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Afatinib in patients with metastatic or recurrent HER2-mutant lung cancers: a retrospective international multicentre study.

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 tumours present 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 seven 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, three partial responses were noted (13%, 95% confidence interval [CI] 4-33%). In addition, 57% of patients (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 are warranted.

SUBMITTER: Lai WV

PROVIDER: S-EPMC6426688 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Afatinib in patients with metastatic or recurrent HER2-mutant lung cancers: a retrospective international multicentre study.

Lai W Victoria WV Lebas Louisiane L Barnes Tristan A TA Milia Julie J Ni Ai A Gautschi Oliver O Peters Solange S Ferrara Roberto R Plodkowski Andrew J AJ Kavanagh John J Sabari Joshua K JK Clarke Stephen J SJ Pavlakis Nick N Drilon Alexander A Rudin Charles M CM Arcila Maria E ME Leighl Natasha B NB Shepherd Frances A FA Kris Mark G MG Mazières Julien J Li Bob T BT

European journal of cancer (Oxford, England : 1990) 20190124

<h4>Introduction</h4>HER2 mutations occur in 1-3% of lung adenocarcinomas. With increasing use of next-generation sequencing at diagnosis, more patients with HER2-mutant tumours present for treatment. Few data are available to describe the clinical course and outcomes of these patients when treated with afatinib, a pan-HER inhibitor.<h4>Methods</h4>We identified patients with metastatic or recurrent HER2-mutant lung adenocarcinomas treated with afatinib among seven institutions across Europe, Au ...[more]

PMID: 30685684

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Project description:BACKGROUND:Human epidermal growth factor receptor 2 (HER2)-mutant lung cancer remains an orphan of specific targeted therapy. The variable responses to anti-HER2 therapies in these patients prompt us to examine impact of HER2 variants and co-mutations on responses to anti-HER2 treatments in lung cancer. PATIENTS AND METHODS:Patients with stage IV/recurrent HER2-mutant lung cancers identified through next-generation sequencings were recruited from seven hospitals. The study comprised a cohort A to establish the patterns of HER2 variants and co-mutations in lung cancer and a cohort B to assess associations between HER2 variants, co-mutations, and clinical outcomes. RESULTS:The study included 118 patients (cohort A, n =?86; cohort B, n =?32). Thirty-one HER2 variants and 35 co-mutations were detected. Predominant variants were A775_G776insYVMA (49/118, 42%), G778_P780dup (11/118, 9%), and G776delinsVC (9/118, 8%). TP53 was the most common co-mutation (61/118, 52%). In cohort B, objective response rates with afatinib were 0% (0/14, 95% confidence interval [CI], 0%-26.8%), 40% (4/10, 14.7%-72.6%), and 13% (1/8, 0.7%-53.3%) in group 1 (A775_G776insYVMA, n =?14), group 2 (G778_P780dup, G776delinsVC, n =?10), and group 3 (missense mutation, n =?8), respectively (p = .018). Median progression-free survival in group 1 (1.2 months; 95% CI, 0-2.4) was shorter than those in group 2 (7.6 months, 4.9-10.4; hazard ratio [HR], 0.009; 95% CI, 0.001-0.079; p < .001) and group 3 (3.6 months, 2.6-4.5; HR, 0.184; 95% CI, 0.062-0.552; p = .003). TP53 co-mutations (6.317; 95% CI, 2.180-18.302; p = .001) and PI3K/AKT/mTOR pathway activations (19.422; 95% CI, 4.098-92.039; p < .001) conferred additional resistance to afatinib. CONCLUSION:G778_P780dup and G776delinsVC derived the greatest benefits from afatinib among HER2 variants. Co-mutation patterns were additional response modifiers. Refining patient population based on patterns of HER2 variants and co-mutations may help improve the efficacy of anti-HER2 treatment in lung cancer. IMPLICATIONS FOR PRACTICE:Human epidermal growth factor receptor 2 (HER2)-mutant lung cancers are a group of heterogenous diseases with up to 31 different variants and 35 concomitant genomic aberrations. Different HER2 variants exhibit divergent sensitivities to anti-HER2 treatments. Certain variants, G778_P780dup and G776delinsVC, derive sustained clinical benefits from afatinib, whereas the predominant variant, A775_G776insYVMA, is resistant to most anti-HER2 treatments. TP53 is the most common co-mutation in HER2-mutant lung cancers. Co-mutations in TP53 and the PI3K/AKT/mTOR pathway confer additional resistance to anti-HER2 treatments in lung cancer. The present data suggest that different HER2 mutations in lung cancer, like its sibling epidermal growth factor receptor, should be analyzed independently in future studies.

Project description:ObjectiveAberrant expression of HER2/neu and PIK3CA gene products secondary to amplification/mutations are common in high-grade-serous-endometrial (USC) and ovarian-cancers (HGSOC). Because scant information is currently available in the literature on the potential negative effect of PIK3CA mutations on the activity of afatinib, in this study we evaluate for the first time the role of oncogenic PIK3CA mutations as a potential mechanism of resistance to afatinib in HGSOC and USC overexpressing HER2/neu.MethodsWe used six whole-exome-sequenced primary HGSOC/USC cell-lines and three xenografts overexpressing HER2/neu and harboring mutated or wild-type PIK3CA/PIK3R1 genes to evaluate the role of PI3K-mutations as potential mechanism of resistance to afatinib, an FDA-approved pan-c-erb-inhibitor in clinical trials in USC. Primary-USC harboring wild-type-PIK3CA gene was transfected with plasmids encoding oncogenic PIK3CA-mutations (H1047R/E545K). The effect of afatinib on HER2/PI3K/AKT/mTOR pathway was evaluated by immunoblotting.ResultsWe found PI3K wild-type cell-lines to be significantly more sensitive (lower IC50) than PI3K-mutated cell-lines p = 0.004). In vivo, xenografts of primary cell-line USC-ARK2, transfected with the PIK3CA-H1047R or E545K hotspot-mutations, exhibited significantly more rapid tumor growth when treated with afatinib, compared to mice harboring ARK2-tumors transfected with wild-type-PIK3CA (p = 0.041 and 0.001, respectively). By western-blot, afatinib effectively reduced total and phospho-HER2 proteins in all cell-lines. However, H1047R/E545K-PIK3CA-transfected-ARK2-cells demonstrated a greater compensatory increase in phosphorylated-AKT proteins after afatinib exposure when compared to controls ARK2.ConclusionsOncogenic PI3K mutations may represent a major mechanism of resistance to afatinib. Combinations of c-erb with PIK3CA, AKT or mTOR inhibitors may be necessary to more efficiently block the PIK3CA/AKT/mTOR pathway.

Project description:BackgroundHER2-low breast cancer (BC) is currently an area of active interest. This study evaluated the impact of low expression of HER2 on survival outcomes in HER2-negative non-metastatic breast cancer (BC).MethodsPatients with HER2-negative non-metastatic BC from 6 centres within the Asian Breast Cancer Cooperative Group (ABCCG) (n = 28,280) were analysed. HER2-low was defined as immunohistochemistry (IHC) 1+ or 2+ and in situ hybridization non-amplified (ISH-) and HER2-zero as IHC 0. Relapse-free survival (RFS) and overall survival (OS) by hormone receptor status and HER2 IHC 0, 1+ and 2+ ISH- status were the main outcomes. A combined TCGA-BRCA and METABRIC cohort (n = 1967) was also analysed to explore the association between HER2 expression, ERBB2 copy number variation (CNV) status and RFS.ResultsABCCG cohort median follow-up was 6.6 years; there were 12,260 (43.4%) HER2-low BC and 16,020 (56.6%) HER2-zero BC. The outcomes were better in HER2-low BC than in HER2-zero BC (RFS: centre-adjusted hazard ratio (HR) 0.88, 95% CI 0.82-0.93, P < 0.001; OS: centre-adjusted HR 0.82, 95% CI 0.76-0.89, P < 0.001). On multivariable analysis, HER2-low status was prognostic (RFS: HR 0.90, 95% CI 0.85-0.96, P = 0.002; OS: HR 0.86, 95% CI 0.79-0.93, P < 0.001). These differences remained significant in hormone receptor-positive tumours and for OS in hormone receptor-negative tumours. Superior outcomes were observed for HER2 IHC1+ BC versus HER2-zero BC (RFS: HR 0.89, 95% CI 0.83-0.96, P = 0.001; OS: HR 0.85, 95% CI 0.78-0.93, P = 0.001). No significant differences were seen between HER2 IHC2+ ISH- and HER2-zero BCs. In the TCGA-BRCA and METABRIC cohorts, ERBB2 CNV status was an independent RFS prognostic factor (neutral versus non-neutral HR 0.71, 95% CI 0.59-0.86, P < 0.001); no differences in RFS by ERBB2 mRNA expression levels were found.ConclusionsHER2-low BC had a superior prognosis compared to HER2-zero BC in the non-metastatic setting, though absolute differences were modest and driven by HER2 IHC 1+ BC. ERBB2 CNV merits further investigation in HER2-negative BC.

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Afatinib in patients with metastatic or recurrent HER2-mutant lung cancers: a retrospective international multicentre study.

Publications

Afatinib in patients with metastatic or recurrent HER2-mutant lung cancers: a retrospective international multicentre study.

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