinária/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Resultado do Tratamento , ImunoterapiaRESUMO
INTRODUCTION: Stage III non-small cell lung cancer (NSCLC) is a composite of the regional spread of lung cancer with different levels of potential lymph node involvement and tumor size that often deem the stage at time of diagnosis to be unresectable and suitable for chemoradiation plus consolidation immunotherapy with durvalumab for 12 months. Chemoradiation plus durvalumab consolidation yielded a landmark 49.2% 5-year overall survival in unresectable NSCLC. AREAS COVERED: Sub-optimal results lead us to focus on the mechanisms of resistance responsible for intractability in a significant proportion of cases that fail with chemoradiation and immunotherapy. In stage III NSCLC it is opportune to explore the accumulated evidence on ferroptosis resistance that can lead to cancer progression and metastasis. Strong data shows that three anti-ferroptosis pathways are principally involved in resistance to chemotherapy, radiation, and immunotherapy. EXPERT OPINION: Because a large part of stage III NSCLCs is resistant to chemoradiation and durvalumab consolidation, a ferroptosis-based therapeutic approach, combined with standard-of-care therapy, can lead to improved clinical outcomes in patients diagnosed with stage III and possibly stage IV NSCLCs.