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  Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 1  |  Page : 188-192
 

Study of gefitinib maintenance in unselected patients with metastatic primary lung adenocarcinoma: A descriptive study


1 Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
2 Department of Radio-diagnosis and Imaging, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
3 Department of Pulmonary Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India

Date of Web Publication1-Dec-2017

Correspondence Address:
Dr. B Dubashi
Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_46_17

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 » Abstract 

BACKGROUND: Maintenance treatment of patients with advanced nonsmall cell lung cancer (NSCLC) without disease progression after first-line chemotherapy is a subject of ongoing research. The aim of this study was to investigate the efficacy, safety, and tolerability of the epidermal growth factor receptor (EGFR)–tyrosine-kinase inhibitor, i.e., gefitinib in the maintenance setting irrespective of EGFR status. METHODS: Patients aged 18 years or older of Indian origin, who had a life expectancy of >12 weeks with histologically or cytologically confirmed Stage IV NSCLC, the WHO performance status of 0–2, and who had completed four to six cycles of first-line platinum-based doublet chemotherapy without disease progression or unacceptable toxic effects were included in the study. The primary endpoint of the study was progression-free survival in the intention-to-treat population. RESULTS: Twenty-five patients with a median age of 55 years (40–68) were included in the study. The median progression-free survival (PFS) for the entire group was 8 months (95% confidence interval [CI] =1.45–14.54) had not reached for EGFR-positive patient, but in the EGFR negative cohort, the PFS was 4.98 months (hazard ratio = 0.092, 95% CI = 3.4–6.5, P = 0.01). The median overall survival (OS) of the study group was 15 months (95% CI = 3.7–26.4), all patients with EGFR positive were alive (100% survival). The median OS for EGFR negative group was about 6.3 months. The major toxicity observed was rash/acne in 15 patients, pruritus in 7 patients, and one patient had Grade 4 pneumonitis. CONCLUSION: Gefitinib maintenance is safe, well-tolerated therapy, produces significant PFS and OS benefit in EGFR mutation-positive patient. It is definitely not a choice for EGFR negative group. In EGFR unknown group, the role of maintenance still needs to be explored.


Keywords: Advanced nonsmall cell lung cancer, gefitinib, maintenance chemotherapy


How to cite this article:
Kumar R, Dubashi B, Kayal S, Lazzar S C, Barathi D, Kumar V. Study of gefitinib maintenance in unselected patients with metastatic primary lung adenocarcinoma: A descriptive study. Indian J Cancer 2017;54:188-92

How to cite this URL:
Kumar R, Dubashi B, Kayal S, Lazzar S C, Barathi D, Kumar V. Study of gefitinib maintenance in unselected patients with metastatic primary lung adenocarcinoma: A descriptive study. Indian J Cancer [serial online] 2017 [cited 2020 Apr 6];54:188-92. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/188/219584



 » Introduction Top


In India, lung cancer represents 6.9% of all new cancers notified and 9.3% of cancer deaths in both sexes related to lung cancer. The majority (two-third) of lung cancer present in an advanced stage (Stage IIIb and IV).[1]

Continuation of induction platinum-based combination chemotherapy beyond four to six cycles results in heightened toxicities and diminished quality of life without providing a survival advantage.[2] Thus, the standard therapeutic approach has entailed stopping treatment at that point, close clinical and radiographic surveillance, and initiation of second-line treatment at the time of progression.

However, the availability of effective newer cytotoxic and molecularly targeted agents that can be tolerated for prolonged periods has led to a reconsideration of the duration of initial therapy for advanced nonsmall cell lung cancer (NSCLC). This approach is known as maintenance therapy. The goal of maintenance therapy is to delay disease progression and consequently improve the overall survival (OS) and maintain health-related quality of life. To achieve these goals, the therapy must have a low rate of Grade 3 or 4 toxicity and limited cumulative toxicity so that patients can tolerate the extended duration of therapy. A Phase III trial of gefitinib compared to docetaxel revealed the noninferiority of gefitinib in an unselected patient population, and a lower rate of Grade 3 or 4 neutropenia febrile neutropenia and all grades of asthenia.[3] Thus, gefitinib may be an attractive maintenance agent following induction platinum doublet chemotherapy.

This study will provide baseline data on the role of gefitinib maintenance in Indian patients with metastatic adenocarcinoma of the lung.


 » Methods Top


Study design and patients

Our study was a descriptive interventional study conducted from December 2013 to October 2015. We recruited 25 patients with metastatic adenocarcinoma of lung who received at least four cycles of platinum doublet chemotherapy and had at least a stable disease (SD). They received maintenance gefitinib at a dose of 250 mg/day until progression or unacceptable side effect or death [Figure 1].
Figure 1: Study design

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Inclusion criteria

Age > 18 years old, primary metastatic lung adenocarcinoma, irrespective of their epidermal growth factor receptor (EGFR) status, and Eastern Cooperative Oncology Group-Performance Status 0–2. Patients with complete response (CR)/partial response (PR)/SD postinduction chemotherapy were included in the study.

Exclusion criteria

Those who received gefitinib as frontline therapy were excluded from the study.

Methodology

Patients were recruited for the study after obtaining informed consent. Patients diagnosed with primary metastatic lung cancer who had nonprogressive disease (i.e., CR/PR/SD) after receiving induction chemotherapy for four cycles were included in the study. EGFR testing was done using formalin-fixed paraffin-embedded tissue collected either by biopsy or slides using Amplification Refractory Mutation System real-time polymerase chain reaction. Patients were enrolled in the study within 6–8 weeks after induction chemotherapy. All patients received gefitinib 250 mg/day irrespective of their EGFR mutation status until disease progression or Grade 3 or 4 toxicity or death. Disease progression was defined based on Response Evaluation Criteria in Solid Tumor criteria by doing contrast-enhanced computed tomography scan every 3 months or earlier if there was clinical suspicion of progression. The toxicity profile was categorized according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version-4.03 every month or whenever the patient has toxicities. Progression-free survival was defined as the time from initiation of gefitinib to disease progression or death from any cause. OS was defined from the date of gefitinib to the date of death due to any cause or last date that the patient was known to be alive [Figure 2].
Figure 2: Consort diagram

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Statistical analysis

Patient demographic characteristics, disease status, EGFR status, and acute toxicities were described using frequency tables with counts and percentages. The probability of survival data was calculated using Kaplan–Meier method, later the null hypothesis was tested by log-rank test and Cox proportional hazard ratio (HR). Survival analysis was carried out using SPSS software version 16.0 (IBM PASW statistics version 9.0). All statistical analyses were carried out for two-tailed significance at 5% level of significance and P < 0.05 was considered statistically significant.


 » Results Top


A total of 25 consecutive patients with metastatic adenocarcinoma of lung who had at least SD after platinum doublet chemotherapy were included in the study.

Patient characteristics

The median age group was 55 years (range = 48–68). Ten patients (40%) were males. In the study group, 18 (72%) patients were nonsmokers and 80% of them were using open-hearth fire for >15 years for their cooking. Histological diagnosis was available for all patients, of which 7 (28%) was by fine-needle aspiration cytology (FNAC) and 18 (72%) by biopsy. Of the 25 patients, 6 (24%) had EGFR mutation positive. We observed about 36.6% overall objective response with platinum doublet in our series [Table 1].
Table 1: Baseline characteristics (n=25)

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Gefitinib-related toxicity

[Table 2] lists the adverse events noticed during the study period. The toxicity profile was categorized according to NCI CTCAE version-4.03 every month or whenever a patient has toxicity. The majority of observed toxicities were Grade 1 and 2, only one patient developed Grade 4 pneumonitis, and he belonged to an EGFR negative group. Dermatological Grade 1 and 2 events were observed in 15 patients. Rash/acne, pruritus, and dry skin were the common skin-related adverse effects noticed. Fourteen (56%) had diarrhea and 4 (16%) had nausea and vomiting. There were no hematological and hepatic-related adverse events.
Table 2: Overall group toxicity with gefitinib maintenance (n=25)

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The median progression-free survival (PFS) for the entire group was 8 months (95% confidence interval [CI] = 1.45–14.54). At the time of analysis, 12 (48%) patients had progressed [Figure 3]. The median duration of gefitinib maintenance was 5 months at a median duration of follow-up of 6.3 months. The median progression had not reached for EGFR-positive group. In the EGFR negative cohort, the PFS was 4.98 months (HR = 0.092, 95% CI = 3.4–6.5, P = 0.01). There was a significant difference in PFS between patients with EGFR positive and EGFR negative group.
Figure 3: Median progression free survival of all patients enrolled in the study

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The median OS of the study group was 15 months (95% CI = 3.7–26.4). Out of 25 patients, 15 patients were alive at the end of the study; at 6 months of treatment follow–up, 68% were alive [Figure 4].
Figure 4: Overall survival of all patients enrolled in the study

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The median OS for EGFR negative group was about 6.3 months, whereas all patients with EGFR positive were alive (100% survival); there was a significant difference between two groups (HR = 0.15, 95% CI = 0.0–7.4, P = 0.01). Three (42.8%) had died in the unknown group at the end of study (HR = 3.26, 95% CI = 0.63–16.9, P = 0.14). The OS was not significantly different between EGFR negative and unknown group.


 » Discussion Top


Maintenance therapy is another novel entity in the past decade, which had improved the overall outlook of these advanced lung cancers.

The current study enrolled a total of 25 consecutive patients who had at least SD for platinum doublet induction chemotherapy irrespective of EGFR status. The median age of presentation was 55 year (40–68 years), a decade younger compared to Western data where median age was sixth decade (30–74 years),[4] nonsmokers were 72% (n = 18), but 80% (n = 20) were using open hearth fire system for their domestic cooking at their homes.

Diagnosis was made based on biopsy in 18 (72%) patients and remaining 7 patients (28%) had FNAC of the lung mass or positive pleural fluid cytology. In well-designed studies, adequate tissue biopsy was possible in around 83%–90%,[5] average rate of histology confirmation in the UK was 73% (range from 25% to 88% across the different cancer network). This is an important limitation as molecular studies cannot be performed if there is no adequate tissue.

EGFR mutation positivity in our study was 24% with most common mutation being L858R in exon 21 was observed in 4 (16%) patients and 2 (8%) had a deletion in exon 19. Uncommon mutations were not observed. EGFR mutation rate is compared to other Indian studies which have reported 23%–33%.[6],[7]

In our study, the overall response rate to platinum doublet was 36.6% (PR + SD), which is similar to published data by Ohe et al.[8] The dermatological adverse events were more common among the EGFR-positive patients, rash and acne were noticed in 5 (83%) out of 6 patients, pruritus in 3 (50%), and dry skin in 4 (66.6%) patients.

In the INFORM trial,[9] Grade 1 and 2 rash was observed in 50% of patients, pruritus in 7%, and dry skin in 6% patients. We noticed the higher frequency of skin toxicity than in the INFORM trial. In EORTC 08021 trial,[10] they had noticed rash in about 47% of participants compared to 13% in placebo arm, but they have not mentioned regarding other dermatological adverse events.

After dermatological adverse events, gastrointestinal tract-related adverse events were more common in our study. No Grade 3 and 4 diarrhea was noticed in our study. Diarrhea was the most common noted in 14 (56%), followed by nausea and vomiting seen in 4 (16%) patients.

We had noticed interstitial pneumonitis in 1 (4%) patient, and he belonged to the EGFR negative group. He developed within 1 month after initiation of gefitinib maintenance treated with supportive care and he finally succumbed. In the INFORM trial, there was one patient who died of interstitial lung disease, but there were no data on the EGFR status.[9] There were no hematological and hepatotoxicity observed in our study.

The median duration of treatment was 5 months (range = 1–17 months), at the cutoff date for analysis. Twelve (48%) patients had progressive disease and 10 (40%) patients had died. Median follow-up was 6.3 months (range = 1–17 months) and median PFS was 8 months (95% CI = 1.45–14.54).

Yang et al. noticed PFS of 8.38 months (95% CI = 6.44–11.14) in pemetrexed and cisplatin (PC), followed by gefitinib arm in their paper published on first-line PC followed by gefitinib (PC/G) as switch maintenance versus gefitinib monotherapy (G) as continuous maintenance.[11] The study was in an unselected East Asian population. There was no significant difference in PFS between the PC/G and G group in the intent-to-treat population (median PFS = 8.38 and 9.63 months in PC/G and G groups accordingly); however, the unadjusted HR favored PC/G (unadjusted HR [PC/G vs. G] 0.85; 95% CI = 0.63–1.13; P = 0.261). These results are comparable with the current study.

Mencoboni et al.[12] noticed in a single-arm trial consisting of cisplatin and gemcitabine, followed by gefitinib maintenance in unselected histology, found PFS of 5 months in overall group. The adenocarcinoma histology group had a median PFS of 9 months compared to nonadenocarcinoma histology of 3 months which was statistically significant, P = 0.002.

In the INFROM trial [9] consisting of gefitinib versus placebo maintenance after platinum doublet in advanced or metastatic NSCLC showed overall PFS of 4.8 months (95% CI = 3.2–8.5) versus 2.6 month (95% CI = 1.6–2.8); with HR 0.42 (95% CI = 0.33–0.55; P < 0.0001). They found similar benefit across all subgroups except nonadenocarcinoma histology (P = 0.027) and EGFR status subgroup (0.0063). This is the only trial that had analyzed subgroup PFS on EGFR status in two groups (gefitinib and placebo). EGFR positive group had greatest PFS benefit with a median PFS of 16.6 months (HR = 0.17, 95% CI = 0.07–0.42 range = 9.4–22.7 months). EGFR negative group had a median PFS of 2.7 months (range = 1.4–2.9 months). EGFR unknown group had a median of PFS 6.0 month (range = 3.2–9.4 months) and the HR favored gefitinib over placebo (HR = 0.40, 95% CI = 0.29–0.54).

The median PFS had not reached in EGFR positive and unknown group at the time of data analysis. Median estimated PFS of EGFR negative group 4.98 months (HR = 0.092; 95% CI = 3.4–6.5; P = 0.01). The median OS was about 15 months irrespective of EGFR status. These patients had a very short follow-up period requiring more follow-up for any conclusion to be drawn.

In INFORM trail,[9] they had noticed OS of 18.7 months (95% CI = 15.6–22.2) in gefitinib group compared to 16.9 months (95% CI = 14.5–19.0) in placebo group which was not significant (HR = 0.84, P = 0.26). All published data have not shown any OS advantage with gefitinib maintenance.

A systematic review done by Chen et al. on gefitinib or erlotinib as maintenance in advanced stage NSCLC found a significant improvement of OS in maintenance group (HR = 0.84, 95% CI = 0.76–0.93).[13] This improvement was seen in erlotinib subgroup (HR = 0.84, 95% CI = 0.75–0.94) but not in gefitinib subgroup (HR = 0.85, 95% CI = 0.65–1.02). When analyzed in detail, it was found that these results had been influenced by the SATURN study. A significant improvement of OS was still detected in the maintenance group (HR = 0.87, 95% CI = 0.76–0.98) but not specific to either erlotinib or gefitinib group.


 » Conclusion Top


Gefitinib maintenance is safe, well-tolerated, produces significant PFS and OS benefit in EGFR mutation-positive patient. It is definitely not a choice for EGFR negative group. In the EGFR unknown group, the role of maintenance still needs to be explored. However, if patients are female, nonsmoker, Asian ethnicity, and response to chemotherapy, maintenance therapy with gefitinib may be considered in the unknown EGFR group.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

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Malik PS, Raina V. Lung cancer: Prevalent trends and emerging concepts. Indian J Med Res 2015;141:5-7.  Back to cited text no. 1
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Socinski MA, Schell MJ, Peterman A, Bakri K, Yates S, Gitten R, et al. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol 2002;20:1335-43.  Back to cited text no. 2
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Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): A randomised phase III trial. Lancet 2008;372:1809-18.  Back to cited text no. 3
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Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92-8.  Back to cited text no. 4
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Choughule A, Noronha V, Joshi A, Desai S, Jambhekar N, Utture S, et al. Epidermal growth factor receptor mutation subtypes and geographical distribution among Indian non-small cell lung cancer patients. Indian J Cancer 2013;50:107-11.  Back to cited text no. 6
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Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, et al. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann Oncol 2007;18:317-23.  Back to cited text no. 8
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Zhang L, Ma S, Song X, Han B, Cheng Y, Huang C, et al. Gefitinib versus placebo as maintenance therapy in patients with locally advanced or metastatic non-small-cell lung cancer (INFORM; C-TONG 0804): A multicentre, double-blind randomised phase 3 trial. Lancet Oncol 2012;13:466-75.  Back to cited text no. 9
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Gaafar RM, Surmont VF, Scagliotti GV, Van Klaveren RJ, Papamichael D, Welch JJ, et al. Adouble-blind, randomised, placebo-controlled phase III intergroup study of gefitinib in patients with advanced NSCLC, non-progressing after first line platinum-based chemotherapy (EORTC 08021/ILCP 01/03). Eur J Cancer 2011;47:2331-40.  Back to cited text no. 10
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Yang JC, Kang JH, Mok T, Ahn MJ, Srimuninnimit V, Lin CC, et al. First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian patients with locally advanced or metastatic non-squamous non-small cell lung cancer: A randomised, phase 3 trial. Eur J Cancer 2014;50:2219-30.  Back to cited text no. 11
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Mencoboni M, Bergaglio M, Serra M, Ivaldi GP, Tredici S, Racchi O, et al. Maintenance therapy with gefitinib after first-line chemotherapy in patients affected by advanced non-small cell lung cancer. Anticancer Res 2007;27:4425-9.  Back to cited text no. 12
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