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Table of Contents
Year : 2019  |  Volume : 2  |  Issue : 2  |  Page : 252-254

Author Reply to: Sahoo, Batra et al. and Mullapally et al.

Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India

Date of Web Publication20-Dec-2019

Correspondence Address:
Vanita Noronha
Department of Medical Oncology, Tata Memorial Hospital, Mumbai - 400 012, Maharashtra; Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CRST.CRST_92_19

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How to cite this article:
Rajendra A, Noronha V, Joshi A, Patil VM, Menon N, Prabhash K. Author Reply to: Sahoo, Batra et al. and Mullapally et al. Cancer Res Stat Treat 2019;2:252-4

How to cite this URL:
Rajendra A, Noronha V, Joshi A, Patil VM, Menon N, Prabhash K. Author Reply to: Sahoo, Batra et al. and Mullapally et al. Cancer Res Stat Treat [serial online] 2019 [cited 2021 Aug 5];2:252-4. Available from: https://www.crstonline.com/text.asp?2019/2/2/252/273706

Dear Editor,

We thank Dr. Sahoo,[1] Dr. Batra et al.,[2] and Dr. Mullapally and Revendran.[3] for their thoughtful letters regarding our review on epidermal growth factor receptor (EGFR)-mutated lung cancer.[4] Although we agree with the points raised in the letters, we would like to counter certain arguments.

  Q – Why not Use Osimertinib as The first-Line Therapy? Top

Undoubtedly, osimertinib prolongs the progression-free survival (PFS) and the overall survival (OS) in comparison with gefitinib or erlotinib. However, there are a few issues with the use of osimertinib in the first line.[5] We do not have an effective agent after the patient progresses on osimertinib. With the current price of osimertinib at Rs. 4.5 lakhs (' 4,50,000) for 1 month, only 3%–5% Indians can afford it.[6] Osimertinib is currently not available in all countries; as on September 4, 2019, osimertinib was approved and available for first-line therapy in 75 out of 195 countries worldwide.[7] Moreover, the updated FLAURA trial analysis (which was presented recently) showed that the OS benefit conferred by osimertinib was not seen in the Asian subset.[8] On the contrary, the use of combination of chemotherapy with gefitinib, albeit with increased toxicity, is a viable option for precisely the same reasons as listed above: widely available, cheap, and with multiple therapeutic options at progression. In our trial, 56% of the patients had a performance status of 0–1 at the time of progressive disease, making them fit for treatment with other active agents.[9]

The FLAURA trial included patients with exon19del mutation and L858R mutation who had a performance status of 0 and 1. Thus, the results of the FLAURA trial cannot be generalized for patients with other mutations, including other EGFR-sensitizing mutations such as exon 18, and patients with performance status of 2 or more.[5] On the contrary, the gefitinib plus chemotherapy combination in the TMH trial was used in patients with performance status of 0–2 with any sensitizing EGFR mutation, including rare mutations and resulted in prolonged PFS and OS in comparison with the gefitinib alone arm.[9]

We agree with the argument of similar PFS2 in both the treatment arms of NEJ009 trial, which make the results of the OS and the post-progression treatment modalities very important.[10]

  Q. Difference between Efficacy of Gefitinib and Erlotinib in Egfr Exon 19 Mutation With Brain Metastasis Top

Comparison between gefitinib and erlotinib was well documented in the WJOG 5108 L and CTONG 0901 studies which showed gefitinib to have comparable efficacy to erlotinib (PFS – 6.5 [G] vs. 7.5 [E] months, HR = 1.125; 95% CI: 0.940–1.347; P = 0 0.257; OS – 22.8 [G] vs. 24.5 [E] months, HR = 1.038; 95% CI: 0.833–1.294; P = 0.768).[11],[12] Meta-analysis of studies performed among East Asian patients with advanced non-small cell lung cancer (NSCLC) also showed comparable efficacy between gefitinib and erlotinib, with erlotinib being associated with higher rate and severity of skin rash, nausea, vomiting, diarrhea, fatigue, and stomatitis.[13] In an exploratory unplanned subgroup analysis of the TMH trial among patients with brain metastasis, gefitinib plus chemotherapy seemed to be more effective than gefitinib alone (HR: 0.53; 95% CI: 0.29–0.98).[9] However, in the retrospective multicenter study performed among Asian patients with exon 19 EGFR mutation NSCLC with brain metastasis, the use of erlotinib resulted in a significant difference in the PFS and OS in comparison with gefitinib.[14] This correlates with the observation that erlotinib achieves better central nervous system concentration in comparison with gefitinib. In the OPTIMAL trial, 40% of the patients with exon 19 deletion who received erlotinib as first-line therapy did not receive any other form of treatment at progression. This difference, however, did not make an impact on the OS of the patients in comparison with the chemotherapy arm.[15] Potential benefit of the combination of chemotherapy and tyrosine kinase inhibitor (TKI) must be utilized, especially in this subset of patients. Thus, in this subset of patients (EGFR exon 19 mutant, Asian patients with brain metastasis), the use of erlotinib may be preferred over gefitinib, provided osimertinib cannot be used (due to logistic issues) and chemotherapy cannot be administered (because of poor general condition).

  Q. Role of Srs in the Management of Nsclc With Brain Metastasis Top

The brain penetration of gefitinib, erlotinib, and afatinib is not sufficient to serve as the sole treatment modality of EGFR-mutant NSCLC patients with brain metastasis. Upfront whole brain radiotherapy (WBRT) and upfront WBRT + TKI had better OS in comparison with TKI alone.[16] In patients with oligometastasis with appropriate tumor size and location, administering focal and aggressive radiation in the form of stereotactic radiosurgery is ideal and recommended. The question of WBRT versus osimertinib in the upfront setting still needs to be answered through randomized trials.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Sahoo TP. Treating EGFR positive advanced cancer lung – Did the water just get muddier? Cancer Res Stat Treat 2019;2:249-50.  Back to cited text no. 1
  [Full text]  
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.  Back to cited text no. 2
Mullapally SK, Revendran J. Sailing through lung cancer charted by EGFR signposts. Cancer Res Stat Treat 2019;2:248-9.  Back to cited text no. 3
  [Full text]  
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.  Back to cited text no. 4
  [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.  Back to cited text no. 5
E-Filing Home Page, Income Tax Department, Government of India. Available from: https://www.incometaxindiaefiling.gov.in/moreStatistics. [Last accessed on 2019 Oct 20].  Back to cited text no. 6
Ramalingam SS, Gray JE, Ohe Y, Cho BC, Vansteenkiste J, Zhou C, et al. LBA5_PRO simertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): Final overall survival analysis. Ann Oncol 2019;30 Suppl 5. [Doi: 10.1093/annonc/mdz394.076].  Back to cited text no. 8
Noronha V, Patil VM, Joshi A, Menon N, Chougule A, Mahajan A, et al. Gefitinib versus gefitinib and pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer. J Clin Oncol 2019:JCO1901154. [Epub ahead of print].  Back to cited text no. 9
Nakamura A, Inoue A, Morita S, Hosomi Y, Kato T, Fukuhara T, et al. 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;15 Suppl 36:9005.  Back to cited text no. 10
Yang JJ, Zhou Q, Yan HH, Zhang XC, Chen HJ, Tu HY, et al. Aphase III randomised controlled trial of erlotinib vs gefitinib in advanced non-small cell lung cancer with EGFR mutations. Br J Cancer 2017;116:568-74.  Back to cited text no. 11
Urata Y, Katakami N, Morita S, Kaji R, Yoshioka H, Seto T, et al. Randomized phase III study comparing gefitinib with erlotinib in patients with previously treated advanced lung adenocarcinoma: WJOG 5108L. J Clin Oncol 2016;34:3248-57.  Back to cited text no. 12
Zhang W, Wei Y, Yu D, Xu J, Peng J. Gefitinib provides similar effectiveness and improved safety than erlotinib for East Asian populations with advanced non-small cell lung cancer: A meta-analysis. BMC Cancer 2018;18:780.  Back to cited text no. 13
Jiang Y, Zhang J, Huang J, Xu B, Li N, Cao L, et al. Erlotinib versus gefitinib for brain metastases in Asian patients with exon 19 EGFR-mutant lung adenocarcinoma: A retrospective, multicenter study. BMC Pulm Med 2018;18:171.  Back to cited text no. 14
Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802). Ann Oncol 2015;26:1877-83.  Back to cited text no. 15
Du XJ, Pan SM, Lai SZ, Xu XN, Deng ML, Wang XH, et al. Upfront cranial radiotherapy vs. EGFR tyrosine kinase inhibitors alone for the treatment of brain metastases from non-small-cell lung cancer: A meta-analysis of 1465 patients. Front Oncol 2018;8:603.  Back to cited text no. 16


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