Accepted Manuscript Anti-Tumour Treatment Beyond EGFR TKI in EGFR-mutant Non-Small Cell Lung Cancer patients: main challenges still to be overcome J. Remon, T. Morán, N. Reguart, M. Majem, E. Carcereny, P. Lianes PII: DOI: Reference:
S0305-7372(14)00049-8 http://dx.doi.org/10.1016/j.ctrv.2014.03.006 YCTRV 1297
To appear in:
Cancer Treatment Reviews Cancer Treatment Reviews
Received Date: Revised Date: Accepted Date:
21 February 2014 17 March 2014 30 March 2014
Please cite this article as: Remon, J., Morán, T., Reguart, N., Majem, M., Carcereny, E., Lianes, P., Beyond EGFR TKI in EGFR-mutant Non-Small Cell Lung Cancer patients: main challenges still to be overcome, Cancer Treatment Reviews Cancer Treatment Reviews (2014), doi: http://dx.doi.org/10.1016/j.ctrv.2014.03.006
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Manuscript type: Review article Beyond EGFR TKI in EGFR-mutant Non-Small Cell Lung Cancer patients: main challenges still to be overcome Remon J1, Morán T2, Reguart N3, Majem M4, Carcereny E2, Lianes P1 1
Hospital de Mataró, Barcelona, Spain; 2 Institut Català d’Oncologia- Badalona,
Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain; 3Hospital Clínic, Barcelona, Spain; 4Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. Running title: Beyond EGFR TKI in EGFR-mutant Non-Small Cell Lung Cancer patients: main challenges still to be overcome
Corresponding author: Jordi Remon, M.D Medical Oncology Department Hospital de Mataró Carretera de la Cirera, s/n 08304. Mataró. Barcelona. Spain Phone:
+34 937 417 700
Fax:
+34 937 417 780
E-mail:
[email protected]
Teresa Morán, M.D, Ph.D Medical Oncology Department Institut Català d’Oncologia -Badalona, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona. Carretera de Canyet s/n. 08916 Badalona. Barcelona. Spain Phone:
+34 934 978925
1
Fax:
+34 934 978950
E-mail:
[email protected]
Noemí Reguart, M. D, Ph. D Medical Oncology Department Hospital Clinic de Barcelona Villarroel 170 08036. Barcelona. Spain Telef:
+34 932 275 400
FAX:
+34 934 546 500
Mail:
[email protected]
Marga Majem, M.D, Ph. D Medical Oncology Department Hospital de la Santa Creu i Sant Pau Sant Antoni Maria Claret, 167 08025. Barcelona Telef:
+34 935 565 638
FAX:
+34 935 565 769
Mail:
[email protected]
Enric Carcereny, M.D. Medical Oncology Department Institut Català d’Oncologia -Badalona, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona. Carretera de Canyet s/n. 08916 Badalona. Barcelona. Spain Phone:
+34 934 978925
Fax:
+34 934 978950
E-mail:
[email protected]
Pilar Lianes, M.D, Ph. D Medical Oncology Department Hospital de Mataró
2
Carretera de la Cirera, s/n 08304. Mataró. Barcelona. Spain Phone:
+34 937 417 700
Fax:
+34 937 417 780
E-mail:
[email protected]
3
Beyond EGFR TKI in EGFR-mutant Non-Small Cell Lung Cancer patients: main challenges still to be overcome
4
Abstract
First line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) is the standard treatment in advanced EGFR-mutant Non Small Cell Lung Cancer (NSCLC) patients, with an improvement in response rate, progression free survival, and quality of life compared with upfront chemotherapy. However, in the real world, EGFR mutation results often return positive once chemotherapy has been started. Different clinical strategies have been tested in this situation: reserve the EGFR TKI until tumor become resistant beyond chemotherapy, stop chemotherapy and switch to EGFR TKI, introduce the EGFR TKI as a maintenance treatment, or combined strategies such as intercalated or concurrent EGFR TKI plus chemotherapy. In this review, we aim to summarize the clinical evidence of first line treatment strategy with EGFR TKI and discuss the potential options in the sequence of treatment in EGFR-mutant patients.
Keywords:
Non-small cell lung cancer; sequence of treatment; Tyrosine
Kinase Inhibitors; EGFR-mutant tumors.
5
Introduction
The identification of activating mutations in the tyrosine kinase domain of the EGFR has changed the standard approach for evaluating advanced NSCLC and established tumor genotyping in daily clinical practice. Moreover, roughly half of Caucasian population with advanced non-squamous lung cancer has some kind of driver mutation1, and EGFR mutation appears in almost 10% of Caucasian European NSCLC patients 2 . The possibility of a personalized treatment has prompted an increase in molecular testing such as the 6-fold increase in one year for EGFR testing in France3. Moreover, those patients who have a driver mutation and receive personalized treatment live longer than those patients who do not have any driver mutation or those with who have a driver mutation but not receive targeted therapy4. First line treatment in EGFR-mutant NSCLC patients. Phase III trials results.
For those patients with advanced non-squamous lung cancer harbouring an EGFR mutation, six randomized phase III trials have demonstrated that firstgeneration of EGFR tyrosine kinase inhibitors (TKI) such as erlotinib or gefitinib, significantly improve the outcome, doubling the response rate (RR) and the progression free survival (PFS), compared with chemotherapy5,6,7,8,9,10,11 (Table 1). However, none of these trials showed a significant difference in overall survival (OS) (only in First-SIGNAL trial the primary end point was OS), likely as a result of a crossover to the other arm at progression. While these results clearly favored the EGFR TKI arm, the chemotherapy schedule used as control arm in these trails was not the optimal as pemetrexed or antiangiogenic therapy as well as maintenance strategy was not proposed. However, any of these strategies were approved when these trials were designed. Recently secondgeneration of EGFR TKI such as afatinib, which is an irreversible inhibitor against all EGFR family members and T790M mutation
12
, has also
demonstrated to be superior to chemotherapy in two randomized phase III trials conducted in EGFR mutated patients (LUX-Lung 313 and LUX-Lung 614 trials).
6
One of the trials included pemetrexed as comparator arm (Table 1). Patients treated with afatinib achieved a consistent median PFS of 11 months, RR of 60% and identical 12 months PFS of 47% in both clinical trials (Table 1). In a pre-planned subgroup analysis in the LUX-Lung 3 trial, those patients whose tumor harboured the common activation mutation in exon 19 and 21, attained a median PFS of almost 14 months13. Recently, a meta-analysis from the six phase III randomized controlled trials involving 1021 patients has been published confirming the role of EGFR TKI therapy as first-line treatment in EGFR-mutant NSCLC patients, with a significant improvement in PFS (HR 0.37, 95%CI: 0.27-0.52, p
S0305-7372(14)00049-8 http://dx.doi.org/10.1016/j.ctrv.2014.03.006 YCTRV 1297
To appear in:
Cancer Treatment Reviews Cancer Treatment Reviews
Received Date: Revised Date: Accepted Date:
21 February 2014 17 March 2014 30 March 2014
Please cite this article as: Remon, J., Morán, T., Reguart, N., Majem, M., Carcereny, E., Lianes, P., Beyond EGFR TKI in EGFR-mutant Non-Small Cell Lung Cancer patients: main challenges still to be overcome, Cancer Treatment Reviews Cancer Treatment Reviews (2014), doi: http://dx.doi.org/10.1016/j.ctrv.2014.03.006
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Manuscript type: Review article Beyond EGFR TKI in EGFR-mutant Non-Small Cell Lung Cancer patients: main challenges still to be overcome Remon J1, Morán T2, Reguart N3, Majem M4, Carcereny E2, Lianes P1 1
Hospital de Mataró, Barcelona, Spain; 2 Institut Català d’Oncologia- Badalona,
Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain; 3Hospital Clínic, Barcelona, Spain; 4Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. Running title: Beyond EGFR TKI in EGFR-mutant Non-Small Cell Lung Cancer patients: main challenges still to be overcome
Corresponding author: Jordi Remon, M.D Medical Oncology Department Hospital de Mataró Carretera de la Cirera, s/n 08304. Mataró. Barcelona. Spain Phone:
+34 937 417 700
Fax:
+34 937 417 780
E-mail:
[email protected]
Teresa Morán, M.D, Ph.D Medical Oncology Department Institut Català d’Oncologia -Badalona, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona. Carretera de Canyet s/n. 08916 Badalona. Barcelona. Spain Phone:
+34 934 978925
1
Fax:
+34 934 978950
E-mail:
[email protected]
Noemí Reguart, M. D, Ph. D Medical Oncology Department Hospital Clinic de Barcelona Villarroel 170 08036. Barcelona. Spain Telef:
+34 932 275 400
FAX:
+34 934 546 500
Mail:
[email protected]
Marga Majem, M.D, Ph. D Medical Oncology Department Hospital de la Santa Creu i Sant Pau Sant Antoni Maria Claret, 167 08025. Barcelona Telef:
+34 935 565 638
FAX:
+34 935 565 769
Mail:
[email protected]
Enric Carcereny, M.D. Medical Oncology Department Institut Català d’Oncologia -Badalona, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona. Carretera de Canyet s/n. 08916 Badalona. Barcelona. Spain Phone:
+34 934 978925
Fax:
+34 934 978950
E-mail:
[email protected]
Pilar Lianes, M.D, Ph. D Medical Oncology Department Hospital de Mataró
2
Carretera de la Cirera, s/n 08304. Mataró. Barcelona. Spain Phone:
+34 937 417 700
Fax:
+34 937 417 780
E-mail:
[email protected]
3
Beyond EGFR TKI in EGFR-mutant Non-Small Cell Lung Cancer patients: main challenges still to be overcome
4
Abstract
First line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) is the standard treatment in advanced EGFR-mutant Non Small Cell Lung Cancer (NSCLC) patients, with an improvement in response rate, progression free survival, and quality of life compared with upfront chemotherapy. However, in the real world, EGFR mutation results often return positive once chemotherapy has been started. Different clinical strategies have been tested in this situation: reserve the EGFR TKI until tumor become resistant beyond chemotherapy, stop chemotherapy and switch to EGFR TKI, introduce the EGFR TKI as a maintenance treatment, or combined strategies such as intercalated or concurrent EGFR TKI plus chemotherapy. In this review, we aim to summarize the clinical evidence of first line treatment strategy with EGFR TKI and discuss the potential options in the sequence of treatment in EGFR-mutant patients.
Keywords:
Non-small cell lung cancer; sequence of treatment; Tyrosine
Kinase Inhibitors; EGFR-mutant tumors.
5
Introduction
The identification of activating mutations in the tyrosine kinase domain of the EGFR has changed the standard approach for evaluating advanced NSCLC and established tumor genotyping in daily clinical practice. Moreover, roughly half of Caucasian population with advanced non-squamous lung cancer has some kind of driver mutation1, and EGFR mutation appears in almost 10% of Caucasian European NSCLC patients 2 . The possibility of a personalized treatment has prompted an increase in molecular testing such as the 6-fold increase in one year for EGFR testing in France3. Moreover, those patients who have a driver mutation and receive personalized treatment live longer than those patients who do not have any driver mutation or those with who have a driver mutation but not receive targeted therapy4. First line treatment in EGFR-mutant NSCLC patients. Phase III trials results.
For those patients with advanced non-squamous lung cancer harbouring an EGFR mutation, six randomized phase III trials have demonstrated that firstgeneration of EGFR tyrosine kinase inhibitors (TKI) such as erlotinib or gefitinib, significantly improve the outcome, doubling the response rate (RR) and the progression free survival (PFS), compared with chemotherapy5,6,7,8,9,10,11 (Table 1). However, none of these trials showed a significant difference in overall survival (OS) (only in First-SIGNAL trial the primary end point was OS), likely as a result of a crossover to the other arm at progression. While these results clearly favored the EGFR TKI arm, the chemotherapy schedule used as control arm in these trails was not the optimal as pemetrexed or antiangiogenic therapy as well as maintenance strategy was not proposed. However, any of these strategies were approved when these trials were designed. Recently secondgeneration of EGFR TKI such as afatinib, which is an irreversible inhibitor against all EGFR family members and T790M mutation
12
, has also
demonstrated to be superior to chemotherapy in two randomized phase III trials conducted in EGFR mutated patients (LUX-Lung 313 and LUX-Lung 614 trials).
6
One of the trials included pemetrexed as comparator arm (Table 1). Patients treated with afatinib achieved a consistent median PFS of 11 months, RR of 60% and identical 12 months PFS of 47% in both clinical trials (Table 1). In a pre-planned subgroup analysis in the LUX-Lung 3 trial, those patients whose tumor harboured the common activation mutation in exon 19 and 21, attained a median PFS of almost 14 months13. Recently, a meta-analysis from the six phase III randomized controlled trials involving 1021 patients has been published confirming the role of EGFR TKI therapy as first-line treatment in EGFR-mutant NSCLC patients, with a significant improvement in PFS (HR 0.37, 95%CI: 0.27-0.52, p
