A clinical trial design applying Bayesian adaptive randomization for targeted therapy development in lung cancer: A step toward personalized medicine

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7697-7697
Author(s):  
X. Zhou ◽  
E. S. Kim ◽  
R. S. Herbst ◽  
S. Liu ◽  
I. I. Wistuba ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Response Rate ◽  
Clinical Trial Design ◽  
Probit Model ◽  
Stopping Rules ◽  
Response To Treatment ◽  
Tumor Biomarker ◽  
Lung Carcinogenesis ◽  
Operating Characteristics

7697 Background: Multiple axes of signaling pathways are associated with lung carcinogenesis. These signaling axes are different in pts (pts) and their cancers. Utilization of molecularly targeted agents may inhibit these specific aberrant pathways and lead to clinical efficacy. Biomarkers expressions can be used as indicators for the aberrant signaling to identify effective targeted therapy. Methods: The program, “Biomarker-integrated Approaches of Targeted Therapy of Lung Cancer Elimination (BATTLE),” consists of an umbrella screening trial and 4 parallel phase II targeted therapies trials (with erlotinib, sorafenib, vandetanib, and the combination of erlotinib and bexarotene) in advanced non-small cell lung cancer pts with prior chemotherapy. All pts will have biopsy samples taken for biomarker profile assessment prior to the randomization. A ‘surrogate response‘ to treatment is defined as progression free at 8 weeks after randomization. The Bayesian ordinal probit model is used to characterize the response rate. Pts with certain biomarker profile will be adaptively randomized (AR) to one of the 4 treatment arms with the randomization rate based on the updated response rate based on accumulated data in the trial. For each biomarker profile, better performing arms will have higher randomization rates and vise versa. Early stopping rules are set so that low-performing arms may be suspended for new patient entry. Results: Based on extensive simulation studies, the proposed design with a total of 200 pts has desirable operating characteristics to: (1) identify effective agents with high probability; (2) suspend ineffective agents; and (3) treat more pts with effective agents according to their biomarker profiles. The Bayesian design incorporates prior data and findings from the current pts to form better estimates of the treatment efficacy for pts with different biomarker profiles. The design continues to “learn” and improve the estimates as the trial moves along. Conclusion: The Bayesian AR design is a smart and ethical design and ideally suitable for the development of targeted therapy. It may help in identifying effective agents based on pts’ tumor biomarker profile and thus treat more pts with effective therapies. No significant financial relationships to disclose.

High Body Mass Index Was Related to Favorable Therapeutic Efficacy of Epidermal Growth Factor Receptor Targeted Therapy in Advanced Non-Small Cell Lung Cancer

2020 ◽  
Author(s):  
Yue-Yun Chen ◽  
Xu-De Yin ◽  
Ke Xie ◽  
Pei-Pei Wang ◽  
Yang Fu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Body Mass Index ◽  
Overall Survival ◽  
Targeted Therapy ◽  
Objective Response Rate ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Objective Response ◽  
Training Group ◽  
Nsclc Patients

Abstract BackgroundIt’s widely accepted that Obesity is closely associated with the elevated risk of various cancers. However, there’s no consensus regarding the impact of body mass index (BMI) on the outcome of targeted therapy targeted-therapy efficacy in lung cancer. MethodsTreatment-naive advanced NSCLC patients harboring EGFR mutation prescribed TKI were screened and enrolled from 3 referral centers. Patients enrolled from West China Hospital were set as the training group, and the others as validation group. Both the demographic features including mutation status and BMI, and therapeutic effects including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were collected.ResultsIn the training group, patients were dichotomized according to their BMI. Those with higher BMI (>22.5) achieved a prolonged PFS compared with those with lower BMI (13.8 and 10.9 mon, HR: 0.68; 95% CI: 0.54-0.86; P = 0.001), and the priority persisted irrespective of different cut-off values. Besides, the favorable association of high BMI with long PFS was confirmed in the validation cohort (14.0 and 11.6 mon, P=0.089) and whole cohort (13.7 and 11.3 mon, P=0.004). In the multivariate analysis, BMI was an independent favorable factor of PFS, together with gender, albumin, and performance. By integration of these factors, a nomogram to predict to 1-,3-year PFS was established. Finally, higher BMI was associated with better objective response rate (ORR, 74% and 69%) and longer overall survival (OS, 41.4 and 33.5 mon, P=0.011). ConclusionHigh BMI was independently associated with efficacy of EGFR-TKI treatment in advanced NSCLC patients.

The role of microRNA in the molecular mechanisms of resistance to EGFR tyrosine kinase inhibitor treatment in NSCLC and the current perspective on its clinical applications

2017 ◽  
Vol 5 ◽  
pp. 45-58
Author(s):  
Adam Szpechciński ◽  
Mateusz Florczuk
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Tyrosine Kinase ◽  
Molecular Mechanisms ◽  
Regulatory Function ◽  
Cancer Tissue ◽  
Lung Carcinogenesis ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tkis

Non-small cell lung cancer (NSCLC) is the leading cause of death from cancer over the world. Currently, a large number of research studies are conducted to develop and implement new treatment strategies. Intensive efforts are also made to improve robustness of modern molecular diagnostics to identify more precisely specific genetic and epigenetic cancer features (predictive biomarkers) and adjust the most effective treatment options for individual patient (personalized therapy). So called targeted therapy based on using epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) is nowadays the most widely chosen form of personalized treatment in advanced NSCLC. Favorable response to treatment with EGFR TKIs depends on the presence of somatic mutations in EGFR gene, detectable in lung cancer tissue. The resistance to EGFR TKIs acquired by most patients during treatment is the main ob-stacle to overcome in NSCLC targeted therapy. miRNAs (microRNAs) are small, noncoding RNA molecules that play a keyrole in the regulation of basic cellular processes, includingdif-ferentiation, proliferation and apoptosis, by controllinggene expression at the posttranscriptional level.Deregulation of miRNA activity results in the loss of homeostasisand the development of a number of pathologies, includinglung cancer. During lung carcinogenesis, miRNAs exhibitdual regulatory function: they act as oncogenes or as tumour suppressors. Better understanding of epigenetic mechanisms re-gulating either the sensitivity or the resistance of NSCLC cells to EGFR TKIs, through activity of miRNAs, may become a breakthrough in targe-ted therapy of lung cancer. The dual regulatory role of miRNA in cancer might drive the further development of personalised therapies in NSCLC. Furthermore, stable forms of tumourrelated miRNAs are detectable in the peripheral blood of patients with NSCLC that offers the potential benefits of using extracellular miRNAs as part of the diagnostic evaluation of cancer.

Factors associated with time to targeted therapy for patients with metastatic lung cancer with driver mutations.

2020 ◽  
Vol 38 (29_suppl) ◽  
pp. 120-120
Author(s):  
Suwei Wang ◽  
Hu Huang ◽  
Elisabeth Scheufele ◽  
Yull Edwin Arriaga ◽  
Gretchen Purcell Jackson ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Liver Disease ◽  
Targeted Therapy ◽  
Targeted Therapies ◽  
Initial Diagnosis ◽  
Driver Mutations ◽  
Tumor Biomarker ◽  
Metastatic Lung Cancer ◽  
Factors Associated ◽  
Metastatic Lung

120 Background: Targeted therapies are superior to chemotherapy in metastatic lung cancer with driver gene mutations. Delays in initiation of targeted therapies may result in faster symptom progression, decline in quality of life, and shortened survival. We examined factors associated with time to initiation of targeted therapy (TTT) in patients with metastatic lung cancer with selected driver mutations. Methods: In this retrospective cohort study, IBM MarketScan claims data was used to identify patients who had an initial diagnosis of metastatic lung cancer, defined as continuous insurance enrollment 12 months pre- to 6 months post-diagnosis, with tumor biomarker (i.e., EGFR, ALK, ROS1, BRAF V600E, NTRK)-directed targeted therapy performed within 6 months of the initial diagnosis, during the timeframe of 1/1/2013 to 12/31/2018. Trends in TTT were evaluated with Wilcoxon–Mann–Whitney. Quantile regression, a robust model that analyzed factors on different outcome-related quantiles, was used to identify associations among TTT and covariates including age, sex, comorbidity, insurance type, and US region. Results: Among 8977 patients identified with an initial diagnosis of metastatic lung cancer, 710 (7.9%) received targeted therapies within the 6-month timeframe, and 1040 (12%) had tumor biomarker testing performed. The overall median TTT was 21 days (IQR = 36 days). Median TTT decreased from 25 days in 2013 to 18 days in 2018 (p = 0.03). Factors associated with longer TTT (median, 50% quantile) were increasing age (p = 0.04), cardiovascular disease (“CVD”, p = 0.03), HIV (p = 0.04), and mild liver disease (p = 0.05). For the lower quantile ( < = 1 day, 5% quantile), female sex (p = 0.01), HIV (p = 0.04), and mild liver disease (p = 0.002) were associated with longer TTT. Having a PPO health plan extended TTT (p = 0.05) at the upper quantile (79 days, 90% quantile). Conclusions: Our study showed an encouraging 5-year trend of the median TTT decreasing by 28%. Numerous factors associated with longer TTT included increasing age, CVD, HIV, mild liver disease, female sex, and PPO plan. This study provides insights into patient-related factors associated with longer time to initiation of targeted therapies for patients with metastatic lung cancer with driver mutations. Additional research is needed to identify the reasons for longer TTT and to develop strategies to expedite delivery of optimal therapies.

scholarly journals Current and future applications of liquid biopsy in nonsmall cell lung cancer from early to advanced stages

2020 ◽  
Vol 29 (155) ◽  
pp. 190052 ◽  
Author(s):  
Nicolas Guibert ◽  
Anne Pradines ◽  
Gilles Favre ◽  
Julien Mazieres
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Cell Lung Cancer ◽  
Liquid Biopsy ◽  
Residual Disease ◽  
Checkpoint Inhibitors ◽  
Immune Therapy ◽  
Nonsmall Cell Lung Cancer ◽  
Response To Treatment ◽  
Genomic Alteration

Liquid biopsy refers to the analysis of any tumour-derived material circulating in the blood or any other body fluid. This concept is particularly relevant in lung cancer as the tumour is often difficult to reach and may need an invasive and potentially harmful procedure. Moreover, the multitude of anticancer drugs and their sequential use underline the importance of conducting an iterative assessment of tumour biology. Liquid biopsies can noninvasively detect any targetable genomic alteration and guide corresponding targeted therapy, in addition to monitoring response to treatment and exploring the genetic changes at resistance, overcoming spatial and temporal heterogeneity.In this article, we review the available data in the field, which suggest the potential of liquid biopsy in the area of lung cancer, with a particular focus on cell-free DNA and circulating tumour cells. We discuss their respective applications in patient selection and monitoring through targeted therapy, as well as immune checkpoint inhibitors. The current data and future applications of liquid biopsy in the early stage setting are also investigated.Liquid biopsy has the potential to help manage nonsmall cell lung cancer throughout all stages of lung cancer: screening, minimal residual disease detection to guide adjuvant treatment, early detection of relapse, systemic treatment initiation and monitoring of response (targeted or immune therapy), and resistance genotyping.

Phase II Trial of Paclitaxel and Carboplatin in Metastatic Small-Cell Lung Cancer: A Groupe Français de Pneumo-Cancérologie Study

2001 ◽  
Vol 19 (5) ◽  
pp. 1320-1325 ◽  
Author(s):  
P. Thomas ◽  
O. Castelnau ◽  
D. Paillotin ◽  
H. Léna ◽  
G. Robinet ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Response Rate ◽  
Eastern Cooperative Oncology Group ◽  
Area Under The Curve ◽  
Small Cell ◽  
Response To Treatment ◽  
Small Cell Lung ◽  
Grade 3

PURPOSE: To evaluate the efficacy and safety of paclitaxel and carboplatin in the treatment of previously untreated patients with metastatic small-cell lung cancer (SCLC). PATIENTS AND METHODS: Eligible patients were aged 18 to 75 years with an Eastern Cooperative Oncology Group (ECOG) score ≤ 2 and life expectancy ≥ 12 weeks. Paclitaxel (200 mg/m2) was infused over 3 hours, before carboplatin (area under the curve [AUC] 6; Calvert formula) infused over 1 hour, once every 3 weeks for six cycles maximum. Prednisolone, dexchlorpheniramine, and ranitidine were standard premedication. Response to treatment was assessed every two cycles, and nonresponding patients were withdrawn from the trial to receive standard chemotherapy. RESULTS: Of the 50 patients entering the study, 48 and 46 patients were assessable for toxicity and response, respectively. The overall response rate was 65%, with complete responses in three patients. Five patients had stable disease (11%) and 11 patients experienced progressive disease (24%). Median survival was 38 weeks, and median duration of response was 20 weeks. One-year survival was 22.5%. For a total of 232 cycles, grade 3 and 4 toxicity was 33% for neutropenia, 3.5% for thrombocytopenia, and 4% for anemia. Four patients had neutropenic fever (one toxic death). Nonhematologic toxicity was mainly grade 1 and 2 paresthesia (21% of patients); grade 3 myalgia/arthralgia was observed in 6.5% of patients. CONCLUSION: First-line chemotherapy with paclitaxel and carboplatin in metastatic SCLC achieved a response rate and survival similar to standard regimens. With 1-day administration and a tolerable toxicity profile, this combination merits further investigation.

Application of Targeted Therapy to Malignant Gliomas and Response to Treatment

2013 ◽  
Vol 8 (1) ◽  
pp. 14-24 ◽  
Author(s):  
Eudocia Q. Lee ◽  
Andrew D. Norden ◽  
Jan Drappatz ◽  
Patrick Y. Wen
Keyword(s):  
Targeted Therapy ◽  
Malignant Gliomas ◽  
Response To Treatment

Phase II study of docetaxel and cisplatin in advanced non-small-cell lung cancer.

1998 ◽  
Vol 16 (5) ◽  
pp. 1948-1953 ◽  
Author(s):  
J Zalcberg ◽  
M Millward ◽  
J Bishop ◽  
M McKeage ◽  
A Zimet ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase Ii ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Phase Ii Study ◽  
Performance Status ◽  
Objective Response ◽  
Small Cell ◽  
Small Cell Lung ◽  
Grade 3

PURPOSE Docetaxel (Taxotere, Rhone-Poulenc Rorer, Antony, France) and cisplatin are two of the most active single agents used in the treatment of non-small-cell lung cancer (NSCLC). A recently reported phase I study of the combination of docetaxel and cisplatin recommended a dose of 75 mg/m2 of both drugs every 3 weeks for subsequent phase II study. PATIENTS AND METHODS Eligible patients were aged 18 to 75 years with a World Health Organization (WHO) performance status < or = 2 and life expectancy > or = 12 weeks, with metastatic and/or locally advanced NSCLC proven histologically or cytologically. Patients were not permitted to have received prior chemotherapy, extensive radiotherapy, or any radiotherapy to the target lesion and must have had measurable disease. Concurrent treatment with colony-stimulating factors (CSFs) or prophylactic antibiotics was not permitted. Docetaxel (75 mg/m2) in 250 mL 5% dextrose was given intravenously (i.v.) over 1 hour immediately before cisplatin (75 mg/m2) in 500 mL normal saline given i.v. over 1 hour in 3-week cycles. Premedication included ondansetron, dexamethasone, promethazine, and standard hyperhydration with magnesium supplementation. RESULTS A total of 47 patients, two thirds of whom had metastatic disease, were entered onto this phase II study. The majority of patients were male (72%) and of good (WHO 0 to 1) performance status (85%). All 47 patients were assessable for toxicity and 36 were for response. Three patients were ineligible and eight (17%) discontinued treatment because of significant toxicity. In assessable patients, the overall objective response rate was 38.9% (95% confidence limits [CL], 23.1% to 56.5%), 36.1% had stable disease, and 25% progressive disease. On an intention-to-treat analysis, the objective response rate was 29.8%. Median survival was 9.6 months and estimated 1-year survival was 33%. Significant (grade 3/4) toxicities included nausea (26%), hypotension (15%), diarrhea (13%), and dyspnea mainly related to chest infection (13%). One patient experienced National Cancer Institute (NCI) grade 3 neurosensory toxicity after eight cycles. Grade 3/4 neutropenia was common and occurred in 87% of patients, but thrombocytopenia > or = grade 3 was rare (one patient). Significant (grade 3/4) abnormalities of magnesium levels were common (24%). Febrile neutropenia occurred in 13% of patients and neutropenic infection in 11%, contributing to two treatment-related deaths. No neutropenic enterocolitis or severe fluid retention was reported. CONCLUSION Compared with other active regimens used in this setting, the combination of docetaxel and cisplatin in advanced NSCLC is an active regimen with a similar toxicity profile to other combination regimens.

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