A phase II study of anlotinib plus whole brain radiation therapy (WBRT) for advanced non-small cell lung cancer with multiple brain metastases.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21063-e21063
Author(s):  
Xiangzhi Zhu ◽  
Hua Tao ◽  
Ming Jiang ◽  
Meiqi Shi ◽  
Cheng Kong ◽  
...  

e21063 Background: The prognosis of non-small-cell lung cancer (NSCLC) patients(pts) with multiple brain metastases is poor. WBRT is the main treatment for the pts, but QUARTZ study showed that the efficacy of WBRT is unsatisfactory. The synergistic effect of the antiangiogenic therapy with radiation therapy has been well established. Anlotinib, an antiangiogenic multi-target TKI, had significantly improved progression-free survival (PFS) of advanced NSCLC with Brain Metastases. This study aimed to evaluate the efficacy and safety of anlotinib combined with WBRT in pts with brain metastases ( > 3) from advanced NSCLC. Methods: Advanced NSCLC pts with brain metastases ( > 3) who were histologically confirmed to be driver gene wild type or positive and pts who had received two or more previous treatments were eligible. Pts with meningeal metastasis were excluded. All pts were treated with anlotinib (12 mg, QD, day 1 to 14 of a 21-day cycle) combined with WBRT (DT 30Gy/12f), followed by maintenance therapy with anlotinib until disease progression or treatment intolerance. The primary endpoint was intracranial progression-free survival (iPFS). Secondary endpoints were extracranial PFS (ePFS), OS and toxicity. Results: As of 25 Jan 2021, 28 pts were enrolled. The median age was 57.5 years with 46.4% male. 89.3% of pts with adenocarcinoma. 21.4% pts harbored EGFR mutation. A total of 25 pts were included in efficacy analysis. In intracranial evaluation, ORR was 64.0%, DCR was 88.0%, median iPFS was 11.1 months (95% CI 5.9 to 12.1). In extracranial evaluation, ORR was 12.0%, DCR was 84.0%, median ePFS was 6.0months (95% CI 3.2 to 8.8). Most common grade 1-2 adverse events (AEs) were hypertension (67.8%), fatigue (64.2%),anorexia (46.4%) and hand and foot skin reaction (37.5%). The most common grade 3-4 AEs were hypertension (12.5%), hand and foot skin reaction (10.7%) and fatigue (7.2%). No intracranial hemorrhage occurred during treatment. Dose adjustment due to AE occurred in 21.4% patients. Conclusions: This prospective study shows that the combination of anlotinib and WBRT for patients with multiple brain metastases after standard treatment resistance exhibited an effective therapeutic approach and manageable AEs. For further investigation, large sample and additional clinical trials are warranted. Clinical trial information: ChiCTR1900022093.

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiaoqun Nie ◽  
Liliang Xia ◽  
Fang Gao ◽  
Lixia Liu ◽  
Yi Yang ◽  
...  

Background: Despite remarkable success of immunotherapies with checkpoint blockade antibodies targeting programmed cell death protein 1 (PD-1), the majority of patients with non-small-cell lung cancer (NSCLC) have yet to receive durable benefits. We used the metabolomic profiling of early on-treatment serum to explore predictors of clinical outcomes of anti-PD-1 treatment in patients with advanced NSCLC.Methods: We recruited 74 Chinese patients who had stage IIIB/IV NSCLC-proven tumor progression and were treated with PD-1 inhibitor. The study was comprised of a discovery cohort of patients treated with nivolumab and two validation cohorts of patients receiving tislelizumab or nivolumab. Serum samples were collected 2–3 weeks after the first infusion of PD-1 inhibitor. Metabolomic profiling of serum was performed using ultrahigh performance lipid chromatograph-mass spectrometry. The serum metabolite biomarkers were identified using an integral workflow of nontargeted metabolomic data analysis.Results: A serum metabolite panel consisting of hypoxanthine and histidine was identified and validated as a predictor of response to PD-1 blockade treatment in patients with advanced NSCLC. High levels of both hypoxanthine and histidine in early on-treatment serum were associated with improved progression-free survival [hazard ratio (HR) = 0.078, 95% confidence interval (CI), 0.027–0.221, p < 0.001] and overall survival (HR = 0.124, 95% CI, 0.039–0.397, p < 0.001) in the discovery cohort. The serum metabolite panel showed a high sensitivity and specificity in distinguishing responders and non-responders in the validation cohorts 1 and 2, with an area under the receiver-operating characteristic curve of 0.933 and 1.000, respectively. High levels of serum hypoxanthine and histidine were correlated with improved progression-free survival in the validation cohort 1 (HR = 0.137, 95% CI, 0.040–0.467, p = 0.001) and in the validation cohort 2 (HR = 0.084, 95% CI, 0.009–0.762, p = 0.028).Conclusion: Our results revealed that hypoxanthine and histidine in early on-treatment serum are predictive biomarkers of response to PD-1 blockade therapy in patients with advanced NSCLC. The serum biomarker panel would enable early identification of NSCLC patients who may benefit from PD-1 blockade therapy.


2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14530-e14530 ◽  
Author(s):  
Stephanie Labomascus ◽  
Ibtihaj Fughhi ◽  
Philip Bonomi ◽  
Mary J. Fidler ◽  
Jeffrey Allen Borgia ◽  
...  

e14530 Background: Baselinehigh neutrophil to lymphocyte ratio (NLR) has been associated with inferior overall survival in patients with stage III/IV NSCLC. Inflammation and neutrophilic infiltrates in the tumor microenvironment appear to inhibit anti-tumor immune response. We suspect that NLR might reflect the level of inflammation in tumor microenvironment. The objectives of this study were to evaluate potential relationships between pretreatment NLR and and PFS and OS in advanced NSCLC patients treated with second-line nivolumab or pembrolizumab. Methods: Patients with stage IV NSCLC who received at least one cycle of nivolumab or pembrolizumab after first-line treatment with a platinum doublet between January 2015 and December 2016 were included. Patient demographics including NLR at baseline, date of starting immunotherapy, and date of progression were recorded. The association between NLR and duration of response was assessed using a Mann-Whitney-Wilcoxon test. A cutoff of NLR of 3.5 and 5.0 based on published data (ref) were analyzed for differences in median overall survival and progression free survival. Results: 113 patients were analyzed: median age 68, male/female 38.9%/61.1%, 15% never smoked. The median PFS for patients with NLR < 5 was 4.14 months vs. 2.27 months in those with NLR > 5 (p = 0.031). Overall survival was also impacted by NLR. There were a total of 29 deaths in the cohort, 24 of these occurred in patients with NLR > 3.5 and 5 were in patients with NLR < 3.5. A lower NLR at baseline was significantly associated with improved overall survival (p = 0.036). Conclusions: A low baseline NLR is associated with superior progression free survival and overall survival in metastatic non-small cell lung cancer patients treated with nivolumab or pembrolizumab. These findings suggest that evaluating mediators of inflammation might help to identify potential therapeutic targets which could enhance effectiveness of PD-1 immune check point inhibitors in advanced NSCLC.


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20509-e20509
Author(s):  
Yutao Liu ◽  
Kai Zhang ◽  
Chengcheng Li ◽  
Xingsheng Hu ◽  
Jun Jiang ◽  
...  

e20509 Background: Response Evaluation Criteria in Solid Tumors (RECIST) has been widely utilized to evaluate the new therapeutic strategies in cancer, however, RECIST fails to differentiate the heterogeneity of response in highly active therapies. Depth of response (DepOR), defined as maximum percent change in tumor size compared with baseline, may provide a new strategy to evaluate disease response. In the present study, we studied the association between DepOR and progression-free survival (PFS) in patients with advanced non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Methods: Advanced NSCLC patients harboring EGFR driver mutation (L858R or 19del) treated with EGFR-TKI from August 2014 to July 2017 in two sites were retrospetively collected for analysis. Patients were divided into four groups by maximal tumor shrinkage (Q1 = 1-25%, Q2 = 26-50%, Q3 = 51-75%, Q4 = 76-100%). Kaplan-Meier curves were plotted for PFS by DepOR and the hazard ratio (HR) was determined through univariable and multivariable Cox regression models. Results: In total, 265 patients were included for analysis. The number for Group Q1-Q4 was 91, 73, 65 and 36, respectively. The greater DepOR was significantly associated with a longer PFS (Log-rank P for trend < 0.0001). The DepOR vs PFS analyses HR were 0.58 (0.42-0.80) for Q2, 0.49 (0.35-0.69) for Q3 and 0.33 (0.22-0.50) for Q4 compared with Q1. In the multivariable cox regression model, abnormal LDH, brain metastasis and male were also found to be associated with poorer PFS (P < 0.05). Conclusions: Greater DepOR was significantly associated with a longer PFS in advanced NSCLC treated with EGFR-TKI, suggesting that it may be a useful clinical outcome to more efficiently evaluate the response of targeted therapy.


2020 ◽  
Vol 38 (14) ◽  
pp. 1505-1517 ◽  
Author(s):  
Shirish Gadgeel ◽  
Delvys Rodríguez-Abreu ◽  
Giovanna Speranza ◽  
Emilio Esteban ◽  
Enriqueta Felip ◽  
...  

PURPOSE In KEYNOTE-189, first-line pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus pemetrexed-platinum in patients with metastatic nonsquamous non‒small-cell lung cancer (NSCLC), irrespective of tumor programmed death-ligand 1 (PD-L1) expression. We report an updated analysis from KEYNOTE-189 (ClinicalTrials.gov: NCT02578680 ). METHODS Patients were randomly assigned (2:1) to receive pemetrexed and platinum plus pembrolizumab (n = 410) or placebo (n = 206) every 3 weeks for 4 cycles, then pemetrexed maintenance plus pembrolizumab or placebo for up to a total of 35 cycles. Eligible patients with disease progression in the placebo-combination group could cross over to pembrolizumab monotherapy. Response was assessed per RECIST (version 1.1) by central review. No alpha was assigned to this updated analysis. RESULTS As of September 21, 2018 (median follow-up, 23.1 months), the updated median (95% CI) OS was 22.0 (19.5 to 25.2) months in the pembrolizumab-combination group versus 10.7 (8.7 to 13.6) months in the placebo-combination group (hazard ratio [HR], 0.56; 95% CI, 0.45 to 0.70]). Median (95% CI) PFS was 9.0 (8.1 to 9.9) months and 4.9 (4.7 to 5.5) months, respectively (HR, 0.48; 95% CI, 0.40 to 0.58). Median (95% CI) time from randomization to objective tumor progression on next-line treatment or death from any cause, whichever occurred first (progression-free-survival-2; PFS-2) was 17.0 (15.1 to 19.4) months and 9.0 (7.6 to 10.4) months, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). OS and PFS benefits with pembrolizumab were observed regardless of PD-L1 expression or presence of liver/brain metastases. Incidence of grade 3-5 adverse events was similar in the pembrolizumab-combination (71.9%) and placebo-combination (66.8%) groups. CONCLUSION First-line pembrolizumab plus pemetrexed-platinum continued to demonstrate substantially improved OS and PFS in metastatic nonsquamous NSCLC, regardless of PD-L1 expression or liver/brain metastases, with manageable safety and tolerability.


2015 ◽  
Vol 33 (9) ◽  
pp. 1008-1014 ◽  
Author(s):  
Gideon M. Blumenthal ◽  
Stella W. Karuri ◽  
Hui Zhang ◽  
Lijun Zhang ◽  
Sean Khozin ◽  
...  

Purpose To conduct analyses exploring trial-level and patient-level associations between overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) in advanced non–small-cell lung cancer (NSCLC) trials. Methods We identified 14 trials (N = 12,567) submitted to US Food and Drug Administration since 2003 of treatments for advanced NSCLC. Only randomized, active-controlled trials with more than 150 patients were included. Associations between trial-level PFS hazard ratio (HR), OS HR, and ORR odds ratio were analyzed using a weighted linear regression model. Patient-level responder analyses comparing PFS and OS between patients with and without an objective response were performed using pooled data from all studies. Results In the trial-level analysis, the association between PFS and ORR was strong (R2 = 0.89; 95% CI, 0.80 to 0.98). There was no association between OS and ORR (R2 = 0.09; 95% CI, 0 to 0.33) and OS and PFS (R2 = 0.08; 95% CI, 0 to 0.31). In the patient-level responder analyses, patients who achieved a response had better PFS and OS compared with nonresponders (PFS: HR, 0.40; 95% CI, 0.38 to 0.42; OS: HR, 0.40; 95% CI, 0.38 to 0.43). Conclusion On a trial level, there is a strong association between ORR and PFS. An association between ORR and OS and between PFS and OS was not established, possibly because of cross-over and longer survival after progression in the targeted therapy and first-line trials. The patient-level analysis showed that responders have a better PFS and OS compared with nonresponders. A therapy in advanced NSCLC with a large magnitude of effect on ORR may have a large PFS effect.


2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21568-e21568
Author(s):  
Rodrigo Motta Guerrero ◽  
Carlos Aliaga Macha ◽  
Carlos F. Carracedo ◽  
Thanya Runciman

e21568 Background: Tirosine Kinasa Inhibitors (TKI) are the standard treatment in patients with non-small cell lung cancer (NSCLC) harboring EGFR mutation. However, eventually patients will progress to TKI. The aim of this study is to determinate if neutrophil-lymphocyte ratio (NLR), RDW-CV and platelet-lymphocyte ratio (PLR) are associated with progression free survival (PFS). Methods: This is a retrospective observational study of a single patient cohort. Clinical records of advanced NSCLC patients that received TKI as first line therapy in ALIADA cancer center since January 2015 and December 2019 were evaluated. NLR, RDW-CV and PLR were calculated from blood counts before beginning of TKI. The statistical analysis was performed with SPSS version 20 and MINITAB 14. Results: 182 patients were diagnosed with advanced NSCLC and 30% of them harbor a EGFR mutation. 43 patients were finally included, 55.8% were women and mean age was 58 years. The 65% of patients had exon19 deletion, 25% exon21 L858R substitution, 7% exon20 T790 mutations and 3% exon18 G719X substitution. 44% of patients received erlotinib, 38% afatinib and 18% osimertinib. The 61.5% of patients achieved partial response; they had a mean NLR, PRL and RDW-CV of 2.98 (0.93–7.41), 238.59 (101.63–863.01) and 13.8 (12.6–15.5) respectively. 17.3% achieved complete response, with a mean NLR, PRL and RDW-CV of 2.93 (1.22–4.64), 204.37 (109.21–417.46) and 13.7 (12.8–15.4). Finally, 9.6% maintain stable disease; with a mean NLR, PRL and RDW-CV of 4.25 (3.6-4.91), 200.7 (196.4-205) and 14.35 (14.3-14.4). 74% of patients progressed. The mean PFS was 24.33 months (95% CI 16.05 - 32.6). Patients that developed progressive disease and those who did not, had no significant difference in the mean NLR (3.98 vs 3.68, p = 0.706) and mean RDW-CV (14.12 vs 14.3, p = 0.655). However, patients with clinical benefit during TKI had a mean PLR of 163.68, meanwhile patients with progressive disease had a mean PLR of 276.54 (T of Student, p = 0.03). Conclusions: In patients with advanced EGFR mutated NSCLC, a high level of PLR is associated with a lower PFS. It is necessary to carry out studies with a bigger amount of population to validate the PLR as a predictive biomarker. To our knowledge this is the first study that analyzes these characteristics in Latin American population.


2016 ◽  
Vol 34 (2) ◽  
pp. 123-129 ◽  
Author(s):  
Kimberly L. Johung ◽  
Norman Yeh ◽  
Neil B. Desai ◽  
Terence M. Williams ◽  
Tim Lautenschlaeger ◽  
...  

Purpose We performed a multi-institutional study to identify prognostic factors and determine outcomes for patients with ALK-rearranged non–small-cell lung cancer (NSCLC) and brain metastasis. Patients and Methods A total of 90 patients with brain metastases from ALK-rearranged NSCLC were identified from six institutions; 84 of 90 patients received radiotherapy to the brain (stereotactic radiosurgery [SRS] or whole-brain radiotherapy [WBRT]), and 86 of 90 received tyrosine kinase inhibitor (TKI) therapy. Estimates for overall (OS) and intracranial progression-free survival were determined and clinical prognostic factors were identified by Cox proportional hazards modeling. Results Median OS after development of brain metastases was 49.5 months (95% CI, 29.0 months to not reached), and median intracranial progression-free survival was 11.9 months (95% CI, 10.1 to 18.2 months). Forty-five percent of patients with follow-up had progressive brain metastases at death, and repeated interventions for brain metastases were common. Absence of extracranial metastases, Karnofsky performance score ≥ 90, and no history of TKIs before development of brain metastases were associated with improved survival (P = .003, < .001, and < .001, respectively), whereas a single brain metastasis or initial treatment with SRS versus WBRT were not (P = .633 and .666, respectively). Prognostic factors significant by multivariable analysis were used to describe four patient groups with 2-year OS estimates of 33%, 59%, 76%, and 100%, respectively (P < .001). Conclusion Patients with brain metastases from ALK-rearranged NSCLC treated with radiotherapy (SRS and/or WBRT) and TKIs have prolonged survival, suggesting that interventions to control intracranial disease are critical. The refinement of prognosis for this molecular subtype of NSCLC identifies a population of patients likely to benefit from first-line SRS, close CNS observation, and treatment of emergent CNS disease.


2021 ◽  
Author(s):  
Jiajia Zhang ◽  
Zi'ning Qi ◽  
Dong Han ◽  
Siying Chen ◽  
Jifeng Sun ◽  
...  

Abstract Background: Palliative thoracic radiotherapy (RT) can improve local control and survival in patients with unresectable locally or systemically advanced non-small cell lung cancer (NSCLC), but the optimal RT dose has not been well-defined. We investigated the survival outcomes of patients with NSCLC who underwent hypofractionated radiotherapy (HFRT).Methods: We retrospectively investigated survival and adverse effects among 74 patients with locally or systemically advanced NSCLC who received HFRT (45 Gy/15 fractions) at our institution.Results: The median overall survival (OS) was 18.7 months, with 1- and 2-year OS rates of 65.9% and 33.9%, respectively. The median local progression-free survival (LPFS) was 7.2 months, with 1- and 2-year LPFS rates of 27.9% and 9.4%, respectively. Sixteen patients (21.6%) developed grade ≤2 pneumonitis and 14 (19%) developed grade ≤2 esophagitis; no grades ≥3 pneumonitis or esophagitis occurred.Conclusions: HFRT is safe, tolerable, and effective for patients with unresectable locally or systemically advanced NSCLC exhibiting poor prognostic factors.


Author(s):  
Shinobu Hosokawa ◽  
Eiki Ichihara ◽  
Akihiro Bessho ◽  
Daijiro Harada ◽  
Koji Inoue ◽  
...  

Abstract Objectives Studies investigating the association between radiation therapy and the efficacy of immune checkpoint inhibitors in advanced non-small-cell lung cancer have provided inconsistent results, likely due to relatively small cohort sizes. This study investigated the effect of previous thoracic radiation therapy on the efficacy of immune checkpoint inhibitor therapy in a large non-small-cell lung cancer cohort. Patients and methods We conducted a retrospective cohort study using data from 531 non-small-cell lung cancer patients who received monotherapy with programmed cell death protein 1/programmed death-ligand 1 inhibitors at nine institutions. The effects of thoracic radiation therapy on the efficacy of immune checkpoint inhibitors were investigated. Results A total of 531 non-small-cell lung cancer patients treated with immune checkpoint inhibitors were included in this study. The progression-free survival period was significantly longer in patients that had received thoracic radiation therapy before immune checkpoint inhibitor therapy compared to those without previous thoracic radiation therapy (median progression-free survival 5.0 vs. 3.0 months, P = 0.0013). A multivariate analysis showed that thoracic radiation therapy was an independent predictive factor of improved progression-free survival (hazard ratio of progression-free survival: 0.79, P = 0.049). In contrast, extra-thoracic radiation therapy was associated with inferior outcomes (median progression-free survival 3.0 vs. 4.2 months, P = 0.0008). Conclusion Previous thoracic radiation therapy, but not prior extra-thoracic radiation therapy, enhanced the efficacy of anti-programmed cell death protein 1/programmed death-ligand 1 therapy in non-small-cell lung cancer patients.


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