|
1
|
Sun SJ, Han JD, Liu W, Wu ZY, Zhao X, Yan X, Jiao SC, Fang J. Sequential chemotherapy and icotinib as first-line treatment for advanced epidermal growth factor receptor-mutated non-small cell lung cancer. World J Clin Cases 2022; 10:6069-6081. [PMID: 35949840 PMCID: PMC9254173 DOI: 10.12998/wjcc.v10.i18.6069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 03/13/2022] [Accepted: 04/15/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Icotinib could have potential effect and tolerability when used sequentially with chemotherapy for advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC).
AIM To evaluate the efficacy and safety of chemotherapy followed by icotinib maintenance therapy as first-line treatment for advanced EGFR-mutated NSCLC.
METHODS This multicenter, open-label, pilot randomized controlled trial enrolled 68 EGFR-mutated stage IIIB/IV NSCLC patients randomized 2:3 to the icotinib alone and chemotherapy + icotinib groups.
RESULTS The median progression-free survival in the icotinib alone and chemotherapy + icotinib groups was 8.0 mo (95%CI: 3.84-11.63) and 13.4 mo (95%CI: 10.18-16.33), respectively (P = 0.0249). No significant differences were found in the curative effect when considering different cycles of chemotherapy or chemotherapy regimen (all P > 0.05).
CONCLUSION A sequential combination of chemotherapy and EGFR-tyrosine kinase inhibitor is feasible for stage IV EGFR-mutated NSCLC patients.
Collapse
Affiliation(s)
- Sheng-Jie Sun
- Department of Medical Oncology, The Fifth Medical Center of General Hospital of Chinese People's Liberation Army, Beijing 100039, China
| | - Jin-Di Han
- Department of Internal Oncology of Chest, Beijing Cancer Hospital, Beijing 100142, China
| | - Wei Liu
- Peking Cancer Hospital Palliative Care Center, Beijing Cancer Hospital, Beijing 100142, China
| | - Zhi-Yong Wu
- Department of Medical Oncology, The Fifth Medical Center of General Hospital of Chinese People's Liberation Army, Beijing 100039, China
| | - Xiao Zhao
- Department of Medical Oncology, The Fifth Medical Center of General Hospital of Chinese People's Liberation Army, Beijing 100039, China
| | - Xiang Yan
- Department of Medical Oncology, The Fifth Medical Center of General Hospital of Chinese People's Liberation Army, Beijing 100039, China
| | - Shun-Chang Jiao
- Department of Oncology, The Fifth Medical Center of General Hospital of Chinese People's Liberation Army, Beijing 100039, China
| | - Jian Fang
- Department of Internal Oncology of Chest, Beijing Cancer Hospital, Beijing 100142, China
| |
Collapse
|
|
2
|
Hendriks LEL, van Meerbeeck J, Cadranel J. Targeted adjuvant therapy in non-small cell lung cancer: trick or treat? Eur Respir J 2021; 58:58/4/2101637. [PMID: 34711606 DOI: 10.1183/13993003.01637-2021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 08/31/2021] [Indexed: 11/05/2022]
Affiliation(s)
- Lizza E L Hendriks
- Dept of Pulmonary Diseases, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Jan van Meerbeeck
- Dept of Thoracic Oncology, CORE- Antwerp University Hospital and Antwerp University, Antwerp, Belgium
| | - Jacques Cadranel
- Dept of Pulmonology and Thoracic Oncology, Assistance Publique Hôpitaux de Paris, Hôpital Tenon and GRC 04 Theranoscan, Sorbonne Université, Paris, France
| |
Collapse
|
|
3
|
First-iGAP: A Randomized Placebo-Controlled Phase II Study of First-line Intercalated Gefitinib and Pemetrexed-Cisplatin Chemotherapy for Never-Smoker Lung Adenocarcinoma Patients. Clin Lung Cancer 2020; 21:e572-e582. [PMID: 32605893 DOI: 10.1016/j.cllc.2020.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 03/25/2020] [Accepted: 05/06/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND We aimed to evaluate whether intercalated combination of EGFR tyrosine kinase inhibitor gefitinib and chemotherapy improves survival outcomes in never-smokers with advanced lung adenocarcinoma. PATIENTS AND METHODS Never-smokers with chemo-naive stage IIIB/IV lung adenocarcinoma were randomly assigned to receive either gefitinib or placebo on days 5 to 18 of a 3-weekly cycle of pemetrexed and cisplatin. Chemotherapy was given up to 9 cycles, after which gefitinib or placebo was given daily. Patients in the placebo arm who had progression were crossed over to receive gefitinib. RESULTS Between June 2012 and December 2014, 76 patients with median age of 58.0 years were randomized, 39 on gefitinib and 37 on the placebo arm. EGFR mutation was positive in 34 (44.7%) patients. Baseline characteristics were well balanced between the 2 arms. The gefitinib arm had a better response rate (79.5% vs. 51.4%, P = .010) and median progression-free survival (PFS) (12.4 vs. 6.7 months, hazard ratio [HR] 0.49, P = .005) than the placebo arm; however, there was no statistically significant difference in median overall survival between the 2 arms (31.8 vs. 22.9 months, HR 0.78, P = .412). The PFS benefit of intercalated use of gefitinib over placebo was more apparent for patients with EGFR-mutant tumors (13.3 vs. 7.8 months, P = .025) than those with EGFR-wild-type tumors (8.2 vs. 6.6 months, P = .063). Overall, there was no difference in the frequency of severe adverse effect between the 2 arms. CONCLUSIONS Intercalated combination of gefitinib with pemetrexed and cisplatin was well tolerated and improved PFS in never-smoker patients with lung adenocarcinoma.
Collapse
|
|
4
|
Abstract
This paper presents the CellCycler, a model of a growing tumour which aims to simulate and predict the effect of treatment on xenograft studies or in the clinic. The model, which is freely available as a web application, uses ordinary differential equations (ODEs) to simulate cells as they pass through the phases of the cell cycle. However the guiding philosophy of the model is that it should only use parameters that can be observed or reasonably well approximated. There is no representation of the complex internal dynamics of each cell; instead the level of analysis is limited to cell state observables such as cell phase, apoptosis, and damage. We show that this approach, while limited in many respects, still naturally accounts for a heteregenous cell population with varying doubling time, and closely captures the dynamics of a growing tumour as it is exposed to treatment. The program is demonstrated using three case studies.
Collapse
Affiliation(s)
| | - Hitesh B. Mistry
- Division of Pharmacy, University of Manchester, Manchester, United Kingdom
| |
Collapse
|
|
5
|
Xu L, Qi Q, Zhang Y, Cui J, Liu R, Li Y. Combination of icotinib and chemotherapy as first-line treatment for advanced lung adenocarcinoma in patients with sensitive EGFR mutations: A randomized controlled study. Lung Cancer 2019; 133:23-31. [PMID: 31200823 DOI: 10.1016/j.lungcan.2019.05.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 04/18/2019] [Accepted: 05/06/2019] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To explore the efficacy and safety of icotinib with chemotherapy as first-line therapy for advanced lung adenocarcinoma in patients with sensitive epidermal growth factor receptor (EGFR) mutations. METHODS This prospective, randomized, controlled trial was conducted in 10 general hospitals in Shandong Province, China. Previously untreated patients with advanced lung adenocarcinoma and sensitive EGFR mutations were recruited between January 16, 2014 and December 31, 2016 and randomly allocated to the combination group (icotinib plus pemetrexed and carboplatin) or the icotinib only group. The patients were followed up until May 23, 2018. The primary endpoint was progression-free survival (PFS). RESULTS The efficacy analysis (intention-to-treat analysis) include 179 patients (n = 90 in the combination group and n = 89 in the icotinib only group). PFS was significantly longer in the combination group than in the icotinib only group (16.0 months vs. 10.0 months, hazard ratio [HR] = 0.59, 95% confidence interval [CI] 0.42-0.84, P = 0.003). The objective response rate and the disease control rate for the combination group were significantly higher than those for the icotinib only group (77.8% vs. 64.0%, χ2 = 4.094, P = 0.043; 91.1% vs. 79.8%, χ2 = 4.632, P = 0.031). However, overall survival did not differ between the two groups (36.0 months vs. 34.0 months, HR = 0.81, 95%CI 0.54-1.22, P = 0.309). The incidence rates of leukopenia and liver function damage of grades 3-4 were higher in the combination group than in the icotinib only group (12.2% vs. 0%, χ2 = 11.086, P = 0.001; 12.2% vs. 3.5%, χ2 = 4.488, P = 0.034). However, adverse events were resolved in most patients. CONCLUSION Use of the combination of icotinib and chemotherapy as first-line therapy significantly improved the PFS of advanced lung adenocarcinoma patients with sensitive EGFR mutations. Although the combination therapy increased the incidence of leukopenia and liver function damage, the observed adverse events were tolerable and manageable.
Collapse
Affiliation(s)
- Lisheng Xu
- Department of Respiratory Medicine, Qilu Hospital of Shandong University, No. 107 West Wenhua Road, Jinan, China
| | - Qian Qi
- Department of Respiratory Medicine, Qilu Hospital of Shandong University, No. 107 West Wenhua Road, Jinan, China; Department of Respiratory Medicine, Jinan City People's Hospital, No. 001 North Changshao Road, Laiwu District, Jinan, China
| | - Yan Zhang
- Department of Respiratory Medicine, The Fourth People's Hospital of Jinan, No. 050 Shifan Road, Jinan, China
| | - Jiadong Cui
- Department of Respiratory Medicine, Qilu Hospital of Shandong University, No. 107 West Wenhua Road, Jinan, China; Department of Respiratory Medicine, Dong'e County People's Hospital, No. 275 Shuguang Street, Dong'e County, Liaocheng, China
| | - Ruijuan Liu
- Department of Respiratory Medicine, Jining No.1 People's Hospital, No. 6 Jiankang Road, Jining, China.
| | - Yu Li
- Department of Respiratory Medicine, Qilu Hospital of Shandong University, No. 107 West Wenhua Road, Jinan, China.
| |
Collapse
|
|
6
|
Li J, Tan W, Xiao W, Carney RP, Men Y, Li Y, Quon G, Ajena Y, Lam KS, Pan T. A Plug-and-Play, Drug-on-Pillar Platform for Combination Drug Screening Implemented by Microfluidic Adaptive Printing. Anal Chem 2018; 90:13969-13977. [PMID: 30358386 DOI: 10.1021/acs.analchem.8b03456] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Traditional high-throughput drug combination screening requires automatic pipetting of drugs into high-density microtiter plates. Here, a drug-on-pillar platform is proposed for efficient combination drug screening. Using the proposed approach, combination drug screening can be carried out in a plug-and-play manner, allowing for high-throughput screening of large permutations of drug combinations at various concentrations, such that drug dispensing and cell-based screening can be temporally separated and therefore can potentially be performed at distant laboratories. The dispensing is implemented using our recently developed microfluidic pneumatic printing platform, which features a low-cost disposable cartridge that minimizes cross contamination. Moreover, our previously developed drug nanoformulation method with amphiphilic telodendrimers has been utilized to maintain drug stability in a dry form, allowing for convenient drug storage, shipping, and subsequent rehydration. Combining the features described above, we have implemented a 1260-spot drug combination array to study the effect of paired drugs against MDA-MB-231 triple negative human breast cancer cells. This study supports the feasibility of the drug-on-pillar platform for combination drug screening and has provided valuable insight into drug combination efficacy against breast cancer.
Collapse
Affiliation(s)
- Jiannan Li
- Micro-Nano Innovations (MiNI) Laboratory, Department of Biomedical Engineering and Department of Electrical and Computer Engineering , University of California , Davis , California 95616 , United States
| | - Wen Tan
- Micro-Nano Innovations (MiNI) Laboratory, Department of Biomedical Engineering and Department of Electrical and Computer Engineering , University of California , Davis , California 95616 , United States.,School of Pharmacy , Lanzhou University , Lanzhou , Gansu , China 730000
| | - Wenwu Xiao
- Department of Biochemistry and Molecular Medicine, School of Medicine, UC Davis NCI-designated Comprehensive Cancer Center , University of California Davis , Sacramento , California 95817 , United States
| | - Randy P Carney
- Department of Biochemistry and Molecular Medicine, School of Medicine, UC Davis NCI-designated Comprehensive Cancer Center , University of California Davis , Sacramento , California 95817 , United States
| | - Yongfan Men
- Micro-Nano Innovations (MiNI) Laboratory, Department of Biomedical Engineering and Department of Electrical and Computer Engineering , University of California , Davis , California 95616 , United States.,Shenzhen Institutes of Advanced Technology , Chinese Academy of Sciences , Shenzhen , Guangdong , China 518055
| | - Yuanpei Li
- Department of Biochemistry and Molecular Medicine, School of Medicine, UC Davis NCI-designated Comprehensive Cancer Center , University of California Davis , Sacramento , California 95817 , United States
| | - Gerald Quon
- Department of Molecular and Cellular Biology , University of California , Davis , California 95616 , United States
| | - Yousif Ajena
- Department of Biochemistry and Molecular Medicine, School of Medicine, UC Davis NCI-designated Comprehensive Cancer Center , University of California Davis , Sacramento , California 95817 , United States
| | - Kit S Lam
- Department of Biochemistry and Molecular Medicine, School of Medicine, UC Davis NCI-designated Comprehensive Cancer Center , University of California Davis , Sacramento , California 95817 , United States
| | - Tingrui Pan
- Micro-Nano Innovations (MiNI) Laboratory, Department of Biomedical Engineering and Department of Electrical and Computer Engineering , University of California , Davis , California 95616 , United States.,Shenzhen Institutes of Advanced Technology , Chinese Academy of Sciences , Shenzhen , Guangdong , China 518055
| |
Collapse
|
|
7
|
Lv T, Li Z, Xu L, Zhang Y, Chen H, Gao Y. Chloroquine in combination with aptamer-modified nanocomplexes for tumor vessel normalization and efficient erlotinib/Survivin shRNA co-delivery to overcome drug resistance in EGFR-mutated non-small cell lung cancer. Acta Biomater 2018; 76:257-274. [PMID: 29960010 DOI: 10.1016/j.actbio.2018.06.034] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 05/23/2018] [Accepted: 06/26/2018] [Indexed: 02/07/2023]
Abstract
Although novel molecular targeted drugs have been recognized as an effective therapy for non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutations, their efficacy fails to meet the expectation due to the acquired resistance in tumors. Up-regulation of the anti-apoptotic protein Survivin was shown to contribute to the resistance to EGFR tyrosine kinase inhibitors (TKI) in EGFR mutation-positive NSCLC. However, the unorganized tumor blood vessels impeded drug penetration into tumor tissue. The resulting insufficient intracellular drug/gene delivery in drug-resistant cancer cells remarkably weakened the drug efficacy in NSCLC. In this work, a multi-functional drug delivery system AP/ES was developed by using anti-EGFR aptamer (Apt)-modified polyamidoamine to co-deliver erlotinib and Survivin-shRNA. Chloroquine (CQ) was used in combination with AP/ES to normalize tumor vessels for sufficient drug/gene delivery to overcome drug resistance in NSCLC cells. The obtained AP/ES possessed desired physicochemical properties, good biostability, controlled drug release profiles, and strong selectivity to EGFR-mutated NSCLC mediated by Apt. CQ not only enhanced endosomal escape ability of AP/ES for efficient gene transfection to inhibit Survivin, but also showed strong vessel-normalization ability to improve tumor microcirculation, which further promoted drug delivery and enhanced drug efficacy in erlotinib-resistant NSCLC cells. Our innovative gene/drug co-delivery system in combination with CQ showed a promising outcome in fighting against erlotinib resistance both in vitro and in vivo. This work indicates that normalization of tumor vessels could help intracellular erlotinib/Survivin-shRNA delivery and the down-regulation of Survivin could act synergistically with erlotinib for reversal of erlotinib resistance in EGFR mutation-positive NSCLC. STATEMENT OF SIGNIFICANCE NSCLC patients who benefited from EGFR-TKIs inevitably developed acquired resistance. Previous research focused on synthesis of new generation of molecular targeted drugs that could irreversibly inhibit EGFR with a particular gene mutation to overcome drug resistance. However, they failed to inhibit EGFR with other gene mutations. Activation of bypass signaling pathway and the changes of tumor microenvironment are identified as two of the mechanisms of acquired resistance to EGFR-TKIs. We therefore constructed multifunctional gene/drug co-delivery nanocomplexes AP/ES co-formulated with chloroquine that could target the both two mechanisms. We found that chloroquine not only enhanced endosomal escape ability of AP/ES for efficient gene transfection to inhibit Survivin, but also showed strong vessel-normalization ability to improve tumor microcirculation, which further promoted drug delivery into tumor tissue and enhanced drug efficacy in erlotinib-resistant NSCLC.
Collapse
|
|
8
|
Zhang M, Guo H, Zhao S, Wang Y, Yang M, Yu J, Yan Y, Wang Y. Efficacy of epidermal growth factor receptor inhibitors in combination with chemotherapy in advanced non-small cell lung cancer: a meta-analysis of randomized controlled trials. Oncotarget 2018; 7:39823-39833. [PMID: 27223081 PMCID: PMC5129973 DOI: 10.18632/oncotarget.9503] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Accepted: 04/16/2016] [Indexed: 12/18/2022] Open
Abstract
The role of a combination of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy for non-small-cell lung cancer (NSCLC) has not been well established. To clarify this problem, we performed a meta-analysis with 15 studies identified from PubMed, EMBASE and the Cochrane Library. We found that the combined regimen had a significant benefit on progression-free survival (PFS) (hazard ratio (HR) = 0.80; 95% CI = 0.71–0.90; P < 0.001) and the objective response rate (ORR) (RR = 1.35; 95% CI = 1.14–1.59; P < 0.001). However, the combined regimen had no significant impact on overall survival (OS) (HR = 0.96; 95% CI = 0.90–1.03; P = 0.25). Subgroup analysis showed significantly higher OS advantages in EGFR mutation positive patients (P = 0.01), never smokers (P = 0.01), Asian patients (P = 0.02), patients receiving second-line treatment (P < 0.001), and those receiving a sequential combination of EGFR-TKIs and chemotherapy (P = 0.005). The combination regimen showed a higher incidence of grade 3–4 toxicities (leucopenia, neutropenia, febrile neutropenia, anemia, rash, fatigue and diarrhea). In summary, the combination of EGFR-TKIs plus chemotherapy in advanced NSCLC achieved a significantly longer PFS and a higher ORR but not longer OS. Well-designed prospective studies are needed to confirm these findings.
Collapse
Affiliation(s)
- Minghui Zhang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Hongsheng Guo
- Department of Medical Oncology, Tianjin Third Central Hospital, Tianjin, 300170, China
| | - Shu Zhao
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Yan Wang
- Department of Medical Oncology, Heilongjiang Provincial Hospital, Harbin, 150000, China
| | - Maopeng Yang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Jiawei Yu
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Yubo Yan
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Yan Wang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| |
Collapse
|
|
9
|
Ubezio P, Falcetta F, Carrassa L, Lupi M. Integrated experimental and simulation study of the response to sequential treatment with erlotinib and gemcitabine in pancreatic cancer. Oncotarget 2017; 7:15492-506. [PMID: 26909860 PMCID: PMC4941256 DOI: 10.18632/oncotarget.7491] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 01/29/2016] [Indexed: 12/29/2022] Open
Abstract
The combination of erlotinib with gemcitabine is one of the most promising therapies for advanced pancreatic cancer. Aiming at optimizing this combination, we analyzed in detail the response to sequential treatments with erlotinib → gemcitabine and gemcitabine → erlotinib with an 18 h interval, adopting a previously established experimental/computational approach to quantify the cytostatic and cytotoxic effects at G1, S and G2M checkpoints. This assessment was achieved by contemporary fits of flow cytometric and time-lapse experiments in two human pancreatic cancer cell lines (BxPC-3 and Capan-1) with a mathematical model reproducing the fluxes of cells through the cycle during and after treatment.The S-phase checkpoint contributes in the response to erlotinib, suggesting that the G1 arrest may hamper S-phase cytotoxicity. The response to gemcitabine was driven by the dynamics of the progressive resumption from the S-phase arrest after drug washout. The effects induced by single drugs were used to simulate combined treatments, introducing changes when required. Gemcitabine → erlotinib was more than additive in both cell lines, strengthening the cytostatic effects on cells recovering from the arrest induced by gemcitabine. The interval in the erlotinib → gemcitabine sequence enabled to overcome the antagonist effect of G1 block on gemcitabine efficacy and improved the outcome in Capan-1 cells.
Collapse
Affiliation(s)
- Paolo Ubezio
- Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
| | - Francesca Falcetta
- Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
| | - Laura Carrassa
- Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
| | - Monica Lupi
- Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
| |
Collapse
|
|
10
|
La Salvia A, De Luca E, Rossi A, Di Maio M. Can intercalating chemotherapy with epidermal growth factor receptor inhibitors delay development of treatment resistance in advanced non-small cell lung cancer? Expert Opin Pharmacother 2017; 18:1899-1902. [DOI: 10.1080/14656566.2017.1409721] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
- Anna La Salvia
- Department of Oncology, University of Turin, Turin, Italy
- Division of Medical Oncology, “San Luigi Gonzaga” Hospital, Orbassano (TO), Italy
| | - Emmanuele De Luca
- Department of Oncology, University of Turin, Turin, Italy
- Division of MedicalOncology, “Ordine Mauriziano” Hospital, Turin, Italy
| | - Antonio Rossi
- OncologyDepartment, IRCSS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo (FG), Italy
| | - Massimo Di Maio
- Department of Oncology, University of Turin, Turin, Italy
- Division of MedicalOncology, “Ordine Mauriziano” Hospital, Turin, Italy
| |
Collapse
|
|
11
|
Zwitter M, Rossi A, Di Maio M, Perme MP, Lopes G. Selection of Non-small Cell Lung Cancer Patients for Intercalated Chemotherapy and Tyrosine Kinase Inhibitors. Radiol Oncol 2017; 51:241-251. [PMID: 28959160 PMCID: PMC5611988 DOI: 10.1515/raon-2017-0029] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 06/09/2017] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND When treating patients with advanced non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitors and chemotherapy, intercalated schedule with time separation between the two classes of drugs should avoid their mutual antagonism. In a survey of published trials, we focus on relation between eligibility criteria and effectiveness of intercalated treatment. METHODS Published documents were identified using major medical databases, conference proceedings and references of published trials. Median progression-free survival (PFS) was taken as the basic parameter of treatment efficacy. Correlation between characteristics of patients and median PFS was assessed through the Pearson's correlation coefficient and the coefficient of determination, separately for first-line and second-line setting. RESULTS The series includes 11 single-arm trials and 18 randomized phase II or phase III trials with a total of 2903 patients. Treatment-naive patients or those in progression after first-line treatment were included in 16 and 13 trials, respectively. In 14 trials, only patients with non-squamous histology were eligible. Proportion of patients with non-squamous carcinoma (in first-line setting), proportion of never-smokers (both in first- and second-line setting) and proportion of epidermal growth factor receptor (EGFR) mutant patients (both in first- and second-line setting) showed a moderate or strong correlation with median PFS. In six trials of intercalated treatment applied to treatment-naive EGFR-mutant patients, objective response was confirmed in 83.1% of cases and median PFS was 18.6 months. CONCLUSIONS Most suitable candidates for intercalated treatment are treatment-naive patients with EGFR-mutant tumors, as determined from biopsy or liquid biopsy. For these patients, experience with intercalated treatment is most promising and randomized trials with comparison to the best standard treatment are warranted.
Collapse
Affiliation(s)
- Matjaz Zwitter
- Institute of Oncology Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Antonio Rossi
- Division of Medical Oncology, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo (FG), Italy
| | - Massimo Di Maio
- Division of Medical Oncology, Mauriziano Hospital, Oncology Department, University of Turin, Torino, Italy
| | - Maja Pohar Perme
- Institute for Biostatistics and Medical Informatics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Gilberto Lopes
- Centro Paulista de Oncologia e HCor Onco, members of the Oncoclinicas do Brasil Group, Sao Paulo, Brazil and Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| |
Collapse
|
|
12
|
Yang JCH, Mok T, Han B, Orlando M, Puri T, Park K. A Review of Regimens Combining Pemetrexed With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in the Treatment of Advanced Nonsquamous Non-Small-Cell Lung Cancer. Clin Lung Cancer 2017; 19:27-34. [PMID: 28743421 DOI: 10.1016/j.cllc.2017.06.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 06/26/2017] [Accepted: 06/27/2017] [Indexed: 11/27/2022]
Abstract
Pemetrexed is a standard first-line treatment for advanced nonsquamous non-small-cell lung cancer (NSCLC), and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a standard first-line treatment for advanced nonsquamous NSCLC with activating EGFR mutations. Pemetrexed and EGFR TKIs have different mechanisms of action and minimally overlapping toxicity profiles; therefore, it is hypothesized that their combination might result in acceptable toxicity, provided that the synergistic antitumor activity observed in preclinical studies is achieved. This review summarizes clinical trials of pemetrexed in combination with an EGFR TKI for the treatment of advanced nonsquamous NSCLC in the first- and second-line settings, using intercalated, sequential, and concurrent treatment strategies. As would be expected, such strategies were most efficacious in patients with the activating EGFR mutations associated with response to an EGFR TKI. In the studies that compared a pemetrexed-EGFR TKI combination with pemetrexed alone or the EGFR TKI alone, the pemetrexed-EGFR TKI combination was more efficacious than the single-agent regimens. The pemetrexed-EGFR TKI combinations were generally associated with a higher incidence of grade 3/4 treatment-related adverse events than the single-agent regimens; however, such toxicities were clinically manageable. Future studies of pemetrexed-EGFR TKI combinations should focus on optimizing treatment strategies in patients with activating EGFR mutations.
Collapse
Affiliation(s)
| | - Tony Mok
- Department of Clinical Oncology, Prince of Wales Hospital, Sha Tin, Hong Kong
| | - Baohui Han
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Mauro Orlando
- Eli Lilly Interamerica, Inc, Buenos Aires, Argentina
| | - Tarun Puri
- Eli Lilly and Company (India) Pvt Ltd, Gurgaon, India
| | - Keunchil Park
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| |
Collapse
|
|
13
|
Juan O, Popat S. Treatment choice in epidermal growth factor receptor mutation-positive non-small cell lung carcinoma: latest evidence and clinical implications. Ther Adv Med Oncol 2017; 9:201-216. [PMID: 28344665 DOI: 10.1177/1758834016687262] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 11/09/2016] [Indexed: 12/21/2022] Open
Abstract
Discovery of sensitizing mutations in epidermal growth factor receptor (EGFR) and the subsequent development of EGFR tyrosine kinase inhibitors (TKIs) have substantially changed the treatment of lung cancer. First-line treatment with EGFR TKIs (gefitinib, erlotinib and afatinib) has demonstrated a superior response rate and progression-free survival (PFS) compared with chemotherapy in EGFR-mutation positive patients. However, a number of open questions remain, such as choice between the three EGFR TKIs licensed, treatment of patients unsuitable for chemotherapy due to morbidity or advanced age, management of acquired resistance and optimal biological sample to determine EGFR status. Recently the first head-to-head trial comparing gefitinib and afatinib (LUX-Lung 7) has been reported. Moreover, third-generation EGFR TKIs such as osimertinib, rociletinib, olmutinib and ASP8273, with preferential activity against T790M mutant tumours, the commonest resistance mechanism to EGFR TKIs, have shown promising results in early clinical trials, with osimertinib now licensed. In this review, we summarize latest advances in the treatment of EGFR-mutation positive patients focusing on controversial areas and emerging challenges to optimally treat these patients in the future.
Collapse
Affiliation(s)
- Oscar Juan
- Department of Medical Oncology, University Hospital La Fe, Valencia, Spain
| | | |
Collapse
|
|
14
|
Gridelli C, Losanno T. A potential new therapeutic option for patients with advanced EGFR mutation-positive non-small cell lung cancer in first-line setting. J Thorac Dis 2017; 8:E1520-E1524. [PMID: 28066649 DOI: 10.21037/jtd.2016.11.91] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Cesare Gridelli
- Division of Medical Oncology, S.G. Moscati Hospital, Avellino, Italy
| | - Tania Losanno
- Department of Experimental Medicine, University "Sapienza", Rome, Italy
| |
Collapse
|
|
15
|
Zhang M, Liu M, Wang Y. Clinical efficacy of EGFR-TKIs in combination with chemotherapy in patients with advanced non-small cell lung cancer harboring EGFR mutations. J Thorac Dis 2016; 8:E1293-E1295. [PMID: 27867610 DOI: 10.21037/jtd.2016.10.87] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Minghui Zhang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Mingyang Liu
- Department of Medical Oncology, Second Tumor Hospital of Heilongjiang Province, Harbin 150088, China
| | - Yan Wang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, China
| |
Collapse
|
|
16
|
Cardilin T, Almquist J, Jirstrand M, Sostelly A, Amendt C, El Bawab S, Gabrielsson J. Tumor Static Concentration Curves in Combination Therapy. AAPS JOURNAL 2016; 19:456-467. [PMID: 27681102 DOI: 10.1208/s12248-016-9991-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 09/09/2016] [Indexed: 11/30/2022]
Abstract
Combination therapies are widely accepted as a cornerstone for treatment of different cancer types. A tumor growth inhibition (TGI) model is developed for combinations of cetuximab and cisplatin obtained from xenograft mice. Unlike traditional TGI models, both natural cell growth and cell death are considered explicitly. The growth rate was estimated to 0.006 h-1 and the natural cell death to 0.0039 h-1 resulting in a tumor doubling time of 14 days. The tumor static concentrations (TSC) are predicted for each individual compound. When the compounds are given as single-agents, the required concentrations were computed to be 506 μg · mL-1 and 56 ng · mL-1 for cetuximab and cisplatin, respectively. A TSC curve is constructed for different combinations of the two drugs, which separates concentration combinations into regions of tumor shrinkage and tumor growth. The more concave the TSC curve is, the lower is the total exposure to test compounds necessary to achieve tumor regression. The TSC curve for cetuximab and cisplatin showed weak concavity. TSC values and TSC curves were estimated that predict tumor regression for 95% of the population by taking between-subject variability into account. The TSC concept is further discussed for different concentration-effect relationships and for combinations of three or more compounds.
Collapse
Affiliation(s)
- Tim Cardilin
- Fraunhofer-Chalmers Centre, Chalmers Science Park, Gothenburg, Sweden. .,Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, Gothenburg, Sweden.
| | - Joachim Almquist
- Fraunhofer-Chalmers Centre, Chalmers Science Park, Gothenburg, Sweden.,Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
| | - Mats Jirstrand
- Fraunhofer-Chalmers Centre, Chalmers Science Park, Gothenburg, Sweden
| | - Alexandre Sostelly
- Global Early Development-Quantitative Pharmacology and Drug Disposition, Quantitative Pharmacology, Merck, Darmstadt, Germany.,Pharmaceutical Research and Early Development, Hoffmann-Le Roche, Basel, Switzerland
| | | | - Samer El Bawab
- Global Early Development-Quantitative Pharmacology and Drug Disposition, Quantitative Pharmacology, Merck, Darmstadt, Germany
| | - Johan Gabrielsson
- Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden
| |
Collapse
|
|
17
|
Cheng Y, Murakami H, Yang PC, He J, Nakagawa K, Kang JH, Kim JH, Wang X, Enatsu S, Puri T, Orlando M, Yang JCH. Randomized Phase II Trial of Gefitinib With and Without Pemetrexed as First-Line Therapy in Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancer With Activating Epidermal Growth Factor Receptor Mutations. J Clin Oncol 2016; 34:3258-3266. [DOI: 10.1200/jco.2016.66.9218] [Citation(s) in RCA: 132] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
Abstract
Purpose To determine whether the addition of pemetrexed to gefitinib (P+G) provides clinical benefit, compared with gefitinib monotherapy, in patients with advanced nonsquamous (NS) non–small-cell lung cancer (NSCLC) and activating epidermal growth factor receptor (EGFR) mutations. Patients and Methods Chemotherapy-naïve for advanced NSCLC patients from China, Japan, Korea, and Taiwan (35 sites) with advanced, EGFR-mutant, NS NSCLC were randomly assigned (2:1; computer-generated, interactive voice response) to open-label pemetrexed (500 mg/m2 on day 1 of every 21-day cycle) plus gefitinib (250 mg/d [n = 129]) or gefitinib alone (n = 66). The primary end point was progression-free-survival (PFS); secondary end points were time to progressive disease, overall survival, tumor response rates, duration of response, and safety. All end points were assessed in the intent-to-treat and safety population (P+G, n = 126; gefitinib alone, n = 65). Results PFS was significantly longer with P+G (median, 15.8 months; 95% CI, 12.6 to 18.3 months) than with gefitinib (median, 10.9 months; 95% CI, 9.7 to 13.8 months; adjusted hazard ratio [HR], 0.68; 95% CI, 0.48 to 0.96; one-sided P = .014; two-sided P = .029). Results of EGFR exon 19 deletion and EGFR exon 21 L858R point mutation subgroup analyses were consistent with the intent-to-treat result. P+G, compared with gefitinib alone, resulted in significantly longer time to progressive disease (median, 16.2 v 10.9 months, respectively; HR, 0.66; 95% CI, 0.47 to 0.93) and numerically longer duration of response (median, 15.4 v 11.3 months, respectively; HR, 0.74; 95% CI, 0.50 to 1.08). Tumor response rates did not differ. Overall survival data are immature. Drug-related grade 3 or 4 adverse events were more common with P+G, but toxicities were manageable. Conclusion P+G improved PFS compared with gefitinib alone in East Asian patients with advanced NS NSCLC and activating EGFR mutations. This combination may offer EGFR mutation–positive patients new treatment options and improved clinical outcomes compared with the current standard of care.
Collapse
Affiliation(s)
- Ying Cheng
- Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin
| | - Haruyasu Murakami
- Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin
| | - Pan-Chyr Yang
- Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin
| | - Jianxing He
- Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin
| | - Kazuhiko Nakagawa
- Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin
| | - Jin Hyoung Kang
- Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin
| | - Joo-Hang Kim
- Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin
| | - Xin Wang
- Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin
| | - Sotaro Enatsu
- Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin
| | - Tarun Puri
- Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin
| | - Mauro Orlando
- Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin
| | - James Chih-Hsin Yang
- Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin
| |
Collapse
|
|
18
|
Zwitter M, Rajer M, Stanic K, Vrankar M, Doma A, Cuderman A, Grmek M, Kern I, Kovac V. Intercalated chemotherapy and erlotinib for non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations. Cancer Biol Ther 2016; 17:833-9. [PMID: 27261103 PMCID: PMC5074447 DOI: 10.1080/15384047.2016.1195049] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Among attempts to delay development of resistance to tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC) with activating mutations of epidermal growth factor receptor (EGFR), intercalated therapy has not been properly evaluated. In a phase II trial, 38 patients with EGFR mutated NSCLC in advanced stage were treated with 4 to 6 3-weekly cycles of intercalated schedule with gemcitabine (1250 mg/m2, days 1 and 4), cisplatin (75 mg/m2, day 2) and erlotinib (150 mg, days 5 - 15), followed by continuous erlotinib as maintenance. In addition to standard radiologic evaluation according to RECIST, PET/CT was done prior to treatment and at 6 months, using PERCIST as a method for assessment of response. The primary endpoint was progression-free survival (PFS). In general, tolerance to treatment was good, even among 8 patients with performance status 2-3 and 13 patients with brain metastases; grade 4 toxicity included 2 cases of neutropenia and 4 thrombo-embolic events. Complete response (CR) or partial response (PR) were seen in 15 (39.5%) and 17 (44.7%) cases, respectively. All cases of CR were confirmed also by PET/CT. Median PFS was 23.4 months and median overall survival (OS) was 38.3 months. After a median follow-up of 35 months, 8 patients are still in CR and on maintenance erlotinib. In conclusion, intercalated treatment for treatment-naive patients with EGFR activating mutations leads to excellent response rate and prolonged PFS and survival. Comparison of the intercalated schedule to monotherapy with TKIs in a randomized trial is warranted.
Collapse
Affiliation(s)
- Matjaz Zwitter
- a Institute of Oncology , Ljubljana , Slovenia.,b Faculty of Medicine , University of Maribor , Slovenia
| | | | | | | | - Andrej Doma
- a Institute of Oncology , Ljubljana , Slovenia
| | - Anka Cuderman
- c Institute for Nuclear Medicine, University Clinical Center Ljubljana , Slovenia
| | - Marko Grmek
- c Institute for Nuclear Medicine, University Clinical Center Ljubljana , Slovenia
| | - Izidor Kern
- d University Hospital for Pulmonary Diseases Golnik , Slovenia
| | | |
Collapse
|
|
19
|
Lara PN, Moon J, Hesketh PJ, Redman MW, Williamson SK, Akerley WL, Hirsch FR, Mack PC, Gandara DR. SWOG S0709: Randomized Phase II Trial of Erlotinib versus Erlotinib Plus Carboplatin/Paclitaxel in Patients with Advanced Non-Small Cell Lung Cancer and Impaired Performance Status as Selected by a Serum Proteomics Assay. J Thorac Oncol 2016; 11:420-5. [PMID: 26725184 PMCID: PMC4775366 DOI: 10.1016/j.jtho.2015.11.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Revised: 11/02/2015] [Accepted: 11/04/2015] [Indexed: 01/12/2023]
Abstract
INTRODUCTION Patients with advanced-stage non-small cell lung cancer (NSCLC) and borderline performance status (performance status 2 [PS2]) are often excluded from clinical trials and platinum-based therapy. In light of the potential role for serum proteomics in predicting the benefit of erlotinib beyond that of epidermal growth factor receptor gene (EGFR) mutational status, we conducted a trial in which the Veristrat proteomics assay was used for data enrichment when selecting a cohort of patients with NSCLC and PS2 to receive erlotinib with and without chemotherapy. METHODS Patients with metastatic NSCLC, PS2, acceptable end-organ function, and Veristrat-good status were randomly assigned to receive either 150 mg of erlotinib orally daily (arm 1) or 150 mg of erlotinib orally daily on days 2 through16 plus four cycles of carboplatin (area under the curve = 5 on day 1) and paclitaxel (200 mg/m(2) intravenously on day 1) followed by 150 mg of erlotinib orally (arm 2). The arm 2 agents were pharmacodynamically separated to mitigate potential antagonism. The arm with superior observed median progression-free survival (PFS) would be selected for further evaluation, but only if PFS lasted for at least 3 months. RESULTS The trial terminated before the planned accrual of 98 patients for regulatory reasons. A total of 156 patients were screened. Of the 83 (59%) who were classified as Veristrat good, 59 met the trial eligibility criteria and were randomly assigned to one of two arms (33 patients in arm 1 and 26 in arm 2). The patients in arm 2 patients had a higher response rate (23% versus 6%, p = 0.06), disease control rate (77% versus 41%, p = 0.0046), median PFS (4.6 versus 1.6 months, p = 0.06), and median overall survival (11 versus 6 months, p = 0.27). Treatment-related grade 4 adverse events were seen in two patients in arm 1 (thrombosis and hypomagnesemia) and in five patients in arm 2 (neutropenia in five, febrile neutropenia in one, and leukopenia in one). CONCLUSIONS In a proteomics-enriched cohort of patients with NSCLC and PS2, pharmacodynamically separated erlotinib plus chemotherapy had better efficacy than did erlotinib alone and surpassed the protocol-specified benchmark of PFS of at least 3 months required for further study.
Collapse
Affiliation(s)
- Primo N Lara
- University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA.
| | - James Moon
- SWOG Statistical Center, Seattle, WA, USA
| | | | | | | | | | | | - Philip C Mack
- University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA
| | - David R Gandara
- University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA
| |
Collapse
|
|
20
|
Huang JQ, Liang HL, Zhang XC, Xie Z, Jin TE. Synergistic antitumor activity of pro-apoptotic agent PAC-1 with cisplatinum by the activation of CASP3 in pulmonary adenocarcinoma cell line H1299. Asia Pac J Clin Oncol 2015; 12:41-51. [PMID: 26620316 DOI: 10.1111/ajco.12419] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Jian-qing Huang
- Affiliated Cancer Hospital; Guangzhou Medical University; Guangzhou China
| | - Hong-ling Liang
- Affiliated Cancer Hospital; Guangzhou Medical University; Guangzhou China
| | - Xu-chao Zhang
- Guangdong Lung Cancer Institute; Guangdong General Hospital; Guangzhou China
| | - Zhi Xie
- Guangdong Lung Cancer Institute; Guangdong General Hospital; Guangzhou China
| | - Tian-en Jin
- Affiliated Cancer Hospital; Guangzhou Medical University; Guangzhou China
| |
Collapse
|
|
21
|
Liu JT, Li WC, Gao S, Wang F, Li XQ, Yu HQ, Fan LL, Wei W, Wang H, Sun GP. Autophagy Inhibition Overcomes the Antagonistic Effect Between Gefitinib and Cisplatin in Epidermal Growth Factor Receptor Mutant Non–Small-Cell Lung Cancer Cells. Clin Lung Cancer 2015; 16:e55-66. [DOI: 10.1016/j.cllc.2015.03.006] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Revised: 03/23/2015] [Accepted: 03/27/2015] [Indexed: 10/23/2022]
|
|
22
|
Yan H, Li H, Li Q, Zhao P, Wang W, Cao B. The Efficacy of Synchronous Combination of Chemotherapy and EGFR TKIs for the First-Line Treatment of NSCLC: A Systematic Analysis. PLoS One 2015; 10:e0135829. [PMID: 26285137 PMCID: PMC4540576 DOI: 10.1371/journal.pone.0135829] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 07/27/2015] [Indexed: 11/19/2022] Open
Abstract
Background The combination of chemotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) currently has become the hotspot issue in the treatment of non-small lung cancer (NSCLC). This systematic review was conducted to compare the efficacy and safety of the synchronous combination of these two treatments with EGFR TKIs or chemotherapy alone in advanced NSCLC. Methods EMBASE, PubMed, the Central Registry of Controlled Trials in the Cochrane Library (CENTRAL), Chinese biomedical literature database (CNKI) and meeting summaries were searched. The Phase II/III randomized controlled trials were selected by which patients with advanced NSCLC were randomized to receive a combination of EGFR TKIs and chemotherapy by synchronous mode vs. EGFR TKIs or chemotherapy alone. Results A total of six randomized controlled trials (RCTs) including 4675 patients were enrolled in the systematic review. The meta-analysis demonstrated that the synchronous combination group of chemotherapy and EGFR TKIs did not reach satisfactory results; there was no significant difference in overall survival (OS), time to progression (TTP) and objective response rate (ORR), compared with monotherapy (OS: HR = 1.05, 95%CI = 0.98–1.12; TTP: HR = 0.94, 95%CI = 0.89–1.00; ORR: RR = 1.07, 95%CI = 0.98–1.17), and no significant difference in OS and progression-free survival (PFS), compared with EGFR TKIs alone (OS: HR = 1.10, 95% CI = 0.83–1.46; PFS: HR = 0.86, 95% CI = 0.67–1.10). The patients who received synchronous combined therapy presented with increased incidences of grade 3/4 anemia (RR = 1.40, 95% CI = 1.10–1.79) and rash (RR = 7.43, 95% CI = 4.56–12.09), compared with chemotherapy, grade 3/4 anemia (RR = 6.71, 95% CI = 1.25–35.93) and fatigue (RR = 9.60, 95% CI = 2.28–40.86) compared with EGFR TKI monotherapy. Conclusions The synchronous combination of chemotherapy and TKIs is not superior to chemotherapy or EGFR TKIs alone for the first-line treatment of NSCLC.
Collapse
Affiliation(s)
- Han Yan
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Huihui Li
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Qin Li
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Pengfei Zhao
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Wei Wang
- Medical Healthcare Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Bangwei Cao
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- * E-mail:
| |
Collapse
|
|
23
|
Yates JWT, Dudley P, Cheng J, D'Cruz C, Davies BR. Validation of a predictive modeling approach to demonstrate the relative efficacy of three different schedules of the AKT inhibitor AZD5363. Cancer Chemother Pharmacol 2015; 76:343-56. [PMID: 26092323 DOI: 10.1007/s00280-015-2795-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 05/28/2015] [Indexed: 11/28/2022]
Abstract
PURPOSE Intermittent dosing of inhibitors of the PI3K/AKT/mTOR network offers the potential to maximize the therapeutic margin. Here, we validate a predictive modeling approach to establish the relative efficacy of continuous and two intermittent dosing schedules of the AKT inhibitor AZD5363. METHODS A mathematical model of pharmacokinetics, pharmacodynamics and anti-tumor effect was constructed based upon experimental data from dosing regimens that give constant and transient inhibition of the AKT pathway. RESULTS Continuous and intermittent dosing of AZD5363 inhibited growth of BT474c xenografts and caused dose- and time-dependent inhibition of AKT substrate phosphorylation. Both dosing schedules inhibited proliferation, but a higher intermittent dose also induced apoptosis. The mathematical model described this pharmacodynamic and efficacy data well, for both monotherapy and combination dosing with docetaxel, and predicted that equivalent efficacy could be achieved at 1.3- and 1.7× continuous dose when AZD5363 was dosed intermittently for 4 and 2 days per week, respectively. These predictions were confirmed in two independent xenograft models. Moreover, the model also correctly predicted the relative efficacy of three different sequences of intermittent dosing of AZD5363 with docetaxel. CONCLUSIONS Equivalent anti-tumor activity to continuous dosing can be achieved at modestly increased intermittent doses of AZD5363. These intermittent dosing regimens may potentially overcome tolerability issues seen with continuous dosing and enable greater flexibility of dosing schedule in combination with other agents, including chemotherapy.
Collapse
Affiliation(s)
- James W T Yates
- Oncology iMED, AstraZeneca, Alderley Park, Mereside, Macclesfield, Cheshire, SK10 4TG, UK,
| | | | | | | | | |
Collapse
|
|
24
|
Landi L, Cappuzzo F. Experience with erlotinib in the treatment of non-small cell lung cancer. Ther Adv Respir Dis 2015; 9:146-63. [PMID: 26063687 DOI: 10.1177/1753465815588053] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths. In the last decade, the epidermal growth factor receptor (EGFR) signalling pathway has emerged as one of the most important molecular aberrations, representing an attractive therapeutic target in NSCLC. Drugs interfering with the tyrosine kinase domain of the EGFR (EGFR TKIs), such as erlotinib and gefitinib, have demonstrated efficacy in patients with advanced NSCLC irrespective of therapy line and particularly in patients harbouring activating mutations in the EGFR gene (EGFR(mut+)). Results of large phase III randomized trials clearly established that EGFR TKIs are superior to chemotherapy as frontline treatment in patients with EGFR(mut+), whereas in the EGFR wild-type (EGFR(WT)) or EGFR unknown population, platinum-based chemotherapy remains the standard of care, with no consistent benefit produced by the addition of EGFR TKI. In pretreated NSCLC, EGFR TKIs are considered more effective than standard monotherapy with cytotoxics in the presence of classical EGFR mutations, whereas in the EGFR(WT) population, a similar efficacy to docetaxel or pemetrexed in terms of survival has been demonstrated. Unfortunately, patients who initially responded to EGFR TKIs invariably develop acquired resistance. For such patients there is an urgent need for more effective strategies able to delay or possibly overcome resistance. In the present review we analysed the available data on erlotinib in the treatment of advanced NSCLC.
Collapse
Affiliation(s)
- Lorenza Landi
- Medical Oncologist at Istituto Toscano Tumori, Medical Oncology Department, Ospedale Civile Livorno, Livorno, Italy
| | - Federico Cappuzzo
- Director of Medical Oncology Department, Istituto Toscano Tumori, Ospedale Civile, Viale Alfieri 36, 57100 Livorno, Italy
| |
Collapse
|
|
25
|
Juan Ó, Aparisi F, Sánchez-Hernández A, Muñoz-Langa J, Esquerdo G, García-Sánchez J, López A, Garde J, Giner V. Intercalated Dosing Schedule of Erlotinib and Docetaxel as a Therapeutic Strategy to Avoid Antagonism and Optimize Its Benefits in Advanced Non–Small-Cell Lung Cancer. A Randomized Phase II Clinical Trial. Clin Lung Cancer 2015; 16:193-9. [DOI: 10.1016/j.cllc.2014.11.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Revised: 11/12/2014] [Accepted: 11/18/2014] [Indexed: 10/24/2022]
|
|
26
|
Yu S, Zhang B, Xiang C, Shu Y, Wu H, Huang X, Yu Q, Yin Y, Guo R. Prospective Assessment of Pemetrexed or Pemetrexed Plus Platinum in Combination With Gefitinib or Erlotinib in Patients With Acquired Resistance to Gefitinib or Erlotinib: A Phase II Exploratory and Preliminary Study. Clin Lung Cancer 2015; 16:121-7. [DOI: 10.1016/j.cllc.2014.09.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Revised: 09/23/2014] [Accepted: 09/24/2014] [Indexed: 01/05/2023]
|
|
27
|
Intercalated chemotherapy and erlotinib for advanced NSCLC: high proportion of complete remissions and prolonged progression-free survival among patients with EGFR activating mutations. Radiol Oncol 2014; 48:361-8. [PMID: 25435849 PMCID: PMC4230556 DOI: 10.2478/raon-2014-0038] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Accepted: 09/08/2014] [Indexed: 12/01/2022] Open
Abstract
Background Pharmaco-dynamic separation of cytotoxic and targeted drugs might avoid their mutual antagonistic effect in the treatment of advanced non-small cell lung cancer (NSCLC). Patients and methods. Eligible patients were treatment-naive with stage IIIB or IV NSCLC. In addition, inclusion was limited to never-smokers or light smokers or, after 2010, to patients with activating epidermal growth-factor receptor (EGFR) mutations. Treatment started with 3-weekly cycles of gemcitabine and cisplatin on days 1, 2 and 4 and erlotinib on days 5 to 15. After 4 to 6 cycles, patients continued with erlotinib maintenance. Results Fifty-three patients were recruited into the trial: 24 prior to 2010 (of whom 9 were later found to be positive for EGFR mutations), and 29 EGFR mutation-positive patients recruited later. Unfavourable prognostic factors included stage IV disease (51 patients - 96%), performance status 2–3 (11 patients - 21%) and brain metastases (15 patients -28%). Grade 4 toxicity included 2 cases of neutropenia and 4 thrombo-embolic events. The 15 EGFR negative patients had 33% objective response rate, median progression-free survival (PFS) 6.0 months and median survival 7.6 months. Among 38 EGFR positive patients, complete response (CR) or partial response (PR) were seen in 16 (42.1%) and 17 (44.7%) cases, respectively. PET-CT scanning was performed in 30 patients and confirmed CR and PR in 16 (53.3%) and 9 (30.0%) cases, respectively. Median PFS for EGFR mutated patients was 21.2 months and median survival was 32.5 months. Conclusions While patients with EGFR negative tumors do not benefit from addition of erlotinib, the intercalated schedule appears most promising for those with EGFR activating mutations.
Collapse
|
|
28
|
Wang MC, Liang X, Liu ZY, Cui J, Liu Y, Jing L, Jiang LL, Ma JQ, Han LL, Guo QQ, Yang CC, Wang J, Wu T, Nan KJ, Yao Y. In vitro synergistic antitumor efficacy of sequentially combined chemotherapy/icotinib in non‑small cell lung cancer cell lines. Oncol Rep 2014; 33:239-49. [PMID: 25370413 DOI: 10.3892/or.2014.3583] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Accepted: 08/25/2014] [Indexed: 01/17/2023] Open
Abstract
The concurrent administration of chemotherapy and epidermal growth factor receptor‑tyrosine kinase inhibitors (EGFR‑TKIs) has previously produced a negative interaction and failed to confer a survival benefit to non‑small cell lung cancer (NSCLC) patients compared with first‑line cytotoxic chemotherapy. The present study aimed to investigate the optimal schedule of the combined treatment of cisplatin/paclitaxel and icotinib in NSCLC cell lines and clarify the underlying mechanisms. HCC827, H1975, H1299 and A549 human NSCLC cell lines with wild‑type and mutant EGFR genes were used as in vitro models to define the differential effects of various schedules of cisplatin/paclitaxel with icotinib treatments on cell growth, proliferation, cell cycle distribution, apoptosis, and EGFR signaling pathway. Sequence‑dependent antiproliferative effects differed among the four NSCLC cell lines, and were not associated with EGFR mutation, constitutive expression levels of EGFR or downstream signaling molecules. The antiproliferative effect of cisplatin plus paclitaxel followed by icotinib was superior to that of cisplatin or paclitaxel followed by icotinib in the HCC827, H1975, H1299 and A549 cell lines, and induced more cell apoptosis and G0/G1 phase arrest. Cisplatin and paclitaxel significantly increased the expression of EGFR phosphorylation in the HCC827 cell line. However, only paclitaxel increased the expression of EGFR phosphorylation in the H1975 cell line. Cisplatin/paclitaxel followed by icotinib influenced the expression of p‑EGFR and p‑AKT, although the expression of p‑ERK1/2 remained unchanged. The results suggest that the optimal schedule of the combined treatment of cisplatin/paclitaxel and icotinib differed among the NSCLC cell lines. The results also provide molecular evidence to support clinical treatment strategies for NSCLC patients.
Collapse
Affiliation(s)
- Min-Cong Wang
- Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Xuan Liang
- Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Zhi-Yan Liu
- Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Jie Cui
- Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Ying Liu
- Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Li Jing
- Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Li-Li Jiang
- Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Jie-Qun Ma
- Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Li-Li Han
- Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Qian-Qian Guo
- Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Cheng-Cheng Yang
- Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Jing Wang
- Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Tao Wu
- Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Ke-Jun Nan
- Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Yu Yao
- Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| |
Collapse
|
|
29
|
Selen A, Dickinson PA, Müllertz A, Crison JR, Mistry HB, Cruañes MT, Martinez MN, Lennernäs H, Wigal TL, Swinney DC, Polli JE, Serajuddin AT, Cook JA, Dressman JB. The Biopharmaceutics Risk Assessment Roadmap for Optimizing Clinical Drug Product Performance. J Pharm Sci 2014; 103:3377-3397. [DOI: 10.1002/jps.24162] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Revised: 08/20/2014] [Accepted: 08/22/2014] [Indexed: 02/06/2023]
|
|
30
|
Pharmacodynamic separation of gemcitabine and erlotinib in locally advanced or metastatic pancreatic cancer: therapeutic and biomarker results. Int J Clin Oncol 2014; 20:518-24. [PMID: 25091263 DOI: 10.1007/s10147-014-0730-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Accepted: 06/27/2014] [Indexed: 12/18/2022]
Abstract
PURPOSE Erlotinib marginally improves survival when administered continuously with gemcitabine to patients with advanced pancreatic cancer; however, preclinical data suggest that there is antagonism between chemotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors when these are delivered concurrently. We tested a pharmacodynamic separation approach for erlotinib plus gemcitabine and interrogated EGFR signaling intermediates as potential surrogates for the efficacy of this strategy. METHODS Patients with measurable, previously untreated locally advanced unresectable or metastatic pancreatic cancer were treated with gemcitabine 1000 mg/m(2) as an intravenous infusion over 30-min on days 1, 8, 15 and erlotinib 150 mg/day on days 2-5, 9-12, 16-26 of each 28-day cycle. The primary endpoint was progression-free survival (PFS); secondary endpoints included RECIST objective response rate (ORR) and safety. The study was terminated after thirty patients due to funding considerations. RESULTS The median PFS was 2.07 months (95% CI; 1.87-5.50 months) and the ORR was 11%. No unexpected safety signals were seen: the most common grade 3 or higher adverse events were neutropenia (23%), lymphopenia (23%), and fatigue (13%). Patients with mutant plasma Kirsten rat sarcoma virus (KRAS) had significantly lower median PFS (1.8 vs. 4.6 months, p = 0.014) and overall survival (3.0 vs. 10.5 months, p = 0.003) than those without detected plasma KRAS mutations. CONCLUSIONS Although pharmacodynamically separated erlotinib and gemcitabine were feasible and tolerable in patients with advanced pancreatic cancer, no signal for increased efficacy was seen in this molecularly unselected cohort. Detection of a KRAS mutation in circulating cell-free DNA was a strong predictor of survival.
Collapse
|
|
31
|
Auliac JB, Chouaid C, Greillier L, Monnet I, Le Caer H, Falchero L, Corre R, Descourt R, Bota S, Berard H, Schott R, Bizieux A, Fournel P, Labrunie A, Marin B, Vergnenegre A. Randomized open-label non-comparative multicenter phase II trial of sequential erlotinib and docetaxel versus docetaxel alone in patients with non-small-cell lung cancer after failure of first-line chemotherapy: GFPC 10.02 study. Lung Cancer 2014; 85:415-9. [PMID: 25082565 DOI: 10.1016/j.lungcan.2014.07.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Revised: 07/07/2014] [Accepted: 07/10/2014] [Indexed: 11/18/2022]
Abstract
BACKGROUND Concomitant administration of erlotinib with standard chemotherapy does not appear to improve survival among patients with non-small-cell lung cancer (NSCLC), but preliminary studies suggest that sequential administration might be effective. OBJECTIVE To assess the efficacy and tolerability of second-line sequential administration of erlotinib and docetaxel in advanced NSCLC. METHODS In an open-label phase II trial, patients with advanced NSCLC, EGFR wild-type or unknown, PS 0-2, in whom initial cisplatin-based chemotherapy had failed were randomized to sequential erlotinib 150 mg/d (day 2-16)+docetaxel (75 mg/m(2) d1) (arm ED) or docetaxel (75 mg/m(2) d1) alone (arm D) (21-day cycle). The primary endpoint was the progression-free survival rate at 15 weeks (PFS 15). Secondary endpoints included PFS, overall survival (OS), the overall response rate (ORR) and tolerability. Based on a Simon optimal two-stage design, the ED strategy was rejected if the primary endpoint was below 33/66 patients at the end of the two Simon stages. RESULTS 147 patients were randomized (median age: 60±8 years, PS 0/1/2: 44/83/20 patients; males: 78%). The ED strategy was rejected, with only 18 of 73 patients achieving PFS15 in arm ED at the end of stage 2 and 17 of 74 patients in arm D. In arms ED and D, respectively, median PFS was 2.2 and 2.5 months and median OS was 6.5 and 8.3 months. CONCLUSION Sequential erlotinib and docetaxel was not more effective than docetaxel alone as second-line treatment for advanced NSCLC with wild-type or unknown EGFR status.
Collapse
Affiliation(s)
- J B Auliac
- Department of Pneumology, Quesnay Hospital, Mantes La Jolie, France.
| | - C Chouaid
- Department of Pneumology, Saint Antoine Hospital, Paris, France
| | | | - I Monnet
- Service de pneumologie, CHI, Creteil, France
| | - H Le Caer
- CH de Draguignan, Draguignan, France
| | - L Falchero
- CH Villefranche Sur Saone, Villefranche-sur-Saone, France
| | - R Corre
- Pneumology, CHU Pontchaillou, Rennes, France
| | | | - S Bota
- Hôpital Charles Nicolle, Rouen, France
| | | | - R Schott
- Centre Paul Strauss, Strasbourg, France
| | - A Bizieux
- CHD La Roche Sur Yon, La Roche Sur Yon, France
| | - P Fournel
- Institut de Cancérologie de la Loire, Saint Priest En Jarez, France
| | | | - B Marin
- CEBIMER, CHU limoges, Limoges, France
| | | |
Collapse
|
|
32
|
Jiang Y, Yuan Q, Fang Q. Schedule-dependent synergistic interaction between docetaxel and gefitinib in NSCLC cell lines regardless of the mutation status of EGFR and KRAS and its molecular mechanisms. J Cancer Res Clin Oncol 2014; 140:1087-95. [PMID: 24728492 DOI: 10.1007/s00432-014-1671-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Accepted: 03/29/2014] [Indexed: 10/25/2022]
Abstract
BACKGROUND Tyrosine-kinase inhibitors (TKIs) and chemotherapy had different pharmacological mechanisms and therefore combined administration of TKIs and chemotherapy agents may have synergy. Our research aimed at exploring the cytotoxic interactions between gefitinib and docetaxel with different concentrations for non-small-cell lung cancer cell lines, and furthermore, the mechanisms underlying the cytotoxic synergism. METHODS NCI-H1650 [epidermal growth factor receptor (EGFR) mutation and KRAS wild-type], NCI-H292 (EGFR wild-type and KRAS wild-type) and A549 (EGFR wild-type and KRAS mutation) cell lines were treated with docetaxel and/or gefitinib. Cytotoxic interactions, cell cycle distribution and cell signal pathway were analyzed, respectively. RESULTS Cytotoxic interactions between docetaxel and gefitinib were dose-dependent and sequence-dependent in all these three cell lines. Docetaxel followed by gefitinib treatment was optimum regimen regardless of the mutation status of EGFR and KRAS. KRAS mutation and EGFR wild-type predicted insensitive to gefitinib and docetaxel combined treatment as well as gefitinib alone. G1 arrest was inconsistently associated with combination index (CI). However, apoptosis induction was schedule-dependent and can explain the synergism completely. Mitogen-activated protein kinase (MAPK) phosphorylation ratio was also schedule-dependent and positively correlated with CI. CONCLUSION Cytotoxic interactions between docetaxel and gefitinib were sequence-dependent regardless of the mutation status of EGFR and KRAS. Cell characteristic, apoptosis induction and MAPK phosphorylation but not cell cycle change may explain the molecular mechanisms of synergism.
Collapse
Affiliation(s)
- Yanwen Jiang
- Department of Respiratory Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People's Republic of China,
| | | | | |
Collapse
|
|
33
|
WU MIN, YUAN YUAN, PAN YUEYIN, ZHANG YING. Combined gefitinib and pemetrexed overcome the acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Mol Med Rep 2014; 10:931-8. [DOI: 10.3892/mmr.2014.2243] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2013] [Accepted: 04/02/2014] [Indexed: 01/16/2023] Open
|
|
34
|
Anticancer activity of the Aurora A kinase inhibitor MK-5108 in non-small-cell lung cancer (NSCLC) in vitro as monotherapy and in combination with chemotherapies. J Cancer Res Clin Oncol 2014; 140:1137-49. [PMID: 24756365 DOI: 10.1007/s00432-014-1675-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Accepted: 04/08/2014] [Indexed: 10/25/2022]
Abstract
PURPOSE Aurora kinases are key regulators of mitotic events. Dysfunction of these kinases can cause polyploidy and chromosomal instability, a contributor to tumorigenesis. MK-5108 is a potent inhibitor of Aurora A kinase that has shown preclinical potent activity in malignancies of breast, cervical, colon, ovarian, and pancreatic origin. We sought to assess the preclinical efficacy of MK-5108 in a panel of non-small-cell lung cancer cell lines as a single agent and in combination with cisplatin and docetaxel. METHODS Eleven lung cancer cell lines were studied. Growth inhibition by MK-5108 was assessed with short- and long-term MTT assays. Cell cycling was measured by flow cytometry. Immunoblotting was used to determine targeted activity of MK-5108 on Aurora A and downstream effects (TACC3 and Plk1). Efficacy of combination studies performed with cisplatin and docetaxel was evaluated by median effect analysis. RESULTS All cell lines demonstrated sustained growth inhibition following MK-5108 at varying nanomolar concentrations. MK-5108 induced G2/M accumulation, polyploidy, and apoptosis (increased sub-G1/PARP cleavage). Levels of Aurora A, TACC3, and Plk1 diminished. Concurrent treatment of MK-5108 with cisplatin or docetaxel synergistically inhibited cell growth with the docetaxel combination performing better. When administered sequentially, treatment with docetaxel first followed by MK-5108 exhibited greater growth inhibition than the inverse; yet concurrent treatment remained superior. CONCLUSIONS MK-5108 has potent anti-proliferative activity in lung cancer cell lines alone and in combination with chemotherapies. Determining how best to integrate Aurora inhibitors into current lung cancer treatment regimens would be beneficial.
Collapse
|
|
35
|
Yu H, Zhang J, Wu X, Luo Z, Wang H, Sun S, Peng W, Qiao J, Feng Y, Wang J, Chang J. A phase II randomized trial evaluating gefitinib intercalated with pemetrexed/platinum chemotherapy or pemetrexed/platinum chemotherapy alone in unselected patients with advanced non-squamous non-small cell lung cancer. Cancer Biol Ther 2014; 15:832-9. [PMID: 24755888 DOI: 10.4161/cbt.28874] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Current pemetrexed/platinum chemotherapy does not produce a satisfactory therapeutic response in advanced lung cancer patients. The aim of this study was to determine whether the administration of gefitinib, a tyrosine kinase inhibitor (TKI), intercalated with pemetrexed/platinum could improve the efficacy in chemotherapy-naïve patients with advanced non-squamous NSCLC without subsequent gefitinib maintenance therapy. Treatment-naïve patients with stage IIIB or IV NSCLC were randomly assigned to receive pemetrexed (500 mg/m (2) d1) and either cisplatin (75 mg/m (2) d1) or carboplatin (AUC = 5 d1) plus gefitinib (250 mg/d on days 3 to 16 of a 3-week cycle) (PC-G) or pemetrexed-platinum (PC) alone. Randomization was stratified according to the tobacco smoking status and EGFR mutational status of the patients. The primary endpoint was the non-progression rate (NPR) at 12 weeks. Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and biosafety. The NPR at 12 weeks was 84.5% for the PC-G treatment arm and 83.1% for the PC treatment arm (P = 0.87). Median PFS was 7.9 months for the PC-G arm and 7.0 months for the PC arm (P = 0.57). The ORR was 50.0% for the PC-G arm and 47.4% for the PC arm (P = 0.78). Median survival was 25.4 mo for the PC-G arm and 20.8 mo for the PC arm (P = 0.54). The incidence of adverse events was similar between the two treatment arms, except for a higher incidence of skin rash with PC-G. Predefined subgroup analyses demonstrated that PC-G significantly increased the PFS compared with the PC regimen in patients with EGFR mutations (P = 0.017). Although gefitinib intercalated with pemetrexed/platinum chemotherapy did not improve the NPR at 12 weeks compared with chemotherapy, an improvement in the PFS for the intercalated treatment arm was seen in the subgroup of patients with EGFR mutations.
Collapse
Affiliation(s)
- Hui Yu
- Department of Medical Oncology; Fudan University Shanghai Cancer Center; Shanghai, PR China; Department of Oncology; Shanghai Medical College; Fudan University; Shanghai, PR China
| | - Jian Zhang
- Department of Medical Oncology; Fudan University Shanghai Cancer Center; Shanghai, PR China; Department of Oncology; Shanghai Medical College; Fudan University; Shanghai, PR China
| | - Xianghua Wu
- Department of Medical Oncology; Fudan University Shanghai Cancer Center; Shanghai, PR China; Department of Oncology; Shanghai Medical College; Fudan University; Shanghai, PR China
| | - Zhiguo Luo
- Department of Medical Oncology; Fudan University Shanghai Cancer Center; Shanghai, PR China; Department of Oncology; Shanghai Medical College; Fudan University; Shanghai, PR China
| | - Huijie Wang
- Department of Medical Oncology; Fudan University Shanghai Cancer Center; Shanghai, PR China; Department of Oncology; Shanghai Medical College; Fudan University; Shanghai, PR China
| | - Si Sun
- Department of Medical Oncology; Fudan University Shanghai Cancer Center; Shanghai, PR China; Department of Oncology; Shanghai Medical College; Fudan University; Shanghai, PR China
| | - Wei Peng
- Department of Medical Oncology; Fudan University Shanghai Cancer Center; Shanghai, PR China; Department of Oncology; Shanghai Medical College; Fudan University; Shanghai, PR China
| | - Jie Qiao
- Department of Medical Oncology; Fudan University Shanghai Cancer Center; Shanghai, PR China; Department of Oncology; Shanghai Medical College; Fudan University; Shanghai, PR China
| | - Yu Feng
- Department of Medical Oncology; Fudan University Shanghai Cancer Center; Shanghai, PR China; Department of Oncology; Shanghai Medical College; Fudan University; Shanghai, PR China
| | - Jialei Wang
- Department of Medical Oncology; Fudan University Shanghai Cancer Center; Shanghai, PR China; Department of Oncology; Shanghai Medical College; Fudan University; Shanghai, PR China
| | - Jianhua Chang
- Department of Medical Oncology; Fudan University Shanghai Cancer Center; Shanghai, PR China; Department of Oncology; Shanghai Medical College; Fudan University; Shanghai, PR China
| |
Collapse
|
|
36
|
WU MIN, YUAN YUAN, PAN YUEYIN, ZHANG YING. Antitumor activity of combination treatment with gefitinib and docetaxel in EGFR-TKI-sensitive, primary resistant and acquired resistant human non-small cell lung cancer cells. Mol Med Rep 2014; 9:2417-22. [DOI: 10.3892/mmr.2014.2082] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2013] [Accepted: 02/24/2014] [Indexed: 11/05/2022] Open
|
|
37
|
Manegold C, Schmid-Bindert G, Pilz LR. Pemetrexed for the treatment of non-small-cell lung cancer. Expert Rev Anticancer Ther 2014; 9:1195-209. [DOI: 10.1586/era.09.97] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
|
|
38
|
Sanborn RE, Davies AM. Erlotinib: applications in therapy and current status of research. Expert Rev Clin Pharmacol 2014; 2:15-36. [DOI: 10.1586/17512433.2.1.15] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
|
|
39
|
OuYang PY, Su Z, Mao YP, Deng W, Xie FY. Combination of EGFR-TKIs and chemotherapy as first-line therapy for advanced NSCLC: a meta-analysis. PLoS One 2013; 8:e79000. [PMID: 24236082 PMCID: PMC3827342 DOI: 10.1371/journal.pone.0079000] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Accepted: 09/21/2013] [Indexed: 11/18/2022] Open
Abstract
The impact of combining epidermal growth factor receptor tyrosine kinase inhibitors (EGFR–TKIs) and chemotherapy as first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) remains controversial. Therefore, randomized trials that compared this combined regimen with chemotherapy or EGFR–TKIs monotherapy were included for this meta-analysis. We used published hazard ratios (HRs), if available, or derived treatment estimates from other survival data. Pooled estimates of treatment efficacy of the combined regimen in the entire unselected population and selected patients by EGFR-mutation status and smoking history were calculated. Eight trials eventually entered into this meta-analysis, including 4585 patients. Overall, the combined regimen significantly delayed disease progression (HR = 0.81, 95% CI 0.69–0.95, P = 0.01); subgroup analysis showed significantly higher progression free survival advantages in Asian patients (P<0.001), with sequential combination of TKIs and chemotherapy (P = 0.02). In selected patients by EGFR-mutation, both mutation positive (HR = 0.48, 95% CI 0.28–0.83, P = 0.009) and negative (HR = 0.84, 95% CI 0.72–0.98, P = 0.02) patients gained progression free survival benefit from the combined regimen, albeit the magnitude of benefit was marginally larger in mutation positive patients (P = 0.05). In selected patients by smoking history, never/light smokers achieved a great progression free survival benefit from the combined regimen (HR = 0.51, 95% CI 0.35–0.74, P = 0.0004). Unfortunately, the combined regimen had no significant impact on overall survival, irrespective of ethnicity, dose schedules or EGFR-mutation status. Severe anorexia (RR = 2.01, 95% CI 1.11–3.63; P = 0.02) and diarrhea (RR = 2.70, 95% CI 1.94–3.76; P<0.001) were more frequent in the combined regimen arm. This strategy of combining EGFR–TKIs and chemotherapy deserved to be considered in the future, although it is not approved for advanced NSCLC at the moment.
Collapse
Affiliation(s)
- Pu-Yun OuYang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhen Su
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yan-Ping Mao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Wuguo Deng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- * E-mail: (FYX); (WGD)
| | - Fang-Yun Xie
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
- * E-mail: (FYX); (WGD)
| |
Collapse
|
|
40
|
Combined epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor and chemotherapy in non-small-cell lung cancer: Chemo-refractoriness of cells harboring sensitizing-EGFR mutations in the presence of gefitinib. Lung Cancer 2013; 82:305-12. [DOI: 10.1016/j.lungcan.2013.08.028] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2013] [Revised: 08/20/2013] [Accepted: 08/31/2013] [Indexed: 11/23/2022]
|
|
41
|
D'Arcangelo M, Cappuzzo F. Erlotinib in the first-line treatment of non-small-cell lung cancer. Expert Rev Anticancer Ther 2013; 13:523-33. [PMID: 23617344 DOI: 10.1586/era.13.23] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related deaths. In the last decade the EGF receptor (EGFR) signaling pathway has emerged as one of the most important molecular aberrations in NSCLC. Drugs interfering with the tyrosine kinase domain of the EGFR (EGFR-TKI), such as erlotinib or gefitinib, demonstrated efficacy in patients with advanced NSCLC irrespective of therapy line and particularly in patients harboring activating mutations of the EGFR gene. Results of large Phase III randomized trials clearly demonstrated that an EGFR-TKI is the best front-line option for patients with classical EGFR mutations, while in the EGFR wild-type or EGFR unknown population platinum-based chemotherapy remains the gold standard. In pretreated patients, EGFR-TKIs are considered more effective than standard chemotherapy in the EGFR-mutated population, with no difference in EGFR wild-type NSCLC. Although EGFR-TKIs are certainly particularly effective in patients with EGFR mutations, at present no biomarker, including KRAS mutations, can be recommended in clinical practice for precluding the therapy to any pretreated patient. In this article, the authors analyzed data of erlotinib in NSCLC, focusing on its role in front-line therapy.
Collapse
Affiliation(s)
- Manolo D'Arcangelo
- Istituto Toscano Tumori, Ospedale Civile, Viale Alfieri 36, 57100, Livorno, Italy
| | | |
Collapse
|
|
42
|
Pandey A, Kulkarni A, Roy B, Goldman A, Sarangi S, Sengupta P, Phipps C, Kopparam J, Oh M, Basu S, Kohandel M, Sengupta S. Sequential application of a cytotoxic nanoparticle and a PI3K inhibitor enhances antitumor efficacy. Cancer Res 2013; 74:675-685. [PMID: 24121494 DOI: 10.1158/0008-5472.can-12-3783] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Nanomedicines that preferentially deploy cytotoxic agents to tumors and molecular targeted therapeutics that inhibit specific aberrant oncogenic drivers are emerging as the new paradigm for the management of cancer. While combination therapies are a mainstay of cancer chemotherapy, few studies have addressed the combination of nanomedicines and molecular targeted therapeutics. Furthermore, limited knowledge exists on the impact of sequencing of such therapeutics and nanomedicines on the antitumor outcome. Here, we engineered a supramolecular cis-platinum nanoparticle, which induced apoptosis in breast cancer cells but also elicited prosurvival signaling via an EGF receptor/phosphoinositide 3-kinase (PI3K) pathway. A combination of mathematical modeling and in vitro and in vivo validation using a pharmacologic inhibitor of PI3K, PI828, demonstrate that administration of PI828 following treatment with the supramolecular cis-platinum nanoparticle results in enhanced antitumor efficacy in breast cancer as compared with when the sequence is reversed or when the two treatments are administered simultaneously. This study addresses, for the first time, the impact of drug sequencing in the case of a combination of a nanomedicine and a targeted therapeutic. Furthermore, our results indicate that a rational combination of cis-platinum nanoparticles and a PI3K-targeted therapeutic can emerge as a potential therapy for breast cancer.
Collapse
Affiliation(s)
- Ambarish Pandey
- Laboratory for Nanomedicine, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital. Department of Medicine, Harvard Medical School. Boston, MA, USA
| | - Ashish Kulkarni
- Laboratory for Nanomedicine, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital. Department of Medicine, Harvard Medical School. Boston, MA, USA
| | - Bhaskar Roy
- Laboratory for Nanomedicine, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital. Department of Medicine, Harvard Medical School. Boston, MA, USA
| | - Aaron Goldman
- Laboratory for Nanomedicine, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital. Department of Medicine, Harvard Medical School. Boston, MA, USA
| | - Sasmit Sarangi
- Laboratory for Nanomedicine, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital. Department of Medicine, Harvard Medical School. Boston, MA, USA
| | - Poulomi Sengupta
- Laboratory for Nanomedicine, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital. Department of Medicine, Harvard Medical School. Boston, MA, USA
| | - Colin Phipps
- Department of Applied Mathematics, University of Waterloo, Waterloo, ON, N2L 3G1, Canada.,Waterloo Institute for Nanotechnology, University of Waterloo, Waterloo, ON, N2L 3G1, Canada
| | - Jawahar Kopparam
- Laboratory for Nanomedicine, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital. Department of Medicine, Harvard Medical School. Boston, MA, USA
| | - Michael Oh
- Laboratory for Nanomedicine, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital. Department of Medicine, Harvard Medical School. Boston, MA, USA
| | - Sudipta Basu
- Laboratory for Nanomedicine, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital. Department of Medicine, Harvard Medical School. Boston, MA, USA
| | - Mohammad Kohandel
- Department of Applied Mathematics, University of Waterloo, Waterloo, ON, N2L 3G1, Canada.,Center for Mathematical Medicine, Fields Institute for Research in Mathematical Sciences, Toronto, ON, M5T 3J1, Canada
| | - Shiladitya Sengupta
- Laboratory for Nanomedicine, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital. Department of Medicine, Harvard Medical School. Boston, MA, USA
| |
Collapse
|
|
43
|
Mok TSK, Wu YL. Intercalated chemotherapy and erlotinib: a viable first-line option for patients with advanced NSCLC? - authors' reply. Lancet Oncol 2013; 14:e438-e439. [PMID: 24079868 DOI: 10.1016/s1470-2045(13)70434-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Affiliation(s)
- Tony S K Mok
- The Chinese University of Hong Kong, Sir YK Pau Cancer Center, State Key Laboratory of Southern China, Prince of Wales Hospital, Hong Kong, China.
| | - Yi-Long Wu
- Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangdong, China
| |
Collapse
|
|
44
|
Martin P, Owen SP, Leighl NB. Gefitinib: re-emerging from the shadows. Lung Cancer Manag 2013. [DOI: 10.2217/lmt.13.42] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
SUMMARY In the past decade, the identification of mutations in the EGFR gene and the sensitivity of activating mutations to EGF receptor–tyrosine kinase inhibitors has improved survival in a subset of non-small-cell lung cancer patients. Over 70% of patients with EGFR mutations have a response to gefitinib therapy. Gefitinib, a first-generation EGF receptor–tyrosine kinase inhibitor, is well tolerated and continues to be widely used. However, eventually most patients develop resistance to gefitinib. This article reviews the pharmacology of gefitinib and summarizes the clinical trials that have resulted in its current day indications.
Collapse
Affiliation(s)
- Petra Martin
- Division of Medical Oncology, Princess Margaret Hospital/University Health Network, University of Toronto, Toronto, ON, Canada
| | - Scott P Owen
- Division of Medical Oncology, Princess Margaret Hospital/University Health Network, University of Toronto, Toronto, ON, Canada
| | - Natasha B Leighl
- Division of Medical Oncology, Princess Margaret Hospital/University Health Network, University of Toronto, Toronto, ON, Canada
| |
Collapse
|
|
45
|
Ma BBY, Lui VWY, Hui CWC, Lau CPY, Wong CH, Hui EP, Ng MHL, Cheng SH, Tsao SW, Tsang CM, Cheung CSF, Ho K, Chan ATC. Preclinical evaluation of the mTOR-PI3K inhibitor BEZ235 in nasopharyngeal cancer models. Cancer Lett 2013; 343:24-32. [PMID: 24041865 DOI: 10.1016/j.canlet.2013.09.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2013] [Revised: 08/30/2013] [Accepted: 09/08/2013] [Indexed: 01/01/2023]
Abstract
The dual PI3K-mTOR inhibitor BEZ235 was evaluated in preclinical models of nasopharyngeal carcinoma (NPC). The IC50 value of BEZ235 for growth was in the nanomolar range in vitro, induce G1 cycle arrest and apoptosis, and inhibited AKT and mTOR signaling in most NPC cell lines. No synergistic effect was observed when BEZ235 was combined with chemotherapy. BEZ235 increased MAPK activation in vitro but not in vivo. A daily schedule was more effective than a weekly schedule on tumor growth and inhibition of downstream mTOR signaling in vivo. The activity of BEZ235 maybe independent of the PIK3CA amplification and mutation status.
Collapse
Affiliation(s)
- Brigette B Y Ma
- State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong Special Administrative Region.
| | - Vivian W Y Lui
- Department of Otolaryngology, University of Pittsburgh, USA
| | - Connie W C Hui
- State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Cecilia P Y Lau
- State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Chi H Wong
- State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Edwin P Hui
- State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Margaret H L Ng
- Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Suk H Cheng
- Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Sai W Tsao
- Department of Anatomy, University of Hong Kong, Hong Kong Special Administrative Region
| | - Chi-Man Tsang
- Department of Anatomy, University of Hong Kong, Hong Kong Special Administrative Region
| | - Crystal S F Cheung
- State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Kakiu Ho
- State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Anthony T C Chan
- State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong Special Administrative Region
| |
Collapse
|
|
46
|
Santarpia M, De Pas TM, Altavilla G, Spaggiari L, Rosell R. Moving towards molecular-guided treatments: erlotinib and clinical outcomes in non-small-cell lung cancer patients. Future Oncol 2013; 9:327-45. [PMID: 23469969 DOI: 10.2217/fon.13.6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
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.
Collapse
Affiliation(s)
- Mariacarmela Santarpia
- Medical Oncology Unit of Respiratory Tract & Sarcomas, New Drugs Development Division, European Institute of Oncology, Milan, Italy.
| | | | | | | | | |
Collapse
|
|
47
|
Fung AS, Yu M, Ye QJ, Tannock IF. Scheduling of paclitaxel and gefitinib to inhibit repopulation for optimal treatment of human cancer cells and xenografts that overexpress the epidermal growth factor receptor. Cancer Chemother Pharmacol 2013; 72:585-95. [PMID: 23851981 DOI: 10.1007/s00280-013-2229-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Accepted: 06/29/2013] [Indexed: 11/26/2022]
Abstract
PURPOSE In clinical studies, evaluating the combination of chemotherapy and the epidermal growth factor receptor (EGFR) inhibitor gefitinib, treatments were administered concurrently, despite it being counter-intuitive to give a cytostatic agent concurrent with cycle-active chemotherapy. One strategy to enhance efficacy might be to give the agents sequentially, thus allowing selective inhibition of repopulation of cancer cells between doses of chemotherapy. Here, we evaluate the hypothesis that sequential administration might allow inhibition of repopulation by gefitinib, with tumor cells re-entering cycle to allow sensitivity to subsequent chemotherapy. METHODS Sequential and concurrent administration of paclitaxel and gefitinib were studied in vitro and in xenografts using EGFR over-expressing, EGFR-mutant, and EGFR wild-type human cancer cell lines. We evaluated cell cycle distribution and repopulation during treatment. RESULTS The sequential use of gefitinib and paclitaxel to treat EGFR over-expressing A431 cells in vitro decreased repopulation compared to chemotherapy alone, and there was greater cell kill compared to concurrent treatment. In contrast, combined treatment led to greater growth delay than use of gefitinib alone for concurrent but not for sequential treatment of mice bearing A431 xenografts; concurrent treatment had greater effects to reduce functional vasculature in the tumors. Conversely, sequential treatment led to greater growth delay than concurrent treatment of EGFR-mutant HCC-827 xenografts that are sensitive to lower doses of gefitinib. CONCLUSIONS These studies highlight the importance of considering effects on the cell cycle, and on the solid tumor microenvironment, including tumor vasculature, when scheduling cytostatic and cytotoxic agents in combination.
Collapse
Affiliation(s)
- Andrea S Fung
- Department of Medical Oncology and Hematology, Princess Margaret Hospital, University of Toronto, 610 University Avenue, Toronto, Ontario, Canada
| | | | | | | |
Collapse
|
|
48
|
Masui K, Gini B, Wykosky J, Zanca C, Mischel PS, Furnari FB, Cavenee WK. A tale of two approaches: complementary mechanisms of cytotoxic and targeted therapy resistance may inform next-generation cancer treatments. Carcinogenesis 2013; 34:725-38. [PMID: 23455378 PMCID: PMC3616676 DOI: 10.1093/carcin/bgt086] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Accepted: 02/26/2013] [Indexed: 02/06/2023] Open
Abstract
Chemotherapy and molecularly targeted approaches represent two very different modes of cancer treatment and each is associated with unique benefits and limitations. Both types of therapy share the overarching limitation of the emergence of drug resistance, which prevents these drugs from eliciting lasting clinical benefit. This review will provide an overview of the various mechanisms of resistance to each of these classes of drugs and examples of drug combinations that have been tested clinically. This analysis supports the contention that understanding modes of resistance to both chemotherapy and molecularly targeted therapies may be very useful in selecting those drugs of each class that will have complementing mechanisms of sensitivity and thereby represent reasonable combination therapies.
Collapse
Affiliation(s)
- Kenta Masui
- Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093-0660, USA
| | | | | | | | | | | | | |
Collapse
|
|
49
|
|
|
50
|
Metro G, Minotti V, Crinò L. Years of sorafenib investigation in advanced non-small cell lung cancer: is there a 'NExUS' linking an unsuccessful treatment and a potentially active one? J Thorac Dis 2013. [PMID: 23205291 DOI: 10.3978/j.issn.2072-1439.2012.10.06] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Affiliation(s)
- Giulio Metro
- Division of Medical Oncology, S. Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, via Dottori, 1, 06156 Perugia, Italy
| | | | | |
Collapse
|