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While PD-1/L1 inhibitors are characterized by durable tumor control, they also prolong survival without prolongation of progression-free survival (PFS) in part of patients. However, little is known about the factors and mechanisms involved in this. Between December 2015 and September 2018, 106 patients with advanced non-small cell lung cancer treated with ICI monotherapy were enrolled in a prospective-observational study. Sixty-nine of whom progressed or died within 6 months after ICI initiation were defined as patients without durable clinical benefit (NDBs). Clinical factors and 39 serum proteins before ICI initiation and at the time of progressive disease (PD) were explored for an association with overall survival (OS) and OS after PD (OS-PD). As a result, median PFS, OS, and OS-PD were 44 days [95% confidence interval (CI): 39-56), 211 days (95% CI: 158-425), and 193 days (95% CI: 118-349), respectively. By multivariate analysis for OS, CRP (> 1.44 mg/dl) [HR 2.59 (95% CI:1.33-5.04), P = 0.005] and follistatin (> 685 pg/ml) [HR 2.29 (95% CI:1.12-4.69), P = 0.023] before ICI initiation were significantly predictive. Notably, no serum protein at the time of PD was predictive for OS-PD. There were also no serum predictive factors of OS in the 33 patients with durable clinical benefit. In conclusion, serum levels of CRP and follistatin before ICI initiation, not at the time of PD, are predictive for OS in NDBs, suggesting long-term survivor in NDBs are predetermined by the immune status before ICI initiation.
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Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/uso terapêutico , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/patologia , Folistatina/uso terapêutico , Humanos , Neoplasias Pulmonares/patologia , Receptor de Morte Celular Programada 1/uso terapêutico , Estudos ProspectivosRESUMO
CD24, a heavily glycosylated glycosylphosphatidylinositol-anchored surface protein, inhibits phagocytosis as potently as CD47. The relationship between such anti-phagocytic factors and the immune response with immune-checkpoint inhibitors (ICI) remains unexplored. We evaluated CD24 and CD47 tumor proportion scores (TPS) in 68 of the 106 patients with advanced non-small-cell lung cancer who participated in a prospective observational study of ICI treatment. We also explored the impact of CD24 TPS and CD47 TPS on ICI efficacy and serum cytokine changes. CD24 positivity (TPS ≥ 1) was negatively associated with progression-free survival (PFS) of ICI when PD-L1 TPS was < 50 (median PFS; 37 vs 127 d, P = .033), but there was no association when PD-L1 TPS was ≥ 50 (median PFS; 494 vs 144 d, P = .168). CD24 positivity was also related to significantly higher increase of CCL2 from baseline to 4-6 wk later, and such increase was notably observed only when PD-L1 TPS < 50 (P = .0004). CCL2 increase after ICI initiation was negatively predictive for survival after initiation of ICI (median survival time; not reached vs 233 d; P = .028). CD47 TPS high (≥60) significantly suppressed the increase in vascular endothelial growth factor (VEGF)-A, D and PDGF-AB/BB after ICI initiation. There was no association, however, between CD47 tumor expression and the efficacy of ICI. In conclusion, CD24, not CD47, is a candidate negative predictive marker of ICI in advanced, non-small-cell lung cancer with PD-L1 TPS < 50. Tumor expression of both CD24 and CD47 was associated with changes in factors related to monocytes and angiogenesis after ICI initiation (UMIN000024414).
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Antígeno B7-H1/metabolismo , Antígeno CD24/metabolismo , Antígeno CD47/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Pontuação de Propensão , Estudos Prospectivos , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Niraparib is the only poly (adenosine diphosphate-ribose)-polymerase (PARP) inhibitor available as oral monotherapy for maintenance, regardless of BRCA mutational status. METHODS: This phase I, open-label, non-randomized, dose-escalation study was conducted in Japan using a 3 + 3 design. Adults (≥20 years) with metastatic or locally advanced solid tumours were enrolled. Niraparib 200 mg (cohort 1) or 300 mg (cohort 2) was administered once daily in 21-day cycles (no drug holiday between cycles) until progressive disease (PD) or unacceptable toxicity. The primary objective was to evaluate the safety and tolerability of niraparib in Japanese patients with advanced solid tumours. The number of patients with dose-limiting toxicities in cycle 1 and number with treatment-emergent adverse events were primary endpoints. Secondary endpoints were pharmacokinetics and tumour response. RESULTS: There were three patients in cohort 1 and six patients in cohort 2. Only one patient, in cohort 2, developed a dose-limiting toxicity (grade 4 platelet count decreased). All patients in both cohorts developed treatment-emergent adverse events. The most common treatment-related treatment-emergent adverse events were decreased appetite (n = 2) in cohort 1, and platelet count decreased as well as aspartate aminotransferase increased (both n = 5) in cohort 2. Mean Cmax and AUC0-24 of niraparib increased dose-proportionally after multiple doses (accumulation ratio of between 1.64 and 3.65); median tmax was 3-4 h. Two patients, both in cohort 2, had a partial response to treatment. CONCLUSIONS: Niraparib (200 or 300 mg/day) was tolerable and had a favourable pharmacokinetic profile in Japanese patients with advanced solid tumours.
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Indazóis/farmacocinética , Indazóis/uso terapêutico , Neoplasias/tratamento farmacológico , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologiaRESUMO
BACKGROUND: Although predictive value of immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) have been suggested by several studies, their assessments were insufficient because patients were categorized only by the occurrence of irAEs. It has not been elucidated whether irAEs also play a significant role even in responders. MATERIALS AND METHODS: Between December 2015 and September 2018, 106 patients with advanced non-small cell lung cancer treated with ICIs were enrolled in our prospective biomarker study. Twenty-three of these were responders, defined as those with complete or partial response. We investigated the proportion of irAEs among overall and responders. For responders, progression-free survival (PFS) and overall survival of ICIs were compared between those with and without irAEs. As an exploratory analysis, we measured 41 proteins from peripheral blood before and after ICI treatment. RESULTS: The proportion of irAEs was significantly higher in responders than nonresponders (65.2% vs. 19.3%, p < .01). Among responders, clinical characteristics did not differ regardless of the occurrence of irAEs. However, there was a significant difference in PFS among responders (irAE group 19.1 months vs. non-irAE group 5.6 months; hazard ratio: 0.30 [95% confidence interval: 0.10-0.85]; p = .02). Of 41 protein analyses, fibroblast growth factor-2 at baseline and monocyte chemoattractant protein fold change showed significant differences between them (p < .04). CONCLUSION: Although this is a small sample-sized study, irAE might be a predictive factor of durable efficacy, even in patients who responded to ICIs. Investigation into the significance of irAEs in responders will contribute to the establishment of optimal administration of ICI. IMPLICATIONS FOR PRACTICE: Although the predictive value of immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) has been suggested by several studies, it has not been elucidated whether irAEs also play a significant role even in responders. This study showed that more than 60% of responders had irAEs. It demonstrated the strong correlation between irAEs and efficacy even in responders. Investigation into the significance of irAEs in responders will contribute to the establishment of optimal administration of ICI.
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Carcinoma Pulmonar de Células não Pequenas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neoplasias Pulmonares , Neoplasias , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias/tratamento farmacológico , Estudos Prospectivos , Estudos RetrospectivosRESUMO
The safety of anti-programmed cell death 1 (PD-1) antibody for patients with preexisting interstitial lung disease (ILD) remains unknown. The aim of this study was to evaluate the dependence of preexisting ILD on anti-PD-1 antibody-induced pneumonitis in non-small cell lung cancer (NSCLC) patients. We retrospectively reviewed the association of preexisting ILD with the incidence, radiographic pattern, and outcome of pneumonitis in NSCLC patients receiving anti-PD-1 antibody. A total of 331 patients were included in this study. Of these patients, 17 had preexisting ILD. The incidence of pneumonitis was higher among the patients with preexisting ILD than among those without preexisting ILD (29% vs. 10%, P = 0.027). The distributions of the CT appearances at the onset of anti-PD-1 antibody-induced pneumonitis were as follows: for the patients with preexisting ILD, two patients (40%) had diffuse alveolar damage (DAD), one patient each with organizing pneumonia-like (OP), hypersensitivity pneumonitis (HP), and other patterns (20% each); for the patients without preexisting ILD, 19 patients (61%) had OP, 8 (26%) had HP, 3 (10%) had DAD, and 1 (3.2%) had other patterns. The median onset time from the initiation of anti-PD-1 antibody treatment until the development of pneumonitis was 1.3 months (range 0.3-2.1 months) for the patients with preexisting ILD and 2.3 months (range 0.2-14.6 months) for the patients without preexisting ILD. Careful attention to the development of pneumonitis is needed, especially within the first 3 months after the start of anti-PD-1 antibody treatment, when using anti-PD-1 antibody to treat patients with preexisting ILD.
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Antineoplásicos Imunológicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Doenças Pulmonares Intersticiais/complicações , Neoplasias Pulmonares/tratamento farmacológico , Pneumonia/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/imunologia , Feminino , Humanos , Incidência , Pulmão/diagnóstico por imagem , Pulmão/imunologia , Doenças Pulmonares Intersticiais/imunologia , Neoplasias Pulmonares/imunologia , Masculino , Pessoa de Meia-Idade , Pneumonia/epidemiologia , Pneumonia/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Estudos Retrospectivos , Fatores de TempoRESUMO
The efficacy of immune checkpoint inhibitors (ICIs) in elderly and poor performance status (PS) patients is controversial, because clinical evidence is limited. This study aimed to find a predictive biomarker for the efficacy of anti-programmed cell death 1 (PD-1) antibodies in these patient populations. We retrospectively reviewed medical records of advanced non-small-cell lung cancer (NSCLC) patients who were ≥ 75 years of age or classified as PS 2 and received anti-PD-1 antibody treatment between December 2015 and May 2018. We evaluated the association between the efficacy of the anti-PD-1 antibody in these patients and the clinical variables thought to affect ICI efficacy. A total of 235 patients with advanced NSCLC were treated with anti-PD-1 antibodies, among whom 31 patients were ≥ 75 years of age and 22 were PS 2. A Cox proportional hazard model showed that only high levels of serum vascular endothelial growth factor (VEGF) were significantly associated with a shorter progression-free survival in patients aged ≥ 75 years and those with PS 2. Among these cohorts, the overall response rate to anti-PD-1 treatment tended to be lower when serum VEGF was high compared to patients with low serum VEGF. Our results demonstrate that serum VEGF concentration may be a negative predictive biomarker in elderly and poor PS advanced NSCLC patients receiving anti-PD-1 antibody treatment. This finding may help identify patients who will not benefit from anti-PD-1 antibody therapy.
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Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma de Células Escamosas/sangue , Neoplasias Pulmonares/sangue , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Several predictive factors of immune checkpoint inhibitor response have been reported, but there has not been sufficient exploration of which patients benefit from immune checkpoint inhibitor rechallenge. We report the case of a patient with non-small cell lung cancer who had 6 years of complete response with initial nivolumab treatment. After relapse, however, rechallenge with nivolumab did not result in tumour shrinkage or long-term response. Even in patients who had an exceptional response to the initial immune checkpoint inhibitor, long-term efficacy may not be achieved by immune checkpoint inhibitor rechallenge. Thorough investigation of biomarkers that predict efficacy of immune checkpoint inhibitor rechallenge is warranted.
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BACKGROUND AND OBJECTIVE: Acute exacerbation of fibrosing interstitial lung disease (AE-FILD) is a serious condition with a high mortality rate. We aimed to comprehensively analyze cytokines in bronchoalveolar lavage fluid and their association with the clinical course of AE-FILD. METHODS: We retrospectively enrolled 60 patients with AE-FILD who underwent bronchoalveolar lavage. We comprehensively measured 44 cytokines and chemokines in the obtained bronchoalveolar lavage fluid using a Luminex analyzer. Patients were grouped into those who died within 90 days (non-survival group) and survived beyond 90 days (survival group) to investigate the association of the levels of cytokines and chemokines with mortality. RESULTS: The levels of matrix metalloproteinase 1 (p = 0.003), granulocyte-macrophage colony-stimulating factor (p = 0.040), interleukin 6 (p = 0.047), interleukin 8 (p = 0.050), monocyte chemoattractant protein-1 (p = 0.043), and eotaxin (p = 0.044) were significantly higher in the non-survival group than in the survival group. In the receiver operating characteristic analysis, their areas under the curve were 0.80, 0.68, 0.71, 0.70, 0.70, and 0.72, respectively. Using machine learning with these six cytokines and chemokines, the predictive accuracy for the survival group was 0.94. CONCLUSIONS: Our study demonstrated that several cytokines and chemokines in bronchoalveolar lavage fluid could be prognostic predictors in patients with AE-FILD.
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Líquido da Lavagem Broncoalveolar , Quimiocinas , Citocinas , Progressão da Doença , Doenças Pulmonares Intersticiais , Humanos , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Feminino , Masculino , Prognóstico , Citocinas/metabolismo , Idoso , Estudos Retrospectivos , Doenças Pulmonares Intersticiais/mortalidade , Doenças Pulmonares Intersticiais/metabolismo , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/diagnóstico , Quimiocinas/metabolismo , Quimiocinas/análise , Pessoa de Meia-Idade , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Quimiocina CCL2/metabolismo , Quimiocina CCL2/análise , Interleucina-6/metabolismo , Interleucina-6/análise , Interleucina-8/metabolismo , Interleucina-8/análise , Quimiocina CCL11/metabolismo , Quimiocina CCL11/análise , Biomarcadores/metabolismo , Biomarcadores/análiseRESUMO
BACKGROUND: Mannitol is exclusively recommended in the National Comprehensive Cancer Network guidelines for diuresis in cisplatin (CDDP)-based chemotherapy. The utility of furosemide, a widely used and convenient diuretic, thus requires clarification. METHODS: This is a prospective, single-centered, open-label, noninferiority phase II study. Patients with thoracic malignancies who planned to receive CDDP-based chemotherapy were randomly assigned to receive either mannitol (arm A) or furosemide (arm B). The primary end point was set as the proportion of patients who experienced any grade of "creatinine (Cr) increased" based on the upper limit of the normal range (ULN) during the first cycle as assessed by Common Terminology Criteria for Adverse Events Version 4.0. Secondary end points were Cr increased based on the baseline value during the first cycle, Cr increased after the completion of CDDP, and the proportion of patients with phlebitis. RESULTS: Between April 2018 and March 2022, 115 patients were enrolled and 106 were analyzed. Any grade of Cr increased based on the ULN during the first cycle was 17.3% (arm A) and 24.1% (arm B), respectively (p = 0.34). Therefore, the primary end point was not met. After completion of chemotherapy, any grade of Cr increased was observed in 23.1% (arm A) and 31.5% (arm B), respectively. However, the actual serum Cr level and Cr clearance during the courses were not different between the arms. Phlebitis occurred more frequently in arm A (28.8%) than arm B (16.7%). CONCLUSIONS: Mannitol should remain the standard diuresis in CDDP-based chemotherapy assessed by conventional CTCAE grading, but furosemide can be room for consideration when assessed by actual serum Cr level and Cr clearance.
Assuntos
Flebite , Neoplasias Torácicas , Humanos , Cisplatino/efeitos adversos , Furosemida/efeitos adversos , Manitol/efeitos adversos , Flebite/induzido quimicamente , Flebite/tratamento farmacológico , Estudos ProspectivosRESUMO
CONTEXT: The efficacy and tolerability of high-flow nasal cannula (HFNC) for relieving dyspnea in advanced cancer patients with limited prognosis requires elucidation. OBJECTIVES: The primary aim of this trial was to assess the efficacy and tolerability of HFNC regarding dyspnea including severe as well as moderate for longer durations in patients under palliative care. METHODS: In this prospective study, hospitalized patients with advanced cancer who had dyspnea at rest (numeric rating scale, NRS≥3) and hypoxemia were enrolled. They were treated with HFNC for five days in the respiratory unit. Primary endpoint was mean change of modified Borg scale at 24 hours. Key secondary endpoints consisted of mean changes in modified Borg scale during the study period and feasibility (Trial Identifier, UMIN000035738). RESULTS: Between February 2019 and February 2022, 25 patients were enrolled and 21 were analyzed. Twenty patients used inspired oxygen and the mean fraction of inspired oxygen (FiO2) was 0.34 (range, 0.21-1.0). At baseline, mean NRS (dyspnea) was 5.9 (range, 3-10). Median survival time was 19 days (range, 3-657). The mean change of modified Borg scale was 1.4 (80% confidence interval [CI]: 0.8-1.9) at 24 hours, 12 patients (57%) showed 1.0 points improvement of modified Borg scale. Within two hours, 15 patients showed 1.0 points improvement of modified Borg scale and such early responders were likely to maintain dyspnea improvement for 24 hours. Nineteen patients could continue HFNC for 24 hours and 11 patients completed five days of HFNC. CONCLUSION: To our knowledge, this trial is the first prospective study to assess the five-day efficacy and tolerability of HFNC for dyspnea in patients under palliative care. Although this did not reach the prespecified endpoint, about half of the patients showed 1.0 point improvement, a minimally clinically important difference (MCID) in the chronic lung disease. HFNC can be a palliative treatment option in advanced cancer patients with dyspnea.
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Neoplasias , Insuficiência Respiratória , Humanos , Cânula , Estudos Prospectivos , Dispneia/etiologia , Dispneia/terapia , Oxigênio , Neoplasias/complicações , Neoplasias/terapia , Oxigenoterapia , Insuficiência Respiratória/terapiaRESUMO
OBJECTIVES: Predicting the prognosis of lung cancer is crucial for providing optimal medical care. However, a method to accurately predict the overall prognosis in patients with stage IV lung cancer, even with the use of machine learning, has not been established. Moreover, the inter-institutional generalizability of such algorithms remains unexplored. This study aimed to establish machine learning-based algorithms with inter-institutional generalizability to predict prognosis. MATERIALS AND METHODS: This multicenter, retrospective, hospital-based cohort study included consecutive patients with stage IV lung cancer who were randomly categorized into the training and independent test cohorts with a 2:1 ratio, respectively. The primary metric to assess algorithm performance was the area under the receiver operating characteristic curve in the independent test cohort. To assess the inter-institutional generalizability of the algorithms, we investigated their ability to predict patient outcomes in the remaining facility after being trained using data from 15 other facilities. RESULTS: Overall, 6,751 patients (median age, 70 years) were enrolled, and 1,515 (22 %) showed mutated epidermal growth factor receptor expression. The median overall survival was 16.6 (95 % confidence interval, 15.9-17.5) months. Algorithm performance metrics in the test cohort showed that the areas under the curves were 0.90 (95 % confidence interval, 0.88-0.91), 0.85 (0.84-0.87), 0.83 (0.81-0.85), and 0.85 (0.82-0.87) at 180, 360, 720, and 1,080 predicted survival days, respectively. The performance test of 16 algorithms for investigating inter-institutional generalizability showed median areas under the curves of 0.87 (range, 0.84-0.92), 0.84 (0.78-0.88), 0.84 (0.76-0.89), and 0.84 (0.75-0.90) at 180, 360, 720, and 1,080 days, respectively. CONCLUSION: This study developed machine learning algorithms that could accurately predict the prognosis in patients with stage IV lung cancer with high inter-institutional generalizability. This can enhance the accuracy of prognosis prediction and support informed and shared decision-making in clinical settings.
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Neoplasias Pulmonares , Aprendizado de Máquina , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/diagnóstico , Masculino , Feminino , Idoso , Prognóstico , Estudos Retrospectivos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Algoritmos , Curva ROC , Idoso de 80 Anos ou mais , Estudos de CoortesRESUMO
BACKGROUND: The optimal subsequent treatment strategy for locally advanced non-small cell lung cancer (LA-NSCLC) after chemoradiotherapy (CRT) and consolidative durvalumab therapy remains unknown. We aimed to determine the optimal subsequent treatment strategy for this clinical population. MATERIALS AND METHODS: We retrospectively enrolled 523 consecutive patients with LA-NSCLC treated with CRT and analyzed the treatment outcomes of subsequent therapy after progression following CRT and consolidative durvalumab therapy. Patients who received tyrosine kinase inhibitors as subsequent therapy were excluded. RESULTS: Out of 122 patients who received subsequent chemotherapy, 55% underwent platinum-based, 25% non-platinum-based, and 20% immune checkpoint inhibitor (ICI)-containing therapies. In the platinum-based group, patients with a durvalumab-progression-free survival (Dur-PFS) ≥ 1 year had a significantly longer median subsequent therapy-PFS (SubTx-PFS) than those with Dur-PFS < 1 year (13.2 months vs. 4.7 months; hazard ratio, 0.45; 95% confidence interval, 0.21-0.97; P = .04). Furthermore, among patients receiving non-platinum-based chemotherapy, the median SubTx-PFS was longer in the combined with angiogenesis inhibitor group than in the without group, although the difference was not statistically significant. No significant difference of SubTx-PFS was observed between the reason for durvalumab discontinuation and the outcomes of ICI-containing therapy. CONCLUSION: In clinical practice, platinum-based chemotherapy rechallenge is frequently employed following progression subsequent to CRT and consolidative durvalumab therapy for LA-NSCLC. Optimal treatment strategies may consider Dur-PFS and angiogenesis inhibitor feasibility. Further research is warranted to identify clinical biomarkers that can help identify patients who would benefit from ICI rechallenge.
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BACKGROUND: In small-cell lung cancer (SCLC), the tumor immune microenvironment (TIME) could be a promising biomarker for immunotherapy, but objectively evaluating TIME remains challenging. Hence, we aimed to develop a predictive biomarker of immunotherapy efficacy through a machine learning analysis of the TIME. METHODS: We conducted a biomarker analysis in a prospective study of patients with extensive-stage SCLC who received chemoimmunotherapy as the first-line treatment. We trained a model to predict 1-year progression-free survival (PFS) using pathological images (H&E, programmed cell death-ligand 1 (PD-L1), and double immunohistochemical assay (cluster of differentiation 8 (CD8) and forkhead box P3 (FoxP3)) and patient information. The primary outcome was the mean area under the curve (AUC) of machine learning models in predicting the 1-year PFS. RESULTS: We analyzed 100,544 patches of pathological images from 78 patients. The mean AUC values of patient information, pathological image, and combined models were 0.789 (range 0.571-0.982), 0.782 (range 0.750-0.911), and 0.868 (range 0.786-0.929), respectively. The PFS was longer in the high efficacy group than in the low efficacy group in all three models (patient information model, HR 0.468, 95% CI 0.287 to 0.762; pathological image model, HR 0.334, 95% CI 0.117 to 0.628; combined model, HR 0.353, 95% CI 0.195 to 0.637). The machine learning analysis of the TIME had better accuracy than the human count evaluations (AUC of human count, CD8-positive lymphocyte: 0.681, FoxP3-positive lymphocytes: 0.626, PD-L1 score: 0.567). CONCLUSIONS: The spatial analysis of the TIME using machine learning predicted the immunotherapy efficacy in patients with SCLC, thus supporting its role as an immunotherapy biomarker.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Progressão , Antígeno B7-H1 , Estudos Prospectivos , Carcinoma de Pequenas Células do Pulmão/terapia , Biomarcadores Tumorais/análise , Imunoterapia/métodos , Aprendizado de Máquina , Fatores de Transcrição Forkhead , Microambiente TumoralRESUMO
Background: An association exists among the diagnostic yield of transbronchial biopsy using endobronchial ultrasonography with a guide sheath (EBUS-GS-TBB) and several factors, such as simple within or adjacent endobronchial ultrasonography (EBUS) findings. Here, we aimed to investigate whether more detailed EBUS findings affect the diagnostic yield of lung cancer in EBUS-GS-TBB. Methods: We conducted this retrospective single-center cohort study, enrolling consecutive patients with lung cancer who underwent EBUS-GS-TBB. The primary outcome was examination of predictive factors affecting the diagnostic yield of lung cancer using EBUS-GS-TBB. The secondary outcome was a subgroup analysis of within and adjacent lesions. The adjacent angle was defined as the angle formed by the midpoint of the probe and the two points where the edge of the probe and shadow of the tumor intersected. Results: Of the 179 lesions investigated, 140 (78.2%) were diagnosed using EBUS-GS-TBB. The diagnostic yields of within and adjacent lesions were 91.6% and 51.7%, respectively. In the multivariable analysis, within lesions had significantly higher diagnostic yields than did the adjacent lesions (P<0.001). The adjacent angle was larger in lesions diagnosed using EBUS-GS-TBB than in undiagnosed lesions (P=0.003). In adjacent lesions, the diagnostic yields were 75.0% and 36.1% for lesions ≥180° and <180°, respectively. Conclusions: In adjacent lesions, the diagnostic yields differed significantly depending on the adjacent angle. Even if EBUS findings are adjacent, the operator should identify the branch of the bronchus with a greater adjacent angle. Future studies should investigate improvements in diagnostic yields via additional procedures for lesions with small adjacent angles.
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OBJECTIVES: Osimertinib is the primary treatment for patients with epidermal growth factor receptor (EGFR) mutation-positive advanced non-small cell lung cancer. However, evidence of the outcomes of osimertinib treatment in patients over 75 years of age in the real-world setting is limited. MATERIALS AND METHODS: This retrospective study analyzed the data of 538 patients (203 elderly and 335 non-elderly) with EGFR mutation-positive lung cancer in whom osimertinib was initiated as first-line treatment between August 2018 and December 2019. Patients over 75 years of age were classified as elderly. The data cut-off date was February 28, 2022. RESULTS: The progression-free survival (PFS) did not significantly differ between the elderly and non-elderly groups [elderly group: median PFS, 16.9 months (95 % confidence interval (CI), 14.3-20.2); non-elderly group: median PFS, 22.1 months (95 % CI: 19.5-26.3); hazard ratio (HR) for the elderly against the non-elderly: 1.21 (95 % CI: 0.98-1.50), p = 0.079]. However, the time to treatment failure (TTF) was significantly shorter in the elderly than in the non-elderly [elderly group: median TTF, 14.0 months (95 % CI: 0.98-1.50); non-elderly group: median TTF, 21.8 months (95 % CI: 18.2-24.6); HR for the elderly against the non-elderly: 1.46 (95 % CI: 1.20-1.77), p < 0.001]. Furthermore, the rate of treatment discontinuation because of adverse events was 28.6 % in the elderly and 14.9 % in the non-elderly (p < 0.001). Among patients who discontinued treatment, the conversion rate to second-line treatment was 39.6 % in the elderly and 72.8 % in the non-elderly. In addition, the median overall survival was 30 months (95 % CI: 25.8-37.7) in the elderly and not reached (NR) (95 % CI: NR-NR) in the non-elderly (p < 0.001). CONCLUSION: In a real-world clinical setting, elderly patients receiving osimertinib as first-line treatment should be aware of the frequent inability to transition to second-line treatment due to adverse events.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Idoso , Pessoa de Meia-Idade , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/induzido quimicamente , Estudos Retrospectivos , Compostos de Anilina/uso terapêutico , Mutação , Receptores ErbB/genética , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Studies elucidating detailed characteristics of pneumonitis in association with chemo-immunotherapy are limited. We aimed to investigate the characteristics of images, prognostic factors, and clinical course of combination therapy associated with pneumonitis. A multicenter, retrospective cohort study of patients with non-squamous non-small cell lung cancer who received a combination of platinum, pemetrexed, and pembrolizumab was conducted. Patients with confirmed pneumonitis established by an independent multidisciplinary team were enrolled. For 53 patients with pneumonitis, radiographic features at diagnosis predominantly comprised an organizing pneumonia pattern (62%, 33/53). Twelve (23%) patients experienced a worsening respiratory status during pneumonitis management, which was associated with a high mortality rate (58%, 7/12) during treatment. Severe grade at pneumonitis diagnosis (p < 0.001), diffuse alveolar damage (DAD) pattern (p = 0.002), and disease extent ≥ 25% in the lungs (p = 0.009) were significantly associated with worsening respiratory status. Furthermore, post-diagnosis survival was significantly worse in severe pneumonitis (p = 0.02) than in mild and in patients with the DAD pattern than in those without (p < 0.0001). We showed detailed clinical course of patients with pneumonitis and reported several important influencing factors. Given the small number of trials on pneumonitis, our findings provide valuable information to guide the development of appropriate management guidelines and improve pneumonitis treatment.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Pneumonia , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Estudos Retrospectivos , Neoplasias Pulmonares/tratamento farmacológico , Progressão da DoençaRESUMO
BACKGROUND: First-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) sometimes causes lung injury, thereby affecting survival. Although pre-existing interstitial lung abnormal shadow (pre-ILS) increases the risk of lung injury by EGFR-TKIs, its impact on osimertinib, a third-generation EGFR-TKI, remains unknown. PATIENTS AND METHODS: This retrospective cohort study consecutively enrolled patients of EGFR-mutated non-small cell lung cancer treated with osimertinib. Computed tomography images were obtained and evaluated independently by three pulmonologists in a blinded manner. Factors associated with lung injury were assessed using a logistic regression model. Survival curves were calculated by the Kaplan-Meier method and compared using a log-rank test. RESULTS: Of the 195 patients, 40 had pre-ILS, and 21 (8 with and 13 without pre-ILS) developed lung injury during the observation period. Multivariate analysis revealed that pre-ILS was independently associated with lung injury (odds ratio, 3.1; 95% confidence interval [CI], 1.1-8.2; p = 0.025). Severe (≥Grade 3) lung injury was observed in eight (4.1%) patients, of whom, two (5%) and six (3.9%) had and did not have pre-ILS (p = 0.67), respectively. Grade 5 lung injury was not observed, and survival curves were similar between the patients who developed lung injury and those who did not (median 11 vs. 12 months; hazard ratio, 1.2; 95% CI, 0.56-2.7; p = 0.60). CONCLUSIONS: Pre-ILS increased the risk of lung injury in patients of non-small cell lung cancer treated with osimertinib, while the severity of lung injury was not clearly affected by the presence of pre-ILS.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Estudos Retrospectivos , Receptores ErbB/genética , Mutação , Inibidores de Proteínas Quinases/efeitos adversos , PulmãoRESUMO
OBJECTIVES: The effectiveness of PD-1 blockade therapy in advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is limited. We investigated whether patient characteristics, PD-L1 expression, and immune cell (IC) status in the tumor microenvironment (TME) were associated with PD-1 blockade therapy outcomes. MATERIALS AND METHODS: We retrospectively reviewed patients with advanced EGFR-mutant NSCLC treated with PD-1 blockade (nivolumab or pembrolizumab) between January 2016 and March 2018. The PD-L1 expression tumor proportion score (TPS) and types and distribution of ICs (CD8, PD-1, CD204, tumoral, and stromal) in the TME were analyzed. RESULTS: Among 57 EGFR-mutant NSCLC patients treated with PD-1 blockade, 39 patients had sufficient tissues for analyzing the TME. The overall response rate (ORR) of PD-1 blockade was 12.3%. Only tumoral CD8 positive (CD8+) IC status was significantly associated with the response (median tumoral CD8+ICs: 299/mm2 vs. 115/mm2, P < .01). Among the 6 patients with concurrent high PD-L1 expression (TPS: ≥ 50%)/high tumoral CD8+ ICs (≥ 205/mm2), 5 (83.3%) showed a response and a significantly longer progression-free survival (PFS) (PFS: 9.4M vs. 1.8M, P < .01). In contrast, none of the 7 patients with high PD-L1 expression/low tumoral CD8+ICs (<205/mm2) showed a response. CONCLUSION: Concurrent high PD-L1 expression and high tumoral CD8+ ICs could predict the response and longer PFS of PD-1 blockade therapy in EGFR-mutant patients.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação/genética , Receptor de Morte Celular Programada 1/metabolismo , Estudos Retrospectivos , Microambiente TumoralRESUMO
BACKGROUND: Osimertinib has demonstrated impressive efficacy as a first-line treatment for patients with advanced epidermal growth factor receptor (EGFR) mutation-positive (m+) lung cancer. Drug-related pneumonitis (DRP) is a potentially lethal complication of osimertinib treatment, but reliable real-world data currently are lacking. RESEARCH QUESTION: What is the prevalence of osimertinib-induced DRP in first-line settings? What are the characteristics, clinical impact, and risk factors of osimertinib-induced DRP? STUDY DESIGN AND METHODS: We conducted a retrospective multicenter cohort study of patients who received osimertinib as a first-line treatment for advanced EGFR m+ non-small cell lung cancer (NSCLC) between August 2018 and December 2019. All chest CT scans and clinical information during osimertinib exposure were collected until June 2020. The primary end point was DRP incidence identified through central review. RESULTS: A total of 452 patients from 18 institutions were evaluated. Eighty patients (18%) had a diagnosis of DRP (all grades), and 21 patients (4.6%) had a diagnosis of grade 3 or more DRP. Among the patients with DRP, 46% were identified as having transient asymptomatic pulmonary opacity (TAPO). Regarding the CT scan patterns, organizing pneumonia, simple pulmonary eosinophilia, hypersensitivity pneumonia, diffuse alveolar damage, and nonspecific interstitial pneumonia were found in 30, 21, 18, 9, and two patients (38%, 26%, 23%, 11%, and 3%), respectively. In multivariate analysis, smoking history was identified as an independent risk factor for DRP (hazard ratio, 1.72; 95% CI, 1.01-2.89; P = .046). In the 3-month landmark analysis, DRP was associated with poor treatment efficacy; however, the presence of TAPO did not affect treatment efficacy negatively. INTERPRETATION: For osimertinib treatment in first-line settings, the frequency of DRP was considerably elevated to 18 %, and half of these patients exhibited TAPO features.