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Table of Contents
GERIATRIC ONCOLOGY SECTION
Year : 2020  |  Volume : 3  |  Issue : 1  |  Page : 44-50

The efficacy and safety of first-line therapy for the epidermal growth factor receptor mutant non-small cell lung cancer in older versus younger patients: A pooled analysis of two randomized controlled trials


1 Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Pathology, Tata Memorial Center, Homi Bhabha National Institute, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Radiodiagnosis, Tata Memorial Center, Homi Bhabha National Institute, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Submission22-Jan-2020
Date of Decision31-Jan-2020
Date of Acceptance02-Feb-2020
Date of Web Publication24-Feb-2020

Correspondence Address:
Vanita Noronha
Department of Medical Oncology, Tata Memorial Hospital, Dr. E Borges Road, Parel West, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_35_20

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  Abstract 


Background: There is a scarcity of data to guide the management of older patients with cancer. We therefore conducted this study to compare the outcomes and toxicities in older versus younger patients with an epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC).
Patients and Methods: For this pooled analysis, we utilized the individual patient databases of two prospective, first-line Phase III randomized controlled trials in patients with EGFR-mutant advanced NSCLC. The therapies in the two trials included gefitinib alone, pemetrexed/carboplatin, followed by maintenance pemetrexed and the combination of gefitinib with pemetrexed/carboplatin chemotherapy. We evaluated the progression-free survival (PFS) and overall survival (OS) of older patients (=/> 60 years) as compared to younger patients. Grade 3 or worse adverse events were also compared.
Results: A total of 640 patients were included in this analysis, of which 156 (24.3%) were 60 years or older. The median PFS with first-line therapy was 8.5 months (95% confidence interval [CI], 7.8–9.2) in younger versus 9 months (95% CI, 6.7–11.4) in older patients (hazard ratio [HR], 2.3; 95% CI, 0.8–6.7; P = 0.575). The median OS of younger patients was 23.2 months (95% CI, 20.6–25.6) compared to 19 months (95% CI, 14.2–23.7) in older patients (HR, 1.18; 95 CI, 0.89–1.54, P = 0.234). On comparing older with younger patients for various known prognostic factors, there was no difference in OS based on any of the factors. On comparing the toxicities between the younger and older patients in the combination group, there was no difference in Grade 3 or 4 toxicities between younger and older patients except higher incidence of diarrhea in older patients (24.4% versus 9.3%, P = 0.010).
Conclusions: In patients with EGFR-mutated NSCLC, similar survival and toxicities were found in patients aged 60 years or older as compared to younger patients with Eastern Cooperative Oncology Group Performance Status of 0–2, except for a higher incidence of diarrhea in older patients.

Keywords: Epidermal growth factor receptor, geriatric, nonsmall cell lung cancer, older patients, EGFR, NSCLC, elderly


How to cite this article:
Kapoor A, Noronha V, Patil VM, Joshi A, Menon N, Chougule A, Chandrani P, Trivedi V, Behel V, Kumar R, Mahajan A, Janu A, Prabhash K. The efficacy and safety of first-line therapy for the epidermal growth factor receptor mutant non-small cell lung cancer in older versus younger patients: A pooled analysis of two randomized controlled trials. Cancer Res Stat Treat 2020;3:44-50

How to cite this URL:
Kapoor A, Noronha V, Patil VM, Joshi A, Menon N, Chougule A, Chandrani P, Trivedi V, Behel V, Kumar R, Mahajan A, Janu A, Prabhash K. The efficacy and safety of first-line therapy for the epidermal growth factor receptor mutant non-small cell lung cancer in older versus younger patients: A pooled analysis of two randomized controlled trials. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Aug 4];3:44-50. Available from: http://www.crstonline.com/text.asp?2020/3/1/44/279110




  Introduction Top


Lung cancer is the most common cancer diagnosed worldwide and is also the leading cause of cancer-related mortality in both sexes combined.[1] The Surveillance, Epidemiology, and End Results statistics review from 1975 to 2016 showed that over 80% of patients living with lung cancer were older than 60 years, the median age being 70 years.[2] According to the GLOBOCAN 2018 data, the incidence of lung cancer in India is 67,795 with 63,475 deaths annually in all ages and both sexes.[1] Most importantly, the incidence rises sharply between 54 and 59 years and peaks at around 65 years, thus making lung cancer mostly a disease of older persons. The age cutoff for the geriatric population in the Western countries is often taken as 65 years and over, while in developing countries with lower life expectancy and poorer health-care infrastructure, the cutoff for the geriatric population is considered to be lower.[3],[4] In our study, we considered the cutoff age as 60 years or over for classifying a patient as older.

Geriatric oncology patients are prone to develop severe toxicities in view of multiple comorbidities, polypharmacy, and potential drug interactions. Most of the pivotal clinical trials have excluded geriatric patients.[5] This has led to the availability of very little data for geriatric patients, and thus, their management requires significant expertise and attention. Most of the time, the data of fit, young patients need to be extrapolated to the geriatric population which may lead to worse outcomes and increased toxicities. We conducted this pooled analysis to evaluate the outcomes and toxicities of older patients and to compare them to those in younger patients.


  Patients and Methods Top


This pooled analysis utilized the individual patients' databases of two prospective, first-line Phase III randomized controlled clinical trials for patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer (NSCLC). In the first study by Patil et al., gefitinib 250 mg orally daily was compared to pemetrexed dosed at 500 mg/m2 and carboplatin (dose calculated by the area under the curve 5 using Calvert formula) doublet for four cycles, followed by maintenance pemetrexed.[6] In the second study by Noronha et al., patients were randomized to receive oral gefitinib with pemetrexed/carboplatin chemotherapy (combination arm) versus gefitinib alone.[7] Both the trials were approved by the institutional ethics committee, were registered with the Clinical Trials Registry of India (CTRI/2015/08/006113 and CTRI/2016/08/007149), and were monitored by the data safety and monitoring subcommittee. All patients provided written informed consent prior to participation in the trials. Both the trials were conducted as per the principles set by the International Conference on Harmonization Good Clinical Practice guidelines, the Helsinki Declaration, and the Schedule Y as per Drugs and Cosmetic Act, 1940, and the directives of Indian Council of Medical Research.

The eligibility criteria of both the studies were similar and are summarized as follows: (1) Stage IIIB/IV NSCLC treated with palliative intent, (2) no prior chemotherapy or targeted therapy in the palliative setting, (3) Eastern Cooperative Oncology Group performance score of 0–2, (4) sensitizing EGFR mutation, and (5) acceptable organ functions.

The patients were divided according to the age into an older cohort consisting of patients aged 60 years or older and a younger cohort comprising patients below the age of 60 years. Older patients were further subgrouped into young–old (60–69 years) and old–old (70 years and older) patients. The outcomes were calculated in terms of progression-free survival (PFS) and overall survival (OS). PFS was calculated from the date of randomization to the date of progressive disease (objective or subjective deterioration) or death due to any cause. OS was calculated from the date of randomization to the date of death from any cause. PFS2 was defined as the time from randomization to the second progression event (either second progression or death, whichever happened earlier) as ascertained by the investigator.

The Kaplan–Meier method was used to estimate survival probabilities, and log-rank test was used to detect any differences between older and younger patients.[8] Cox proportional hazards model was used to compare survival with age group as a covariate.[9],[10] Grade 3 or higher adverse events were evaluated, as the homogeneously high frequency of adverse events of the lower grade was expected to complicate a clinically meaningful comparison of toxicities between older and younger patients. SPSS version 20.0 (Armonk, NY, USA) was used for all statistical calculations.


  Results Top


The two trials included a total of 640 patients, of which 156 (24.3%) were 60 years or older. In the overall cohort, the median age was 54 years (range, 26–80) with 53.9% (n = 345) patients being males; 18% (n = 115) patients had a history of smoking; 17% (n = 109) had brain metastasis at diagnosis, and 14.4% (n = 92) patients had Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 2. In the cohort of older patients (n = 156), the median age was 66 years (range, 60–80) with 52.6% males and 22.4% had ECOG PS of 2. There were 116 patients in the young–old subgroup (60–69 years) and 40 patients in old–old subgroup (70 years and above).

Comparison of survival between older and younger patients

The median PFS with first-line therapy was 8.5 months (95% confidence interval [CI], 7.8–9.2) in younger versus 9 months (95% CI, 6.7–11.4) in older patients (hazard ratio [HR], 2.3; 95% CI, 0.8–6.7, P = 0.575) [Figure 1]. The median OS of younger patients was 23.2 months (95% CI, 20.6–25.6), while it was 19 months (95% CI, 14.2–23.7) for older patients (HR, 1.18; 95 CI, 0.89–1.54, P = 0.234) [Figure 2]. On comparing older versus younger patients for gender, stage, ECOG PS, smoking status, and EGFR exon 19 mutation versus others, there was no difference in OS based on any of the factors [Table 1]. These results suggest that there was no difference in survival (both PFS and OS) of younger and older patients. The two subgroups of older patients had similar median PFS and OS. The median PFS in young–old patients was 8.6 months (95% CI: 5.1–12.1) versus 10.7 months (95% CI: 7.4–14.0) in old–old patients (P = 0.529). The corresponding median OS was 22.8 months (95% CI: 17.6–28.0) versus 17.0 months (95% CI: 7.5–26.5), respectively (P = 0.423). Among smokers (n = 215), the survival was significantly worse in older patients with a median OS of 12.1 months (95% CI, 4.3–19.9) as compared to younger patients who had a median OS of 19.1 months (95% CI, 15.2–23.1) (P = 0.012). Similarly, among males (n = 345), the survival was significantly worse in older patients with a median OS of 17 months (95% CI, 11.5–22.5) as compared to younger patients who had a median OS of 20.9 months (95% CI, 17.5–24.3) (P = 0.033).
Figure 1: Kaplan–Meier survival curve showing the progression-free survival of older versus younger patients

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Figure 2: Kaplan–Meier survival curve showing the overall survival of older versus younger patients

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Table 1: Survival analysis of factors comparing older and younger patients

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Survival of older patients according to the type of treatment received

The older patients from both the trials were grouped according to the therapy received into gefitinib alone, chemotherapy alone, and the combination. Gefitinib alone was given to 88 (56.4%) older patients and 45 (28.8%) received gefitinib + chemotherapy while 23 (14.8%) older patients were given chemotherapy alone. The median PFS of the older patients who were randomized to receive gefitinib alone was 9 months (95% CI, 6.6–11.4), while it was 16 months (95% CI, 10.6–21.3) for those who received gefitinib + chemotherapy (P = 0.009, HR: 1.8 [95% CI: 1.1–2.7]). The corresponding PFS rate at 1 year was 35.3% (standard deviation [SD] 5.3) versus 59.4% (SD: 7.4). The median OS in the gefitinib alone arm was 17.7 months (95% CI: 15.4–20.1) versus 28 months in the combination arm (P = 0.260). The 2-year OS in the gefitinib alone arm was 39% (SD: 6.8), while in the combination arm, it was 63% (SD: 7.8). The median PFS of older patients who received chemotherapy alone (n = 23) was 3.2 months (95% CI: 1.8–4.6), while the median OS was 18.8 months (95% CI: 8.2–29.2). The corresponding PFS at 1 year was 4.7% (SD, 4.5), whereas OS at 2 years was 56.4% (SD, 11.2).

Toxicities in older patients as per the treatment received

The comparison of the Grade 3 or 4 toxicities in these three groups is depicted in [Table 2]. On comparing the combination group with gefitinib alone, Grade 3 or 4 anemia occurred in 20% versus 5.7% (P = 0.011), febrile neutropenia in 11.1% versus 0% (P = 0.001), and diarrhea in 24.4% versus 11.4% (P = 0.050). Overall, the incidence of Grade 3 or 4 toxicities in older patients receiving gefitinib alone (n = 88) was 43.2% versus 62.2% in patients receiving combination therapy (n = 45) (P = 0.038). On comparing the toxicities between the younger and older patients in the combination group, there was no difference in Grade 3 or 4 toxicities between younger and older patients in terms of anemia, neutropenia, thrombocytopenia, febrile neutropenia, and fatigue. Only diarrhea was significantly higher in older patients (24.4% versus 9.3%, P = 0.010) [Supplementary Table 1]. These results point toward a similar toxicity profile of the combination of gefitinib and chemotherapy among younger and older patients. Furthermore, among the older patients, there was no difference in overall Grade 3 or 4 toxicities in patients with ECOG PS 0–1 versus 2. Older patients with PS 0–1 had 42.9% (52 out of 121 patients) incidence of any Grade 3 or 4 toxicities as compared to 54.2% (19 out of 35 patients) with PS of 2 (P = 0.237).
Table 2: Comparison of Grade 3 or 4 toxicities in the pooled data of older patients from the two trials

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Outcomes and toxicities in older patients in the study by Noronha et al.

Of the 350 patients in gefitinib + chemotherapy (combination arm of pemetrexed/carboplatin + gefitinib) versus gefitinib alone study by Noronha et al., 113 patients (32.3%) were older; 68 (60.2%) received gefitinib alone, while 45 (39.8%) were randomized to the combination arm. The median PFS2 in the gefitinib alone arm was 13 months (95% CI, 9.9–16.1) versus 16 months (95% CI, 10.6–21.3) in the combination arm (P = 0.775) for the older patients. Details of comorbidities were available in this study; 74 (65.4%) older patients had at least one comorbidity. The median PFS was 14 months (95% CI, 7.8–20.2) in patients without any comorbidity versus 11 months (95% CI, 9.5–12.5) in patients with at least one comorbidity (P = 0.231). The median OS was not reached for older patients with no comorbidities, while it was 19 months (95% CI, 16.0–21.9) in patients with at least one comorbidity (P = 0.725). Overall Grade 3 or higher toxicities were recorded in 74 (65.5%) patients; after excluding asymptomatic hypertension, neutropenia, and hyponatremia, 48 (42.5%) had clinically significant Grade 3 or higher toxicities. On comparing the toxicities in patients with and without comorbidities, older patients experienced similar Grade 3 or 4 toxicities [Table 3] except for a higher incidence of Grade 3 or 4 diarrhea in older patients with at least one comorbidity (18.9% vs. 4.1%, P = 0.002).
Table 3: Comparison of Grade 3 or 4 toxicities between older and younger patients on the basis of presence or absence of comorbidities (from the study by Noronha et al.)

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Outcomes and toxicities in older patients in the study by Patil et al.

Of 290 patients enrolled in gefitinib versus chemotherapy (pemetrexed/carboplatin) study by Patil et al., 43 (14.8%) patients were older. The median PFS of older patients was 6.2 months (95% CI, 5.6–6.8) versus 6.6 months (95% CI, 5.5–7.6) in younger patients (P = 0.172). One-year PFS in older patients was 19.2% (SD: 6.1), while it was 27.1% (SD, 3.0) in younger patients. The median OS in the two groups was 18.8 months (95% CI, 16.4–21.0) and 20.5 months (95% CI, 17.2–23.8), respectively (P = 0.916). Two-year OS was 36.1% (SD, 9.3) and 41.6% (SD, 3.8), respectively. On comparing the Grade 3 or 4 toxicities between older and younger patients in the chemotherapy alone arm of this study, there was no difference in any of the toxicities in the two groups [Supplementary Table 2]. For chemotherapy alone, the overall incidence of Grade 3 or 4 anemia was 12.4%, neutropenia 11%, thrombocytopenia 9%, febrile neutropenia 6.9%, hyponatremia 16.6%, nausea/vomiting 4.1%, and fatigue and diarrhea each 4.8%.




  Discussion Top


We found that the older patients with EGFR-mutated NSCLC treated with first-line therapy had similar survival and toxicities as compared to the younger patients. The treatment decision in older patients with NSCLC planned for palliative intent systemic therapy remains challenging due to nihilism with perceived higher rates of toxicities and reduced benefit with the standard management. An analysis of South West Oncology Group which pooled 616 patients (of which 20% were of age 70 years or older) reported inferior OS in older patients (median 7 vs. 9 months; P = 0.04) despite PFS being the same in both the groups (median 4 months).[11] The same study also reported that Grade 3–5 toxicities were higher among older patients (94% versus 87%; P = 0.04). At the same time, ECOG published the results of a secondary analysis of a randomized controlled trial of four platinum-based doublet chemotherapy regimens for advanced NSCLC. This study showed similar survival results and toxicities between patients aged 70 years or older (n = 227) versus younger than 70 years (n = 912).[12] This is in agreement with our study in which there was no difference in survival or toxicities between older and younger patients. Thus, the age should not be a criterion to select patients for the combination therapy for EGFR-mutated NSCLC. It should be noted that the median age of all the patients in our study was 54 years which is at least 10–12 years younger than that reported in the Western data. We defined older patients as those 60 years or older as against the usual standard of 65–70 years. This age cutoff is in agreement with Indian guidelines and the National policy on older persons.[13]

In our study, there was no difference in survival between older and younger patients even after analyzing for various known prognostic factors including gender, ECOG PS, smoking history, EGFR mutation (exon 19 versus other), and stage. These results provide a rationale for offering similar therapy to an older person as his/her younger counterpart if the patient is fit for the same, disregarding the age of the patient. Another important point that needs to be highlighted is that both the studies included ECOG PS 2 patients as well, which is beyond the usual clinical trial practice of including only PS 0–1 patients. This provides more confidence in managing patients in the clinic, as a sizeable number of patients in day-to-day practice are PS 2. In our study, 14.8% of the patients had ECOG PS of 2. The subgroup analysis of older patients from the study of Noronha et al. showed significant PFS benefit of the combination of gefitinib and chemotherapy over gefitinib alone. The median OS was numerically longer in patients treated with the combination compared to gefitinib alone (28 versus 17 months); however, it did not reach statistical significance likely due to fewer patients in the subgroups. This suggests that intensification of therapy is worthwhile even in older patients. When the data of patients who were smokers were analyzed separately, it was found that older patients had shorter OS than their younger counterparts. A possible explanation is the development of chronic obstructive pulmonary disease in smokers and its worsening with age which can lead to reduced life span independently. Similarly, in a separate analysis of males, the older patients had lower survival which is possibly related to a higher prevalence of consuming smoked tobacco in males in India. The Global Adult Tobacco Survey 2 India reported that 19% of men in India consumed smoked tobacco as against 2% women.[14]

It should be noted that in both the studies, pemetrexed/platinum doublet chemotherapy was given irrespective of the age. In the 2010 recommendations of International Society of Geriatric Oncology and European Organization for Research and Treatment of Cancer, platinum-based doublet chemotherapy was recommended to treat advanced NSCLC in fit, younger adults, but monotherapy was suggested for patients over 70 years old.[15] This was challenged by the results of the IFCT-0501 trial published in The Lancet in 2011.[16] In this Phase III trial, 451 patients of age 70–89 years with advanced NSCLC and WHO performance scores of 0–2 were randomized to receive either four cycles of paclitaxel/carboplatin doublet (carboplatin on day 1 and paclitaxel on days 1, 8, and 15 delivered four weekly) or five cycles of vinorelbine or gemcitabine monotherapy (days 1 and 8 given three weekly). They reported that doublet chemotherapy resulted in significantly better survival (HR 0.64, 95% CI 0.52–0.78; P < 0.001); 1-year survival was 44.5% as compared to 25.4% in the monotherapy arm.[16] As expected, there were significantly more adverse effects in the doublet chemotherapy group. The incidence of Grade 3 or 4 neutropenia was reported as 48.4%, anemia 9.4%, thrombocytopenia 6.7%, and febrile neutropenia 9.7%. These are grossly similar to those in patients in our study who received doublet chemotherapy alone except for the higher rates of neutropenia which may be explained by the use of paclitaxel as against pemetrexed in our study.

Gridelli et al. reported a combined analysis of two parallel Phase III trials, MILES-3 and MILES-4, which were done to test the efficacy of adding cisplatin to first-line chemotherapy for elderly patients (>70 years) with advanced NSCLC.[17] They reported significantly better response rates and PFS but no difference in OS (HR, 0.86; 95% CI, 0.70–1.05; P = 0.14). In our study, older patients had similar OS as younger patients, but there were two important differences: older patients were defined as 60 years or more and carboplatin was used instead of cisplatin. A systematic review by Santos et al. included Conchrane, Medline, and Embase databases and concluded that platinum combination therapy probably improves OS (HR: 0.76, 95% CI 0.69–0.85; n = 1705).[18] However, the benefit came at the cost of a significant increase in hematological toxicities, emesis, and peripheral neuropathy. We noted similar rates of toxicities in our study in the chemotherapy alone arm except for the absence of peripheral neuropathy in our patients due to the use of carboplatin instead of cisplatin.

In patients with EGFR-mutated advanced NSCLC, oral tyrosine kinase inhibitors have been used even in patients with poor PS due to their safety and tolerability. NEJ001 study was a Japanese multicenter Phase II study in which 30 patients with NSCLC and poor PS (73% had PS 3 or 4) received gefitinib 250 mg daily.[19] The median PFS and OS were 6.5 and 17.8 months respectively, with 1-year survival rate of 63% and no treatment-related deaths. Notably, 68% of patients with baseline PS 3 or 4 had significant benefit improving to PS 0–1 after gefitinib. Morikawa et al. conducted a pooled analysis combining the NEJ001, NEJ002, and NEJ003 trials (included only patients >70 years) and showed better PFS in the gefitinib group (median 14.3 versus 5.7 months, P < 0.001) compared to chemotherapy (paclitaxel/carboplatin), but the OS was similar.[20] The subgroup analysis of the FLAURA study found a similar benefit of osimertinib in older patients (HR: 0.49; 95% CI, 0.35–0.67) as compared to younger patients (HR: 0.44; 95% CI, 0.33–0.58).[21] These results are in congruence with those reported by Patil et al.[9] The analysis comparing older and younger patients in this study found no difference in PFS and OS according to the age group validating the results for older patients as well.

An important shortcoming of our study was the lack of comprehensive geriatric assessment (CGA) in older patients which would have given a better idea of the actual physiological status of the patients included in the study. There is a need to perform a CGA in older patients to discover various age-related vulnerabilities and to help plan therapies; this need is not yet well-recognized in India.[22],[23] However, our study emphasizes that age alone should not be a barrier to the cancer treatment.


  Conclusions Top


This pooled analysis of 640 patients from two randomized controlled trials of EGFR-mutated NSCLC patients found similar survival and toxicities in 60 years or older patients and younger patients with ECOG PS of 0–2 with the exception of a higher incidence of diarrhea in older patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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    Tables

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  In this article
Abstract
Introduction
Patients and Methods
Results
Discussion
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