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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 6  |  Issue : 1  |  Page : 26-30

comparison of maintenance strategy in EGFR mutation positive and negative locally advanced and metastatic non squamous lung carcinoma.A tertiary center experience


1 Department of Medical Oncology, Indira Gandhi Institute of Medical Sciences, Patna, India
2 Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, India

Date of Submission21-Dec-2019
Date of Acceptance08-Jan-2020
Date of Web Publication16-Nov-2020

Correspondence Address:
Avinash Pandey
Assistant Professor, Department of Medical Oncology, IGIMS
India
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Source of Support: None, Conflict of Interest: None


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  Abstract 


Background and Rationale: Induction platin based doublet is standard of care in locally advanced and metastatic NSCLC. Maintenance pemetrexed and tyrosine kinase inhibitior both have shown to improve outcomes in patients with favourable response to induction therapy.
Aim: To evaluate and compare outcomes with maintenance pemetrexed and maintenance TKI in EGFR mutation positive and negative patients.
Objectives: To calculate and compare Progression free survival, overall survival and factor affecting outcomes with maintenance pemetrexed and maintenance TKI.
Material and Methods: Data of patients with locally advanced and metastatic non squamous NSCLC who received induction pemetrexed platin doublet were retrieved from prospectively maintained lung cancer database registered between June 2011 and March 2014.Patients who received maintenance pemetrexed and maintenance TKI being EGFR mutation negative and positive respectively were chosen for final analysis. Kaplan Meir survival analysis was used for Progression free survival and overall survival. Log rank test was used to evaluate and compare factors affecting outcome.
Result: Median follow up is 16 months. Out of 268 patients who had favourable response to induction pemetrexed platin doublet, EGFR mutation result was available in 238 (89%) patients. Patients who were EGFRF mutation negative and received maintenance pemetrexed were 138, while those with EGFR mutation positive and received maintenance TKI were 80.Median PFS with maintenance TKI in EGFR mutation positive patients was significantly better than that of maintenance pemetrexed in EGFR mutation negative (11 months versus 8 months; p=0.01), while the overall survival was 19 months and 20 months respectively. Older age, females, non smoker, no baseline effusion and partial response to induction did better with maintenance TKI.
Conclusion: Maintenance TKI in EGFR mutation positive non squamous NSCLC delays disease progression more than maintenance pemetrexed in EGFR mutation negative NSCLC. Both option fare favourably to improve outcomes after response to induction therapy.

Keywords: Maintenance, Tyrosine kinase inhibitors, pemetrexed.


How to cite this article:
Pandey A, Noronha V, Joshi A, Prabhash K. comparison of maintenance strategy in EGFR mutation positive and negative locally advanced and metastatic non squamous lung carcinoma.A tertiary center experience. J Indira Gandhi Inst Med Sci 2020;6:26-30

How to cite this URL:
Pandey A, Noronha V, Joshi A, Prabhash K. comparison of maintenance strategy in EGFR mutation positive and negative locally advanced and metastatic non squamous lung carcinoma.A tertiary center experience. J Indira Gandhi Inst Med Sci [serial online] 2020 [cited 2020 Nov 26];6:26-30. Available from: http://www.jigims.co.in/text.asp?2020/6/1/26/300734




  Introduction: Top


Lung carcinoma is responsible for highest cancer related death worldwide. In India, approximately 63,000 new lung cancer cases are reported every year. More than 85% of which are Non Small Cell Lung Carcinoma (NSCLC) and 40% of them present with either malignant effusion or metastatic disease.[1],[2] Standard treatment of choice of locally advanced and metastatic NSCLC is platin based doublet chemotherapy[3]. With adenocarcinoma histology, induction pemetrexed platinum doublet has better outcomes than non pemetrexed combination[4]. Despite these advances majority of these patients suffer from early disease progression and premature death. Maintenance therapy has been recently shown to improve outcomes and delay progression in patients with favourable response to induction therapy. Continuation pemetrexed maintenance and switch maintenance TKI in separate large randomised studies have shown modest benefit in outcomes.5,6 We conducted clinical audit of patients receiving maintenance TKI and maintenance pemetrexed in EGFR mutation positive and negative patients respectively.


  Material and Methods Top


We retrieved data of patients with locally advanced and metastatic NSCLC from our prospectively maintained database between June 2011 and March 2014. All patients having histological diagnosis of locally advanced and metastatic non squamous NSCLC (Stage IIIB and Stage IV) with no previous systemic therapy and adequate organ function were included. We selected patients with non squamous NSCLC histology who received induction pemetrexed platin doublet chemotherapy and also had EGFR mutation result available. All patients who achieved favourable response to above induction chemotherapy and received maintenance TKI and maintenance pemetrexed in view of EGFR mutation positive and negative respectively were chosen for final analysis. This study was approved by Institutional Ethics Committee.

During induction phase, patients were treated with intravenous pemetrexed 500 mg /m2 and intravenous cisplatin 75mg/m2 or intravenous carboplatin AUC=5 on Day 1 of 21 day cycle for six cycles. All patients received folic acid, Vitamin B12 and prophylactic dexamethasone as per standard recommendation with pemetrexed based therapy. For EGFR mutation analysis, DNA was isolated from FFPE blocks of patients with non squamous NSCLC and extracted DNA was amplified for exons 18,19,20 and 21 using rested PCR method. Mutation analysis was done by Taqman based real time PCR technique. Patients who had favourable response to induction chemotherapy went on to receive maintenance pemetrexed 500 mg/m[2] every three weekly or tyrosine kinase inhibitors ,either gefitinb 250 mg OD daily or Erlotinib 150 mg OD daily.

Information collected included demographics, baseline characteristics including smoking status, performance status, TKI drug, co-morbidities, baseline pleural effusion, type of EGFR mutation and response to induction therapy. Follow up was taken from case records, electronic medical records (EMR) and telephonic conversation with patient or their relatives. Response evaluation was done every 3 monthly with contrast enhanced CT scan and measured as per RECIST criteria (version 1.1). Progression free survival was defined as time interval from date of first induction chemotherapy till date of progression or death from any cause. Overall survival was defined as time interval from date of first induction chemotherapy till death from any cause. Median follow up was calculated from date of diagnosis to date of last follow up.

All statistical analysis was carried out using SPSS software version 16. Kaplan Meir curve was plotted for progression free survival and overall survival in months. Log rank test was used to compare the PFS and OS in different groups.


  Results Top


Between June 2011 and March 2014, 464 patients were registered as locally advanced and metastatic non squamous NSCLC and received induction pemetrexed platin doublet. After careful scrutiny of data, 52 patients were excluded from database due to erroneous entry, like wrong histology, received previous chemotherapy, received TKI upfront, no maintenance, wrong case file number etc. (See [Figure 1]). Out of remaining 412 patients, 66 patients had disease progression after three cycles of induction therapy while 78 patients had progressive disease after six cycles and hence excluded for analysis. Out of remaining 268 patients, 188 patients received maintenance pemetrexed and 80 patients received maintenance TKI. EGFR mutation status was available in 238/268(89%) patients. Among patients who received maintenance pemetrexed, 20 patients were EGFR mutation positive hence excluded while remaining 138 patients with mutation negative were included for final analysis. All patients (N+80) receiving maintenance TKI were EGFR mutation positive. Gefitinib was the most common TKI used as maintenance in 54 patients (67%) followed by erloti’nib in 26 patients (33%).
Figure 1: CONSORT diagram representing the schema for patients selected for final analysis.

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Median follow up is 16 months. Median progression free survival with maintenance TKI in EGFR mutation positive non squamous NSCLC was 11 months compared to 8 months with maintenance pemetrexed in EGFR mutation negative patients.(p=0.02). Median OS of patients receiving maintenance TKI and maintenance pemetrexed was 20 months and 19 months respectively.(p=0.53). Older age (>65 years), females, co-morbidities (HT/DM), non smoker, good performance status(PS 0-1) and no baseline pleural effusion patients did better with maintenance TKI compared to maintenance pemetrexed. [Table 2]. Patients who had partial response to induction chemotherapy had longer progression free survival with maintenance TKI compared to maintenance pemetrexed, 15 months versus 9 months (p=0.02)
Table 1: Demographic profile of patients receiving maintenance TKI

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Table 2: Factors affecting outcomes (Log rank test) and comparison between maintenance pemetrexed and TKI

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Figure 2: Survival plot showing comparison of PFS with maintenance pemetrexed and TKI

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Figure 3: Survival plot showing comparison of OS with maintenance pemetrexed and TKI

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Total 73 out of 138 patients (53%) receiving maintenance pemetrexed went on to receive second line therapy, with majority of patients received single agent docetaxel (N+35) followed by Erloti’nib (N+16), Gefitinib (N+11), Paclitaxel (N+9) and gemcitabine (N+2). Similarly, 22 out of 32 (68%) patient who progressed on maintenance TKI received second line chemotherapy alone (N+10) or TKI and Second line chemotherapy (N+12), while remaining patients soon succumbed to disease within 8 weeks of progression. As the primary aim of our study was to evaluate the outcomes with maintenance treatment only, we did not report the toxicity pattern of either maintenance option. Moreover, being retrospective, toxicity data could not be retrieved from each consecutive individual case files due to lack of meticulous recording of side-effect profile.


  Discussion Top


Over the years, platinum based combination chemotherapy has established itself as standard of care in locally advanced and metastatic NSCLC with pemetrexed platinum doublet superior to other combination in adenocarcinoma histology.[3],[4] Despite these improvements, majority of patients suffer from early disease progression with median survival between 8-11 months.[4] Moreover 3040% patients fail to receive effective second line agents after progression due to worsening of performance status.[7],[8] Recently, maintenance therapy in patients achieving favourable response to induction and good performance status has shown to delay disease progression and improve survival, albeit modestly.[5],[6] Two types of maintenance strategy have been advocated switch and continuation maintenance. This includes either continuation of non platinum agent used in induction called continuation maintenance or initiating new agent as ‘early second line’ after induction therapy as switch maintenance.

Since 2006, several agents with minimal toxicity profile such as bevazizumab and cetuximab have shown to improve PFS and OS when used as maintenance after favourable response to induction chemotherapy.[9],[10] Use of novel agents in switch maintenance as ‘early second line’ therapy helps in exposing patients to effective drug early in the course of natural history though at the cost of new toxicities. On the contrary advocates of continuation therapy believe in continuing non-platinum component of therapy as it has shown ‘in vivo’ efficacy in form of favourable clinical response and has known minor toxicities with good tolerance. Example of continuation therapy are bevacizumab, cetuximab, gemcitabine, pemetrexed while that for switch maintenance include docetaxel, pemetrexed ,gefitinib and erloti’nib.[5],[6],[7],[8],[9],[10],[11],[12],[13]

We report clinical audit of our prospectively maintained lung cancer database patients of locally advanced and metastatic non squamous NSCLC who received induction pemetrexed platin doublet followed by switch maintenance TKI and continuation maintenance pemetrexed. Patients with EGFR mutation positive and received maintenance TKI was compared with EGFR mutation negative patients receiving maintenance pemetrexed. Median follow up is 16 months. Median PFS with maintenance TKI in EGFR mutation positive patients was significantly better than that of maintenance pemetrexed in EGFR mutation negative (11 months versus 8 months; p=0.01), while the overall survival was 19 months and 20 months respectively. Our data compares well to reported outcomes in Chinese patients by Jia B et al where also maintenance TKI had better PFS than maintenance pemetrexed.[14] Similarly, patients receiving maintenance pemetrexed after pemetrexed induction with EGFR mutation negative had better PFS (12.6 months) than EGFR mutation positive in their data, however they had much lesser patients compared to our data (39 versus 138)[14]. It is important to note that with maintenance pemetrexed even EGFR negative patients enjoy overall survival similar to that of EGFR positive patients (19 months versus 20 months) Another study of East Asian never- smoker patients with advanced NSCLC, known to be enriched for EGFR mutation showed better PFS with gefitinib maintenance (49 patients) after pemetrexed induction similar to our study (80 patients) which had higher number of patients (9.9 months versus 11 months).[15]

In another phase 3 randomised trial in East Asian patients, benefit of maintenance TKI after induction pemetrexed was better with EGFR mutation positive NSCLC compared to mutation negative patients.[16] In SATURN trial too, patients with EGFR mutation positive patients had better PFS with erlotinib compared to mutation negative, though both groups had benefit with erlotinib maintenance.[12] Hence, both major studies support our outcomes of switch TKI maintenance for mutation positive patients. Unlike in SATURN trial, patients who had partial response to induction chemotherapy had longer progression free survival with maintenance TKI compared to maintenance pemetrexed, 15 months versus 9 months (p=0.02).

Among patients who progressed, 53% in maintenance pemetrexed and 68% in maintenance TKI received effective second line therapy. Remaining patients who progressed had rapid disease progression and succumbed to disease within 8-12 weeks of stopping induction therapy. Compared with data from early versus late docetaxel trial (Fidias et al.) 8 and JMEN trial 7 of switch maintenance where 30-40% patients didn’t receive second line due to worsening of performance status and rapid disease progression, our result suggest that by maintaining response achieved after induction with maintenance TKI or pemetrexed significantly helped in delaying symptomatic disease progression.

Due to lack of meticulous recording of toxicities, we could not report detailed toxicity profile of maintenance therapy. However, seven out of 138 patients (5.5%) discontinued maintenance pemetrexed, out of which 3 patients developed renal toxicity while remaining 4 patients had social and financial constraints. None of the patient had discontinued TKI due to severe toxicity, small treatment interruption and dose reduction was done as per standard recommendation. Being retrospective, we do not rule out any selection bias and inadvertent omission of patients which might have inflated the outcome as only patients entered in our database were analysed which might not have included all patients with locally advanced and metastatic NSCLC treated or referred in our institute.

Switch and continuation maintenance therapy are feasible options to delay progression of disease and worsening of symptoms in selected patients who achieve favourable response to induction therapy. Maintenance TKI and pemetrexed have better outcomes in EGFR mutation positive and negative patients respectively. Maintenance pemetrexed in EGFR mutation negative patients help in achieving outcomes similar to that in EGFR mutation positive patients.



 
  References Top

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