|LETTER TO EDITOR
|Year : 2019 | Volume
| Issue : 2 | Page : 251-252
First-line treatment of EGFR-mutant NSCLC: Spoiled for choice?
Ullas Batra, Mansi Sharma, Srujana Joga, Parveen Jain
Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
|Date of Web Publication||20-Dec-2019|
Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, Sector 5, New Delhi - 110 085
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Batra U, Sharma M, Joga S, Jain P. First-line treatment of EGFR-mutant NSCLC: Spoiled for choice?. Cancer Res Stat Treat 2019;2:251-2
Lung cancer is the poster child for personalized medicine. In the last decade, the treatment of lung cancer has undergone a paradigm shift with the development of biomarkers such as epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase rearrangement. The treatment of EGFR-mutant non-small cell lung cancer (NSCLC) itself has undergone a major change with various treatment options available for first-line treatment.
Various factors should be taken into account while choosing the first-line treatment for EGFR-mutant NSCLC. These include efficacy, toxicity, quality of life, and cost–benefit analysis. The results of IRESSA Pan-Asia Study and EURopean TArceva vs. Chemotherapy trials established gefitinib/erlotinib as the first-line treatment of EGFR-mutant NSCLC. However, patients invariably progress after 9–12 months. Various strategies have been used to increase the progression-free survival (PFS)/overall survival (OS) including the combination of EGFR tyrosine kinase inhibitors (TKIs) with chemotherapy, combination with anti-angiogenics, and use of third-generation TKIs.
The results of AZD9291 Versus Gefitinib or Erlotinib in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer (FLAURA) trial established osimertinib as the standard of care in the first-line treatment of this subgroup of patients. Osimertinib not only prolongs the PFS, but also results in improved OS. The drug is also very well tolerated and has the added advantage of penetrating the blood–brain barrier. Nearly 26% of the patients who received the drug are still continuing the drug at 3 years.
It should also be noted that 30% of patients in both the arms of the FLAURA trial could not take second-line treatment. In addition, only 50% of the patients would develop T790M mutation while on progression on the first-/second-generation TKIs., Thus, a majority of eligible patients may not be able to take osimertinib if not used in the first-line setting.
The other strategies used to increase the PFS are a combination of EGFR with anti-angiogenic agents and EGFR chemotherapy combinations. The results of EGFR chemotherapy combinations are promising, but this regimen is associated with higher toxicity and high rates of discontinuation of treatment. The OS data of Tata Memorial Hospital trial are not yet mature, and the results of the NEJ009 trial have not yet been published. The addition of anti-angiogenics to EGFR TKIs has similarly yielded an improvement in PFS but is again associated with higher rates of toxicity in the combination arm.
Osimertinib is the only TKI that has shown OS advantage in head-to-head comparison with another TKI. Even in the Alectinib with Crizotinib in Treatment-Naive Anaplastic Lymphoma Kinase-Positive Advanced Non-Small Cell Lung Cancer trial (ALEX), alectinib has not shown OS advantage till date. Even in other cancers such as chronic myeloid leukemia and gastrointestinal stromal tumor, later-generation TKIs have not been able to show increased OS advantage compared to first-generation TKIs. Thus, in view of overall OS, improved central nervous system penetration rates, and better toxicity profile, osimertinib should be considered as the standard of care first-line treatment of EGFR-mutant NSCLC in 2019.
However, the last word on the combination of chemotherapy and EGFR TKIs has not yet been delivered. The FLAURA 2 trial, which is a Phase III clinical trial comparing osimertinib to a combination of osimertinib/pemetrexed and cisplatin, is currently recruiting patients. The results of this trial should provide a clear answer to the optimal first-line management of EGFR-mutant NSCLC.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Rajendra A, Noronha V, Joshi A, Patil VM, Menon N, Prabhash K. Epidermal growth factor receptor-mutated non-small-cell lung cancer: A primer on contemporary management. Cancer Res Stat Treat 2019;2:36-53. [Full text]
Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al.
Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N
Engl J Med 2018;378:113-25.
Ramalingam S, Gray J, Ohe Y, Cho B, Vansteenkiste J, Zhou C et al
. LBA5_PROsimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): Final overall survival analysis. Ann Oncol 2019;30 Suppl 5:v851-v934.
Lee CK, Novello S, Rydén A, Mann H, Mok T. Patient-reported symptoms and impact of treatment with osimertinib versus chemotherapy in advanced non-small-cell lung cancer: the AURA3 trial. J Clin Oncol 2018;36:1853-60.
Planchard D, Boyer M, Lee J, Dechaphunkul A, Cheema P, Takahashi T, et al
. 128O osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with untreated EGFRm advanced NSCLC: FLAURA post-progression outcomes. J Thorac Oncol 2018;13:S72-3.
Oxnard GR, Arcila ME, Sima CS, Riely GJ, Chmielecki J, Kris MG, et al.
Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: Distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res 2011;17:1616-22.
Babu Koyyala VP, Batra U, Jain P, Sharma M, Goyal P, Medisetty P, et al.
Frequency of T790M mutations after progression on epidermal growth factor receptor tyrosine kinase inhibitor in metastatic non-small cell lung cancer in Indian patients: Real-time data from tertiary cancer hospital. Lung India 2018;35:390-4.
Noronha V, Patil VM, Joshi A, Menon N, Chougule A, Mahajan A, et al
. Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR
-mutated lung cancer. J Clin Oncol 2019:JCO1901154.
Nakamura A, Inoue A, Morita S, Hosomi Y, Kato T, Fukuhara T
. Phase III study comparing gefitinib monotherapy (G) to combination therapy with gefitinib, carboplatin, and pemetrexed (GCP) for untreated patients (pts) with advanced non-small cell lung cancer (NSCLC) with EGFR mutations (NEJ009). J Clin Oncol 2018;36 Suppl 9005:viii493-viii547.
Rosell R, Dafni U, Felip E, Curioni-Fontecedro A, Gautschi O, Peters S, et al.
Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): An international, multicentre, single-arm, phase 2 trial. Lancet Respir Med 2017;5:435-44.
Camidge DR, Dziadziuszko R, Peters S, Mok T, Noe J, Nowicka M, et al.
Updated efficacy and safety data and impact of the EML4-ALK fusion variant on the efficacy of alectinib in untreated ALK-positive advanced non-small cell lung cancer in the global phase III ALEX study. J Thorac Oncol 2019;14:1233-43.
Pandey A, Singh A, Singh S, Kumar A. Osimertinib in G719A mutated non-small cell lung cancer with leptomeningealmetastases. Cancer Res Stat Treat 2019;2:121-3. [Full text]