Lung Cancer 87 (2015) 148–154
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Efficacy of EGFR tyrosine kinase inhibitors in patients with EGFR-mutated non-small cell lung cancer except both exon 19 deletion and exon 21 L858R: A retrospective analysis in Korea Jin Ho Baek a,1 , Jong-Mu Sun d,1 , Young Joo Min a,∗ , Eun Kyung Cho b , Byoung Chul Cho c , Joo-Hang Kim c , Myung-Ju Ahn d , Keunchil Park d a Division of Oncology, Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-714, Republic of Korea b Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea c Yonsei Cancer Center, Yonsei University Health System, Seoul, Republic of Korea d Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 29 August 2014 Received in revised form 18 November 2014 Accepted 23 November 2014 Keywords: NSCLC EGFR Rare or complex mutations Clinical trials Mortality Morbidity
a b s t r a c t Background: NSCLC can be defined by various molecular criteria, especially by the type of EGFR mutations present. Besides two major EGFR mutations, other rare or complex types have not been fully described. We performed this study to investigate the clinical significance and efficacy of EGFR-TKIs in NSCLC patients with rare or complex EGFR mutations. Methods: We retrospectively reviewed data for consecutive patients with advanced NSCLC. Subjects with wild type EGFR, EGFR del-19 alone, or EGFR L858R alone were excluded. A rare mutation was defined as any mutation other than del-19 or L858R in exon 21 and a complex mutation was defined as two or more different mutations co-existing within the same tumor sample. Results: A total of 1738 patients underwent EGFR genotyping. Among them, 88 (5.1%) had rare or complex mutations and 54 were treated with TKIs. Thirty-three patients had single rare mutations and 21 had complex mutations. The response was evaluated in 50 patients. Partial response was achieved in 11 (20.4%) patients, and stable disease was achieved in 20 (37.0%) patients. The median progression-free survival was 2.6 months (95% CI; 0.0–5.4 months) at a median follow-up duration of 381.0 days (range; 10–1307 days). The median overall survival was 12.7 months (95% CI; 7.2–18.2 months). Conclusions: These results suggest that rare or complex EGFR mutations confer inferior response and survival to the EGFR-TKI treatment compared to common mutations. Further studies using larger numbers of patients are needed to determine better subclassifications for these patients. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung cancer is the leading cause of cancer-related death in the United States [1] and a major cause of cancer mortality and morbidity worldwide [2]. Non-small-cell lung cancer (NSCLC) constitutes more than 80% of all the cases of lung cancer [3]. Today, types
∗ Corresponding author at: Division of Oncology, Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, 877 Baneojinsunhwan-doro, Dong-gu, Ulsan 682-714, Republic of Korea. Tel.: +82 52 250 8832; fax: +82 52 250 7048. E-mail address: [email protected] (Y.J. Min). 1 Jin Ho Baek and Jong-Mu Sun equally contributed to this study. http://dx.doi.org/10.1016/j.lungcan.2014.11.013 0169-5002/© 2014 Elsevier Ireland Ltd. All rights reserved.
of NSCLC can be defined by various molecular criteria. Especially, somatic mutations within the epidermal growth factor receptor (EGFR) gene were discovered in a subset of NSCLC patients. The presence of mutations in the kinase domain of the EGFR gene has been regarded as both a positive prognostic and predictive marker, and most EGFR mutation-positive patients respond well to tyrosine kinase inhibitors (TKIs) such as gefitinib or erlotinib [4,5]. Recent clinical trials have also suggested that for advanced NSCLC patients with EGFR mutant tumors, initial therapy with a TKI instead of platinum-based chemotherapy has been clinically validated as the most effective first-line treatment [6–8]. Two major activating mutations in EGFR are an in-frame deletion in exon 19 (del-19) and the L858R substitution in exon 21. These mutations account for 85% of all clinically important mutations related to EGFR-TKI
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sensitivity [9–11]. They have also been associated with females, non-smokers, people of Asian descent, and adenocarcinoma histology [11]. Besides the two activating mutations in EGFR, other mutations have been discovered in EGFR exons 18–21 [12–14]. These rare mutations have not been fully described, and the response of such tumors to EGFR-TKIs is still unclear. Complex mutations, which are defined as two or more different mutations co-occurring within the same tumor, have also been reported [15,16]. The efficacy of EGFRTKIs in treating patients with complex mutations is also unclear. Therefore, we performed this study to investigate the clinical significance of rare or complex mutations, and the efficacy of EGFRTKIs in these patients. 2. Patients and methods 2.1. Study design and patient population This study conducted a retrospective review of data for consecutive patients from four centers (Samsung Medical Center, Severance Hospital, Gachon University Gil Medical Center, and Ulsan University Hospital in Korea) with advanced NSCLC who were treated with TKIs, either gefitinib or erlotinib, and whose EGFR genotyping was performed successfully. Subjects were not entered into the study if any of the following exclusion criteria were fulfilled: wild type EGFR, EGFR del-19 alone, or EGFR L858R in exon 21 alone. A rare mutation was defined as any mutation other than del-19 or L858R in exon 21, and a complex mutation was defined as two or more different mutations co-occurring within the same tumor sample. The timing of different EGFR-TKI treatments depended on the physicians’ discretion. Erlotinib was taken at 150 mg daily, whereas gefitinib was taken at 250 mg daily orally until tumor progression, death, significant uncontrolled toxicity, or patient refusal. Chest radiography was routinely carried out and assessed every 2 to 3 weeks to evaluate the response to treatment. A chest CT scan, including the liver and adrenal glands, was carried out every 2 to 3 months as per routine clinical practice, and additionally as needed to confirm response and disease progression. The response was evaluated using Response Evaluation Criteria In Solid Tumors version 1.1 [17]. Patients with a partial or complete response were regarded as responders, and the rest were classified as nonresponders to antitumor therapy. The disease control status was classified as complete response (CR), partial response (PR), or stable disease (SD) [18]. The protocol was reviewed and approved by the Institutional Review Board of respective hospitals and registered at http://www.clinicaltrials.gov (NCT01775943). 2.2. Analysis of EGFR mutations Tumor specimens for each patient in this study were obtained by either diagnostic or surgical procedures. Samples consisted of either frozen tumor specimens or paraffin-embedded materials. For patients with sufficient amounts of tissue to undergo analyses by direct DNA sequencing, tumor cells were isolated from the normal cells by microdissection, so that >50% tumor cells were present in the specimen sent for sequencing. EGFR mutation analysis was performed using standard DNA sequencing techniques with direct sequencing of exons 18–21 of EGFR. Exons 18–21 were amplified by PCR and analyzed bidirectionally by direct sequencing for the presence of somatic mutations [9]. All mutations were confirmed by independent PCR amplifications. 2.3. Statistical analysis The primary objective of the study was to evaluate the efficacy of EGFR-TKIs as defined by the objective response rate (ORR),
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disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) in the patients with rare or complex EGFRmutated NSCLC. The secondary objectives were to assess the incidence and clinical characteristics of patients with rare or complex EGFR mutated NSCLC. PFS and OS were estimated using the Kaplan–Meier method. The ORR and DCR were described based on each variable. PFS was calculated from the date of the first dosing of EGFR-TKIs to the date of disease progression or death, and the OS was measured from the date of the first dosing of EGFR-TKIs to the date of the last follow-up or death. Comparisons of PFS and OS between individual rare or complex EGFR mutations were performed using the log-rank test. Univariate analyses were performed to analyze the clinical characteristics between individual EGFR mutations and between the different responses to EGFR-TKIs. For categorical variables, the Chi-square test or Fisher’s exact test was used, and for continuous variables the Student’s t-test or the Mann–Whitney U test was used. All statistical analyses were performed using PASW Statistics 18.0 (SPSS Inc, Chicago, IL, USA). 3. Results 3.1. Frequency of rare and complex mutations Between January 2008 and December 2011, 1738 patients received EGFR genotyping analysis. Among them, 1115 patients (64.2%) were EGFR wild type, 283 patients (16.3%) had only the EGFR del-19 mutation, and 200 patients (11.5%) had only the EGFR L858R mutation in exon 21. Eighty-eight patients (5.1%) had rare or complex mutations. Of these, this study included 54 patients who had rare or complex EGFR mutations and were treated with TKIs. The characteristics of the patients are summarized in Table 1. The median age was 58.0 (range, 28–79) years. There were 25 males (46.3%) and 29 females (53.7%). Thirty patients (55.6%) were neversmokers. Fifty-one patients had a performance status of 0 or 1, and three patients had a performance status of 2 or 3. Histology revealed adenocarcinoma in 48 patients (88.9%), squamous cell carcinoma in four, and unspecified NSCLC in two. At the start of EGFR-TKI treatment, 50 were stage IIIB or IV patients, and four were patients with recurred disease. Gefitinib was administered to 35 patients and the other 19 received erlotinib. EGFR-TKIs were used as the first-line treatment for nine patients, the second-line for 24, the third-line for 18, and the fourth or later lines for three patients. Thirty-three patients (61.1%) had single rare mutations and 21 patients had complex mutations (Table 2). The single rare mutation, G719, was found in four patients. Fourteen patients had an insertion and six had a duplication in exon 20. Complex mutations with del-19 or L858R were found in 12 patients (22.2%) and two patients among them had complex mutations of del-19 or L858T and T790M. Complex mutations with G719 were found in six patients and two patients had complex mutations with S768I. A total of 75 mutations were identified (Table 3). The most frequent mutation was an insertion in exon 20 (22.7%), followed by L858R (10.7%), duplication in exon 20 (9.3%), del-19 (8.0%), G719A (6.7%), G719S (5.3%), and S768I (5.3%). 3.2. Efficacy Fifty of the 54 patients (92.6%) were assessable for response to TKIs, with two of the remaining being lost to follow-up and two to early death. No case of CR and 11 cases of PR were confirmed, giving an overall response rate of 20.4% (95% CI; 9.6–31.1%). Twenty (37.0%) patients had SD. The disease control rate (DCR) was 57.4% (95% CI; 44.2–70.6%). The response characteristics are shown in Table 4. The median duration of response in the 11 responding patients was 13.8 months (95% CI; 4.9–22.6 months), while the median PFS for all patients was 2.6 months (95% CI; 0.0–5.4 months)
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Table 1 Patient characteristics.
No. of patients Age (years) Median (range) Gender Male Female Smoking status Smoker Never-smoker Unknown ECOG performance status 0 or 1 2 or 3 Pathology Adenocarcinoma Non-adenocarcinoma Disease status Stage IIIB or IV Recurred Treatment drug Gefitinib Erlotinib Lines of treatment 1st line 2nd line 3rd line 4th or later line
All patients, number (%)
Patients with single rare mutations in exon 18 (Group 1)
Patients with single rare mutations in exon 20 (Group 2)
Patients with complex mutations with del-19 or L858R (Group 3)
Patients with other single rare or complex mutations (Group 4)
54 58.0 (28–79)
7 59.0 (47–71)
24 57.0 (28–77)
12 60.5 (38–79)
11 56.0 (48–79)
25 (46.3) 29 (53.7)
4 3
11 13
4 8
6 5
0.695
23 (42.6) 30 (55.6) 1 (1.9)
5 2 0
8 15 1
3 9 0
7 4 0
0.254
51 (94.4) 3 (5.6)
6 1
24 0
10 2
11 0
0.117
48 (88.9) 6 (11.1)
6 1
21 3
12 0
9 2
0.537
50 (92.6) 4 (7.4)
7 0
22 2
10 2
11 0
0.396
35 (64.8) 19 (35.2)
3 4
17 7
8 4
7 4
0.596
9 (16.7) 24 (44.4) 18 (33.3) 3 (5.6)
1 1 5 0
4 13 5 2
2 4 5 1
2 6 3 0
0.474
at a median follow-up duration of 381.0 days (range; 10–1307 days). Forty-two patients had died at the time of the present evaluation. The median OS was 12.7 months (95% CI; 7.2–18.2 months) with a 1-year survival rate of 53.5%. We categorized the patients into four groups. Group 1 patients had single rare mutations in exon 18. Group 2 patients had single rare mutations in exon 20. Group 3 patients had complex mutations with del-19 or L858R. Group 4 was comprised of 11 patients who had other single rare or complex mutations. Two of these patients had single L861Q, and six had complex mutations with G719. The response rates to TKIs were significantly different (p = 0.034) and the disease control rates were also significantly different (p = 0.034) between each group (Table 4). Groups 3 and 4 showed favorable
Group 2 (n = 24)
Group 4 (n = 11)
0.832
responses, but Groups 1 and 2 showed unfavorable responses. PFSs were also significantly different (p = 0.006). PFSs were better in Groups 3 and 4, and worse in Groups 1 and 2 (Table 4 and Fig. 1). OSs were not significantly different (p = 0.479), but were also better in Groups 3 and 4 and worse in Groups 1 and 2 (Table 4 and Fig. 2).
4. Discussion In the current study, wild type EGFR was found in 64.2% of patients with NSCLC, and classical mutations such as del-19 alone or L858R alone were found in 27.8%. Rare or complex mutations such as any mutation other than del-19 or L858R alone, or two or
Table 2 Frequency of rare and complex mutations.
Group 1 (n = 7)
p-value
Characteristics
Number of patients (n = 54, %)
Characteristics
Number of patients (n = 54, %)
Single rare mutations
33 (61.1)
Complex mutations
21 (38.9)
18 G719 18 G719A 18 G719C 18 G719S 18 S720F 18 F723L 20 S768I 20 V786M 20 G796S 20 insertion 20 duplication 21 L861Q
4 2 1 1 2 1 1 2 1 14 6 2
Del 19 or L858R + other Del 19 + 20 T790M Del 19 + 20 insertion Del 19 + 21 L858R Del 19 + 21 L833V 21 L858R + 18 S720P 21 L858R + 20 H733Y 21 L858R + 20 R776H 21 L858R + 20 T790M 21 L858R + 20 duplication 21 L858R + 21 A871G Other complex mutations 18 G719 + other 18 G719A + 18 E709A 18 G719A + 18 E709K 18 G719A + 18 S720F 18 G719S + 18 G721S 18 G719S + 20 S768I 18 G719S + 20 R776H 20 S768I + 20 V769L 20 S768I + 21 L861R 20 P772H + 20 insertion
12 1 2 2 1 1 1 1 1 1 1 9 6 1 1 1 1 1 1 1 1 1
Group 3 (n = 12)
Group 4 (n = 11)
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Table 3 Overall mutation frequency: 75 mutations in 54 patients. Exon
Mutation
Number (%)
Exon Exon 20
18 E709A 18 E709K 18 G719A 18 G719C 18 G719S 18 S720F 18 S720P 18 G721S 18 F723L
18 (24.0) 1 1 5 1 4 3 1 1 1
Deletion 19
6 (8.0) 6
Exon 18
Exon 19
Mutation
Number (%)
20 S768I 20 V769L 20 P772H 20 H773Y 20 R776H 20 V786M 20 T790M 20 G796S Insertion
38 (50.7) 4 1 1 1 2 2 2 1 17
Duplication Exon 21 21 L833V 21 L858R 21 L861Q 21 L861R 21 A871G
more different mutations co-occurring within the same tumor sample, were found in 5.1% of patients. After TKI treatment, the overall response rate and DCR of these patients were 20.4% and 57.4%, respectively. The median PFS and OS were 2.6 months and 12.7 months, respectively. However, the heterogeneous Groups (1–4) showed different survival rates and responses to EGFR-TKIs. The response rates to EGFR TKIs were significantly different between each group and higher in Groups 3 and 4 than in Groups 1 and 2 (33.3%, 45.5%, 0.0%, and 8.3%, respectively). The median PFSs after EGFR-TKI treatment were also significantly different and longer in Groups 3 and 4 than in Groups 1 and 2 (7.4 months, 5.1 months, 1.3 months, and 2.6 months, respectively). The OSs after EGFR-TKI treatment were not significantly different but were also longer in Groups 3 and 4 and shorter in Groups 1 and 2 (17.9 months, 18.3 months, 6.3 months, and 9.4 months, respectively). EGFR is a transmembrane receptor that is detectable in approximately 80–85% of patients with NSCLC. The activation of EGFR leads to activation of proliferation and invasion [19]. Activating or sensitizing mutations cause constitutive activation of the tyrosine kinase domain of the EGFR protein by destabilizing the auto-inhibiting conformation [20]. EGFR-TKIs such as gefitinib or erlotinib have increased binding affinities to these mutant proteins. The two most common sensitizing EGFR mutations to EGFR-TKI are the del-19 and L858R, which account for almost 85% of all EGFR mutations. These drug-sensitive mutations are found in approximately 10% of
7 13 (17.3) 1 8 2 1 1
Caucasian patients and up to 50% of Asian patients with NSCLC [21]. A previous study reported that response rates (RRs) to EGFR-TKIs exceed 60–70%, with median PFSs of more than 9–10 months and OSs beyond 20 months in these patients [22]. The frequency of rare or complex mutations has been reported to range from 2.6% to 14% [12,15,23–28]. In this study, the frequency of rare or complex mutations was 5.1%. Thirty-three patients (61.1%) had single rare mutations and 21 patients had complex mutations. These rare or complex mutations are not so infrequent that the efficacy of EGFR-TKIs for patients with these mutations should be elucidated. In our study, the efficacy of EGFR-TKIs was heterogeneous in patients with rare or complex mutations. The group of patients with complex mutations with del-19 or L858R and other single rare or complex mutations showed better responses and survival rates than patients with a single rare mutation in exon 18 or 20. Hata et al. [15] reported that patients with complex mutations of del-19 and L858R showed an 86.0% RR and 16.5 months of median PFS after EGFR-TKI treatment. Keam et al. [27] also reported a 68.8% RR and 8.1 months of median PFS for patients with complex mutations with del-19 or L858R. In this study, patients with complex mutations with del-19 or L858R showed a 33.3% RR, 7.4 months of median PFS, and 17.9 months of median OS after EGFR-TKI treatment. This efficacy is slightly inferior to what has been seen in other studies. However, it is comparable to that in patients with a single mutation of del-19 or L858R.
Table 4 Responses and survivals. All patients, number (%)
Patients with single rare mutations in exon 18 (Group 1)
Patients with single rare mutations in exon 20 (Group 2)
Patients with complex mutations with del-19 or L858R (Group 3)
Patients with other single rare or complex mutations (Group 4)
p-value
Best response Complete response Partial response Stable disease Progressive disease Not evaluable Disease control Yes No Not evaluable PFS (months) Median (95% CI)
0 (0.0) 11 (20.4) 20 (37.0) 19 (35.2) 4 (7.4)
0 0 1 6 0
0 2 10 9 3
0 4 5 2 1
0 5 4 2 0
0 .034
31 (57.4) 19 (35.2) 4 (7.4)
1 6 0
12 9 3
9 2 1
9 2 0
0 .034
2.6 (0.0–5.4)
1.3 (0.0–3.5)
2.6 (1.7–3.5)
7.4 (0.0–17.4)
5.1 (0.7–9.6)
0 .006
OS (months) Median (95% CI)
12.7 (7.2–18.2)
6.3 (0.0–14.7)
9.4 (2.6–16.2)
17.9 (0.0–37.2)
18.3 (14.5–22.1)
0 .479
PFS, progression free survival; OS, overall survival, CI, confidence interval.
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Fig. 1. Kaplan–Meier curves for progression free survival by mutation status. Group 1, patients with single rare mutations in exon 18; Group 2, patients with single rare mutations in exon 20; Group 3, patients with complex mutations with del-19 or L858R; Group 4, patients with other single rare or complex mutations.
Fig. 2. Kaplan–Meier curves for overall survival by mutation status. Group 1, patients with single rare mutations in exon 18; Group 2, patients with single rare mutations in exon 20; Group 3, patients with complex mutations with del-19 or L858R; Group 4, patients with other single rare or complex mutations.
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In this study, G719 and L861 mutations were discovered infrequently, but are known to be associated with favorable responses to EGFR-TKIs. Wu et al. [12] reported that patients with a single or complex mutation accompanying G719 showed a 53.3% RR, 8.1 months of median PFS, and 16.4 months of median OS after EGFR-TKI treatment. Patients with a single or complex mutation accompanying L861 also showed favorable results such as a 60.0% RR, 6.0 months of median PFS, and 15.2 months of median OS. Recently, Watanabe et al. [29] reported that patients with G719X or L861Q showed a 20% RR, 2.2 months of median PFS, and 12 months of median OS to gefitinib. They reported that NSCLC patients with G719X or L861Q had shorter survival than those with del-19 or L858R. In this study, six patients had complex mutations accompanying G719, four had single mutations at G719, two had single mutations at L861, and one had a complex mutation with L861. These 13 patients with single or complex mutations accompanying either G719 or L861 showed a 38.5% RR, 5.1 months of median PFS, and 18.6 months of median OS after EGFR-TKI treatment. The efficacy in these cases was not as favorable as for patients with del-19 or L858R, but was still positive. Group 4 included two patients with single L861Q and six patients with complex mutations with G719, this might reflect favorable efficacy of this group. The frequency of exon 20 insertions ranges from 1 to 10% of all the EGFR mutations, with the majority conferring resistance to EGFR-TKIs [30]. Exon 20 insertions add residues within the Nterminal position or at the opposite end of the C-helix. Most EGFR exon 20 insertions occur at the N-lobe of EGFR after the C-helix and have been reported as far as amino acid C775 (A767–C775). This region plays a critical role in catalytic activity, as well as drug affinity, resulting in resistance to EGFR-TKIs [30,31]. Some proximal insertions that affect E762 to Y764 were reported and could be associated with disease control to EGFR-TKIs [30,32]. In this study, 24 cases of insertions or duplications in exon 20 were observed. Twenty-one cases were detected within A767 to C775, and two cases were proximal insertions. One case could not be specified. Both patients with proximal insertions in exon 20 showed PR to EGFR-TKIs. Their PFSs were 13.3 months and 13.7 months, and their OSs were 13.7 months and 14.0 months, respectively. These results suggest that the more specific sequence of insertion should be detailed for more information about EGFR-TKI sensitivity. These results suggest that rare or complex EGFR mutations confer lower rates of survival and inferior responses to EGFR-TKI treatment than common mutations. The set of patients used in this study was composed of heterogeneous groups, which each showed different responses to EGFR-TKIs and different rates of survival. Further studies with larger numbers of patients will be needed to sub-classify these rare or complex mutations and develop optimal treatment strategies. Further investigation is also needed to clarify the molecular mechanisms behind the varying efficacy of EGFRTKI treatment in patients with these mutations. And the efficacy of a new generation EGFR-TKIs to these mutations also should be elucidated. Conflicts of Interest Statement None declared. Acknowledgment This research was conducted with support from Investigator-Sponsored Study Programme of AstraZeneca.
the
References [1] Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics. CA Cancer J Clin 2007;57:43–66.
153
[2] Parkin DM, Ferlay J, Curado MP, Bray F, Edwards B, Shin HR, et al. Fifty years of cancer incidence: CI5 I-IX. Int J Cancer 2010;127:2918–27. [3] Gridelli C, Aapro M, Ardizzoni A, Balducci L, De Marinis F, Kelly K, et al. Treatment of advanced non-small-cell lung cancer in the elderly: results of an international expert panel. J Clin Oncol 2005;23:3125–37. [4] Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947–57. [5] Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123–32. [6] Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, 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;12:735–42. [7] Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, 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;13:239–46. [8] Petrelli F, Borgonovo K, Cabiddu M, Barni S. Efficacy of EGFR tyrosine kinase inhibitors in patients with EGFR-mutated non-small-cell lung cancer: a meta-analysis of 13 randomized trials. Clin Lung Cancer 2012;13: 107–14. [9] Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129–39. [10] Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497–500. [11] Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, et al. EGF receptor gene mutations are common in lung cancers from never smokers and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 2004;101:13306–11. [12] Wu JY, Yu CJ, Chang YC, Yang CH, Shih JY, Yang PC. Effectiveness of tyrosine kinase inhibitors on uncommon epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin Cancer Res 2011;17:3812–21. [13] Wu JY, Wu SG, Yang CH, Gow CH, Chang YL, Yu CJ, et al. Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response. Clin Cancer Res 2008;14:4877–82. [14] Balak MN, Gong Y, Riely GJ, Somwar R, Li AR, Zakowski MF, et al. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 2006;12:6494–501. [15] Hata A, Yoshioka H, Fujita S, Kunimasa K, Kaji R, Imai Y, et al. Complex mutations in the epidermal growth factor receptor gene in non-small cell lung cancer. J Thorac Oncol 2010;5:1524–8. [16] Hsieh MH, Fang YF, Chang WC, Kuo HP, Lin SY, Liu HP, et al. Complex mutation patterns of epidermal growth factor receptor gene associated with variable responses to gefitinib treatment in patients with non-small cell lung cancer. Lung Cancer 2006;53:311–22. [17] Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–47. [18] Lara Jr PN, Redman MW, Kelly K, Edelman MJ, Williamson SK, Crowley JJ, et al. Disease control rate at 8 weeks predicts clinical benefit in advanced non-smallcell lung cancer: results from Southwest Oncology Group randomized trials. J Clin Oncol 2008;26:463–7. [19] Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med 2008;359:1367–80. [20] Farina Sarasqueta A, Moerland E, de Bruyne H, de Graaf H, Vrancken T, van Lijnschoten G, et al. SNaPshot and StripAssay as valuable alternatives to direct sequencing for KRAS mutation detection in colon cancer routine diagnostics. J Mol Diagn 2011;13:199–205. [21] Hirsch FR, Bunn Jr PA. EGFR testing in lung cancer is ready for prime time. Lancet Oncol 2009;10:432–3. [22] Gaughan EM, Costa DB. Genotype-driven therapies for non-small cell lung cancer: focus on EGFR, KRAS and ALK gene abnormalities. Ther Adv Med Oncol 2011;3:113–25. [23] De Pas T, Toffalorio F, Manzotti M, Fumagalli C, Spitaleri G, Catania C, et al. Activity of epidermal growth factor receptor-tyrosine kinase inhibitors in patients with non-small cell lung cancer harboring rare epidermal growth factor receptor mutations. J Thorac Oncol 2011;6:1895–901, http://dx.doi.org/10.097/JTO.0b013e318227e8c6. [24] Yokoyama T, Kondo M, Goto Y, Fukui T, Yoshioka H, Yokoi K, et al. EGFR point mutation in non-small cell lung cancer is occasionally accompanied by a second mutation or amplification. Cancer Sci 2006;97:753–9. [25] Zhang GC, Lin JY, Wang Z, Zhou Q, Xu CR, Zhu JQ, et al. Epidermal growth factor receptor double activating mutations involving both Exons 19 and 21 exist in Chinese non-small cell lung cancer patients. Clin Oncol 2007;19:499–506. [26] Wu S-G, Chang Y-L, Hsu Y-C, Wu J-Y, Yang C-H, Yu C-J, et al. Good response to Gefitinib in lung adenocarcinoma of complex epidermal growth factor receptor (EGFR) mutations with the classical mutation pattern. Oncologist 2008;13:1276–84.
154
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[27] Keam B, Kim DW, Park JH, Lee JO, Kim TM, Lee SH, et al. Rare and complex mutations of epidermal growth factor receptor, and efficacy of tyrosine kinase inhibitor in patients with non-small cell lung cancer. Int J Clin Oncol 2013;19:594–600. [28] Kobayashi S, Canepa HM, Bailey AS, Nakayama S, Yamaguchi N, Goldstein MA, et al. Compound EGFR mutations and response to EGFR tyrosine kinase inhibitors. J Thorac Oncol 2013;8:45–51. [29] Watanabe S, Minegishi Y, Yoshizawa H, Maemondo M, Inoue A, Sugawara S, et al. Effectiveness of Gefitinib against non-small-cell lung cancer with the uncommon EGFR mutations G719X and L861Q. J Thorac Oncol 2014;9:189–94.
[30] Yasuda H, Kobayashi S, Costa DB. EGFR exon 20 insertion mutations in nonsmall-cell lung cancer: preclinical data and clinical implications. Lancet Oncol 2012;13:e23–31. [31] Arcila ME, Nafa K, Chaft JE, Rekhtman N, Lau C, Reva BA, et al. EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther 2013;12:220–9. [32] Massarelli E, Johnson FM, Erickson HS, Wistuba II, Papadimitrakopoulou V. Uncommon epidermal growth factor receptor mutations in non-small cell lung cancer and their mechanisms of EGFR tyrosine kinase inhibitors sensitivity and resistance. Lung Cancer 2013;80:235–41.
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Efficacy of EGFR tyrosine kinase inhibitors in patients with EGFR-mutated non-small cell lung cancer except both exon 19 deletion and exon 21 L858R: A retrospective analysis in Korea Jin Ho Baek a,1 , Jong-Mu Sun d,1 , Young Joo Min a,∗ , Eun Kyung Cho b , Byoung Chul Cho c , Joo-Hang Kim c , Myung-Ju Ahn d , Keunchil Park d a Division of Oncology, Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-714, Republic of Korea b Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea c Yonsei Cancer Center, Yonsei University Health System, Seoul, Republic of Korea d Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 29 August 2014 Received in revised form 18 November 2014 Accepted 23 November 2014 Keywords: NSCLC EGFR Rare or complex mutations Clinical trials Mortality Morbidity
a b s t r a c t Background: NSCLC can be defined by various molecular criteria, especially by the type of EGFR mutations present. Besides two major EGFR mutations, other rare or complex types have not been fully described. We performed this study to investigate the clinical significance and efficacy of EGFR-TKIs in NSCLC patients with rare or complex EGFR mutations. Methods: We retrospectively reviewed data for consecutive patients with advanced NSCLC. Subjects with wild type EGFR, EGFR del-19 alone, or EGFR L858R alone were excluded. A rare mutation was defined as any mutation other than del-19 or L858R in exon 21 and a complex mutation was defined as two or more different mutations co-existing within the same tumor sample. Results: A total of 1738 patients underwent EGFR genotyping. Among them, 88 (5.1%) had rare or complex mutations and 54 were treated with TKIs. Thirty-three patients had single rare mutations and 21 had complex mutations. The response was evaluated in 50 patients. Partial response was achieved in 11 (20.4%) patients, and stable disease was achieved in 20 (37.0%) patients. The median progression-free survival was 2.6 months (95% CI; 0.0–5.4 months) at a median follow-up duration of 381.0 days (range; 10–1307 days). The median overall survival was 12.7 months (95% CI; 7.2–18.2 months). Conclusions: These results suggest that rare or complex EGFR mutations confer inferior response and survival to the EGFR-TKI treatment compared to common mutations. Further studies using larger numbers of patients are needed to determine better subclassifications for these patients. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung cancer is the leading cause of cancer-related death in the United States [1] and a major cause of cancer mortality and morbidity worldwide [2]. Non-small-cell lung cancer (NSCLC) constitutes more than 80% of all the cases of lung cancer [3]. Today, types
∗ Corresponding author at: Division of Oncology, Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, 877 Baneojinsunhwan-doro, Dong-gu, Ulsan 682-714, Republic of Korea. Tel.: +82 52 250 8832; fax: +82 52 250 7048. E-mail address: [email protected] (Y.J. Min). 1 Jin Ho Baek and Jong-Mu Sun equally contributed to this study. http://dx.doi.org/10.1016/j.lungcan.2014.11.013 0169-5002/© 2014 Elsevier Ireland Ltd. All rights reserved.
of NSCLC can be defined by various molecular criteria. Especially, somatic mutations within the epidermal growth factor receptor (EGFR) gene were discovered in a subset of NSCLC patients. The presence of mutations in the kinase domain of the EGFR gene has been regarded as both a positive prognostic and predictive marker, and most EGFR mutation-positive patients respond well to tyrosine kinase inhibitors (TKIs) such as gefitinib or erlotinib [4,5]. Recent clinical trials have also suggested that for advanced NSCLC patients with EGFR mutant tumors, initial therapy with a TKI instead of platinum-based chemotherapy has been clinically validated as the most effective first-line treatment [6–8]. Two major activating mutations in EGFR are an in-frame deletion in exon 19 (del-19) and the L858R substitution in exon 21. These mutations account for 85% of all clinically important mutations related to EGFR-TKI
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sensitivity [9–11]. They have also been associated with females, non-smokers, people of Asian descent, and adenocarcinoma histology [11]. Besides the two activating mutations in EGFR, other mutations have been discovered in EGFR exons 18–21 [12–14]. These rare mutations have not been fully described, and the response of such tumors to EGFR-TKIs is still unclear. Complex mutations, which are defined as two or more different mutations co-occurring within the same tumor, have also been reported [15,16]. The efficacy of EGFRTKIs in treating patients with complex mutations is also unclear. Therefore, we performed this study to investigate the clinical significance of rare or complex mutations, and the efficacy of EGFRTKIs in these patients. 2. Patients and methods 2.1. Study design and patient population This study conducted a retrospective review of data for consecutive patients from four centers (Samsung Medical Center, Severance Hospital, Gachon University Gil Medical Center, and Ulsan University Hospital in Korea) with advanced NSCLC who were treated with TKIs, either gefitinib or erlotinib, and whose EGFR genotyping was performed successfully. Subjects were not entered into the study if any of the following exclusion criteria were fulfilled: wild type EGFR, EGFR del-19 alone, or EGFR L858R in exon 21 alone. A rare mutation was defined as any mutation other than del-19 or L858R in exon 21, and a complex mutation was defined as two or more different mutations co-occurring within the same tumor sample. The timing of different EGFR-TKI treatments depended on the physicians’ discretion. Erlotinib was taken at 150 mg daily, whereas gefitinib was taken at 250 mg daily orally until tumor progression, death, significant uncontrolled toxicity, or patient refusal. Chest radiography was routinely carried out and assessed every 2 to 3 weeks to evaluate the response to treatment. A chest CT scan, including the liver and adrenal glands, was carried out every 2 to 3 months as per routine clinical practice, and additionally as needed to confirm response and disease progression. The response was evaluated using Response Evaluation Criteria In Solid Tumors version 1.1 [17]. Patients with a partial or complete response were regarded as responders, and the rest were classified as nonresponders to antitumor therapy. The disease control status was classified as complete response (CR), partial response (PR), or stable disease (SD) [18]. The protocol was reviewed and approved by the Institutional Review Board of respective hospitals and registered at http://www.clinicaltrials.gov (NCT01775943). 2.2. Analysis of EGFR mutations Tumor specimens for each patient in this study were obtained by either diagnostic or surgical procedures. Samples consisted of either frozen tumor specimens or paraffin-embedded materials. For patients with sufficient amounts of tissue to undergo analyses by direct DNA sequencing, tumor cells were isolated from the normal cells by microdissection, so that >50% tumor cells were present in the specimen sent for sequencing. EGFR mutation analysis was performed using standard DNA sequencing techniques with direct sequencing of exons 18–21 of EGFR. Exons 18–21 were amplified by PCR and analyzed bidirectionally by direct sequencing for the presence of somatic mutations [9]. All mutations were confirmed by independent PCR amplifications. 2.3. Statistical analysis The primary objective of the study was to evaluate the efficacy of EGFR-TKIs as defined by the objective response rate (ORR),
149
disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) in the patients with rare or complex EGFRmutated NSCLC. The secondary objectives were to assess the incidence and clinical characteristics of patients with rare or complex EGFR mutated NSCLC. PFS and OS were estimated using the Kaplan–Meier method. The ORR and DCR were described based on each variable. PFS was calculated from the date of the first dosing of EGFR-TKIs to the date of disease progression or death, and the OS was measured from the date of the first dosing of EGFR-TKIs to the date of the last follow-up or death. Comparisons of PFS and OS between individual rare or complex EGFR mutations were performed using the log-rank test. Univariate analyses were performed to analyze the clinical characteristics between individual EGFR mutations and between the different responses to EGFR-TKIs. For categorical variables, the Chi-square test or Fisher’s exact test was used, and for continuous variables the Student’s t-test or the Mann–Whitney U test was used. All statistical analyses were performed using PASW Statistics 18.0 (SPSS Inc, Chicago, IL, USA). 3. Results 3.1. Frequency of rare and complex mutations Between January 2008 and December 2011, 1738 patients received EGFR genotyping analysis. Among them, 1115 patients (64.2%) were EGFR wild type, 283 patients (16.3%) had only the EGFR del-19 mutation, and 200 patients (11.5%) had only the EGFR L858R mutation in exon 21. Eighty-eight patients (5.1%) had rare or complex mutations. Of these, this study included 54 patients who had rare or complex EGFR mutations and were treated with TKIs. The characteristics of the patients are summarized in Table 1. The median age was 58.0 (range, 28–79) years. There were 25 males (46.3%) and 29 females (53.7%). Thirty patients (55.6%) were neversmokers. Fifty-one patients had a performance status of 0 or 1, and three patients had a performance status of 2 or 3. Histology revealed adenocarcinoma in 48 patients (88.9%), squamous cell carcinoma in four, and unspecified NSCLC in two. At the start of EGFR-TKI treatment, 50 were stage IIIB or IV patients, and four were patients with recurred disease. Gefitinib was administered to 35 patients and the other 19 received erlotinib. EGFR-TKIs were used as the first-line treatment for nine patients, the second-line for 24, the third-line for 18, and the fourth or later lines for three patients. Thirty-three patients (61.1%) had single rare mutations and 21 patients had complex mutations (Table 2). The single rare mutation, G719, was found in four patients. Fourteen patients had an insertion and six had a duplication in exon 20. Complex mutations with del-19 or L858R were found in 12 patients (22.2%) and two patients among them had complex mutations of del-19 or L858T and T790M. Complex mutations with G719 were found in six patients and two patients had complex mutations with S768I. A total of 75 mutations were identified (Table 3). The most frequent mutation was an insertion in exon 20 (22.7%), followed by L858R (10.7%), duplication in exon 20 (9.3%), del-19 (8.0%), G719A (6.7%), G719S (5.3%), and S768I (5.3%). 3.2. Efficacy Fifty of the 54 patients (92.6%) were assessable for response to TKIs, with two of the remaining being lost to follow-up and two to early death. No case of CR and 11 cases of PR were confirmed, giving an overall response rate of 20.4% (95% CI; 9.6–31.1%). Twenty (37.0%) patients had SD. The disease control rate (DCR) was 57.4% (95% CI; 44.2–70.6%). The response characteristics are shown in Table 4. The median duration of response in the 11 responding patients was 13.8 months (95% CI; 4.9–22.6 months), while the median PFS for all patients was 2.6 months (95% CI; 0.0–5.4 months)
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Table 1 Patient characteristics.
No. of patients Age (years) Median (range) Gender Male Female Smoking status Smoker Never-smoker Unknown ECOG performance status 0 or 1 2 or 3 Pathology Adenocarcinoma Non-adenocarcinoma Disease status Stage IIIB or IV Recurred Treatment drug Gefitinib Erlotinib Lines of treatment 1st line 2nd line 3rd line 4th or later line
All patients, number (%)
Patients with single rare mutations in exon 18 (Group 1)
Patients with single rare mutations in exon 20 (Group 2)
Patients with complex mutations with del-19 or L858R (Group 3)
Patients with other single rare or complex mutations (Group 4)
54 58.0 (28–79)
7 59.0 (47–71)
24 57.0 (28–77)
12 60.5 (38–79)
11 56.0 (48–79)
25 (46.3) 29 (53.7)
4 3
11 13
4 8
6 5
0.695
23 (42.6) 30 (55.6) 1 (1.9)
5 2 0
8 15 1
3 9 0
7 4 0
0.254
51 (94.4) 3 (5.6)
6 1
24 0
10 2
11 0
0.117
48 (88.9) 6 (11.1)
6 1
21 3
12 0
9 2
0.537
50 (92.6) 4 (7.4)
7 0
22 2
10 2
11 0
0.396
35 (64.8) 19 (35.2)
3 4
17 7
8 4
7 4
0.596
9 (16.7) 24 (44.4) 18 (33.3) 3 (5.6)
1 1 5 0
4 13 5 2
2 4 5 1
2 6 3 0
0.474
at a median follow-up duration of 381.0 days (range; 10–1307 days). Forty-two patients had died at the time of the present evaluation. The median OS was 12.7 months (95% CI; 7.2–18.2 months) with a 1-year survival rate of 53.5%. We categorized the patients into four groups. Group 1 patients had single rare mutations in exon 18. Group 2 patients had single rare mutations in exon 20. Group 3 patients had complex mutations with del-19 or L858R. Group 4 was comprised of 11 patients who had other single rare or complex mutations. Two of these patients had single L861Q, and six had complex mutations with G719. The response rates to TKIs were significantly different (p = 0.034) and the disease control rates were also significantly different (p = 0.034) between each group (Table 4). Groups 3 and 4 showed favorable
Group 2 (n = 24)
Group 4 (n = 11)
0.832
responses, but Groups 1 and 2 showed unfavorable responses. PFSs were also significantly different (p = 0.006). PFSs were better in Groups 3 and 4, and worse in Groups 1 and 2 (Table 4 and Fig. 1). OSs were not significantly different (p = 0.479), but were also better in Groups 3 and 4 and worse in Groups 1 and 2 (Table 4 and Fig. 2).
4. Discussion In the current study, wild type EGFR was found in 64.2% of patients with NSCLC, and classical mutations such as del-19 alone or L858R alone were found in 27.8%. Rare or complex mutations such as any mutation other than del-19 or L858R alone, or two or
Table 2 Frequency of rare and complex mutations.
Group 1 (n = 7)
p-value
Characteristics
Number of patients (n = 54, %)
Characteristics
Number of patients (n = 54, %)
Single rare mutations
33 (61.1)
Complex mutations
21 (38.9)
18 G719 18 G719A 18 G719C 18 G719S 18 S720F 18 F723L 20 S768I 20 V786M 20 G796S 20 insertion 20 duplication 21 L861Q
4 2 1 1 2 1 1 2 1 14 6 2
Del 19 or L858R + other Del 19 + 20 T790M Del 19 + 20 insertion Del 19 + 21 L858R Del 19 + 21 L833V 21 L858R + 18 S720P 21 L858R + 20 H733Y 21 L858R + 20 R776H 21 L858R + 20 T790M 21 L858R + 20 duplication 21 L858R + 21 A871G Other complex mutations 18 G719 + other 18 G719A + 18 E709A 18 G719A + 18 E709K 18 G719A + 18 S720F 18 G719S + 18 G721S 18 G719S + 20 S768I 18 G719S + 20 R776H 20 S768I + 20 V769L 20 S768I + 21 L861R 20 P772H + 20 insertion
12 1 2 2 1 1 1 1 1 1 1 9 6 1 1 1 1 1 1 1 1 1
Group 3 (n = 12)
Group 4 (n = 11)
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Table 3 Overall mutation frequency: 75 mutations in 54 patients. Exon
Mutation
Number (%)
Exon Exon 20
18 E709A 18 E709K 18 G719A 18 G719C 18 G719S 18 S720F 18 S720P 18 G721S 18 F723L
18 (24.0) 1 1 5 1 4 3 1 1 1
Deletion 19
6 (8.0) 6
Exon 18
Exon 19
Mutation
Number (%)
20 S768I 20 V769L 20 P772H 20 H773Y 20 R776H 20 V786M 20 T790M 20 G796S Insertion
38 (50.7) 4 1 1 1 2 2 2 1 17
Duplication Exon 21 21 L833V 21 L858R 21 L861Q 21 L861R 21 A871G
more different mutations co-occurring within the same tumor sample, were found in 5.1% of patients. After TKI treatment, the overall response rate and DCR of these patients were 20.4% and 57.4%, respectively. The median PFS and OS were 2.6 months and 12.7 months, respectively. However, the heterogeneous Groups (1–4) showed different survival rates and responses to EGFR-TKIs. The response rates to EGFR TKIs were significantly different between each group and higher in Groups 3 and 4 than in Groups 1 and 2 (33.3%, 45.5%, 0.0%, and 8.3%, respectively). The median PFSs after EGFR-TKI treatment were also significantly different and longer in Groups 3 and 4 than in Groups 1 and 2 (7.4 months, 5.1 months, 1.3 months, and 2.6 months, respectively). The OSs after EGFR-TKI treatment were not significantly different but were also longer in Groups 3 and 4 and shorter in Groups 1 and 2 (17.9 months, 18.3 months, 6.3 months, and 9.4 months, respectively). EGFR is a transmembrane receptor that is detectable in approximately 80–85% of patients with NSCLC. The activation of EGFR leads to activation of proliferation and invasion [19]. Activating or sensitizing mutations cause constitutive activation of the tyrosine kinase domain of the EGFR protein by destabilizing the auto-inhibiting conformation [20]. EGFR-TKIs such as gefitinib or erlotinib have increased binding affinities to these mutant proteins. The two most common sensitizing EGFR mutations to EGFR-TKI are the del-19 and L858R, which account for almost 85% of all EGFR mutations. These drug-sensitive mutations are found in approximately 10% of
7 13 (17.3) 1 8 2 1 1
Caucasian patients and up to 50% of Asian patients with NSCLC [21]. A previous study reported that response rates (RRs) to EGFR-TKIs exceed 60–70%, with median PFSs of more than 9–10 months and OSs beyond 20 months in these patients [22]. The frequency of rare or complex mutations has been reported to range from 2.6% to 14% [12,15,23–28]. In this study, the frequency of rare or complex mutations was 5.1%. Thirty-three patients (61.1%) had single rare mutations and 21 patients had complex mutations. These rare or complex mutations are not so infrequent that the efficacy of EGFR-TKIs for patients with these mutations should be elucidated. In our study, the efficacy of EGFR-TKIs was heterogeneous in patients with rare or complex mutations. The group of patients with complex mutations with del-19 or L858R and other single rare or complex mutations showed better responses and survival rates than patients with a single rare mutation in exon 18 or 20. Hata et al. [15] reported that patients with complex mutations of del-19 and L858R showed an 86.0% RR and 16.5 months of median PFS after EGFR-TKI treatment. Keam et al. [27] also reported a 68.8% RR and 8.1 months of median PFS for patients with complex mutations with del-19 or L858R. In this study, patients with complex mutations with del-19 or L858R showed a 33.3% RR, 7.4 months of median PFS, and 17.9 months of median OS after EGFR-TKI treatment. This efficacy is slightly inferior to what has been seen in other studies. However, it is comparable to that in patients with a single mutation of del-19 or L858R.
Table 4 Responses and survivals. All patients, number (%)
Patients with single rare mutations in exon 18 (Group 1)
Patients with single rare mutations in exon 20 (Group 2)
Patients with complex mutations with del-19 or L858R (Group 3)
Patients with other single rare or complex mutations (Group 4)
p-value
Best response Complete response Partial response Stable disease Progressive disease Not evaluable Disease control Yes No Not evaluable PFS (months) Median (95% CI)
0 (0.0) 11 (20.4) 20 (37.0) 19 (35.2) 4 (7.4)
0 0 1 6 0
0 2 10 9 3
0 4 5 2 1
0 5 4 2 0
0 .034
31 (57.4) 19 (35.2) 4 (7.4)
1 6 0
12 9 3
9 2 1
9 2 0
0 .034
2.6 (0.0–5.4)
1.3 (0.0–3.5)
2.6 (1.7–3.5)
7.4 (0.0–17.4)
5.1 (0.7–9.6)
0 .006
OS (months) Median (95% CI)
12.7 (7.2–18.2)
6.3 (0.0–14.7)
9.4 (2.6–16.2)
17.9 (0.0–37.2)
18.3 (14.5–22.1)
0 .479
PFS, progression free survival; OS, overall survival, CI, confidence interval.
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Fig. 1. Kaplan–Meier curves for progression free survival by mutation status. Group 1, patients with single rare mutations in exon 18; Group 2, patients with single rare mutations in exon 20; Group 3, patients with complex mutations with del-19 or L858R; Group 4, patients with other single rare or complex mutations.
Fig. 2. Kaplan–Meier curves for overall survival by mutation status. Group 1, patients with single rare mutations in exon 18; Group 2, patients with single rare mutations in exon 20; Group 3, patients with complex mutations with del-19 or L858R; Group 4, patients with other single rare or complex mutations.
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In this study, G719 and L861 mutations were discovered infrequently, but are known to be associated with favorable responses to EGFR-TKIs. Wu et al. [12] reported that patients with a single or complex mutation accompanying G719 showed a 53.3% RR, 8.1 months of median PFS, and 16.4 months of median OS after EGFR-TKI treatment. Patients with a single or complex mutation accompanying L861 also showed favorable results such as a 60.0% RR, 6.0 months of median PFS, and 15.2 months of median OS. Recently, Watanabe et al. [29] reported that patients with G719X or L861Q showed a 20% RR, 2.2 months of median PFS, and 12 months of median OS to gefitinib. They reported that NSCLC patients with G719X or L861Q had shorter survival than those with del-19 or L858R. In this study, six patients had complex mutations accompanying G719, four had single mutations at G719, two had single mutations at L861, and one had a complex mutation with L861. These 13 patients with single or complex mutations accompanying either G719 or L861 showed a 38.5% RR, 5.1 months of median PFS, and 18.6 months of median OS after EGFR-TKI treatment. The efficacy in these cases was not as favorable as for patients with del-19 or L858R, but was still positive. Group 4 included two patients with single L861Q and six patients with complex mutations with G719, this might reflect favorable efficacy of this group. The frequency of exon 20 insertions ranges from 1 to 10% of all the EGFR mutations, with the majority conferring resistance to EGFR-TKIs [30]. Exon 20 insertions add residues within the Nterminal position or at the opposite end of the C-helix. Most EGFR exon 20 insertions occur at the N-lobe of EGFR after the C-helix and have been reported as far as amino acid C775 (A767–C775). This region plays a critical role in catalytic activity, as well as drug affinity, resulting in resistance to EGFR-TKIs [30,31]. Some proximal insertions that affect E762 to Y764 were reported and could be associated with disease control to EGFR-TKIs [30,32]. In this study, 24 cases of insertions or duplications in exon 20 were observed. Twenty-one cases were detected within A767 to C775, and two cases were proximal insertions. One case could not be specified. Both patients with proximal insertions in exon 20 showed PR to EGFR-TKIs. Their PFSs were 13.3 months and 13.7 months, and their OSs were 13.7 months and 14.0 months, respectively. These results suggest that the more specific sequence of insertion should be detailed for more information about EGFR-TKI sensitivity. These results suggest that rare or complex EGFR mutations confer lower rates of survival and inferior responses to EGFR-TKI treatment than common mutations. The set of patients used in this study was composed of heterogeneous groups, which each showed different responses to EGFR-TKIs and different rates of survival. Further studies with larger numbers of patients will be needed to sub-classify these rare or complex mutations and develop optimal treatment strategies. Further investigation is also needed to clarify the molecular mechanisms behind the varying efficacy of EGFRTKI treatment in patients with these mutations. And the efficacy of a new generation EGFR-TKIs to these mutations also should be elucidated. Conflicts of Interest Statement None declared. Acknowledgment This research was conducted with support from Investigator-Sponsored Study Programme of AstraZeneca.
the
References [1] Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics. CA Cancer J Clin 2007;57:43–66.
153
[2] Parkin DM, Ferlay J, Curado MP, Bray F, Edwards B, Shin HR, et al. Fifty years of cancer incidence: CI5 I-IX. Int J Cancer 2010;127:2918–27. [3] Gridelli C, Aapro M, Ardizzoni A, Balducci L, De Marinis F, Kelly K, et al. Treatment of advanced non-small-cell lung cancer in the elderly: results of an international expert panel. J Clin Oncol 2005;23:3125–37. [4] Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947–57. [5] Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123–32. [6] Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, 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;12:735–42. [7] Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, 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;13:239–46. [8] Petrelli F, Borgonovo K, Cabiddu M, Barni S. Efficacy of EGFR tyrosine kinase inhibitors in patients with EGFR-mutated non-small-cell lung cancer: a meta-analysis of 13 randomized trials. Clin Lung Cancer 2012;13: 107–14. [9] Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129–39. [10] Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497–500. [11] Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, et al. EGF receptor gene mutations are common in lung cancers from never smokers and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 2004;101:13306–11. [12] Wu JY, Yu CJ, Chang YC, Yang CH, Shih JY, Yang PC. Effectiveness of tyrosine kinase inhibitors on uncommon epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin Cancer Res 2011;17:3812–21. [13] Wu JY, Wu SG, Yang CH, Gow CH, Chang YL, Yu CJ, et al. Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response. Clin Cancer Res 2008;14:4877–82. [14] Balak MN, Gong Y, Riely GJ, Somwar R, Li AR, Zakowski MF, et al. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 2006;12:6494–501. [15] Hata A, Yoshioka H, Fujita S, Kunimasa K, Kaji R, Imai Y, et al. Complex mutations in the epidermal growth factor receptor gene in non-small cell lung cancer. J Thorac Oncol 2010;5:1524–8. [16] Hsieh MH, Fang YF, Chang WC, Kuo HP, Lin SY, Liu HP, et al. Complex mutation patterns of epidermal growth factor receptor gene associated with variable responses to gefitinib treatment in patients with non-small cell lung cancer. Lung Cancer 2006;53:311–22. [17] Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–47. [18] Lara Jr PN, Redman MW, Kelly K, Edelman MJ, Williamson SK, Crowley JJ, et al. Disease control rate at 8 weeks predicts clinical benefit in advanced non-smallcell lung cancer: results from Southwest Oncology Group randomized trials. J Clin Oncol 2008;26:463–7. [19] Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med 2008;359:1367–80. [20] Farina Sarasqueta A, Moerland E, de Bruyne H, de Graaf H, Vrancken T, van Lijnschoten G, et al. SNaPshot and StripAssay as valuable alternatives to direct sequencing for KRAS mutation detection in colon cancer routine diagnostics. J Mol Diagn 2011;13:199–205. [21] Hirsch FR, Bunn Jr PA. EGFR testing in lung cancer is ready for prime time. Lancet Oncol 2009;10:432–3. [22] Gaughan EM, Costa DB. Genotype-driven therapies for non-small cell lung cancer: focus on EGFR, KRAS and ALK gene abnormalities. Ther Adv Med Oncol 2011;3:113–25. [23] De Pas T, Toffalorio F, Manzotti M, Fumagalli C, Spitaleri G, Catania C, et al. Activity of epidermal growth factor receptor-tyrosine kinase inhibitors in patients with non-small cell lung cancer harboring rare epidermal growth factor receptor mutations. J Thorac Oncol 2011;6:1895–901, http://dx.doi.org/10.097/JTO.0b013e318227e8c6. [24] Yokoyama T, Kondo M, Goto Y, Fukui T, Yoshioka H, Yokoi K, et al. EGFR point mutation in non-small cell lung cancer is occasionally accompanied by a second mutation or amplification. Cancer Sci 2006;97:753–9. [25] Zhang GC, Lin JY, Wang Z, Zhou Q, Xu CR, Zhu JQ, et al. Epidermal growth factor receptor double activating mutations involving both Exons 19 and 21 exist in Chinese non-small cell lung cancer patients. Clin Oncol 2007;19:499–506. [26] Wu S-G, Chang Y-L, Hsu Y-C, Wu J-Y, Yang C-H, Yu C-J, et al. Good response to Gefitinib in lung adenocarcinoma of complex epidermal growth factor receptor (EGFR) mutations with the classical mutation pattern. Oncologist 2008;13:1276–84.
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[27] Keam B, Kim DW, Park JH, Lee JO, Kim TM, Lee SH, et al. Rare and complex mutations of epidermal growth factor receptor, and efficacy of tyrosine kinase inhibitor in patients with non-small cell lung cancer. Int J Clin Oncol 2013;19:594–600. [28] Kobayashi S, Canepa HM, Bailey AS, Nakayama S, Yamaguchi N, Goldstein MA, et al. Compound EGFR mutations and response to EGFR tyrosine kinase inhibitors. J Thorac Oncol 2013;8:45–51. [29] Watanabe S, Minegishi Y, Yoshizawa H, Maemondo M, Inoue A, Sugawara S, et al. Effectiveness of Gefitinib against non-small-cell lung cancer with the uncommon EGFR mutations G719X and L861Q. J Thorac Oncol 2014;9:189–94.
[30] Yasuda H, Kobayashi S, Costa DB. EGFR exon 20 insertion mutations in nonsmall-cell lung cancer: preclinical data and clinical implications. Lancet Oncol 2012;13:e23–31. [31] Arcila ME, Nafa K, Chaft JE, Rekhtman N, Lau C, Reva BA, et al. EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther 2013;12:220–9. [32] Massarelli E, Johnson FM, Erickson HS, Wistuba II, Papadimitrakopoulou V. Uncommon epidermal growth factor receptor mutations in non-small cell lung cancer and their mechanisms of EGFR tyrosine kinase inhibitors sensitivity and resistance. Lung Cancer 2013;80:235–41.
