Journal of Thoracic Oncology:
Clinical Experience with Gefitinib in Indian Patients
Parikh, Purvish MD*; Chang, Alex Yuang-Chi BM†; Nag, Shona MD‡; Digumarti, Raghunadharao MD§; Bhattacharyya, Gouri Shankar MD|; Doval, Dinesh Chandra MD¶; Babu, Govind MD#; Chacko, Raju Titus MD**; Advani, Suresh MD††; Ranade, Anantbhushan MD‡‡; Aggarwal, Shyam MD§§; Jagannathan, Ramesh MD||; Hargreaves, Laura MSc¶¶; Thatcher, Nick PhD##
*Tata Memorial Hospital, Mumbai, India; †Johns Hopkins Singapore International Medical Centre, Singapore; ‡Jehangir Hospital and Medical Centre, Pune, India; §Nizam's Institute of Medical Sciences, Hyderabad, India; |Institute of Pulmocare and Research, Kolkata, India; ¶Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India; #Kidwai Memorial Institute of Oncology, Bangalore, India; **Department of Medical Oncology, Christian Medical College, Vellore, India; ††Jaslok Hospital and Research Centre, Mumbai, India; ‡‡Deenanath Mangeshkar Hospital and Research Centre, Pune, India; §§Sir Ganga Ram Hospital, New Delhi, India; ||AstraZeneca Pharma India Limited, Bangalore, India; ¶¶AstraZeneca Pharmaceuticals, Charnwood, Leicestershire, United Kingdom; and ##Christie Hospital NHS Trust, Manchester, United Kingdom.
Disclosure: The authors declare no conflict of interest.
Address correspondence to: Purvish Parikh, MD, Tata Memorial Hospital, Mumbai, India. E-mail: firstname.lastname@example.org
Introduction: Treatment options are limited in patients with advanced or refractory non-small cell lung cancer and lead to suboptimal outcome and/or benefit. The epidermal growth factor tyrosine kinase inhibitor gefitinib (IRESSA) has been approved in many countries. Increased responsiveness to gefitinib has been demonstrated in particular subsets of patients, for example never smokers and patients of Asian origin. However, to date, little is known of its use specifically in patients from India.
Methods: Retrospective ad hoc analysis of clinical data from experience with gefitinib in patients with advanced NSCLC from India enrolled in the IRESSA Survival Evaluation in Lung (ISEL) study (n = 77) or included in the gefitinib expanded-access program in India (n = 133).
Results: Among Indian patients enrolled in the ISEL study, median survival was 6.4 months with gefitinib and 5.1 month with placebo. The objective response rate in Indian patients was 14% with gefitinib versus 0% with placebo. In ISEL, tolerability data from Indian patients were consistent with the overall study population. In the Indian gefitinib expanded-access program, median survival was 6 months and gefitinib was well tolerated.
Conclusions: Gefitinib seems well tolerated in Indian patients with advanced NSCLC, with some clinical benefit observed.
Until recently, lung cancer was considered rare in India, but has quickly become a significant cause of morbidity and mortality1; it is estimated that 43,500 Indian patients are diagnosed with lung cancer every year and 37,500 will die of the disease.2 Furthermore, the Indian Council of Medical Research reports that lung cancer is one of the commonest cancers among Indian men, and is particularly prevalent in Delhi, Mumbai, and Bhopal.3
The lung cancer treatment regimens currently in use in India follow the internationally accepted standard schedules and protocols that are applicable to the distinctive clinical profile of the disease in this patient population. Interestingly, Indian patients tend to present with the disease at an earlier age than Western patients.4 Such differences may partly be due to the unique smoking habits of the Indian population, for example bidi smoking (smoking aged Indian tobacco wrapped in a temburni leaf), which has a higher risk of lung cancer than cigarette smoking.5 In India, first-line treatment for advanced (stage IIIb–IV) non-small cell lung cancer (NSCLC) is usually with platinum-based doublet chemotherapy, and second-line treatment is commonly monotherapy with gemcitabine or paclitaxel. These treatment options are applicable in patients with a good performance status. In addition, radiotherapy is the preferred option for pain control and palliative treatment in patients in whom other organs have been compromised due to tumor growth.1,6,7
Gefitinib (IRESSA) is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that has been extensively investigated in NSCLC.8–10 Several studies have shown increased responsiveness to gefitinib in specific patient populations, most notably in patients of Asian origin.11–15 Response rates of 15 to 71% have been reported in patients of Asian origin compared with 5.3 to 29% in patients of non-Asian origin.11–15
The recent international Phase III study—IRESSA Survival Evaluation in Lung cancer (ISEL)—of gefitinib in the treatment of advanced NSCLC showed some improvement in survival in the overall population with gefitinib compared with placebo, but this improvement did not reach statistical significance (hazard ratio [HR] 0.89; 95% confidence interval [CI]: 0.77–1.02; p = 0.087).10 However, preplanned subgroup analyses showed significantly longer survival in the gefitinib group than the placebo group for patients of Asian origin (HR 0.66; 95% CI: 0.48–0.91; p = 0.01) [Figure 1]. Significant improvements with gefitinib compared with placebo in time to treatment failure (time to treatment failure [TTF], median 3.0 versus 2.6 months, respectively; HR 0.82; 95% CI: 0.73–0.92; p = 0.0006) and OR rate (8% versus 1.3%, respectively; odds ratio 7.28; 95% CI: 3.13–16.91; p < 0.0001) were seen in the overall population (Figures 1 and 2).10 On the basis of the significant interactions observed in survival for racial origin, it was judged that exploratory subgroup analyses for these secondary endpoints would be appropriate to ascertain whether the trial was internally consistent with respect to the findings on survival in subsets. The results for TTF were similar to those for survival for patients of Asian origin with a median TTF of 4.4 months for gefitinib and 2.2 months for placebo (HR: 0.69, 95% CI: 0.52–0.91; p = 0.0084) (Figure 2). Objective response (OR) rates were also higher for gefitinib than for placebo in patients of Asian origin (Figure 3).16
Subset analyses are conducted to assess whether different subgroups of patients respond differently to the intervention under investigation.17,18 In the ISEL study, subset analyses were preplanned, and a rigorous statistical approach was used to reduce the chance of false-positive results. However, there is a lack of published data on the use of gefitinib in patients in India. Therefore, it is not yet known whether Indian patients respond to gefitinib in a similar manner to Western populations or to patients of Asian origin. Here we review the current clinical experience with gefitinib in such Indian patients, with data from patients in India enrolled in the ISEL trial and those treated as part of the gefitinib compassionate-use expanded-access program (EAP) in India.
Gefitinib in Patients from India: Phase III Data from ISEL
ISEL (study no: 1838IL/709) was a double-blind, placebo-controlled, parallel-group, multicenter, randomized study that enrolled 1692 patients with locally advanced or metastatic NSCLC from 28 countries in Europe, Asia, Central and South America, Australia, and Canada. All patients had received one or two prior chemotherapy regimens and were refractory or intolerant to the most recent regimen. Patients were randomized in a 2:1 ratio to receive gefitinib 250 mg/d or placebo plus best supportive care. The primary end point was survival in both the overall population and in patients with adenocarcinoma histology. Secondary endpoints were TTF, OR rate, quality of life, and tolerability. Details of the ISEL study design, including inclusion and exclusion criteria, are described by Thatcher et al.10
A retrospective ad hoc analysis of the 77 patients from Indian centers who were enrolled on the ISEL study was carried out. This was not a preplanned analysis; therefore, no statistical analyses were performed on the data. The patients included in the ISEL study were defined by their country of origin rather than their ethnicity, and all Indian patients in the ISEL trial were classified as Caucasian according to protocol definitions. Of the 77 Indian patients, 57 (74%) were randomized to gefitinib and 20 (26%) to placebo (Table 1). The patients’ median age was 56 years (range, 32–75) across both treatment groups, which was lower than observed in the overall ISEL population (median ages 62 and 61 years in the gefitinib and placebo groups, respectively); however, this was expected for the Indian patient population.6 In Indian patients, there was a higher proportion with adenocarcinoma histology (60%) than in the overall ISEL population (45% in both treatment groups). There was also a higher proportion of never smokers in the Indian patients (52%) than in the overall ISEL population (22% in both treatment groups); however, the consumption of smokeless tobacco was not documented. All other baseline demographic and disease characteristics were similar to the overall ISEL population10 and were generally well balanced between the two treatment groups.
In Indian patients at data cut-off, 29 (51%) patients in the gefitinib treatment group had died compared with 12 (60%) patients in the placebo group. Median survival was 6.4 months in patients who received gefitinib and 5.1 month in those who received placebo (Figure 1). In addition, longer TTF was seen in the gefitinib group compared with the placebo group (5.5 months versus 3.0 months, respectively; Figure 2). Seven (14%) ORs (complete or partial) were seen in the gefitinib group (95% CI: 5.9–27.2) and no ORs occurred in the placebo group (Figure 3). Six of the 25 never smokers had an objective response, and one of the 24 ever smokers was a responder; however, no conclusions can be made from this as this is a nonprotocolled subgroup of a subpopulation analysis.
The proportion of patients who discontinued treatment was similar between the two groups: 35 (61%) patients withdrew from the gefitinib group compared with 13 (65%) patients from the placebo group. There was a low incidence of withdrawals due to adverse events (AEs): 3 (5%) patients in the gefitinib group and 3 (15%) patients in the placebo group. AEs were experienced by 51 (90%) patients in the gefitinib group and 19 (95%) patients in the placebo group. National Cancer Institute common toxicity criteria (NCI-CTC) grade 3/4 AEs were observed in 22 (39%) patients receiving gefitinib and 10 (50%) patients receiving placebo. Deaths due to AEs occurred in 6 (11%) patients in the gefitinib group (primary cause of death; NSCLC [1 patient] and respiratory tract infection [1 patient]; silent myocardial infarction [1 patient]; cardiopulmonary failure [1 patient]; respiratory distress [1 patient]; unknown cause [1 patient]), and 3 (15%) patients in the placebo group (primary cause of death; cardiopulmonary failure [1 patient]; unknown cause [2 patients]). Of the nine deaths from AEs, none were considered related to treatment.
Gefitinib in Patients from India: Compassionate-Use Data from the EAP
One hundred and thirty-three patients with advanced NSCLC received gefitinib 250 mg/d in the gefitinib EAP from January 2002 to May 2004. Patients were recommended for the EAP if they had previously documented histologically or cytologically confirmed advanced NSCLC, and had received at least one course of chemotherapy and/or radiotherapy or were ineligible for chemotherapy or radiotherapy.
Baseline demographics of Indian patients in the EAP were similar to those of Indian patients from the ISEL study: most were male (70%), had stage IV disease (54%) and adenocarcinoma histology (77%) (Table 2). Most patients in the Indian EAP had previously received treatment for NSCLC, and only 7 (5%) patients had received no prior chemotherapy.
The median duration of gefitinib treatment was 6 months (range, 0.5–26 months) and median survival was 6 months (range, 0.5–38 months) (Figure 4). Fifty-four (41%) patients survived for a period of 1 to 3 months, 16 (12%) patients survived for 4 to 6 months, 39 (29%) patients survived for 7 to 12 months, and 24 (18%) patients survived for over 12 months.
Although objective and subjective efficacy (including symptomatic improvement) data were not collected prospectively in all patients enrolled in the EAP, objective and subjective responses were observed in some patients.19
Gefitinib was generally well tolerated; skin rash and diarrhea were observed in some patients. Three patients experienced serious AEs that led to withdrawal from the EAP: one patient had a maculopapular rash (NCI-CTC grade 3); one patient had generalized convulsions with sudden loss of vision20; and one patient had suspected interstitial pneumonia.
We have analyzed the clinical experience of gefitinib in Indian patients from the large Phase III ISEL study and the compassionate-use EAP. Results from the subgroup of Indian patients in ISEL showed a median survival of 6.4 months with gefitinib and 5.1 month with placebo. In the overall ISEL population, the median survival in patients treated with gefitinib compared with placebo was 5.6 versus 5.1 month in the overall ISEL population and 9.5 versus 5.5 months in patients of Asian origin.10,16
Analysis of the secondary end point data from the Indian patients in the ISEL study was not preplanned; however, gefitinib seems to provide clinical benefit in terms of TTF (5.5 months with gefitinib versus 3.0 months with placebo) and OR rate (14% [95% CI: 5.9–27.2] with gefitinib versus 0% with placebo). Caution must be used when interpreting these results as no formal statistical analyses were performed. As the median life expectancy in India is 58.5 years for males and 59.6 years for females, the apparent lack of survival benefit in Indian patients from the ISEL study may be due to a greater proportion of non cancer-related deaths.
The EAP was not a clinical trial; therefore, there was no protocol in place for formal collection of efficacy data. Retrospective analysis of data from the Indian gefitinib EAP shows a median survival time of 6 months, which is similar to the median survival observed in Indian patients in ISEL.
Safety data from both the Indian subset in ISEL and the Indian EAP indicate that gefitinib is well tolerated in this patient population.
Differences in the baseline demography of the Indian, Asian, and overall ISEL populations may be at least partially responsible for the observed differences in responsiveness to gefitinib compared with placebo. A higher proportion of patients in the Indian and Asian subgroups in ISEL were never smokers (52% and 41%, respectively) compared with the overall population (22%). However, these results should be approached with caution as consumption of smokeless tobacco is very common in India; hence, the subgroup of Indian never smokers may contain up to 70% of men and 49% of women who chew tobacco, but are recorded as never smokers. Similarly, there was a higher proportion of patients with adenocarcinoma histology in the Indian and Asian subgroups (60% and 61% of patients, respectively) compared with the overall population (45%). Adenocarcinoma histology and a history of never smoking are associated with improved response to gefitinib.14,21–24 Furthermore, mutations in the EGFR gene confer increased sensitivity to gefitinib, and these mutations have been observed at a higher frequency in never smokers and patients with adenocarcinoma histology.22,25–32 It has been suggested that the improved clinical benefit with gefitinib observed in the Asian subgroup could be due to these predictive demographics.16 Similarly, the apparent clinical benefit of gefitinib in Indian patients could be due to the higher proportion of patients who were never smokers or had adenocarcinoma histology. However, it is not yet known whether EGFR mutations also occur in a population that uses smokeless tobacco, and to our knowledge, no data exists on the frequency of such mutations in Indian patients.
Tolerability data from Indian patients in the ISEL study were consistent with the overall population, in that there was a low incidence of withdrawals due to AEs (5% versus 11% with gefitinib and 15% versus 5% with placebo in the Indian and overall ISEL populations, respectively). A similar incidence of AEs was observed in the gefitinib and placebo groups in both the Indian subgroup (90% and 95%, respectively) and the overall ISEL population (82% and 71%, respectively). A similar pattern was observed with grade 3/4 AEs in the gefitinib and placebo groups in both the Indian subgroup (39% and 50%, respectively) and the overall ISEL population (30% and 27%, respectively). The frequency of deaths due to AEs was slightly higher in Indian patients than in the overall ISEL population (11% versus 5% with gefitinib and 15% versus 4% with placebo, respectively), but the difference between the treatment arms was small. Therefore, the observed difference in deaths due to AEs is likely to be a population effect rather than a treatment effect.
The results presented here from Indian patients in the Phase III ISEL study and the Indian EAP suggest that gefitinib is well tolerated in Indian patients with advanced NSCLC, with some clinical benefit observed. Further prospective studies are needed to confirm the efficacy of gefitinib in Indian patients and to determine whether specific subsets of Indian patients may derive increased benefit from gefitinib.
Principal and Main Coinvestigators in the Indian EAP
Shyam Aggarwal, Sir Gangaram Hospital, New Delhi; Harsh Dua, Indraprastha Apollo Hospitals, New Delhi; D.C. Doval, Rajiv Gandhi Cancer Institute & Research Centre, New Delhi; Sunil Kumar Gupta, Fortis Hospital, Noida; Malay Nandy, Dharamshila Cancer Hospital and Research Centre, New Delhi; Dinesh Pendharkar, Batra Cancer Centre, Batra Hospital, New Delhi; P.K. Julka, All India Institute of Medical Sciences, New Delhi; P.K. Das, Indraprastha Apollo Hospitals, New Delhi; Col. Ranga Rao, Rajiv Gandhi Cancer Institute & Research Centre, New Delhi; Rakesh Chopra, Indraprastha Apollo Hospitals, New Delhi; Charanjeev Kapoor, Sir Gangaram Hospital, New Delhi; A.K. Vaid, Rajiv Gandhi Cancer Institute & Research Centre, New Delhi; A.J. Venniyoor, Army Hospital, Research & Referral, New Delhi; Hemant Malhotra, Birla Cancer Centre, Sms Medical College, Jaipur; Anish Maru, Bhagwan Mahaveer Cancer Hospital, Jaipur; Naresh Somani, Bhagwan Mahaveer Cancer Hospital, Jaipur; Pawan Kumar Aggarwal, Bhagwan Mahaveer Cancer Hospital, Jaipur; Umang Mithal, Mithal Cancer Centre, Meerut; Chanchal Goswami, Amri Apollo Hospitals, Kolkata; Anil Kumar Dhar, Command Hospital, Kolkata; S.H. Advani, Jaslok Hospital & Research Centre, Mumbai; R. Gopal, Lilavati Hospital & Research Centre, Mumbai; Boman Nariman Dhabhar, Jaslok Hospital & Research Centre, Mumbai; Purvish Parikh, Tata Memorial Hospital, Mumbai; Ashok R Mehta, Ashok R Mehta; B.K. Smruti, Bombay Hospital, Mumbai; Anantbhushan A. Ranade, Deenanath Mangeshkar Hospital & Research Centre, Pune; Shona Nag, Jehangir Hospital & Research Centre, Pune; Jayantilal G. Patel, Ramakrishna Cancer Care Centre, Surat; Chirag Shah, Hem-Onc Associates, Ahmedabad; Bhavin Shah, Shrey Hospital, Ahmedabad; Pankaj Shah, Gujarat Cancer & Research Institute, Ahmedabad; Shekhar Patil, Bangalore Institute of Oncology, Bangalore; T. Raja, Apollo Cancer Hospitals, Chennai; Nalini Kilara, M.S. Ramaiah Hospital, Bangalore; A. Raghavan, Bhagwan Mahaveer Jain Hospital, Bangalore; S.V.S.S. Prasad, Apollo Cancer Hospitals, Hyderabad; G. Sudharshan, Medwin Hospitals, Hyderabad; Govind Babu, Curie Centre Of Oncology, Bangalore; R.V. Rao, Apollo Hospitals, Hyderabad; G.Srinivas Chakravarthy, Apollo Hospitals, Hyderabad; M.G. Nagakishore, Balaji Cancer Care Centre, Guntur; Ramesh Nimmagadda, Apollo Cancer Hospitals, Chennai; Raju Titus Chacko, Narayan Kutty Warrier, Medical College, Kozhikode.
The authors thank the monitors, nurses, data managers, support staff, and patients involved in ISEL and the EAP, and Mark English from Complete Medical Communications, who provided medical writing support funded by AstraZeneca.
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Clinical; Gefitinib; Indian patients; IRESSA
© 2008International Association for the Study of Lung Cancer
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