Abstract
Introduction:
HER2 mutations occur in 1-3% of lung adenocarcinomas. With increasing use of next-generation sequencing at diagnosis, more patients with HER2-mutant tumors are presenting for treatment. Few data are available to describe the clinical course and outcomes of these patients when treated with afatinib, a pan-HER inhibitor.
Methods:
We identified patients with metastatic or recurrent HER2-mutant lung adenocarcinomas treated with afatinib among 7 institutions across Europe, Australia, and North America between 2009 and 2017. We determined the partial response rate to afatinib, types of HER2 mutations, duration of response, time on treatment, and survival.
Results:
We collected information on 27 patients with stage IV or recurrent HER2-mutant lung adenocarcinomas treated with afatinib. Of 23 patients evaluable for response, 3 partial responses were noted (13%, 95% CI 4-33%). In addition, 57% (13/23) had stable disease, and 30% (7/23) had progressive disease. We documented partial responses in patients with HER2 exon 20 insertions, including two with YVMA insertion and one with VAG insertion. Two patients with partial responses were previously treated with trastuzumab and pertuzumab. Median duration of response to afatinib was 6 months (range 5-10); median time on treatment was 3 months (range 1-30); and median overall survival from the date of diagnosis of metastatic or recurrent disease was 23 months (95% CI 18-53 months).
Conclusions:
Afatinib is modestly active in patients with HER2-mutant lung adenocarcinomas, including responses after progression on prior HER2-targeted therapies. However, investigations into the biology of HER2-mutant lung adenocarcinomas and development of better HER2-directed therapies is warranted.
INTRODUCTION
Research into the molecular basis of lung cancers has led to an improved understanding of pathways that are deregulated in the process of tumorigenesis. These key biological pathways are often deregulated through single gene alterations, including mutations, amplifications, rearrangements or fusions, and this process has been described as an oncogene addiction model.1 This model is well characterized in lung adenocarcinomas with approved targeted therapies for certain driver oncogenes including EGFR, ALK, ROS1, and BRAF. Human epidermal growth factor 2 (HER2) has been identified as an additional key oncogenic driver in approximately 1-3% of lung adenocarcinomas.2-4
HER2 is a member of the erbB receptor tyrosine kinase family and acts through downstream effectors in the PI3K-AKT and MEK-ERK pathways.5 The majority of HER2 mutations in lung cancer involve a 12-base pair in-frame insertion in exon 20, known as the YVMA mutation, which leads to constitutive activation of downstream effectors through the AKT and MEK pathways.6-8 This mutation is most often found in female patients, never smokers and in patients with adenocarcinomas.6,9,10 Overall, patients with HER2-mutant lung adenocarcinomas have previously been reported to have a median overall survival of 1.6-1.9 years from the date of metastatic or recurrent disease diagnosis and carry a poorer prognosis compared to other oncogenic drivers.2,3,10 Treatment responses to both chemotherapy and HER2-targeted therapies have been reported, but there are no approved agents for HER2-mutant lung cancers and there is limited data available to guide optimal treatments.
Afatinib is an irreversible ErbB family inhibitor that has been demonstrated to have pre-clinical activity in human lung cancer cell lines with an exon 20 insertion in HER2.11,12 Along with other HER2-targeted agents including dacomitinib and trastuzumab, afatinib has been reported to have clinical activity in patients with HER2-mutant lung adenocarcinomas, though conclusions and recommendations for its clinical use are not possible due to the small sample size of these series.10,13-17
To increase our sample size and to improve our understanding of the clinical activity of afatinib in this subset of patients with lung adenocarcinomas, we combined data from seven institutions. In this article, we present the results of our international multicenter study on clinical outcomes of patients with HER2-mutant lung adenocarcinomas who were treated with afatinib.
MATERIAL AND METHODS
Patient Selection
An international, multicenter network of 7 institutions across Europe, Australia and North America combined data on patients with HER2-mutant lung adenocarcinomas who were treated with afatinib between April 2009 to May 2017. Patients were selected to be included in the study at each of the participating study centers through independent comprehensive chart reviews. Eligible patients had a pathologic diagnosis of advanced (stage IV or recurrent) lung adenocarcinoma and a HER2 mutation by a validated molecular diagnostic test that was performed in an accredited local laboratory. Accepted test methods included reverse transcriptase polymerase chain reaction (PCR) or next-generation sequencing (NGS). Patients were administered afatinib at a starting dose of 20 mg, 30 mg or 40 mg daily depending on the patient’s performance status and other comorbidities. This retrospective study was approved by local institutional review boards. The study was an academic collaboration and not funded by industry, and all investigators were trained in good clinical practice.
Data Collection and Response Assessment
Anonymized clinical data, including age, sex, HER2 mutation subtype, tumor stage, date of diagnosis, initiation and discontinuation of afatinib therapy, duration of afatinib therapy, response to afatinib, disease progression and death, were recorded for all patients. Clinical data were collected by each contributing institution and pooled for analysis. All patients were treated outside of a clinical trial setting, and the date for data cutoff was May 25, 2017. Best response to afatinib, defined as a complete or partial response achieved at least once during the course of therapy, was determined using Response Evaluation Criteria in Solid Tumors (RECIST v1.1) by dedicated study radiologists at each study center.18 The selection of target lesions was performed retrospectively.
Statistical Methods
Data were summarized according to the frequency and percentage for qualitative variables and by medians and ranges for quantitative variables. Overall survival was measured as the time from the date of initial diagnosis of metastatic disease to the date of death from any cause. Patients who were alive at the time of analysis were censored at their last follow-up. Survival rates were estimated by using the Kaplan-Meier method. Statistical analyses were performed using R software (version 3.3.2).
RESULTS
Clinicopathologic and Molecular Features
We collected data on 27 patients who were diagnosed with metastatic or recurrent HER2-mutant lung adenocarcinomas and treated with afatinib (Table 1). The median age at diagnosis was 63 years (range, 40-84 years), and 59% (16/27) of patients were male. Most patients (67%; 18/27) were never smokers. Molecular testing for HER2 mutations was performed locally via NGS or real-time PCR (Table 2). Twenty-one patients (78%; 21/27) had insertion mutations in HER2 exon 20. The most common HER2 mutation found was the YVMA mutation, a 12-base pair (bp) insertion in HER2 exon 20 (56%; 12/27). Five (19%; 5/27) had single bp substitutions, and one (4%; 1/27) had a single-nucleotide polymorphism (SNP).
Table 1. Clinicopathologic characteristics.
Clinicopathologic characteristics of patients with stage IV or recurrent HER2-mutant lung cancers who were treated with afatinib (n=27).
| Clinicopathologic characteristics (n=27) | |
|---|---|
| Median age at diagnosis (%) | 63 (range 40-84) |
| Sex (%) | |
| Female | 11 (41) |
| Male | 16 (59) |
| Histology (%) | |
| Adenocarcinoma | 27 (100) |
| Cigarette smoking status (%) | |
| Former smokers | 9 (33) |
| Never smokers | 18 (67) |
| Reason for afatinib cessation (%) | |
| Progression of disease or death | 19 (70) |
| Toxicity | 6 (22) |
| Unknown | 1 (4) |
| Remains on afatinib (%) | 1 (4) |
Table 2. HER2 mutations.
Spectrum of mutations in patients with HER2-mutant lung cancers who were treated with afatinib (n=27).
| HER2 mutations (n=27) | |||||
|---|---|---|---|---|---|
| HER2 mutation | Mutation amino acid change (Nucleotide change) |
Alternate nomenclature (HGVS guidelines) |
Frequency (%) |
Partial response |
Progressive disease |
| Exon 20 insertion (12bp) | p.A775_G776insYVMA (c.2324_2325ins12) | p.Y772_A775dup (c.2313_2324dup) | 15 (54) | n=2 | n=2 |
| Exon 20 insertion (12bp) | p.A775_G776insAVMA | 1 (4) | |||
| Exon 20 insertion (9bp) | p.A775_G776insVAG (c.2325_2326ins 9) | 2 (7) | n=1 | ||
| Exon 20 insertion (9bp) | p.P780_Y781insGSP (c.2339_2340ins 9) | p.G778_P780dup (c.2331_2339dup) | 1 (4) | n=1 | |
| Exon 20 insertion (3bp) | p.G776>VC (c.2326_2327insTGT) | p.G776delinsVC (c.2326_2327insTGT) | 1 (4) | ||
| Exon 20 insertion (3bp) | Not specified | Not specified | 1 (4) | n=1 | |
| Exon 20 single bp substitution | p.D769H (c.2305 G>C) | 1 (4) | n=1 | ||
| Exon 20 single bp substitution | p.L755F | 1 (4) | n=1 | ||
| Exon 17 single bp substitution | P.V659E (c.1976_1977delinsAA) | 1 (4) | n=1 | ||
| Exon 8 single bp substitution | p.S310F (c.929C>T) | 2 (7) | |||
| Single-nucleotide polymorphism | lle655Val | 1 (4) | |||
Outcomes with Afatinib Treatment in Patients with HER2-mutant Lung Adenocarcinomas
Twenty-seven patients with advanced HER2-mutant lung adenocarcinomas received afatinib as a single agent. The median line of systemic therapy for afatinib was third line (range first to sixth). Median time from the initial diagnosis of metastatic disease to the start of afatinib therapy was 11 months (range 1 to 57 months).
Of the 27 patients, data on response to therapy by RECIST was available in 23 patients (Figure 1). The best response to afatinib was partial response (PR) in 3 patients (13%, 3/23, 95% CI 4-33%), stable disease (SD) in 13 patients (57%), progressive disease (PD) in 7 patients (30%), and not evaluable in 4 patients. All partial responses were noted in patients with HER2 exon 20 insertions, two with YVMA mutations and one with a VAG mutation (Table 3). Out of the 7 patients with PD, the following mutations were observed: YVMA (2); exon 20 insGSP (1); unspecific exon 20 insertion (1); exon 20 single bp substitutions (2); and an exon 17 single bp substitution (1) (Table 2). The median duration of response to afatinib was 6 months (range 5-10 months). Two out of three patients with partial response were previously treated with HER2-targeted therapies; one experienced a partial response to trastuzumab and the other had stable disease in response to pertuzumab given in combination with erlotinib as part of a clinical trial (Table 3).16
Figure 1. Waterfall plot of overall objective response rate to afatinib.
Waterfall plot of overall objective response rate to afatinib per RECIST v1.1. ORR was 13% (3 out of 23 patients). RECIST was unable to be measured in 4 patients.
Table 3. Molecular and clinical characteristics.
Molecular and clinical characteristics of patients with HER2-mutant lung cancers who experienced partial responses when treated with afatinib (n=3).
| Partial response to afatinib (n=3) | |||||||
|---|---|---|---|---|---|---|---|
| Mutation | RECIST | Duration of PR to afatinib (months) |
Line of treatment for afatinib |
Reason for afatinib cessation |
Response to prior HER2-targeted therapy |
OS (months) |
Vital status |
| insVAG | −50% | 5 | 3 | Death | N/A | 62 | Deceased |
| insYVMA | −39% | 10 | 6 | PD | Pertuzumab (SD) | 73 | Deceased |
| insYVMA | −34% | 6 | 3 | Death | Trastuzumab (PR) | 23 | Deceased |
The duration of afatinib therapy for each of the 27 patients is shown in Figure 2. Median time on treatment with afatinib was 3 months (range 1 to 30 months). Five patients were treated for over 6 months, including 4 patients with YVMA mutations and one with a single bp substitution in exon 8 (S310F). At data cutoff, 1 patient with stable disease (YVMA mutation) still remained on afatinib treatment after 30 months. Of the remaining 26 patients, 6 patients (22%) had discontinued treatment due to toxicity, with diarrhea being the primary reported toxicity. None of the 27 patients were treated with afatinib beyond disease progression. Five patients (19%) were alive at the time of data analysis. Median OS from the start of afatinib treatment was 7 months, while median OS from the date of metastatic disease diagnosis was 23 months (95% CI, 17.6-53.2 months). Kaplan-Meier survival curve is shown in Figure 3.
Figure 2. Duration of treatment on afatinib in patients with HER2-mutant lung cancers.
Duration of treatment on afatinib in patients with HER2-mutant lung cancers from April 2009 through May 2017. Objective response as per RECIST could not be determined for 4 patients due to either the lack of baseline imaging prior to starting afatinib or absence of on-treatment or post-treatment imaging.
Figure 3. Overall survival.
Overall survival (OS) of patients with HER2-mutant lung cancers treated with afatinib between April 2009 through May 2017. OS was defined from the date of initial diagnosis of metastatic or recurrent disease.
DISCUSSION
To the best of our knowledge, our study represents one of the largest single cohort of patients with HER2-mutant lung adenocarcinomas treated with afatinib. Though there are limitations in our retrospective series, it is one of the largest international efforts to date to assess the activity of afatinib in this uncommon molecular subset of lung cancers.
Our patient characteristics were similar to prior series of HER2-mutant lung cancers, including a similar median age of 63, primarily never smokers, and exclusively adenocarcinomas.6,10,17,19 However, there were two key differences: our patients were predominantly male as compared to predominantly female in previous studies, and heavy smokers with up to 60 pack years were identified. Our study highlights that molecular testing for HER2 mutations should be considered in all adenocarcinomas, even if patients do not fit the usual clinical profile of female and never smokers. Comparable to prior studies, most of our patients were found to have mutations involving exon 20 insertions in HER2, with the most common being the YVMA mutation.
The 13% overall response rate to afatinib is comparable to a 19% response rate reported by Peters et al. in a separate retrospective series investigating the use of afatinib in more heavily pretreated patients with HER2-mutant lung adenocarcinomas.20 Our 13% response rate is also comparable to an earlier phase II trial that yielded a 12% response rate using dacomitinib, a selective and irreversible pan-HER inhibitor, in stage IIIB/IV patients with HER2-mutant lung adenocarcinomas.15 Overall, the activity of afatinib seen in this study confirms the earlier reports of activity in small case series; De Greve et al. reported PR in all of 3 patients on afatinib, and Mazières et al. reported PR in 1 out of 3 patients.10,13 While the common YVMA mutation was found in 2 out of 3 responders to afatinib in our study, it was also found in 2 out of 7 patients with progressive disease (Table 2). These findings emphasize the need for better understanding of the underlying biology of the various HER2 mutation subtypes and potential differences in their response to HER2-targeted therapies.
One patient treated with afatinib was found to have a single-nucleotide polymorphism (SNP) in HER2, which resulted in the substitution of valine for isoleucine at codon 655 (Ile655Val) of the HER2 protein. The role of Ile655Val in driving oncogenesis has been explored in prior studies in breast cancer patients with conflicting results, and this SNP has not been well characterized in HER2-mutant lung adenocarcinomas.21 While RECIST data were unavailable for this patient, the patient experienced clinical benefit while on treatment with afatinib for 4 months. Thus, larger clinical series of this variant are needed to help draw conclusions regarding its predicted response to afatinib and other HER2-targeted agents. The identification of this SNP further underscores the molecular heterogeneity of HER2 alterations in lung adenocarcinomas.
In our study, afatinib was used primarily in a heavily pretreated population and may underestimate the activity of afatinib, as patients might derive more clinical benefit if they were treated at an earlier point of their disease course with better performance status. Though the number of patients is small, we also note that two out of three patients with PR were previously treated with HER2-targeted therapies. This suggests that afatinib can still induce a PR in patients who have previously progressed on other HER2-targeted therapies, including trastuzumab and pertuzumab.
While the median duration of treatment on afatinib for all patients was 3 months, the range varied from 1 month to ongoing treatment at 30 months (YVMA mutation). Five patients (19%; 5/27) remained on treatment for over 6 months, including a patient with an YVMA mutation who experienced PR. This demonstrates that afatinib has the potential for durable disease control in a subset of patients with HER2-mutant lung adenocarcinomas. Median overall survival (OS) of all patients treated with afatinib in our study was 23 months, which was comparable to prior studies that examined survival of advanced stage (stages IIIB-stage IV) HER2-mutant lung adenocarcinomas.6,10,17
There are several limitations to this study due to its retrospective nature, including reporting bias, lack of central molecular assessment and variable imaging intervals. Nevertheless, as our study was conducted in a heavily pretreated patient population with higher likelihood for development of drug resistance, it is unlikely to overestimate the efficacy of afatinib. Moreover, our study was conducted outside of a clinical trial, which broadens its applicability and generalizability to patients worldwide who have either poor performance status or lack of access to therapies on clinical trial. The use of afatinib in HER2-mutant lung adenocarcinomas currently is being studied in two separate prospective Phase II clinical trials: the ETOP-NICHE Trial (NCT02369484) in Europe and the NCI-MATCH Trial (NCT02465060) in the US. Interim results from ETOP-NICHE were reported at the 2017 ASCO Annual Meeting and did not demonstrate the expected ability of afatinib to control disease, and final results of the study are still yet to be reported.22 These upcoming results may help to confirm our findings of afatinib use outside of a clinical trial in a real-world setting.
Other HER2-targeted agents are being explored in patients with HER2-mutant lung adenocarcinomas. Single agent neratinib recently demonstrated only a 4% overall response rate for HER2-mutant lung adenocarcinomas in a Phase II basket trial, and the combination of neratinib with trastuzumab is being explored in a cohort expansion of the trial (NCT01953926).23 Neratinib is also being tested in combination with temsirolimus, and preliminary results from a phase II trial testing this combination in HER2-mutant lung adenocarcinomas reported a response rate of 19% (8 out of 43 patients) (NCT NCT01827267).24 In addition, early results from a Phase II study examining the effects of poziotinib, a novel irreversible pan-HER inhibitor, reported a PR in 8 out of 11 (73%) patients with lung adenocarcinomas harboring EGFR exon 20 insertions (NCT03066206).25 In a recent study published by Oh et al., poziotinib was found to induce PR in 2 patients and SD in 3 patients out of 6 total treated patients.26 Due to these promising results, poziotinib is currently being tested in patients with lung adenocarcinomas harboring HER2 exon 20 mutations (NCT03318939). Likewise, pyrotinib, another irreversible pan-HER inhibitor is also being investigated in a Phase I trial cohort expansion for HER2-mutant lung adenocarcinomas (NCT02500199). Recently, a phase II trial using ado-trastuzumab emtansine (T-DM1) in patients with HER2-mutant lung adenocarcinomas reported an overall response rate of 44%, and this has been incorporated as a treatment recommendation for HER2-mutant lung adenocarcinomas by the 2018 National Comprehensive Cancer Network Clinical Practice Guidelines.27 A further expansion study of T-DM1 in both HER2-amplified and HER2-mutant solid tumors is ongoing (NCT02675829).
Afatinib demonstrated modest activity in a subset of patients with HER2-mutant lung adenocarcinomas and is a viable treatment option even after prior HER2-targeted agents. Our experience with afatinib confirms that HER2-mutant lung adenocarcinomas are clinically actionable and emphasizes the need to identify HER2 mutations in lung adenocarcinomas early in the patients’ disease course. Moreover, our study underscores the unmet clinical need for novel HER2-targeted therapies to improve patient outcomes.
Highlights.
Response rate of advanced HER2-mutant lung cancers treated with afatinib was 13%
All responses were seen in patients with HER2 exon 20 insertion mutations
Responses were observed even in patients treated with prior HER2-targeted therapies
Afatinib led to durable disease control in a subset of patients (up to 30 months)
Afatinib was well-tolerated in most patients
Acknowledgments:
This study was supported in part by the Comprehensive Cancer Center Core Grant (646-) at Memorial Sloan Kettering Cancer Center from the National Institutes of Health, USA.
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Prior Presentations: Part of this study was presented at the 17th Annual Targeted Therapies of the Treatment of Lung Cancer meeting in Santa Monica, CA, USA, and the 2017 ASCO Annual Meeting in Chicago, IL, USA.
Conflict of Interest Statement: NP has received consulting fees from Boehringer Ingelheim; all other authors declare no competing interests.
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