- Email: [email protected]
Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: results from the European EUHER2 cohort
Annals of Oncology Advance Access published November 23, 2015
1 Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: Results from the European EUHER2 cohort
J. Mazières1, F. Barlesi2, T. Filleron3, B. Besse4, I. Monnet5, M. Beau-Faller6, S. Peters7, E. Dansin8, M. Früh9, M. Pless10, R. Rosell11, M. Wislez12, P. Fournel13, V. Westeel14, F. Cappuzzo15, A. Cortot16, D. Moro-Sibilot17, J. Milia1, O. Gautschi18
Thoracic Oncology unit, Larrey Hospital, Centre Hospitalier Universitaire de
Toulouse, Toulouse University III (Paul Sabatier), Toulouse, France 2
Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille,
France 3
Clinical research unit, Biostatistics, Cancer University Institute of Toulouse Oncopole,
Toulouse, France 4
Thoracic Oncology Section, Gustave Roussy Cancer Campus, Villejuif, France
5
Pulmonology department, Centre hospitalier intercommunal, Créteil, France
6
Chest Department, Strasbourg University Hospital, Strasbourg, France
7
Medical Oncology department, Centre Hospitalier Universitaire Vaudois (CHUV),
Lausanne, Switzerland 8
Medical Oncology department, Centre Oscar Lambret, Lille, France
9
Department of Oncology and Hematology, Cantonal Hospital of St. Gallen, St.
Gallen, Switzerland 10
Department of Medical Oncology, Kantonsspital Winterthur, Winterthur, Switzerland
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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1
2 11
Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Barcelona, Spain
12
Pulmonary Medicine Unit, AP-HP, Hôpital Tenon, Paris, France
13
Medical Oncology Department, Lucien Neuwirth Cancer Institute, Saint Priest en
Jarez, France 14
Pulmonology department, Centre Hospitalier Régional Universitaire, Hôpital Jean
15
Medical Oncology Department, Istituto Toscano Tumori, Ospedale Civile, Livorno,
Italy 16
Pulmonology department Centre Hospitalier Universitaire, Lille, France
17
Department of Thoracic Oncology, Centre Hospitalier Universitaire, Grenoble,
France 18
Medical Oncology, Cantonal Hospital Luzern, Luzern, Switzerland
Corresponding author: Prof Julien Mazières, Thoracic Oncology Unit, Pulmonary Disease Department, Larrey Hospital, CHU Toulouse, Chemin de Pouvourville, 31059 Toulouse Cedex, France, Tel: + (33) 5 67 77 18 37, Fax: + (33) 5 67 77 14 86, Email: [email protected]
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Minjoz, Besançon, France
3
Abstract (232 words) Background: HER2 mutations have been identified as oncogenic drivers in lung cancers and are found in 1-2% of lung adenocarcinomas. There is, to date, no standard of care for these patients. We thus aim to study the therapeutic outcomes of patients harboring HER2 mutations and establish the efficacy of various drug regimens.
assessed patients with advanced non-small cell lung cancer (NSCLC), a known HER2 exon-20 insertion, treated with chemotherapy and/or HER2-targeted drugs. Results: We identified 101 eligible patients from 38 centers: median age 61 years (range: 30–87), 62.4% women, 60.4% never smokers. All tumors were adenocarcinomas. Concomitant EGFR mutations, ALK translocations, and ROS translocations were observed in 5, 1, and 1 patients, respectively. Median number of treatment lines was three (range: 1–11). Median overall survival was 24 months. Overall response rate (ORR) and median progression-free survival (PFS) with conventional chemotherapy (excluding targeted therapies) were 43.5% and 6 months in first-line (n = 93), and 10% and 4.3 months in second-line (n=52) therapies. Sixty-five patients received HER2-targeted therapies: trastuzumab=57, neratinib=14, afatinib=9, lapatinib=5, T-DM1=1. ORR was 50.9% and PFS was 4.8 months with trastuzumab or T-DM1. Conclusion: This series shows the chemosensitivity of HER2-driven NSCLC, and the potential interest of HER2-targeted agents. Our results should help to define the best therapeutic strategy for these patients and to orient future clinical trials.
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Patients and methods: This retrospective cohort study in European centers
4 Keywords: HER2, lung cancer, trastuzumab, chemotherapy, biomarker.
Key Message This series of lung cancer patients harboring HER2 mutation, the largest to date, shows the chemosensitivity of HER2+ NSCLC, and the potential interest of HER2 targeting drugs in combination with chemotherapy. Our results will help to define the best therapeutic strategy for these patients and to orient future clinical trials. Downloaded from http://annonc.oxfordjournals.org/ at Monash University on November 27, 2015
5
Introduction Recent progress has been achieved in the management of patients with advanced non-small cell lung cancer (NSCLC) with the identification of tumor-specific molecular alterations and the development of drugs that target the respective deregulated signaling pathways [1]. To date, tyrosine-kinase inhibitors have been approved for the treatment of advanced NSCLC with EGFR mutations [2] or ALK
including MET and FGFR1 amplification, PIK3CA, AKT, KRAS, NRAS, BRAF, and HER2 mutations, as well as RET and ROS1 rearrangements. Drugs that target these alterations are currently being investigated in clinical trials. We reported in 2013 that HER2 was mutated at an incidence of 1-2% on a series of 65 patients among which 16 were treated with anti-HER2 drugs with promising results [4]. Since this date some case reports and very few clinical trials have been reported for this population and all suggest that anti-HER2 drugs such as afatinib, dacomitinib, neratinib and trastuzumab can be associated with tumor response [5] [6]. During the same time, large biomarker screening programs, such as the French National Program or the US Lung Cancer Mutation Consortium (LCMC), propose systematic testing for HER2 mutations [7, 8]. We thus aimed to launch the EUHER2 cohort to provide further insights into the management of these patients by analyzing the largest cohort to date (n = 101 treated patients), particularly for the response to conventional chemotherapy and to HER2-targeted drugs. We anticipated that our findings might help to orient future clinical trials in this population.
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translocations [3]. Other actionable genetic alterations are also known in NSCLC,
6 Patients and methods Study design and selection of patients This study was conducted in France, Switzerland, Spain, Italy, Poland, Portugal, and the Netherlands. Eligible patients had advanced NSCLC with an exon 20 HER2 mutation/insertion, had undergone at least one line of systemic anticancer treatment, and had received an adequate follow-up that included documented evaluation of the tumor (CT-scan every 2 or 3 months). Clinical and pathological data were collected
institution, and then collected and centralized by the study coordinator (JM) at the coordinating center in Toulouse. Histology was assessed by experienced local pathologists using WHO criteria and the last IASLC (International Association for the Study of Lung Cancer) classification [9]. Clinico-pathological stage was assigned locally according to the 7th Tumor-Node Metastasis classification [10]. We collected clinical data, outcome variables, and the use of systemic therapies (including chemotherapy and HER2-targeted drugs) for all patients. Centers performed follow-up CT-scans at 6–8 week intervals and brain imaging in the presence of symptoms only. Responses were defined as the best response from the start of treatment until disease progression according to response-evaluation criteria in the solid-tumor [RECIST version 1.1] guidelines. All investigators were GCP (Good Clinical Practice) certified. All tumor assessments were performed locally: only indeterminate cases were reassessed by the coordinating center. The study was conducted with approval from the IRB at the coordinating center (14.424) and from a national ethic committee (CEPRO 2015-019).
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from each patient by the treating physician. Data were de-identified at the local
7 Molecular diagnostics All participating centers had accredited and quality controlled diagnostic laboratories that routinely tested NSCLC for EGFR, HER2, KRAS, BRAF, and ALK. Some centers also tested for ROS1, MET, and RET. For HER2 mutations, most centers performed direct sequencing after PCR amplification of HER2 exon 20, using formalin-fixed, paraffin-embedded, and micro-dissected tumor material as previously published [4]. Some centers used next generation sequencing to validate their results.
Data were summarized according to frequency and percentage for qualitative variables, and by medians and ranges for quantitative variables. Progression-free survival (PFS) was measured as the time from the beginning of treatment to progression or death from any cause. PFS for trastuzumab and other HER2 targeted drugs was calculated from the first administration of the drug. Patients alive without progression at the time of analysis were censored at their last follow-up assessment. Survival rates were estimated according to the Kaplan–Meier method. Statistical analyses were performed using STATA 13.0 software (StataCorp, TX, USA).
Results Characteristics of the population We identified 101 patients with a HER2 mutation who had been treated by chemotherapy and/or anti-HER2 drugs. All tumors displayed an in-frame insertions within the exon 20 of HER2-gene coding sequence. Most of the mutations were exclusive, but in seven cases (7%) they were concomitant EGFR mutations (n = 5, including one exon 19, one exon 21, two exon 20 and one exon 19 + T790M), ALK
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Statistics
8 translocation (n = 1), and ROS1 (n = 1) translocation on the same analysis. The clinical characteristics of the patients are shown in Table 1. Our cohort was characterized by a median age of 61 years (range: 30–87), a high proportion of women (n=63, 62.4%), and of never smokers (n=61, 60.4%), with a median of 15 pack-years for current and former smokers, and only four (4%) current smokers. All tumors were adenocarcinomas, including one adenosquamous tumor. All patients had stage-IV NSCLC at the time of entering the study.
First, we analyzed PFS and OS for the whole cohort (n = 101), irrespective of the type of systemic treatment. Median survival from the start of the first-line treatment was 23.4 (95%CI [18.7;31.8]) months. The median number of treatment lines was 3 (range: 1–11). By definition, all patients received at least one line of systemic treatment, with a median PFS of 6 months [CI95%: 5;7.3]. Seventy-seven (76.2%) patients received a second-line of treatment with a median PFS of 4.3 months [95%CI: 3.1;4.5](Fig. 1). Fifty-two (51.5%) patients received three or more lines of treatment.
Outcome with conventional therapy Next, we analyzed the outcomes with conventional therapy including chemotherapy and EGFR-tyrosine-kinase inhibitors (TKI), but excluding HER2-targeted drugs. Response rate (RR) and median PFS for patients receiving a first-line therapy were 43.5% and 6 months [CI95% 5;7.1], respectively (n=93) (Table 2). Most patients had first-line therapy with a platinum-based doublet (n=71) with pemetrexed as the preferred combination partner (n=54), others had a doublet with bevacizumab (n=16),
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Treatment and survival of the whole cohort
9 a monotherapy (n=2), or erlotinib (n=2). In those receiving second-line therapies, RR and PFS were 10% and 4.3 months, respectively (n=52). Most of these patients had monotherapy (15 erlotinib, 9 docetaxel and 7 pemetrexed), fewer had a platinumbased doublet (n=5), or a doublet with bevacizumab (n=3). Twenty-six patients were treated with EGFR-TKI (excluding afatinib). RR with EGFRTKI was 7.6% (one complete and one partial response), and responses were restricted to patients with a concomitant EGFR-activating mutation. Stable Disease
patients (73.1%). Median PFS was 2.9 months [CI95%:1.87;4.47] (Table 2). Details on all the treatment regimens are given in Table 3.
Outcome with HER2-targeted drugs Thirty-six patients did not receive any anti-HER2 drugs, whereas 65 (64.4%) patients received at least one HER2-targeted drug, of which 47 received one line, 14 patients two lines, and four patients more than two lines of anti-HER2 drugs. Overall, 88 targeted treatments against HER2 were given and evaluated, including trastuzumab (n = 57), trastuzumab emtansine (T-DM1, n = 1). neratinib (n = 14), afatinib (n = 11), and lapatinib (n = 5). RR, Disease Control Rate (DCR), and PFS were 50%, 75%, and 5.1 months, respectively, for trastuzumab in combination with chemotherapy. Chemotherapy included vinorelbine (n=24), docetaxel (n=12), paclitaxel (n=12), cisplatin (n=7), whereas 2 patients had trastuzumab alone. PFS and OS for patients treated with trastuzumab-based combination is shown in Figure 2. RR, DCR, and PFS were 18.2%, 63.7%, and 3.9 months, respectively, for afatinib. Patients receiving neratinib were included in a clinical trial (PUMA-NER). Preliminary results have been reported [5], and the final results are awaited. Lapatinib was prescribed to
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(SD) was observed in five patients (19.2%) and progressive disease (PD) in 19
10 5 patients in third- or fourth-line, all 5 patients had progressive disease when the first response assessment was made. One patient had a rapid response to T-DM1, as reported elsewhere [11]. Putting together the results of trastuzumab-based treatment and T-DM1, we observed a RR of 50.9% and a PFS of 4.8 months[CI95%: 3.4;6.5]. Details concerning responses to HER2-targeting drugs are listed in Table 2.
Discussion
-mutant NSCLC. We confirmed the clinical characteristics of patients presenting with HER2-mutated NSCLC, as envisioned in previous series, including our own [4, 1214]. Our patients were more often female, never-smokers, and all had adenocarcinoma histology. Looking at the natural history of HER2-mutated NSCLC, irrespective of the type of systemic therapy, we found that median OS was approximately 2 years, which was very similar to the OS observed in previous series [4, 14]. This favorable prognosis might be due to the selection of the patients (mainly women who have never smoked and patients referred to big centers with good performans status), or to a potential prognostic value of HER2 mutation. Further studies are needed to validate this hypothesis. We also analyzed the clinical outcomes of different HER2-targeted drugs. In contrast to breast cancer, the role of HER2-targeting drugs as monotherapy or in combination with chemotherapy remains unclear in lung cancer [15, 16]. Trastuzumab in combination with chemotherapy failed to show a benefit in unselected patients in a previous study [17] [18]. These early trials suggested a potential but not proven benefit for trastuzumab in patients with an overexpression or amplification of HER2. This might be due to an overlap between these patients and HER2 mutated patients.
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Herein, we report the largest series to date (n = 101) of patients with advanced HER2
11 In HER2-amplified NSCLC, there was no clear clinical benefit from lapatinib [19]. Afatinib used as a monotherapy showed a response in 3 of 3 evaluable patients with an HER2-mutated adenocarcinoma in an exploratory study of 5 patients [20]. Dacomitinib has been recently evaluated in a subpopulation of patients with a HER2 mutation or amplification in a recent trial and was associated with a low PFS (3 months) but produced undoubtedly objectives responses in three patients (12%) [21]. Similarly, no response was observed in seven patients treated with lapatinib in a
and in combination with temsirolimus. When used in combination, it gave a promising response rate of 21% and a PFS of 4 months [5]. As trastuzumab in our study was given concomitantly with chemotherapy, we can also anticipate that a combination of HER2-TKI and chemotherapy can lead to better results. This hypothesis should be tested in clinical trials. The European Thoracic Oncology Platform (ETOP) is currently conducting a trial (ETOP-NICHE) with afatinib in patients with advanced NSCLC and an HER2 mutation (NCT02369484). In 2006, one of us reported the seminal case of a patient with chemotherapy-refractory HER2-mutant NSCLC responding to trastuzumab in combination with paclitaxel [23]. Our previous series, which included 16 patients treated with HER2-targeted drugs, showed encouraging rates of disease control and PFS in patients who received trastuzumab after heavy pretreatment [4]. Although no dedicated trials are currently ongoing for trastuzumab therapy for HER2 mutations, our new results show an impressive response rate and PFS. Thus, further prospective studies should be conducted with trastuzumab in combination with chemotherapy in patients with HER2-mutant NSCLC. T-DM1 also represents an attractive novel option, as it combines trastuzumab with chemotherapy and has given impressive results in breast cancer [24]. One patient in the EUHER2 cohort had a
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large BASKET trial [22]. Neratinib has been tested in a phase II clinical trial alone
12 remarkable response to T-DM1, which has been recently published in a separate paper [11]. T-DM1 is currently being tested in a phase-II trial in patients with NSCLC and HER2 overexpression (NCT02289833). We cannot conclude about the superiority of a HER2 targeted drug from our study as the treatment has not been given at the same time of the disease and as trastuzumab is most of the time given in combination with chemotherapy whereas HER2-TKIs are given alone. Due to a lack of prospective data and randomized trials, it will take more years until a
meantime, we hope that our data can help for the management of these patients, by showing that chemotherapy is active and should remain the basis of systemic therapy, and that trastuzumab is potentially beneficial in combination with chemotherapy. Although limited, our report suggests that small-molecule inhibitors of HER2 may be also of potential use in patients for whom no alternative treatment is available.
Acknowledgments: We thank all the investigators including Dr A. D’Incecco, Dr N. Karachaliou, Dr G. Olivero, Dr H. Schefer, Dr R. Chiari, Dr T. Urban, Dr S. Bota, Dr J. Chapron, Dr A. Chella, Pr C. Chouaid, Dr D. Weiler, Dr T. Egenod, Dr E. Felip, Dr A. Curioni, Dr JL Biltiu, Dr H. Lena, Dr AC. Metivier, Dr P Laurent, Dr JM Peloni, Dr D. Planchard, Dr R. Dziadziuszko, Dr S. Rothschild, Dr E. Smit, and Dr Dominique Spaeth.
Disclosure: The authors have declared no conflict of interest.
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targeted drug can be approved for patients with HER2-mutant NSCLC. In the
13 Legends Figure 1 : PFS and OS of the whole cohort (n = 101) irrespective of the type of systemic treatment and according to the line (first or second) of treatment. Figure 2: PFS and OS of patients treated with trastuzumab-based combination.
Funding:
0001 and by Puma Biotechnology (Los Angeles, CA, USA).
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The study was partly supported by the CAPTOR academic project: ANR-11-PHUC-
14
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18 Table 1: Clinical and biological characteristics of patients with a HER2 mutation (n=101).
Concomitant mutations EGFR mutations ALK translocation ROS translocation
Value 61 30–87 years
38 63
37.6% 62.4%
61 36 4
60.4% 35.6% 4% 15 (3-48)
4 2 14 81
4% 2% 13.9% 80.2%
22 6 10 33 7 15 8
22% 6% 10% 33% 7% 15% 8%
5 1 1
5% 1% 1%
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Age at initial diagnosis, years Median Range Gender Male Female Tobacco use never former current Median pack-years consumption (current and former) Range Tumor stage I II III IV Metastatic sites of stage IV lung brain bone multiple organs other none unknown
Number n = 101
19
Table 2: Overall response rate (ORR), disease control (DC), progression-free survival (PFS, weeks), and overall survival (OS, weeks) according to drug type. ND: not determined. Treatment
ORR
DC
PFS median
OS median
[CI95%]
[CI95%]
93
43.5%
70.7%
6 [5;7.1]
24[19.1;36.4]
52
10%
36%
4.3 [3.1;5]
19.4 [9.6;24.7]
EGFR-TKI *
26
7.6%
26.8%
2.99[1.87;4.47]
20.14[7.14;32.95]
Trastuzumab combination,
58
50.9%
75.5%
4.8[3.4;6.5]
13.3[8.1;15]
29
7.4%
55.5%
3.4[2.4;4]
6.5[4.7;30.6]
targeting treatment Second-line: without HER2 targeting treatment
T-DM1 * Neratinib, Lapatinib and Afatinib * * if the same drug has been given more than one time, the results presented here are from their first administration.
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First-line: without HER2
n
20 Table 3: Details of treatments administred Treatments regimen names Platin based doublet platin gemcitabin platin paclitaxel platin pemetrexed platin vinorelbin Platin based doublet and bevacizumab
platin docetaxel bevacizumab
L1 (n)
L2 (n)
4 9 54 4
2 2 1 0
1
1
2
0
12 1
2 0
platin gemcitabine vinorelbin
1
0
docetaxel bevacizumab docetaxel irinotecan
0 0
3 1
pemetrexed docetaxel gemcitabin paclitaxel vinorelbin
2 0 0 0 0
7 9 1 2 1
erlotinib erlotinib bevacizumab
1 1
15 0
docetaxel trastuzumab platin paclitaxel trastuzumab platin pemetrexed trastuzumab vinorelbin trastuzumab trastuzumab afatinib neratinib neratinib everolimus neratinib temsirolimus paclitaxel trastuzumab
1 2
5 0
2 2 2 0 0 0 0 0
0 7 1 1 2 1 4 2
EC145 (TARGET trial) masitinib docetaxel MK3475 (immunotherapy) crizotinib
0 0 0 0
1 1 1 1
Platin based doublet and other agent
Bevacizumab based doublet
Monotherapy based
TKI based
Anti HER2 specific treatment based
Others
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platin gemcitabin bevacizumab platin pemetrexed bevacizumab platin vinorelbin bevacizumab
21
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22
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1 Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: Results from the European EUHER2 cohort
J. Mazières1, F. Barlesi2, T. Filleron3, B. Besse4, I. Monnet5, M. Beau-Faller6, S. Peters7, E. Dansin8, M. Früh9, M. Pless10, R. Rosell11, M. Wislez12, P. Fournel13, V. Westeel14, F. Cappuzzo15, A. Cortot16, D. Moro-Sibilot17, J. Milia1, O. Gautschi18
Thoracic Oncology unit, Larrey Hospital, Centre Hospitalier Universitaire de
Toulouse, Toulouse University III (Paul Sabatier), Toulouse, France 2
Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille,
France 3
Clinical research unit, Biostatistics, Cancer University Institute of Toulouse Oncopole,
Toulouse, France 4
Thoracic Oncology Section, Gustave Roussy Cancer Campus, Villejuif, France
5
Pulmonology department, Centre hospitalier intercommunal, Créteil, France
6
Chest Department, Strasbourg University Hospital, Strasbourg, France
7
Medical Oncology department, Centre Hospitalier Universitaire Vaudois (CHUV),
Lausanne, Switzerland 8
Medical Oncology department, Centre Oscar Lambret, Lille, France
9
Department of Oncology and Hematology, Cantonal Hospital of St. Gallen, St.
Gallen, Switzerland 10
Department of Medical Oncology, Kantonsspital Winterthur, Winterthur, Switzerland
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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1
2 11
Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Barcelona, Spain
12
Pulmonary Medicine Unit, AP-HP, Hôpital Tenon, Paris, France
13
Medical Oncology Department, Lucien Neuwirth Cancer Institute, Saint Priest en
Jarez, France 14
Pulmonology department, Centre Hospitalier Régional Universitaire, Hôpital Jean
15
Medical Oncology Department, Istituto Toscano Tumori, Ospedale Civile, Livorno,
Italy 16
Pulmonology department Centre Hospitalier Universitaire, Lille, France
17
Department of Thoracic Oncology, Centre Hospitalier Universitaire, Grenoble,
France 18
Medical Oncology, Cantonal Hospital Luzern, Luzern, Switzerland
Corresponding author: Prof Julien Mazières, Thoracic Oncology Unit, Pulmonary Disease Department, Larrey Hospital, CHU Toulouse, Chemin de Pouvourville, 31059 Toulouse Cedex, France, Tel: + (33) 5 67 77 18 37, Fax: + (33) 5 67 77 14 86, Email: [email protected]
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Minjoz, Besançon, France
3
Abstract (232 words) Background: HER2 mutations have been identified as oncogenic drivers in lung cancers and are found in 1-2% of lung adenocarcinomas. There is, to date, no standard of care for these patients. We thus aim to study the therapeutic outcomes of patients harboring HER2 mutations and establish the efficacy of various drug regimens.
assessed patients with advanced non-small cell lung cancer (NSCLC), a known HER2 exon-20 insertion, treated with chemotherapy and/or HER2-targeted drugs. Results: We identified 101 eligible patients from 38 centers: median age 61 years (range: 30–87), 62.4% women, 60.4% never smokers. All tumors were adenocarcinomas. Concomitant EGFR mutations, ALK translocations, and ROS translocations were observed in 5, 1, and 1 patients, respectively. Median number of treatment lines was three (range: 1–11). Median overall survival was 24 months. Overall response rate (ORR) and median progression-free survival (PFS) with conventional chemotherapy (excluding targeted therapies) were 43.5% and 6 months in first-line (n = 93), and 10% and 4.3 months in second-line (n=52) therapies. Sixty-five patients received HER2-targeted therapies: trastuzumab=57, neratinib=14, afatinib=9, lapatinib=5, T-DM1=1. ORR was 50.9% and PFS was 4.8 months with trastuzumab or T-DM1. Conclusion: This series shows the chemosensitivity of HER2-driven NSCLC, and the potential interest of HER2-targeted agents. Our results should help to define the best therapeutic strategy for these patients and to orient future clinical trials.
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Patients and methods: This retrospective cohort study in European centers
4 Keywords: HER2, lung cancer, trastuzumab, chemotherapy, biomarker.
Key Message This series of lung cancer patients harboring HER2 mutation, the largest to date, shows the chemosensitivity of HER2+ NSCLC, and the potential interest of HER2 targeting drugs in combination with chemotherapy. Our results will help to define the best therapeutic strategy for these patients and to orient future clinical trials. Downloaded from http://annonc.oxfordjournals.org/ at Monash University on November 27, 2015
5
Introduction Recent progress has been achieved in the management of patients with advanced non-small cell lung cancer (NSCLC) with the identification of tumor-specific molecular alterations and the development of drugs that target the respective deregulated signaling pathways [1]. To date, tyrosine-kinase inhibitors have been approved for the treatment of advanced NSCLC with EGFR mutations [2] or ALK
including MET and FGFR1 amplification, PIK3CA, AKT, KRAS, NRAS, BRAF, and HER2 mutations, as well as RET and ROS1 rearrangements. Drugs that target these alterations are currently being investigated in clinical trials. We reported in 2013 that HER2 was mutated at an incidence of 1-2% on a series of 65 patients among which 16 were treated with anti-HER2 drugs with promising results [4]. Since this date some case reports and very few clinical trials have been reported for this population and all suggest that anti-HER2 drugs such as afatinib, dacomitinib, neratinib and trastuzumab can be associated with tumor response [5] [6]. During the same time, large biomarker screening programs, such as the French National Program or the US Lung Cancer Mutation Consortium (LCMC), propose systematic testing for HER2 mutations [7, 8]. We thus aimed to launch the EUHER2 cohort to provide further insights into the management of these patients by analyzing the largest cohort to date (n = 101 treated patients), particularly for the response to conventional chemotherapy and to HER2-targeted drugs. We anticipated that our findings might help to orient future clinical trials in this population.
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translocations [3]. Other actionable genetic alterations are also known in NSCLC,
6 Patients and methods Study design and selection of patients This study was conducted in France, Switzerland, Spain, Italy, Poland, Portugal, and the Netherlands. Eligible patients had advanced NSCLC with an exon 20 HER2 mutation/insertion, had undergone at least one line of systemic anticancer treatment, and had received an adequate follow-up that included documented evaluation of the tumor (CT-scan every 2 or 3 months). Clinical and pathological data were collected
institution, and then collected and centralized by the study coordinator (JM) at the coordinating center in Toulouse. Histology was assessed by experienced local pathologists using WHO criteria and the last IASLC (International Association for the Study of Lung Cancer) classification [9]. Clinico-pathological stage was assigned locally according to the 7th Tumor-Node Metastasis classification [10]. We collected clinical data, outcome variables, and the use of systemic therapies (including chemotherapy and HER2-targeted drugs) for all patients. Centers performed follow-up CT-scans at 6–8 week intervals and brain imaging in the presence of symptoms only. Responses were defined as the best response from the start of treatment until disease progression according to response-evaluation criteria in the solid-tumor [RECIST version 1.1] guidelines. All investigators were GCP (Good Clinical Practice) certified. All tumor assessments were performed locally: only indeterminate cases were reassessed by the coordinating center. The study was conducted with approval from the IRB at the coordinating center (14.424) and from a national ethic committee (CEPRO 2015-019).
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from each patient by the treating physician. Data were de-identified at the local
7 Molecular diagnostics All participating centers had accredited and quality controlled diagnostic laboratories that routinely tested NSCLC for EGFR, HER2, KRAS, BRAF, and ALK. Some centers also tested for ROS1, MET, and RET. For HER2 mutations, most centers performed direct sequencing after PCR amplification of HER2 exon 20, using formalin-fixed, paraffin-embedded, and micro-dissected tumor material as previously published [4]. Some centers used next generation sequencing to validate their results.
Data were summarized according to frequency and percentage for qualitative variables, and by medians and ranges for quantitative variables. Progression-free survival (PFS) was measured as the time from the beginning of treatment to progression or death from any cause. PFS for trastuzumab and other HER2 targeted drugs was calculated from the first administration of the drug. Patients alive without progression at the time of analysis were censored at their last follow-up assessment. Survival rates were estimated according to the Kaplan–Meier method. Statistical analyses were performed using STATA 13.0 software (StataCorp, TX, USA).
Results Characteristics of the population We identified 101 patients with a HER2 mutation who had been treated by chemotherapy and/or anti-HER2 drugs. All tumors displayed an in-frame insertions within the exon 20 of HER2-gene coding sequence. Most of the mutations were exclusive, but in seven cases (7%) they were concomitant EGFR mutations (n = 5, including one exon 19, one exon 21, two exon 20 and one exon 19 + T790M), ALK
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Statistics
8 translocation (n = 1), and ROS1 (n = 1) translocation on the same analysis. The clinical characteristics of the patients are shown in Table 1. Our cohort was characterized by a median age of 61 years (range: 30–87), a high proportion of women (n=63, 62.4%), and of never smokers (n=61, 60.4%), with a median of 15 pack-years for current and former smokers, and only four (4%) current smokers. All tumors were adenocarcinomas, including one adenosquamous tumor. All patients had stage-IV NSCLC at the time of entering the study.
First, we analyzed PFS and OS for the whole cohort (n = 101), irrespective of the type of systemic treatment. Median survival from the start of the first-line treatment was 23.4 (95%CI [18.7;31.8]) months. The median number of treatment lines was 3 (range: 1–11). By definition, all patients received at least one line of systemic treatment, with a median PFS of 6 months [CI95%: 5;7.3]. Seventy-seven (76.2%) patients received a second-line of treatment with a median PFS of 4.3 months [95%CI: 3.1;4.5](Fig. 1). Fifty-two (51.5%) patients received three or more lines of treatment.
Outcome with conventional therapy Next, we analyzed the outcomes with conventional therapy including chemotherapy and EGFR-tyrosine-kinase inhibitors (TKI), but excluding HER2-targeted drugs. Response rate (RR) and median PFS for patients receiving a first-line therapy were 43.5% and 6 months [CI95% 5;7.1], respectively (n=93) (Table 2). Most patients had first-line therapy with a platinum-based doublet (n=71) with pemetrexed as the preferred combination partner (n=54), others had a doublet with bevacizumab (n=16),
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Treatment and survival of the whole cohort
9 a monotherapy (n=2), or erlotinib (n=2). In those receiving second-line therapies, RR and PFS were 10% and 4.3 months, respectively (n=52). Most of these patients had monotherapy (15 erlotinib, 9 docetaxel and 7 pemetrexed), fewer had a platinumbased doublet (n=5), or a doublet with bevacizumab (n=3). Twenty-six patients were treated with EGFR-TKI (excluding afatinib). RR with EGFRTKI was 7.6% (one complete and one partial response), and responses were restricted to patients with a concomitant EGFR-activating mutation. Stable Disease
patients (73.1%). Median PFS was 2.9 months [CI95%:1.87;4.47] (Table 2). Details on all the treatment regimens are given in Table 3.
Outcome with HER2-targeted drugs Thirty-six patients did not receive any anti-HER2 drugs, whereas 65 (64.4%) patients received at least one HER2-targeted drug, of which 47 received one line, 14 patients two lines, and four patients more than two lines of anti-HER2 drugs. Overall, 88 targeted treatments against HER2 were given and evaluated, including trastuzumab (n = 57), trastuzumab emtansine (T-DM1, n = 1). neratinib (n = 14), afatinib (n = 11), and lapatinib (n = 5). RR, Disease Control Rate (DCR), and PFS were 50%, 75%, and 5.1 months, respectively, for trastuzumab in combination with chemotherapy. Chemotherapy included vinorelbine (n=24), docetaxel (n=12), paclitaxel (n=12), cisplatin (n=7), whereas 2 patients had trastuzumab alone. PFS and OS for patients treated with trastuzumab-based combination is shown in Figure 2. RR, DCR, and PFS were 18.2%, 63.7%, and 3.9 months, respectively, for afatinib. Patients receiving neratinib were included in a clinical trial (PUMA-NER). Preliminary results have been reported [5], and the final results are awaited. Lapatinib was prescribed to
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(SD) was observed in five patients (19.2%) and progressive disease (PD) in 19
10 5 patients in third- or fourth-line, all 5 patients had progressive disease when the first response assessment was made. One patient had a rapid response to T-DM1, as reported elsewhere [11]. Putting together the results of trastuzumab-based treatment and T-DM1, we observed a RR of 50.9% and a PFS of 4.8 months[CI95%: 3.4;6.5]. Details concerning responses to HER2-targeting drugs are listed in Table 2.
Discussion
-mutant NSCLC. We confirmed the clinical characteristics of patients presenting with HER2-mutated NSCLC, as envisioned in previous series, including our own [4, 1214]. Our patients were more often female, never-smokers, and all had adenocarcinoma histology. Looking at the natural history of HER2-mutated NSCLC, irrespective of the type of systemic therapy, we found that median OS was approximately 2 years, which was very similar to the OS observed in previous series [4, 14]. This favorable prognosis might be due to the selection of the patients (mainly women who have never smoked and patients referred to big centers with good performans status), or to a potential prognostic value of HER2 mutation. Further studies are needed to validate this hypothesis. We also analyzed the clinical outcomes of different HER2-targeted drugs. In contrast to breast cancer, the role of HER2-targeting drugs as monotherapy or in combination with chemotherapy remains unclear in lung cancer [15, 16]. Trastuzumab in combination with chemotherapy failed to show a benefit in unselected patients in a previous study [17] [18]. These early trials suggested a potential but not proven benefit for trastuzumab in patients with an overexpression or amplification of HER2. This might be due to an overlap between these patients and HER2 mutated patients.
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Herein, we report the largest series to date (n = 101) of patients with advanced HER2
11 In HER2-amplified NSCLC, there was no clear clinical benefit from lapatinib [19]. Afatinib used as a monotherapy showed a response in 3 of 3 evaluable patients with an HER2-mutated adenocarcinoma in an exploratory study of 5 patients [20]. Dacomitinib has been recently evaluated in a subpopulation of patients with a HER2 mutation or amplification in a recent trial and was associated with a low PFS (3 months) but produced undoubtedly objectives responses in three patients (12%) [21]. Similarly, no response was observed in seven patients treated with lapatinib in a
and in combination with temsirolimus. When used in combination, it gave a promising response rate of 21% and a PFS of 4 months [5]. As trastuzumab in our study was given concomitantly with chemotherapy, we can also anticipate that a combination of HER2-TKI and chemotherapy can lead to better results. This hypothesis should be tested in clinical trials. The European Thoracic Oncology Platform (ETOP) is currently conducting a trial (ETOP-NICHE) with afatinib in patients with advanced NSCLC and an HER2 mutation (NCT02369484). In 2006, one of us reported the seminal case of a patient with chemotherapy-refractory HER2-mutant NSCLC responding to trastuzumab in combination with paclitaxel [23]. Our previous series, which included 16 patients treated with HER2-targeted drugs, showed encouraging rates of disease control and PFS in patients who received trastuzumab after heavy pretreatment [4]. Although no dedicated trials are currently ongoing for trastuzumab therapy for HER2 mutations, our new results show an impressive response rate and PFS. Thus, further prospective studies should be conducted with trastuzumab in combination with chemotherapy in patients with HER2-mutant NSCLC. T-DM1 also represents an attractive novel option, as it combines trastuzumab with chemotherapy and has given impressive results in breast cancer [24]. One patient in the EUHER2 cohort had a
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large BASKET trial [22]. Neratinib has been tested in a phase II clinical trial alone
12 remarkable response to T-DM1, which has been recently published in a separate paper [11]. T-DM1 is currently being tested in a phase-II trial in patients with NSCLC and HER2 overexpression (NCT02289833). We cannot conclude about the superiority of a HER2 targeted drug from our study as the treatment has not been given at the same time of the disease and as trastuzumab is most of the time given in combination with chemotherapy whereas HER2-TKIs are given alone. Due to a lack of prospective data and randomized trials, it will take more years until a
meantime, we hope that our data can help for the management of these patients, by showing that chemotherapy is active and should remain the basis of systemic therapy, and that trastuzumab is potentially beneficial in combination with chemotherapy. Although limited, our report suggests that small-molecule inhibitors of HER2 may be also of potential use in patients for whom no alternative treatment is available.
Acknowledgments: We thank all the investigators including Dr A. D’Incecco, Dr N. Karachaliou, Dr G. Olivero, Dr H. Schefer, Dr R. Chiari, Dr T. Urban, Dr S. Bota, Dr J. Chapron, Dr A. Chella, Pr C. Chouaid, Dr D. Weiler, Dr T. Egenod, Dr E. Felip, Dr A. Curioni, Dr JL Biltiu, Dr H. Lena, Dr AC. Metivier, Dr P Laurent, Dr JM Peloni, Dr D. Planchard, Dr R. Dziadziuszko, Dr S. Rothschild, Dr E. Smit, and Dr Dominique Spaeth.
Disclosure: The authors have declared no conflict of interest.
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targeted drug can be approved for patients with HER2-mutant NSCLC. In the
13 Legends Figure 1 : PFS and OS of the whole cohort (n = 101) irrespective of the type of systemic treatment and according to the line (first or second) of treatment. Figure 2: PFS and OS of patients treated with trastuzumab-based combination.
Funding:
0001 and by Puma Biotechnology (Los Angeles, CA, USA).
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The study was partly supported by the CAPTOR academic project: ANR-11-PHUC-
14
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18 Table 1: Clinical and biological characteristics of patients with a HER2 mutation (n=101).
Concomitant mutations EGFR mutations ALK translocation ROS translocation
Value 61 30–87 years
38 63
37.6% 62.4%
61 36 4
60.4% 35.6% 4% 15 (3-48)
4 2 14 81
4% 2% 13.9% 80.2%
22 6 10 33 7 15 8
22% 6% 10% 33% 7% 15% 8%
5 1 1
5% 1% 1%
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Age at initial diagnosis, years Median Range Gender Male Female Tobacco use never former current Median pack-years consumption (current and former) Range Tumor stage I II III IV Metastatic sites of stage IV lung brain bone multiple organs other none unknown
Number n = 101
19
Table 2: Overall response rate (ORR), disease control (DC), progression-free survival (PFS, weeks), and overall survival (OS, weeks) according to drug type. ND: not determined. Treatment
ORR
DC
PFS median
OS median
[CI95%]
[CI95%]
93
43.5%
70.7%
6 [5;7.1]
24[19.1;36.4]
52
10%
36%
4.3 [3.1;5]
19.4 [9.6;24.7]
EGFR-TKI *
26
7.6%
26.8%
2.99[1.87;4.47]
20.14[7.14;32.95]
Trastuzumab combination,
58
50.9%
75.5%
4.8[3.4;6.5]
13.3[8.1;15]
29
7.4%
55.5%
3.4[2.4;4]
6.5[4.7;30.6]
targeting treatment Second-line: without HER2 targeting treatment
T-DM1 * Neratinib, Lapatinib and Afatinib * * if the same drug has been given more than one time, the results presented here are from their first administration.
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First-line: without HER2
n
20 Table 3: Details of treatments administred Treatments regimen names Platin based doublet platin gemcitabin platin paclitaxel platin pemetrexed platin vinorelbin Platin based doublet and bevacizumab
platin docetaxel bevacizumab
L1 (n)
L2 (n)
4 9 54 4
2 2 1 0
1
1
2
0
12 1
2 0
platin gemcitabine vinorelbin
1
0
docetaxel bevacizumab docetaxel irinotecan
0 0
3 1
pemetrexed docetaxel gemcitabin paclitaxel vinorelbin
2 0 0 0 0
7 9 1 2 1
erlotinib erlotinib bevacizumab
1 1
15 0
docetaxel trastuzumab platin paclitaxel trastuzumab platin pemetrexed trastuzumab vinorelbin trastuzumab trastuzumab afatinib neratinib neratinib everolimus neratinib temsirolimus paclitaxel trastuzumab
1 2
5 0
2 2 2 0 0 0 0 0
0 7 1 1 2 1 4 2
EC145 (TARGET trial) masitinib docetaxel MK3475 (immunotherapy) crizotinib
0 0 0 0
1 1 1 1
Platin based doublet and other agent
Bevacizumab based doublet
Monotherapy based
TKI based
Anti HER2 specific treatment based
Others
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platin gemcitabin bevacizumab platin pemetrexed bevacizumab platin vinorelbin bevacizumab
21
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22
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