Ann Surg Oncol DOI 10.1245/s10434-014-3586-9
ORIGINAL ARTICLE – THORACIC ONCOLOGY
Pemetrexed-Carboplatin Adjuvant Chemotherapy With or Without Gefitinib in Resected Stage IIIA-N2 Non-Small Cell Lung Cancer Harbouring EGFR Mutations: A Randomized, Phase II Study Ning Li, MD1, Wei Ou, MD1, Xiong Ye, MD2, Hai-Bo Sun, MD3, Liang Zhang, MD4, Qin Fang, MD5, Song-Liang Zhang, MD1, Bao-Xiao Wang6, and Si-Yu Wang, MD1 1
Department of Thoracic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China; 2Department of Thoracic Surgery, Guangdong General Hospital, Guangzhou, China; 3Department of Thoracic Surgery, Henan Cancer Hospital, Zhengzhou, China; 4Department of Thoracic Surgery, Tianjin First Center Hospital, Tianjin, China; 5Department of Medical Oncology, The Third People’s Hospital of Huizhou, Huizhou, China; 6College of Clinical Medicine, Guangzhou Medical University, Guangzhou, China
ABSTRACT Background. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) show great efficacy in patients with advanced non-small cell lung cancer (NSCLC) with EGFR mutations. The efficacy and safety of gefitinib following adjuvant chemotherapy in patients with EGFR mutation are unknown. Methods. In this open-label, phase II study, patients with resected stage IIIA-N2 NSCLC harbouring EGFR mutations (either exon 19 deletion or L858R point mutation) were assigned randomly to receive pemetrexed (500 mg/ m2) and carboplatin (AUC = 5), administered every 21 days for 4 cycles, followed with or without gefitinib (250 mg/day) for 6 months. The primary end point was disease-free survival (DFS). Results. From August 2008 to September 2011, 60 patients were included in our center. DFS was significantly longer among those who received pemetrexed and carboplatin (PC)-gefitinib than among those who received PC
Presented in part as a poster discussion at the 49th Annual Meeting of the American Society of Clinical Oncology, May 31–June 4, 2013, Chicago, IL. Ning Li and Wei Ou contributed equally to this work. Ó Society of Surgical Oncology 2014 First Received: 23 September 2013 S.-Y. Wang, MD e-mail: [email protected]
alone [hazard ratio (HR), 0.37; 95 % confidence interval (CI) 0.16–0.85; P = 0.014; median, 39.8 vs. 27.0 months]. The rates of 2-year DFS were 78.9 % in the PC-gefitinib group and 54.2 % in the PC alone group. The rates of 2-year overall survival (OS) were 92.4 % in the PC-gefitinib group and 77.4 % in the PC alone group (HR, 0.37; 95 % CI 0.12–1.11, P = 0.076). The most common adverse event was rash (43.3 %, 13/30) in the PC-gefitinib group and the administration of gefitinib following chemotherapy was well tolerated. Conclusions. The administration of gefitinib following PC adjuvant therapy shows significant improvement in DFS in patients with resected stage IIIA-N2 NSCLC harbouring EGFR mutations.
Lung cancer is the most common cancer worldwide and approximately accounts for 13 % of total cases and 18 % of total deaths globally.1 With curative intent, surgical resection (lobectomy and pneumonectomy) is widely used. Although many patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) undergo complete resection, they are not cured, and the 5-year survival is just 23 % for patients treated with surgery alone.2 The management of stage IIIAN2 NSCLC is fraught with more difficulties. Based on several large randomized trials and meta-analyses concerning adjuvant platinum-based chemotherapy on lung cancer, its efficacy is established.3–8 Pemetrexed was approved for second-line treatment of advanced NSCLC after findings of a phase III trial by Hanna et al.9 showed
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equivalent outcomes with fewer side effects to docetaxel. Results from a phase III trial of pemetrexed and cisplatin compared with gemcitabine and cisplatin in the first-line setting showed a similar overall survival (OS) between two treatment arms, with fewer toxicities in the pemetrexed arm.10 In a phase III trial comparing pemetrexed plus carboplatin with gemcitabine plus carboplatin as first-line treatment, patients in the pemetrexed arm experienced similar OS and significantly less hematologic toxicity.11 Gefitinib, which is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has showed its superiority as first-line treatment for patients with advanced NSCLC harbouring EGFR mutations compared with chemotherapy in three large randomized trials.12–14 Gefitinib is not associated with the toxicities that typically occur with chemotherapy, such as nausea, vomiting, leukopenia, and alopecia.12 Four phase III trials investigating the therapeutic pattern of combining an EGFR-TKI with platinum-based chemotherapy on unselected patients with advanced NSCLC showed that simultaneous administration of an EGFR-TKI with platinum-based chemotherapy did not confer improved OS compared with chemotherapy alone.15–18 Given the established efficacy of platinumbased chemotherapy in the treatment of NSCLC, the interaction of efficacy between EGFR-TKIs and chemotherapy is concerns on these trials. The objectives of this study were to compare the efficacy and safety of pemetrexed-carboplatin (PC) followed with gefitinib and PC alone in patients with resected stage IIIA-N2 NSCLC harbouring EGFR mutations. PC were chosen in this study because compared with cisplatin combinations, they have potentially better compliance and less toxicity.9–11
Patients with resected stage IIIA-N2 NSCLC harbouring EGFR mutations were randomly assigned in a 1:1 ratio to receive pemetrexed (500 mg/m2) plus carboplatin (AUC = 5) followed with gefitinib or pemetrexed plus carboplatin alone. Randomization was stratified according to gender (male vs. female) and smoking history (current or former vs. never). Chemotherapy was administered in 3-week cycles for a total of four cycles. Subsequently, patients in the PC-gefitinib group continued to receive gefitinib 250 mg/day orally for 6 months. Treatment continued until disease recurrence, unacceptable toxicity, or a request by the patient to withdraw. Upon disease recurrence, all patients were offered optional gefitinib therapy. The primary endpoint was disease-free survival (DFS). Secondary end points were OS, toxicity, and safety. Eligibility and Exclusion Criteria Patients were included if they were aged ‡18 years, had Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and had pathologically confirmed resected stage IIIA-N2 NSCLC harbouring EGFR mutations. Patients were excluded when they had had previous chemotherapy, thoracic irradiation, biologic therapy, immunologic therapy, or incomplete resection of the tumor (patients who had undergone sleeve or wedge resection of the lung tumor were not included in this study). Other exclusion criteria were significant weight loss (‡5 %), inadequate haematological function, and inadequate liver or renal function. Patients with prior malignancy, active infection, coexisting serious unstabilized disease, or neurologic or psychiatric disorders also were ineligible. Patients’ eligibility was checked, and they were randomized within 3 weeks after surgery.
PATIENTS AND METHODS Assessments Study Design and Study Treatment This phase II, prospective, randomized, open-label study was conducted in Sun Yat-sen University Cancer Center and approved by the Ethics Committee and Clinical Trial Review Committee of our center. This trial followed the Declaration of Helsinki and Good Clinical Practice guidelines. EGFR mutations have been routinely tested at Sun Yat-sen University Cancer Center on all resected lung cancers by polymerase chain reaction (PCR) assay or direct sequencing. In this study, patients were classified as EGFR mutation-positive if they had either an exon 19 deletion or an exon 21 L858R point mutation by PCR assay. TNM was identified according to the 1997 classification.2 All patients signed a written, informed consent form before randomization.
Disease-free survival was assessed from randomization to disease recurrence or death as a result of any cause. Overall survival was assessed from randomization to death as a result of any cause. Follow-up examinations were arranged every 2 months during the first 6 months after randomization, then every 3 months between 6 and 36 months, and thereafter every 6 months until death. Follow-up examinations involved thoracic and upper abdominal CT, brain magnetic resonance imaging, and physical examination. Routine laboratory assessments were performed. An isotopic bone scan was performed every 6 months or when bone metastasis was suspected. All adverse events (AEs) were recorded and graded according to the National Cancer Institute Common Terminology Criteria (CTC) for AEs, version 3.0.
Pemetrexed-Carboplatin and Gefitinib in NSCLC
Statistical Analysis This trial was designed to detect a 20 % improvement in the rate of 2-year DFS, from 50 to 70 % (assuming the actual rate of 2-year DFS was 50 %). Approximately, a total of 60 patients (30 patients per group) were needed to provide the study with 80 % power at a one-sided 5 % significance level. Kaplan–Meier curves were drawn for DFS and OS, and a two-sided, log-rank test was used to compare survival between the two treatment groups. Estimates of the treatment effect were described as a hazard ratio (HR) for PCgefitinib versus PC, with a two-sided 95 % confidence interval (CI). The characteristics of patients were compared between the two groups with t test or Chi squared test or Fisher’s exact test. DFS was analyzed by preplanned subgroups with the Cox proportional hazards model, including age (‡65 and \65), gender, smoking status, and EGFR mutation site. P values \0.05 were considered statistically significant; all P values were two-tailed. The software used for statistical analyses was SPSS13.0 for Windows software (SPSS Inc., Chicago, IL). RESULTS Patient Characteristics At the cutoff date for the analysis (January 1, 2013), the median follow-up period was 30.6 (range 3.7–52.7) months. All of the enrolled patients were Chinese. The cohort consisted predominantly of patients with adenocarcinomas (56/60). The two groups were generally well balanced with respect to baseline demographics and disease characteristics (Table 1). Of the 60 patients, 56 (93.3 %) completed four cycles of chemotherapy. Four patients (one in the PC-gefitinib group and three in the PC group) did not complete four cycles of chemotherapy, of whom two received three cycles and the other two received two cycles (Fig. 1). The reasons for the withdrawal from chemotherapy included disease recurrence during chemotherapy (N = 2), severe AEs (N = 1), and patient refusal (N = 1). Of the 30 patients in the PC-gefitinib group, 29 received gefitinib for 6 months after chemotherapy successfully and 1 received gefitinib for 3.7 months for the reason of death (Fig. 1).
TABLE 1 Baseline demographics and disease characteristics Characteristics
PC-gefitinib N = 30 PC N = 30 P
Age (yr) Median
59.5
54.6
Range
32–78
39–74
Male
17 (56.7 %)
18 (60 %)
Female
13 (43.3 %)
12 (40 %)
0
9 (30 %)
11 (36.7 %)
1
21 (70 %)
19 (63.3 %)
Current Former
10 (33.3 %) 3 (10 %)
11 (36.7 %) 3 (10 %)
Never
17 (56.7 %)
16 (53.3 %)
0.077
Gender 0.793
ECOG PS 0.584
Smoking status 0.784
Histology Adenocarcinoma
28 (93.3 %)
28 (93.3 %) [0.99
Nonadenocarcinoma
2 (6.7 %)
2 (6.7 %)
Surgery type Lobectomy
28 (93.3 %)
29 (96.7 %) [0.99
Pneumonectomy
2 (6.7 %)
1 (3.3 %)
11 (36.7 %)
9 (30 %)
EGFR mutation site Exon 19 deletion
L858R point mutation 19 (63.3 %)
0.584
21 (70 %)
Data are median (range) or number of patients (%). Some percentages may not sum to 100 because of rounding PC pemetrexed plus carboplatin, ECOG PS eastern cooperative oncology group performance status
Assessed for eligibility (n=63)
Not eligible (n=3)
Randomized (n=60)
Assigned to PC-gefitinib group (n=30)
Completed 4 cycles of PC and 6-month gefitinib (n=28) Didn’t complete 4 cycles of PC and 6-month gefitinib (n=2)
Assessable for efficacy Assessable for safety
(n=30) (n=30)
Assigned to PC group (n=30)
Completed 4 cycles of PC
(n=27)
Didn’t complete 4 cycles of PC (n=3)
Assessable for efficacy Assessable for safety
(n=30) (n=30)
Survival Analysis
FIG. 1 Trial profile
All of the 60 assigned patients who had received at least one dose of study drug were included in the efficacy analyses. DFS was significantly longer among those who received PC-gefitinib than among those who received PC alone (HR, 0.37; 95 % CI 0.16–0.85; log-rank P = 0.014;
median, 39.8 vs. 27.0 months; Fig. 2a). The rates of 2-year DFS were 78.9 % in the PC-gefitinib group and 54.2 % in the PC group, respectively. Preplanned subgroup analyses showed that the DFS was improved in all subgroups with gefitinib (Table 2).
N. Li et al.
Disease-free Survival (Probability)
A
1.0
PC-gefitinib
0.8 0.6
PC
0.4 0.2 0 5
0
10
15
20
25
30
35
40
Months since surgery
No. at risk PC-gefitinib 30
30
30
27
24
24
20
17
11
PC
29
26
22
18
16
8
5
0
B
1.0
Overall survival (Probability)
30
0.8
PC-gefitinib PC
0.6 0.4 0.2 0
0
5
10
15
20
25
30
35
40
45
50
Months since surgery
No. at risk PC-gefitinib 30
30
30
28
28
28
28
26
22
11
11
PC
30
30
27
23
23
21
12
12
12
12
30
FIG. 2 Kaplan-Meier curves. a DFS, b OS
TABLE 2 Subgroup analyses of DFS Variable
PC-gefitinib no. PC no. HR
95 % CI
Age (yr) ‡65
9
6
0.122 0.014–1.099
\65
21
24
0.489 0.19–1.257
17 13
18 12
0.452 0.153–1.333 0.316 0.069–1.443
Current/former
13
14
0.315 0.077–1.288
Never
17
16
0.413 0.146–1.167
To date, a total of 27 recurrences (45 %) have occurred, including 10 in the PC-gefitinib group and 17 in the PC group. The most common recurrence site was brain, with 3 in the PC-gefitinib group and 9 in the PC group. Of the 17 recurred patients in the PC group, 15 received gefitinib, and 11 (73.3 %) obtained objective response. Of the 10 recurred patients in the PC-gefitinib group, 8 received further gefitinib, and 4 (50 %) obtained objective response. Safety All of the 60 randomly assigned patients who received at least one dose of study drug were included in the safety analyses. Table 3 summarized the common AEs. Twentyeight (93.3 %) patients in the PC-gefitinib group and 26 (86.7 %) in the PC group had at least one AE, which was thought to be possibly related to the treatment of the study. Most reported AEs were grade 1 or 2; six patients (20 %) in the PC-gefitinib group and five patients (16.7 %) in the PC group had a grade 3 or higher AE. Only one patient in the PC-gefitinib group had a grade 4 rash. The incidence of AEs in the PC-gefitinib group was similar to that in the PC group, except an increased incidence of rash and diarrhea. Compared with the PC group, the addition of gefitinib was associated with a higher rate of skin rash (43.3 %, 13/30) and diarrhea (30 %, 9/30), but they were mostly grade 1 to 2 (rash, 92.3 %; diarrhea, 88.9 %). No patient withdrew as a result of AEs in the PC-gefitinib group, and only one patient in the PC group withdrew as a result of severe vomiting.
Gender Male Female Smoking status
Mutation site Exon 19 deletion 11 Exon 21 L858R
19
9 21
0.016 0–25.45 0.407 0.164–1.011
The HR (PC-gefitinib versus PC) derived from a Cox proportional hazards model inclusive of only treatment as a factor; HR \ 1 favors PC-gefitinib DFS disease-free survival, PC pemetrexed plus carboplatin, HR hazard ratio, CI confidence interval
The rates of 2-year OS were 92.4 % in the PC-gefitinib group and 77.4 % in the PC alone group (HR, 0.37; 95 % CI 0.12–1.11, P = 0.076). The median survival time was 41.6 months for the PC-gefitinib group, as compared with 32.6 months for the PC group (Fig. 2b).
DISCUSSION To our knowledge, this is the first prospective, phase II study to examine the efficacy and safety of PC followed by gefitinib versus PC as adjuvant therapy for resected EGFR mutant stage IIIA-N2 NSCLC. Because studies have demonstrated that EGFR-TKIs are superior to chemotherapy in patients with advanced NSCLC harbouring EGFR mutations, we can hypothesize that adjuvant EGFR-TKIs following chemotherapy could obtain better outcomes than platinum-based chemotherapy alone in fully resected EGFR mutant lung cancer patients.12–14,19,20 The results of this study show that PC followed by gefitinib as adjuvant therapy provides significantly longer DFS in patients with resected stage IIIA-N2 NSCLC harbouring activating EGFR mutations (exons 19 or 21), prolonging median DFS by 12.8 months. The DFS benefit with additional gefitinib was consistent across all preplanned subgroups. Which—an EGFR-TKI or chemotherapy—is better in the adjuvant setting for lung cancer harbouring activating
Pemetrexed-Carboplatin and Gefitinib in NSCLC TABLE 3 Treatment-related adverse events AEs
PC-gefitinib (N = 30)
PC (N = 30)
All grades Grades ‡3 All grades Grades ‡3 Rash
13
2
2
0
Diarrhea
9
1
4
0
Dry skin
3
0
0
0
Anorexia
10
1
10
2
Pruritus
4
0
1
0
Fatigue
8
0
13
1
Nausea/vomiting Mucositis
7 6
0 0
12 4
1 0
Constipation
0
0
2
0
Fever
2
0
3
0
Anemia
8
0
6
0
Leukopenia
9
2
11
1
Thrombocytopenia
3
0
2
0
Data are number of patients (%) PC pemetrexed plus carboplatin
EGFR mutations remains undetermined. The phase 3 BR19 study comparing adjuvant gefitinib versus placebo in patients with completely resected NSCLC enrolled 503 of planned 1,160 patients, and no DFS or OS advantage was observed in overall population. Of the 359 patients who were examined for EGFR mutations, only 15 patients had an EGFR mutation.21 In contrast, the rate of activating EGFR mutations was 20–30 % for patients with resected NSCLC in our center.22,23 The retrospective study by Janjigian et al.24 investigating the impact of adjuvant TKIs on patients with lung adenocarcinomas harbouring EGFR mutations showed that adjuvant EGFR-TKIs in patients with resected stages I to III lung adenocarcinomas harbouring EGFR mutations had a trend toward improvement in DFS compared with patients who did not receive adjuvant TKIs. In the SELECT study of adjuvant erlotinib in resected EGFR mutation-positive NSCLC, the 2-year DFS rate was an excellent 94 %.25 Recently, a Chinese trial (NCT01405079) and a Japanese trial investigating adjuvant EGFR-TKIs versus platinum-based chemotherapy for resected NSCLC harbouring activating EGFR mutations are currently ongoing. The results of the efficacy analysis showed that adjuvant therapy with PC-gefitinib conferred longer DFS compared with PC in patients with stage IIIA-N2 NSCLC harbouring activating EGFR mutations. When recurrence occurred, 88.2 % patients in the PC group and 80 % patients in the PC-gefitinib group received gefitinib. Considering the median DFS in the PC-gefitinib group was 12.8 months longer than that in the PC group, we believe that the administration of gefitinib following chemotherapy as
adjuvant therapy is effective compared with the administration of gefitinib as postrecurrence medication. Indeed, although the OS difference did not reach significance, the observed DFS benefit appeared to translate into a marginal OS benefit with PC-gefitinib. However, there are some points that should be noted. First, 2-year OS may be too short to reflect the population outcome. Second, because the sample size was small, the study was not powered to detect a difference in OS. Third, the separation of the Kaplan–Meier curves for OS was sustained only during 15–40 months. Therefore, one should be cautious when the results of OS are interpreted. The best scheduling of an EGFR-TKI relative to chemotherapy for patients with resected stage IIIA-N2 NSCLC remains undetermined. In our study, we assigned the patients in the PC-gefitinib group to receive gefitinib 250 mg/day orally for 6 months immediately after chemotherapy, and this schedule led to a significant improvement in DFS. Upon disease recurrence, eight patients in the PC-gefitinib group received further gefitinib and four patients experienced objective response. The high postrecurrence response rate of receiving further gefitinib was thought-provoking: maybe 6 months of gefitinib is not enough. In the SELECT trial, patients were treated with erlotinib for 2 years after completion of adjuvant chemotherapy and/or radiotherapy. In that trial, 25 of 36 patients received erlotinib for 2 full years, and the 2-year DFS was 94 %.25 The optimal length of time of EGFR-TKIs after chemotherapy as adjuvant therapy remains to be confirmed. The most frequent initial recurrence site was brain in our study, which is consistent with the results of our previous study.26 In our study, we observed a lower recurrence incidence of brain in the PC-gefitinib group. Thus, the addition of gefitinib could reduce the risk of developing brain recurrence. Also, given the high risk of brain recurrence, prophylactic cranial irradiation should be considered. Previously, we reported a prophylactic cranial irradiation model to predict the risk of developing brain metastases in patients with locally advanced NSCLC.27 The role of prophylactic cranial irradiation needs to be further investigated. As expected, the addition of gefitinib was associated with increased risk of rash and diarrhea. However, of those gefitinib-related AEs, most could be managed and no patient withdrew as a result of gefitinib-related AEs. The addition of gefitinib to chemotherapy was well tolerated, with no added hematologic toxicity. Although this is not a placebo-controlled study and the number of patients is small, our study has led to some valuable conclusions for adjuvant therapy in patients with EGFR mutant stage IIIA-N2 NSCLC. Further studies are needed to investigate the efficacy and safety of EGFRTKIs following chemotherapy versus chemotherapy, and
N. Li et al.
the optimal length of time of EGFR-TKIs following chemotherapy as adjuvant therapy for patients with EGFR mutations. CONCLUSIONS The results of our study suggest that the administration of gefitinib following PC adjuvant therapy can significantly prolong DFS of patients with resected stage IIIA-N2 NSCLC harbouring EGFR mutations compared with PC alone, with acceptable toxicity. The DFS benefit of additional gefitinib indicates that patients in whom an EGFR mutation has been identified will benefit from gefitinib following chemotherapy as adjuvant therapy. CONFLICT OF INTEREST interest.
All authors have no conflicts of
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12. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947–57. 13. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11(2):121–8. 14. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362(25):2380–8. 15. Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 1. J Clin Oncol. 2004;22(5):777–84. 16. Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 2. J Clin Oncol. 2004;22(5):785–94. 17. Herbst RS, Prager D, Hermann R, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2005;23(25):5892–9. 18. Gatzemeier U, Pluzanska A, Szczesna A, et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol. 2007;25(12):1545–52. 19. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutationpositive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735–42. 20. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239–46. 21. Goss GD, O’Callaghan C, Lorimer I, et al. Gefitinib versus placebo in completely resected non-small-cell lung cancer: results of the NCIC CTG BR19 Study. J Clin Oncol. 2013;31:3320–6. 22. Sun HB, Zheng Y, Ou W, et al. Association between hormone receptor expression and epidermal growth factor receptor mutation in patients operated on for non-small cell lung cancer. Ann Thorac Surg. 2011;91(5):1562–7. 23. Sun HB, Ou W, Li Y, et al. Epidermal growth factor receptor mutation status and adjuvant chemotherapy in resected advanced non-small-cell lung cancer. Clin Lung Cancer. 2013;14(4):376–382. 24. Janjigian YY, Park BJ, Zakowski MF, et al. Impact on diseasefree survival of adjuvant erlotinib or gefitinib in patients with resected lung adenocarcinomas that harbor EGFR mutations. J Thorac Oncol. 2011;6(3):569–75. 25. Neal JW, Pennell NA, Govindan R, Launuti M, Pam R, Rosovsky G. The SELECT study: A multicenter phase II trial of adjuvant erlotinib in resected epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). J Clin Oncol. 2012;30(Suppl; abstr 7010). 26. Ou W, Sun HB, Ye X, et al. Adjuvant carboplatin-based chemotherapy in resected stage IIIA-N2 non-small cell lung cancer. J Thorac Oncol. 2010;5(7):1033–41. 27. Wang SY, Ye X, Ou W, Lin YB, Zhang BB, Yang H. Risk of cerebral metastases for postoperative locally advanced non-smallcell lung cancer. Lung Cancer. 2009;64(2):238–43.
ORIGINAL ARTICLE – THORACIC ONCOLOGY
Pemetrexed-Carboplatin Adjuvant Chemotherapy With or Without Gefitinib in Resected Stage IIIA-N2 Non-Small Cell Lung Cancer Harbouring EGFR Mutations: A Randomized, Phase II Study Ning Li, MD1, Wei Ou, MD1, Xiong Ye, MD2, Hai-Bo Sun, MD3, Liang Zhang, MD4, Qin Fang, MD5, Song-Liang Zhang, MD1, Bao-Xiao Wang6, and Si-Yu Wang, MD1 1
Department of Thoracic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China; 2Department of Thoracic Surgery, Guangdong General Hospital, Guangzhou, China; 3Department of Thoracic Surgery, Henan Cancer Hospital, Zhengzhou, China; 4Department of Thoracic Surgery, Tianjin First Center Hospital, Tianjin, China; 5Department of Medical Oncology, The Third People’s Hospital of Huizhou, Huizhou, China; 6College of Clinical Medicine, Guangzhou Medical University, Guangzhou, China
ABSTRACT Background. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) show great efficacy in patients with advanced non-small cell lung cancer (NSCLC) with EGFR mutations. The efficacy and safety of gefitinib following adjuvant chemotherapy in patients with EGFR mutation are unknown. Methods. In this open-label, phase II study, patients with resected stage IIIA-N2 NSCLC harbouring EGFR mutations (either exon 19 deletion or L858R point mutation) were assigned randomly to receive pemetrexed (500 mg/ m2) and carboplatin (AUC = 5), administered every 21 days for 4 cycles, followed with or without gefitinib (250 mg/day) for 6 months. The primary end point was disease-free survival (DFS). Results. From August 2008 to September 2011, 60 patients were included in our center. DFS was significantly longer among those who received pemetrexed and carboplatin (PC)-gefitinib than among those who received PC
Presented in part as a poster discussion at the 49th Annual Meeting of the American Society of Clinical Oncology, May 31–June 4, 2013, Chicago, IL. Ning Li and Wei Ou contributed equally to this work. Ó Society of Surgical Oncology 2014 First Received: 23 September 2013 S.-Y. Wang, MD e-mail: [email protected]
alone [hazard ratio (HR), 0.37; 95 % confidence interval (CI) 0.16–0.85; P = 0.014; median, 39.8 vs. 27.0 months]. The rates of 2-year DFS were 78.9 % in the PC-gefitinib group and 54.2 % in the PC alone group. The rates of 2-year overall survival (OS) were 92.4 % in the PC-gefitinib group and 77.4 % in the PC alone group (HR, 0.37; 95 % CI 0.12–1.11, P = 0.076). The most common adverse event was rash (43.3 %, 13/30) in the PC-gefitinib group and the administration of gefitinib following chemotherapy was well tolerated. Conclusions. The administration of gefitinib following PC adjuvant therapy shows significant improvement in DFS in patients with resected stage IIIA-N2 NSCLC harbouring EGFR mutations.
Lung cancer is the most common cancer worldwide and approximately accounts for 13 % of total cases and 18 % of total deaths globally.1 With curative intent, surgical resection (lobectomy and pneumonectomy) is widely used. Although many patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) undergo complete resection, they are not cured, and the 5-year survival is just 23 % for patients treated with surgery alone.2 The management of stage IIIAN2 NSCLC is fraught with more difficulties. Based on several large randomized trials and meta-analyses concerning adjuvant platinum-based chemotherapy on lung cancer, its efficacy is established.3–8 Pemetrexed was approved for second-line treatment of advanced NSCLC after findings of a phase III trial by Hanna et al.9 showed
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equivalent outcomes with fewer side effects to docetaxel. Results from a phase III trial of pemetrexed and cisplatin compared with gemcitabine and cisplatin in the first-line setting showed a similar overall survival (OS) between two treatment arms, with fewer toxicities in the pemetrexed arm.10 In a phase III trial comparing pemetrexed plus carboplatin with gemcitabine plus carboplatin as first-line treatment, patients in the pemetrexed arm experienced similar OS and significantly less hematologic toxicity.11 Gefitinib, which is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has showed its superiority as first-line treatment for patients with advanced NSCLC harbouring EGFR mutations compared with chemotherapy in three large randomized trials.12–14 Gefitinib is not associated with the toxicities that typically occur with chemotherapy, such as nausea, vomiting, leukopenia, and alopecia.12 Four phase III trials investigating the therapeutic pattern of combining an EGFR-TKI with platinum-based chemotherapy on unselected patients with advanced NSCLC showed that simultaneous administration of an EGFR-TKI with platinum-based chemotherapy did not confer improved OS compared with chemotherapy alone.15–18 Given the established efficacy of platinumbased chemotherapy in the treatment of NSCLC, the interaction of efficacy between EGFR-TKIs and chemotherapy is concerns on these trials. The objectives of this study were to compare the efficacy and safety of pemetrexed-carboplatin (PC) followed with gefitinib and PC alone in patients with resected stage IIIA-N2 NSCLC harbouring EGFR mutations. PC were chosen in this study because compared with cisplatin combinations, they have potentially better compliance and less toxicity.9–11
Patients with resected stage IIIA-N2 NSCLC harbouring EGFR mutations were randomly assigned in a 1:1 ratio to receive pemetrexed (500 mg/m2) plus carboplatin (AUC = 5) followed with gefitinib or pemetrexed plus carboplatin alone. Randomization was stratified according to gender (male vs. female) and smoking history (current or former vs. never). Chemotherapy was administered in 3-week cycles for a total of four cycles. Subsequently, patients in the PC-gefitinib group continued to receive gefitinib 250 mg/day orally for 6 months. Treatment continued until disease recurrence, unacceptable toxicity, or a request by the patient to withdraw. Upon disease recurrence, all patients were offered optional gefitinib therapy. The primary endpoint was disease-free survival (DFS). Secondary end points were OS, toxicity, and safety. Eligibility and Exclusion Criteria Patients were included if they were aged ‡18 years, had Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and had pathologically confirmed resected stage IIIA-N2 NSCLC harbouring EGFR mutations. Patients were excluded when they had had previous chemotherapy, thoracic irradiation, biologic therapy, immunologic therapy, or incomplete resection of the tumor (patients who had undergone sleeve or wedge resection of the lung tumor were not included in this study). Other exclusion criteria were significant weight loss (‡5 %), inadequate haematological function, and inadequate liver or renal function. Patients with prior malignancy, active infection, coexisting serious unstabilized disease, or neurologic or psychiatric disorders also were ineligible. Patients’ eligibility was checked, and they were randomized within 3 weeks after surgery.
PATIENTS AND METHODS Assessments Study Design and Study Treatment This phase II, prospective, randomized, open-label study was conducted in Sun Yat-sen University Cancer Center and approved by the Ethics Committee and Clinical Trial Review Committee of our center. This trial followed the Declaration of Helsinki and Good Clinical Practice guidelines. EGFR mutations have been routinely tested at Sun Yat-sen University Cancer Center on all resected lung cancers by polymerase chain reaction (PCR) assay or direct sequencing. In this study, patients were classified as EGFR mutation-positive if they had either an exon 19 deletion or an exon 21 L858R point mutation by PCR assay. TNM was identified according to the 1997 classification.2 All patients signed a written, informed consent form before randomization.
Disease-free survival was assessed from randomization to disease recurrence or death as a result of any cause. Overall survival was assessed from randomization to death as a result of any cause. Follow-up examinations were arranged every 2 months during the first 6 months after randomization, then every 3 months between 6 and 36 months, and thereafter every 6 months until death. Follow-up examinations involved thoracic and upper abdominal CT, brain magnetic resonance imaging, and physical examination. Routine laboratory assessments were performed. An isotopic bone scan was performed every 6 months or when bone metastasis was suspected. All adverse events (AEs) were recorded and graded according to the National Cancer Institute Common Terminology Criteria (CTC) for AEs, version 3.0.
Pemetrexed-Carboplatin and Gefitinib in NSCLC
Statistical Analysis This trial was designed to detect a 20 % improvement in the rate of 2-year DFS, from 50 to 70 % (assuming the actual rate of 2-year DFS was 50 %). Approximately, a total of 60 patients (30 patients per group) were needed to provide the study with 80 % power at a one-sided 5 % significance level. Kaplan–Meier curves were drawn for DFS and OS, and a two-sided, log-rank test was used to compare survival between the two treatment groups. Estimates of the treatment effect were described as a hazard ratio (HR) for PCgefitinib versus PC, with a two-sided 95 % confidence interval (CI). The characteristics of patients were compared between the two groups with t test or Chi squared test or Fisher’s exact test. DFS was analyzed by preplanned subgroups with the Cox proportional hazards model, including age (‡65 and \65), gender, smoking status, and EGFR mutation site. P values \0.05 were considered statistically significant; all P values were two-tailed. The software used for statistical analyses was SPSS13.0 for Windows software (SPSS Inc., Chicago, IL). RESULTS Patient Characteristics At the cutoff date for the analysis (January 1, 2013), the median follow-up period was 30.6 (range 3.7–52.7) months. All of the enrolled patients were Chinese. The cohort consisted predominantly of patients with adenocarcinomas (56/60). The two groups were generally well balanced with respect to baseline demographics and disease characteristics (Table 1). Of the 60 patients, 56 (93.3 %) completed four cycles of chemotherapy. Four patients (one in the PC-gefitinib group and three in the PC group) did not complete four cycles of chemotherapy, of whom two received three cycles and the other two received two cycles (Fig. 1). The reasons for the withdrawal from chemotherapy included disease recurrence during chemotherapy (N = 2), severe AEs (N = 1), and patient refusal (N = 1). Of the 30 patients in the PC-gefitinib group, 29 received gefitinib for 6 months after chemotherapy successfully and 1 received gefitinib for 3.7 months for the reason of death (Fig. 1).
TABLE 1 Baseline demographics and disease characteristics Characteristics
PC-gefitinib N = 30 PC N = 30 P
Age (yr) Median
59.5
54.6
Range
32–78
39–74
Male
17 (56.7 %)
18 (60 %)
Female
13 (43.3 %)
12 (40 %)
0
9 (30 %)
11 (36.7 %)
1
21 (70 %)
19 (63.3 %)
Current Former
10 (33.3 %) 3 (10 %)
11 (36.7 %) 3 (10 %)
Never
17 (56.7 %)
16 (53.3 %)
0.077
Gender 0.793
ECOG PS 0.584
Smoking status 0.784
Histology Adenocarcinoma
28 (93.3 %)
28 (93.3 %) [0.99
Nonadenocarcinoma
2 (6.7 %)
2 (6.7 %)
Surgery type Lobectomy
28 (93.3 %)
29 (96.7 %) [0.99
Pneumonectomy
2 (6.7 %)
1 (3.3 %)
11 (36.7 %)
9 (30 %)
EGFR mutation site Exon 19 deletion
L858R point mutation 19 (63.3 %)
0.584
21 (70 %)
Data are median (range) or number of patients (%). Some percentages may not sum to 100 because of rounding PC pemetrexed plus carboplatin, ECOG PS eastern cooperative oncology group performance status
Assessed for eligibility (n=63)
Not eligible (n=3)
Randomized (n=60)
Assigned to PC-gefitinib group (n=30)
Completed 4 cycles of PC and 6-month gefitinib (n=28) Didn’t complete 4 cycles of PC and 6-month gefitinib (n=2)
Assessable for efficacy Assessable for safety
(n=30) (n=30)
Assigned to PC group (n=30)
Completed 4 cycles of PC
(n=27)
Didn’t complete 4 cycles of PC (n=3)
Assessable for efficacy Assessable for safety
(n=30) (n=30)
Survival Analysis
FIG. 1 Trial profile
All of the 60 assigned patients who had received at least one dose of study drug were included in the efficacy analyses. DFS was significantly longer among those who received PC-gefitinib than among those who received PC alone (HR, 0.37; 95 % CI 0.16–0.85; log-rank P = 0.014;
median, 39.8 vs. 27.0 months; Fig. 2a). The rates of 2-year DFS were 78.9 % in the PC-gefitinib group and 54.2 % in the PC group, respectively. Preplanned subgroup analyses showed that the DFS was improved in all subgroups with gefitinib (Table 2).
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Disease-free Survival (Probability)
A
1.0
PC-gefitinib
0.8 0.6
PC
0.4 0.2 0 5
0
10
15
20
25
30
35
40
Months since surgery
No. at risk PC-gefitinib 30
30
30
27
24
24
20
17
11
PC
29
26
22
18
16
8
5
0
B
1.0
Overall survival (Probability)
30
0.8
PC-gefitinib PC
0.6 0.4 0.2 0
0
5
10
15
20
25
30
35
40
45
50
Months since surgery
No. at risk PC-gefitinib 30
30
30
28
28
28
28
26
22
11
11
PC
30
30
27
23
23
21
12
12
12
12
30
FIG. 2 Kaplan-Meier curves. a DFS, b OS
TABLE 2 Subgroup analyses of DFS Variable
PC-gefitinib no. PC no. HR
95 % CI
Age (yr) ‡65
9
6
0.122 0.014–1.099
\65
21
24
0.489 0.19–1.257
17 13
18 12
0.452 0.153–1.333 0.316 0.069–1.443
Current/former
13
14
0.315 0.077–1.288
Never
17
16
0.413 0.146–1.167
To date, a total of 27 recurrences (45 %) have occurred, including 10 in the PC-gefitinib group and 17 in the PC group. The most common recurrence site was brain, with 3 in the PC-gefitinib group and 9 in the PC group. Of the 17 recurred patients in the PC group, 15 received gefitinib, and 11 (73.3 %) obtained objective response. Of the 10 recurred patients in the PC-gefitinib group, 8 received further gefitinib, and 4 (50 %) obtained objective response. Safety All of the 60 randomly assigned patients who received at least one dose of study drug were included in the safety analyses. Table 3 summarized the common AEs. Twentyeight (93.3 %) patients in the PC-gefitinib group and 26 (86.7 %) in the PC group had at least one AE, which was thought to be possibly related to the treatment of the study. Most reported AEs were grade 1 or 2; six patients (20 %) in the PC-gefitinib group and five patients (16.7 %) in the PC group had a grade 3 or higher AE. Only one patient in the PC-gefitinib group had a grade 4 rash. The incidence of AEs in the PC-gefitinib group was similar to that in the PC group, except an increased incidence of rash and diarrhea. Compared with the PC group, the addition of gefitinib was associated with a higher rate of skin rash (43.3 %, 13/30) and diarrhea (30 %, 9/30), but they were mostly grade 1 to 2 (rash, 92.3 %; diarrhea, 88.9 %). No patient withdrew as a result of AEs in the PC-gefitinib group, and only one patient in the PC group withdrew as a result of severe vomiting.
Gender Male Female Smoking status
Mutation site Exon 19 deletion 11 Exon 21 L858R
19
9 21
0.016 0–25.45 0.407 0.164–1.011
The HR (PC-gefitinib versus PC) derived from a Cox proportional hazards model inclusive of only treatment as a factor; HR \ 1 favors PC-gefitinib DFS disease-free survival, PC pemetrexed plus carboplatin, HR hazard ratio, CI confidence interval
The rates of 2-year OS were 92.4 % in the PC-gefitinib group and 77.4 % in the PC alone group (HR, 0.37; 95 % CI 0.12–1.11, P = 0.076). The median survival time was 41.6 months for the PC-gefitinib group, as compared with 32.6 months for the PC group (Fig. 2b).
DISCUSSION To our knowledge, this is the first prospective, phase II study to examine the efficacy and safety of PC followed by gefitinib versus PC as adjuvant therapy for resected EGFR mutant stage IIIA-N2 NSCLC. Because studies have demonstrated that EGFR-TKIs are superior to chemotherapy in patients with advanced NSCLC harbouring EGFR mutations, we can hypothesize that adjuvant EGFR-TKIs following chemotherapy could obtain better outcomes than platinum-based chemotherapy alone in fully resected EGFR mutant lung cancer patients.12–14,19,20 The results of this study show that PC followed by gefitinib as adjuvant therapy provides significantly longer DFS in patients with resected stage IIIA-N2 NSCLC harbouring activating EGFR mutations (exons 19 or 21), prolonging median DFS by 12.8 months. The DFS benefit with additional gefitinib was consistent across all preplanned subgroups. Which—an EGFR-TKI or chemotherapy—is better in the adjuvant setting for lung cancer harbouring activating
Pemetrexed-Carboplatin and Gefitinib in NSCLC TABLE 3 Treatment-related adverse events AEs
PC-gefitinib (N = 30)
PC (N = 30)
All grades Grades ‡3 All grades Grades ‡3 Rash
13
2
2
0
Diarrhea
9
1
4
0
Dry skin
3
0
0
0
Anorexia
10
1
10
2
Pruritus
4
0
1
0
Fatigue
8
0
13
1
Nausea/vomiting Mucositis
7 6
0 0
12 4
1 0
Constipation
0
0
2
0
Fever
2
0
3
0
Anemia
8
0
6
0
Leukopenia
9
2
11
1
Thrombocytopenia
3
0
2
0
Data are number of patients (%) PC pemetrexed plus carboplatin
EGFR mutations remains undetermined. The phase 3 BR19 study comparing adjuvant gefitinib versus placebo in patients with completely resected NSCLC enrolled 503 of planned 1,160 patients, and no DFS or OS advantage was observed in overall population. Of the 359 patients who were examined for EGFR mutations, only 15 patients had an EGFR mutation.21 In contrast, the rate of activating EGFR mutations was 20–30 % for patients with resected NSCLC in our center.22,23 The retrospective study by Janjigian et al.24 investigating the impact of adjuvant TKIs on patients with lung adenocarcinomas harbouring EGFR mutations showed that adjuvant EGFR-TKIs in patients with resected stages I to III lung adenocarcinomas harbouring EGFR mutations had a trend toward improvement in DFS compared with patients who did not receive adjuvant TKIs. In the SELECT study of adjuvant erlotinib in resected EGFR mutation-positive NSCLC, the 2-year DFS rate was an excellent 94 %.25 Recently, a Chinese trial (NCT01405079) and a Japanese trial investigating adjuvant EGFR-TKIs versus platinum-based chemotherapy for resected NSCLC harbouring activating EGFR mutations are currently ongoing. The results of the efficacy analysis showed that adjuvant therapy with PC-gefitinib conferred longer DFS compared with PC in patients with stage IIIA-N2 NSCLC harbouring activating EGFR mutations. When recurrence occurred, 88.2 % patients in the PC group and 80 % patients in the PC-gefitinib group received gefitinib. Considering the median DFS in the PC-gefitinib group was 12.8 months longer than that in the PC group, we believe that the administration of gefitinib following chemotherapy as
adjuvant therapy is effective compared with the administration of gefitinib as postrecurrence medication. Indeed, although the OS difference did not reach significance, the observed DFS benefit appeared to translate into a marginal OS benefit with PC-gefitinib. However, there are some points that should be noted. First, 2-year OS may be too short to reflect the population outcome. Second, because the sample size was small, the study was not powered to detect a difference in OS. Third, the separation of the Kaplan–Meier curves for OS was sustained only during 15–40 months. Therefore, one should be cautious when the results of OS are interpreted. The best scheduling of an EGFR-TKI relative to chemotherapy for patients with resected stage IIIA-N2 NSCLC remains undetermined. In our study, we assigned the patients in the PC-gefitinib group to receive gefitinib 250 mg/day orally for 6 months immediately after chemotherapy, and this schedule led to a significant improvement in DFS. Upon disease recurrence, eight patients in the PC-gefitinib group received further gefitinib and four patients experienced objective response. The high postrecurrence response rate of receiving further gefitinib was thought-provoking: maybe 6 months of gefitinib is not enough. In the SELECT trial, patients were treated with erlotinib for 2 years after completion of adjuvant chemotherapy and/or radiotherapy. In that trial, 25 of 36 patients received erlotinib for 2 full years, and the 2-year DFS was 94 %.25 The optimal length of time of EGFR-TKIs after chemotherapy as adjuvant therapy remains to be confirmed. The most frequent initial recurrence site was brain in our study, which is consistent with the results of our previous study.26 In our study, we observed a lower recurrence incidence of brain in the PC-gefitinib group. Thus, the addition of gefitinib could reduce the risk of developing brain recurrence. Also, given the high risk of brain recurrence, prophylactic cranial irradiation should be considered. Previously, we reported a prophylactic cranial irradiation model to predict the risk of developing brain metastases in patients with locally advanced NSCLC.27 The role of prophylactic cranial irradiation needs to be further investigated. As expected, the addition of gefitinib was associated with increased risk of rash and diarrhea. However, of those gefitinib-related AEs, most could be managed and no patient withdrew as a result of gefitinib-related AEs. The addition of gefitinib to chemotherapy was well tolerated, with no added hematologic toxicity. Although this is not a placebo-controlled study and the number of patients is small, our study has led to some valuable conclusions for adjuvant therapy in patients with EGFR mutant stage IIIA-N2 NSCLC. Further studies are needed to investigate the efficacy and safety of EGFRTKIs following chemotherapy versus chemotherapy, and
N. Li et al.
the optimal length of time of EGFR-TKIs following chemotherapy as adjuvant therapy for patients with EGFR mutations. CONCLUSIONS The results of our study suggest that the administration of gefitinib following PC adjuvant therapy can significantly prolong DFS of patients with resected stage IIIA-N2 NSCLC harbouring EGFR mutations compared with PC alone, with acceptable toxicity. The DFS benefit of additional gefitinib indicates that patients in whom an EGFR mutation has been identified will benefit from gefitinib following chemotherapy as adjuvant therapy. CONFLICT OF INTEREST interest.
All authors have no conflicts of
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