Accepted Manuscript Examining Treatment Outcomes with Erlotinib in Patients with Advanced Non-SmallCell Lung Cancer Whose Tumors Harbor Uncommon Epidermal Growth Factor Receptors Mutations Barbara Klughammer, Wolfram Brugger, Federico Cappuzzo, Tudor Ciuleanu, Tony Mok, Martin Reck, Eng Huat Tan, Paul Delmar, Gaelle Klingelschmitt, Anny-Yue Yin, Olivia Spleiss, Lin Wu, David S. Shames PII:
S1556-0864(16)00283-5
DOI:
10.1016/j.jtho.2015.12.107
Reference:
JTHO 82
To appear in:
Journal of Thoracic Oncology
Received Date: 9 September 2015 Revised Date:
16 December 2015
Accepted Date: 17 December 2015
Please cite this article as: Klughammer B, Brugger W, Cappuzzo F, Ciuleanu T, Mok T, Reck M, Tan EH, Delmar P, Klingelschmitt G, Yin A-Y, Spleiss O, Wu L, Shames DS, Examining Treatment Outcomes with Erlotinib in Patients with Advanced Non-Small-Cell Lung Cancer Whose Tumors Harbor Uncommon Epidermal Growth Factor Receptors Mutations, Journal of Thoracic Oncology (2016), doi: 10.1016/j.jtho.2015.12.107. 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.
ACCEPTED MANUSCRIPT
Examining Treatment Outcomes with Erlotinib in Patients with Advanced Non-Small-Cell Lung Cancer Whose Tumors Harbor
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Uncommon Epidermal Growth Factor Receptors Mutations
Barbara Klughammer,* Wolfram Brugger,† Federico Cappuzzo,‡ Tudor Ciuleanu,§ Tony Mok,ǁ Martin Reck,¶ Eng Huat Tan,# Paul Delmar,* Gaelle Klingelschmitt,*
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Anny-Yue Yin,* Olivia Spleiss,* Lin Wu,* and David S. Shames**
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*F. Hoffmann-La Roche Ltd, Basel, Switzerland; †Schwarzwald-Baar Klinikum, Academic Teaching Hospital, University of Freiburg, Villingen-Schwenningen, Germany; ‡Istituto Toscano Tumori, Ospedale Civile, Livorno, Italy; §Prof Dr Ion Chiricuta Institute of Oncology, Department of Medical Oncology and UMF Iuliu Hatieganu, Cluj-Napoca, Romania; ǁState Key Laboratory of Southern China, Hong Kong Cancer Institute, Department of Clinical
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Oncology, Prince of Wales Hospital, Hong Kong, China; ¶Department of Thoracic Oncology, LungenClinic Grosshansdorf, Airway Research Center North (ARCN), member of the German Research Center for Lung Diseases (DZL), Grosshansdorf, Germany; #Department
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of Medical Oncology, National Cancer Centre, Singapore; and **Oncology Biomarker
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Development, Genentech Inc., San Francisco, CA, USA.
Target journal: J Thorac Oncol (first choice, max. word count is 4,000 with 6 tables/figures); Mol Cancer (second choice)
Current word count: 4,033
Corresponding author: 1
ACCEPTED MANUSCRIPT Barbara Klughammer F. Hoffmann-La Roche Ltd Basel Switzerland
E-mail:
[email protected]
Conflicts of Interest and Source of Funding
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Tel: +41 61 68 86386
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P. Delmar, B. Klughmammer, D. Shames and L. Wu are employees of F. Hoffmann-La
Roche and own stocks in F. Hoffmann-La Roche. G. Klingelschmitt, O. Spleiss and A. Yue
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are employees of F. Hoffmann-La Roche. T. Ciuleanu has recieved honorarium from F. Hoffmann-La Roche. T. Mok has consulted for, and recieved honoraria for symposia and advisory boards for F. Hoffmann-La Roche. M. Reck has served as an advisor for F.
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Hoffmann-La Roche.
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This manuscript was funded by F. Hoffmann-La Roche .
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Abstract (250 word limit; word count 240) Introduction: Exon 19 deletions and exon 21 L858R mutation of the epidermal growth factor receptor (EGFR) predict activity of EGFR tyrosine kinase inhibitors (TKIs) including erlotinib; however, the ability of less common EGFR mutations to predict efficacy of erlotinib is
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unclear. Methods: The efficacy of erlotinib in individual patients with rare EGFR mutations from the MERIT, SATURN, TITAN, TRUST, ATLAS, BeTa, and FASTACT-2 trials was analyzed and
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compared with data from the literature.
Results: Of the patients tested for biomarkers, the frequency of rare mutations identified
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here ranged from 1.7% (8/467) in the SATURN study, to 7.4% (27/364) in ATLAS. Some rare mutations were associated with greater clinical benefit with EGFR TKI therapy, or with improved prognosis independent of treatment, while others appeared to have a poorer prognosis. In particular, exon 18 G719 mutations, exon 19 K757R and E746G mutations, the exon 20 S768I mutation, and the exon 21 G836S mutation appeared to confer a good
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outcome with erlotinib treatment while exon 18 S720I showed a particularly poor outcome. However, due to the small number of patients with each mutation, it is difficult to confirm whether these rare mutations do indeed confer sensitivity or resistance to erlotinib.
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Conclusions: Erlotinib can have differential efficacy depending on the specific EGFR mutation. More research is needed to create a central database such as the ‘My Cancer
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Genome’ database of rare mutations to definitively confirm whether these mutations are activating, resistant, or neutral.
Key Words: NSCLC, Erlotinib, EGFR mutations, Uncommon, Rare.
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ACCEPTED MANUSCRIPT INTRODUCTION The epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) erlotinib has been at the forefront of changes in treatment practice for advanced non-small-cell lung cancer (NSCLC) over the last 10 years. Erlotinib was initially approved for use in the second-
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/third-line setting in an unselected population, based on statistically significant improvements in overall survival (OS) versus placebo.1 Erlotinib was subsequently approved for
maintenance treatment of unselected NSCLC based on data from the SATURN trial.2
Finally, erlotinib was also approved for the first-line treatment of patients whose tumors
trials of single-agent erlotinib versus chemotherapy.3–5
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harbor activating mutations of EGFR, based on compelling evidence from several clinical
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The most common activating mutations used to guide treatment decisions in NSCLC are deletions in exon 19 of EGFR and the specific point mutation L858R in exon 21. However, many testing methods are actually able to identify other less common activating mutations, as well as the most frequent resistance mutations (e.g. T790M in exon 20).
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Genetic profiling suggests that some patients with advanced NSCLC whose tumors harbor these less common mutations of EGFR may derive a greater or lesser benefit from treatment with erlotinib or other EGFR TKIs (e.g. afatinib, gefitinib) than those with classical activating
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mutations, but full mutation profiling is still in its infancy. In order to allow for truly personalized treatment, a greater understanding of these
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‘rare’ mutations is required, to allow for individual patient profiling and accurate prediction of response to EGFR TKI therapy. Examining existing data and tumor samples can provide valuable guidance in building these disease profiles for application to clinical practice, particularly in cases where the number of patients with a specific mutation is insufficient to carry out a full clinical trial. De Pas et al. investigated the frequency of rare mutations in 681 cases of NSCLC screened between 2006 and 2010. Out of the 99 cases with EGFR mutations, 18 harbored rare mutations. Of these patients, 10 were treated with erlotinib or gefitinib, with varying responses depending on the specific mutations.6 In an observational, 4
ACCEPTED MANUSCRIPT prospective cohort of 188 NSCLC patients, common and rare mutations were assessed with regards to EGFR TKI response by Arrieta et al. Patients with rare mutations had significantly (p < 0.001) lower response rates to EGFR TKIs than those with common mutations.7Similarly, Chiu et al. examined 639 patients with activating EGFR mutations (478
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with common mutations; 161 with rare mutations). When treated with EFGR TKIs, the response rate was significantly lower for patients with rare mutations compared with
common mutations (41.6 vs 66.5%, p = 0.001) and the median progression-free survival (PFS) was also lower (7.7 vs 11.4 months, p = 0.001).8 A retrospective analysis by Baek et
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al. also reported that patients with rare or complex mutations had inferior response and
survival when treated with EGFR TKIs compared with patients whose tumors had common
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EGFR mutations.9
In a post-hoc analysis from three clinical studies of afatinib (LUX-Lung 2, LUX-Lung 3 and LUX-Lung 6), 75/600 (12%) patients had rare EGFR mutations and, following afatinib treatment the median PFS varied depending on the type of mutation.10 Patients with point
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mutations or duplications had a median PFS of 10.7 months and a median OS of 19.4 months, whereas patients with de-novo T790M mutations had a median PFS of 2.9 months and a median OS of 14.9 months. Patients with an exon 20 insertion had a median PFS of
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2.7 months and median OS of 9.2 months.10
Here we report individual patient data in a case report style, from patients with rare
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mutations as assessed from baseline tumor samples from several well-controlled clinical studies of erlotinib to assess the efficacy outcomes for patients with uncommon mutations.
METHODS
Clinical Studies Included in This Analysis Data from the SATURN (NCT00556712), TITAN (NCT00556322), TRUST (NCT00949910), ATLAS (NCT00257608), BeTa (NCT00130728), FASTACT-2 (NCT00883779), and MERIT (BO18279) studies were assessed in this analysis. MERIT was 5
ACCEPTED MANUSCRIPT a single-arm, open-label, phase II gene expression profiling study that aimed to identify candidate genes to predict outcomes in patients receiving erlotinib.11 The TRUST study was a phase IV expanded access study, which assessed efficacy and safety outcomes with erlotinib (regardless of line of therapy) in a large patient population reflective of real-life
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clinical practice (>7000 patients).12 Biomarker samples were obtained where possible and several prior analyses were carried out, including EGFR mutations.13,14 SATURN and TITAN were twin phase III studies conducted in the post-first-line setting. Patients were initially
enrolled into a chemotherapy run-in phase, following which they could be enrolled into either
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SATURN (if their disease had not yet progressed) or TITAN (if their disease had progressed during the initial cycles of first-line chemotherapy). Patients in SATURN were randomized to
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receive either erlotinib maintenance therapy or placebo,2 while those in TITAN were randomized to receive either second-line erlotinib or chemotherapy (docetaxel or pemetrexed, at the investigators’ discretion).15 Tumor sampling was mandatory in both studies and extensive biomarker analyses have been reported.15,16 FASTACT-2 was a phase
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III, randomized, controlled study assessing the efficacy and safety of an intercalated regimen of erlotinib and first-line chemotherapy versus intercalated placebo and chemotherapy in Asian patients with advanced NSCLC. Patients were not selected based on EGFR mutation
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status, but biomarker analysis did demonstrate that the significant efficacy benefit of intercalated erlotinib was driven by this patient subgroup.17 BeTa was a phase III
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randomized study evaluating bevacizumab plus erlotinib for the treatment of recurrent or refractory NSCLC. Patients were not selected based on EGFR mutation status but tumor biopsy material was requested at study entry for biomarker analysis.18 The phase III ATLAS study assessed bevacizumab with or without erlotinib in the maintenance treatment setting.19 Provision of tumor tissue for biomarker assessment was optional.
Mutation Testing Methodology
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ACCEPTED MANUSCRIPT Tumor sampling was mandatory for MERIT, SATURN, and TITAN and optional for TRUST, ATLAS, BeTa, and FASTACT-2; informed consent was obtained from all patients contributing samples. EGFR mutation testing was carried out using different methods across the different clinical studies. For MERIT and TRUST, microdissection (manual or laser
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capture) of tumor cells was carried out on formalin-fixed paraffin-embedded tissue samples. DNA was then extracted from the microdissected cells and EGFR exons 18–21 were
amplified by polymerase chain reaction (PCR) then sequenced for EGFR mutation status assessment. In SATURN and TITAN, DNA lysates were obtained from macro- or
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microdissected tissue samples; these samples had to have at least 5000 tumor cells and a minimum 60% tumor cell content. Exons 18–21 were amplified by PCR, with multiple
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independent products sequenced. Mutations other than the most commonly known resistance and activating mutations had to be identified in at least two PCR products, in order to be confirmed. For FASTACT-2, EGFR mutation analysis was carried out using the cobas® 4800 system (Roche Molecular Diagnostics, Pleasanton, CA, USA), which is able to
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detect the most common activating and resistance mutations, as well as less common mutations in exons 18–21. In addition, blood samples were tested using the cobas® 4800 EGFR mutation blood test (in development). In the ATLAS study, analyses of EGFR
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mutations in exons 18–21 were performed using Somatic Mutation Scanning by Surveyor® Endonuclease Digestion and Analysis on WAVE HS (Transgenomics Inc., Omaha, NE,
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USA) using cells captured by manual macrodissection or laser microdissection. In the BeTa study, EGFR mutations in exons 18–21 were analyzed by denaturing high performance liquid chromatography (Transgenomics Inc., Omaha, NE, USA).
RESULTS To effectively assess the efficacy of erlotinib in patients with the rare mutations identified, it is important to consider the intent-to-treat population results and, where
7
ACCEPTED MANUSCRIPT available, subgroups with classical EGFR mutations from each study shown in Supplementary Table 1.
Individual Patient Data for Rare Mutations
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Efficacy results for individual patients with rare mutations in MERIT, SATURN, TITAN, TRUST, ATLAS, BeTa, and FASTACT-2 are presented in Tables 1–4 (Table 1, rare
mutations in exon 18; Table 2, rare mutations in exon 19; Table 3, rare mutations in exon 20; Table 4, rare mutations in exon 21). Of the samples tested for biomarkers, the frequency of
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rare mutations identified in this analysis ranged from 1.7% (8/467) in the SATURN study to 7.4% (27/364) in ATLAS. Some mutations were associated with greater clinical benefit with
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EGFR TKI therapy, or with improved prognosis regardless of treatment, showing both predictive and prognostic effects of certain rare mutations, while others appeared to have a detrimental effect on survival. Some of these rare mutations are detailed below, evaluating
Exon 18 Mutations G719
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the results from this analysis compared with data from the literature.
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One of the more frequently observed ‘rare’ mutations is the point mutation at G719 (n = 10 out of 24 exon 18 mutations in this analysis). The mutation to cysteine (G719C)
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appears to confer a PFS and OS benefit, with one patient from the SATURN study reporting a partial response, PFS of 500 days and OS of 795 days (over 2 years). When combined with the K714N mutation in one patient in BeTa, an OS of 973 days (longer than 2.5 years) was observed. A point mutation to alanine was also seen at G719. In SATURN, a G719A mutation plus T725M resulted in PFS of 169 days and OS of 343 days; while in TRUST, a patient with G719A had PFS of 463 days and OS of 488 days. A patient with an unknown G719 mutation in FASTACT-2 achieved OS of 1008 days (over 2.5 years). When compared
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ACCEPTED MANUSCRIPT with the PFS and OS results from the overall populations of each study, the G719A mutation appeared to be sensitizing, but to a lesser extent than the G719C mutation.
Literature Review
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Substitutions at G719 with alanine or cysteine have been shown to confer sensitivity to EGFR TKIs in several previous studies. This is because the point mutation alters the P-loop of the receptor structure to allow the receptor a higher affinity to adenosine triphosphate (ATP), therefore favoring activation.20 Han et al. reported three gefitinib-treated patients with
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G719A mutations. Of these patients, two achieved partial responses, with one patient
reporting time to progression of 22 months (~669 days) and OS of longer than 26 months
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(~791 days).21 Point mutations at G719 resulted in patients (n = 15) achieving a response rate of 53.3%, median PFS of 8.1 months (~247 days) and median OS of 16.4 months (~499 days) when treated with gefitinib or erlotinib.22 Baek et al. reported that in a subgroup where 6/11 patients had G719 mutations, median PFS was 5.1 months (~155 days) and median
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OS was 18.3 months (~557 days) in a retrospective analysis.9 When patients with point mutations at G719 (n = 18) were treated with afatinib, they achieved an objective response rate (ORR) of 77.8%, PFS of 13.8 months and OS of 26.9 months in a study by Yang et al.10
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Chui et al. reported 78/161 (48.4%) patients with rare mutations had a single G719 mutation. Following treatment with gefitinib or erlotinib, the ORR was 36.8% with a disease control rate
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(DCR) of 72.4%. However, a compound mutation of G719 + L861Q (exon 21) (5.6%) or G719+S768I (exon 20) (6.2%) demonstrated a higher ORR (88.9% and 50%, respectively) and a greater DCR (100% for both).8
S720 Poor response and short OS was observed with the S720P mutation with OS of 1 year (MERIT 435 days and BeTa 462 days). Other exon 19 mutations generally had shorter PFS and OS than the previously mentioned mutations, with
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best response of progression or stable disease. However, these results were comparable with the overall study population results, so EGFR TKI treatment is unlikely to be of reduced
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benefit in these patients.
Literature Review
To our knowledge, no previous publications have reported K757R mutations. The E746G mutation was reported in combination with an L861Q mutation in a study by Wu et al., with the patient achieving partial response to EGFR TKI therapy.22 Deletions at E746 were reported in a study by Peng et al. in two patients, who both received gefitinib treatment. One patient had a stable disease status, a PFS of 8 months and an OS of >8 months, and 10
ACCEPTED MANUSCRIPT the other patient achieved a partial response, a PFS of 15 months and an OS of >58 months.24 Exon 19 insertions, L747F and P733L, have both been reported as sensitizing rare exon 19 mutations20 and several rare mutations in exon 19 have been reported as resistance mutations including D761Y, E746V, and L747S, showing the varied responses
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different point mutations in one exon can elicit.20 The L747F mutation may confer sensitivity by inhibiting the αC-helix adopting the inactive position,25 while the D761Y resistance
mutation appears to confer resistance by altering the receptor interaction with ATP.20 In two case studies by Agbarya et al. and Chan et al., data from female patients with
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p.K745_E746insIPVAIK exon 19 insertions were reported and in both cases the patients
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responded to EGFR TKI treatment.26,27
Exon 20 Mutations
T790M is known to cause EGFR TKI resistance,28 which is generally consistent with the short PFS seen in patients with this mutation in our analysis. However, when combined
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with exon 18 mutations, response of stable disease and PFS of >1 year was seen in two patients from the TRUST study. However, in the case of double mutations, the mutant allele frequency (MAF) must be considered as if the MAF for T790M was particularly low when in
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combination with another mutation, the outcome would be skewed towards the other mutation, while still detecting the presence of the T790M resistance mutation. S768I
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appeared to confer sensitivity to erlotinib, with a patient from FASTACT-2 reaching OS of 1909 days (>5 years) and a female Asian patient from the TRUST study with an additional V774M mutation having OS of 1106 days (>3 years). Across the exon 20 mutations reported, eight appeared to be insertions. P.A767_S768INSSVSS and P.M766_A767INSASV from the TITAN study were associated with short PFS and OS. Conversely, the P.D770_N771INSSVD mutation was associated with longer OS (599 and 881 days) in two patients in the SATURN study.
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ACCEPTED MANUSCRIPT Literature Review Masago et al. published a case report of a patient with an S768I mutation who had achieved a partial response and PFS of >1 year on second-line gefitinib treatment.29 Other reports have identified the S768I mutation as a resistance mutation22,30 or as a mutation less
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sensitive to erlotinib or gefitinib than to dual EGFR and vascular endothelial growth factor receptor inhibitor AEE788.31Chiu et al. reported seven patients with the S768I mutation who achieved an ORR of 33.3% and DCR of 66.7%, although patients with a compound S768 mutation (n = 10) showed a greater PFS of 11.9 months compared with 6.5 months for the
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single mutation.8 A study in Norway identified three patients with S768I mutations, two of whom went on to receive EGFR TKI treatment. One patient had a partial response to first-
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line gefitinib, with time on treatment of 14 months, whereas the other patient received second-line erlotinib for 1 month until disease progression. 32 The conflicting reports highlight how difficult it can be to obtain a consensus on whether a mutation is resistant, activating, or neutral when so few cases are reported. Exon 20 mutations may function by altering the
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kinase domain conformation.20
While many exon 20 mutations have reported conferring resistance to erlotinib by altering the P-loop and thus reducing the ATP-binding pocket,25 a retrospective study by
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Naidoo et al. reported a V769_770insASV insertion that resulted in PFS of 19.8 months (~602 days) and OS of 24 months (~730 days) and a patient with a D770_N771insGT
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insertion achieving OS of 55 months (~1674 days), demonstrating the variability of rare mutation effects.33 Another retrospective study analyzed 1086 patients for EGFR mutations and identified 27 (2.5%) patients with exon 20 insertions, with the most common variant being V769_D770insASV.34 In this study, exon 20 insertions were associated with a median PFS of 16 months and were more commonly found in never-smokers and Asian patients.34
Exon 21 Mutations 12
ACCEPTED MANUSCRIPT Response varied among the specific exon 21 mutations. Generally rare mutations in exon 21 resulted in PFS of ATC in exon 20 (S768I). Jpn J Clin Oncol 2010;40:1105– 1109.
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30. Pallan L, Taniere P, Koh P. Rare EGFR exon 20 S768I mutation predicts resistance to targeted therapy: a report of two cases. J Thorac Oncol 2014;9:75.
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31. Kancha R, von Bubnoff N, Peschel C, et al. Functional analysis of epidermal growth factor receptor (EGFR) mutations and potential implications for EGFR targeted therapy. Clin Cancer Res 2009;15:460–467. 32. Lund-Iversen M, Kleinberg L, Fjellbirkeland L, et al. Clinicopathological characteristics of 11 NSCLC patients with EGFR-exon 20 mutations. J Thorac Oncol. 2012;7:1471–1473.
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ACCEPTED MANUSCRIPT 33. Naidoo J, Sima C, Rodriguez K, et al. Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: clinical outcomes and response to erlotinib. Cancer 2015;Epub ahead of print. 34. Oxnard GR, Lo P, Nishino M, et al. Natural history and molecular characteristics of
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lung cancers harboring EGFR exon 20 insertions. J Thor Oncol. 2013;8:179–184. 35. Wantanbe S, Minegishi Y, Yoshizawa H, et al. Effectiveness of gefitinib against non– small-cell lung cancer with the uncommon EGFR mutations G719X and L861Q. J Thorac Oncol. 2014;9:189–194.
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36. Imielinski M, Greulich H, Kaplan B, et al. Oncogenic and sorafenib-sensitive ARAF
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mutations in lung adenocarcinoma. J Clin Invest 2014;124;1582–1586.
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TABLE 1. Efficacy Data for Rare Mutations in Exon 18 of EGFR
Smoking
First Trial
PS
Line
Status
Medication Docetaxel
Sex
Race
TITAN
64
Male
Caucasian
0
2
Current
SATURN
58
Male
Caucasian
1
1
Former
SATURN
58
Female
Asian
1
1
Never
SATURN
59
Male
Caucasian
0
1
Current
MERIT
50
Male
Asian
1
2
TRUST
67
Female
Caucasian
1
2
TRUST
50
Female
Asian
1
TRUST
38
Male
Asian
2
FASTACT-2
61
Female
Asian
FASTACT-2
63
Female
Asian
0
1
Actual Mutation Exon 18
or Censored (C) at Database
PFS, Response
days
OS, days
Closure
P.G719Aa
PD
25
25
C
Erlotinib
P.E709A; P.G719S
SD
253
509
C
Erlotinib
P.G719C
PR
500
795
C
Erlotinib
P.G719A; P.T725M
SD
169
343
D
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years
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Tx
Erlotinib
P.E709K; P.G719A
PD
42
259
D
Never
Erlotinib
P.G719Ab
SD
463
488
D
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Never
2
Never
Erlotinib
P.E709_T710DELINSD
PD
38
52
D
2
Never
Erlotinib
P.V689Mb
SD
491
873
D
1
Never
Carboplatin/
P.G719UNKc
SD
225
1084
D
P.G719UNKd
PR
130
1008
D
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Protocol
ECOG
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Age,
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Death (D)
1
gemcitabine Never
Carboplatin/ gemcitabine
22
ATLAS
72
Male
Caucasian
1
1
Former
Bevacizumab +
P.L707Se
PD
42
235
C
P.I715V
SD
413
413
C
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P.S720P
PD
78
285
C
T727STOP
PD
1
464
D
P.S720P
SD
109
302
C
P.F723L
PD
81
311
C
P.G719C
SD
453
673
D
erlotinib ATLAS
41
Male
Caucasian
1
1
Current
Bevacizumab + erlotinib
ATLAS
73
Male
Caucasian
1
1
Former
Bevacizumab + erlotinib
67
Female
Black
1
1
Former
Bevacizumab + erlotinib
61
Male
Caucasian
1
1
Current
Bevacizumab +
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ATLAS
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ATLAS
erlotinib
ATLAS
64
Male
Caucasian
1
1
Current
Bevacizumab + erlotinib
73
Female
Hispanic
1
1
ATLAS
70
Male
Hispanic
0
1
ATLAS
59
Male
Caucasian
1
1
Current
Bevacizumab
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ATLAS
Former
Bevacizumab
P.G719A
PD
84
227
C
Former
Bevacizumab +
P.S720F
PD
2
89
C
P.V736A
NE
177
183
D
70
Male
Asian
BETA
77
Female
Caucasian
BETA
74
Female
Caucasian
BETA
64
Female
Caucasian
1
1
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ATLAS
EP
erlotinib
Former
Bevacizumab + erlotinib
1
2/3
Former
Erlotinib + placebo
P.K714N; P.G719C
SD
359
973
C
0
2/3
Former
Erlotinib + placebo
P.Y727C
SD
191
269
D
0
2/3
Former
Erlotinib +
P.I706T; P.G874S
SD
423
444
C
23
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bevacizumab Caucasian
a
Exon 21 L833F mutation in addition.
b
Exon 20 mutation in addition.
c
Patient received second-line erlotinib.
d
Patient received second-line gefitinib.
e
Exon 19 N7565 mutation in addition.
f
Exon 19 deletion in addition.
0
2/3
Former
Erlotinib + placebo
P.A722Vf
PD
39
429
C
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Female
SC
61
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BETA
ECOG PS, Eastern Cooperative Oncology Group performance status; NE, non-evaluable; OS, overall survival; PFS, progression-free survival; PR, partial response; PD,
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progressive disease; SD, stable disease; Tx, treatment.
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TABLE 2. Efficacy Data for Rare Mutations in Exon 19 of EGFR
Smoking
PS
Line
Status
Sex
Race
TITAN
69
Male
Caucasian
0
2
Current
MERIT
77
Female
Asian
2
2
Former
MERIT
73
Female
Asian
1
2
Never
MERIT
41
Male
Asian
1
2
ATLAS
72
Male
Caucasian
1
1
58
Male
Caucasian
BETA
63
Female
Caucasian
BETA
54
Male
Caucasian
1
2/3
Censored
Actual Mutation Exon 19
Docetaxel
(C) at PFS,
Database
Response
days
OS, days
Closure
P.D761N
SD
101
178
D
Erlotinib
P.I744V
PD
82
136
D
Erlotinib
P.L747FS
PD
122
211
D
Never
Erlotinib
P.K757R
SD
250
435
D
Former
Bevacizumab +
P.N756Sa
PD
42
235
C
P.K745Eb
NE
85
282
D
EP
BETA
Medication
TE D
years
First Trial
or
SC
Tx
AC C
Protocol
ECOG
M AN U
Age,
Death (D)
Former
erlotinib Bevacizumab + erlotinib
0
2/3
Never
Erlotinib + placebo
P.E746G
NE
415
462
C
0
2/3
Former
Bevacizumab +
P.V717A
SD
79
292
D
erlotinib
25
ACCEPTED MANUSCRIPT
67
Female
Caucasian
1
a
Exon 18 L7675 mutation in addition.
b
Y827C, V845M, H870Y exon 21 mutations in addition.
c
V851A exon 21 mutation in addition.
2/3
Former
Erlotinib + placebo
P.A755Tc
SD
215
329
C
RI PT
BETA
ECOG PS, Eastern Cooperative Oncology Group performance status; NE, non-evaluable; OS, overall survival; PFS, progression-free survival; PR, partial response; PD,
AC C
EP
TE D
M AN U
SC
progressive disease; SD, stable disease; Tx, treatment.
26
ACCEPTED MANUSCRIPT
TABLE 3. Efficacy Data for Rare Mutations in Exon 20 of EGFR
Tx
Smoking
First Trial
Sex
Race
PS
Line
Status
Medication
TITAN
54
Male
Asian
1
2
Current
Docetaxel
TITAN
56
Male
Asian
1
2
Never
SATURN
64
Female
Caucasian
1
1
Former
SATURN
53
Female
Caucasian
1
1
Never
SATURN
51
Female
Caucasian
1
1
TRUST
67
Male
Caucasian
2
2
TRUST
60
Male
Caucasian
2
TRUST
67
Female
Caucasian
1
TRUST
70
Male
Caucasian
TRUST
62
Female
Asian
Actual Mutation Exon 20
or Censored (C) at Database
PFS, Response
days
OS, days
Closure
P.A767_S768INSSVSS
PD
17
64
D
Docetaxel
P.M766_A767INSASV
SD
81
115
D
Erlotinib
P.T790M
PD
47
134
C
Erlotinib
P.D770_N771INSSVD
SD
84
599
C
TE D
M AN U
years
Erlotinib
P.D770_N771INSSVD
PR
128
881
C
Never
Erlotinib
P.ALA767_VAL769DUP
SD
71
155
D
EP
Never
2
Never
Erlotinib
P.A763_Y764INSFQEA
PR
532
731
D
2
Never
Erlotinib
P.T790Ma
SD
463
488
D
1
2
Never
Erlotinib
P.H773_V774INSAH
PD
53
390
D
1
2
Never
Erlotinib
P.S768I; P.V774M
SD
166
1106
C
AC C
Protocol
ECOG
SC
Age,
RI PT
Death (D)
27
ACCEPTED MANUSCRIPT
85
Female
Caucasian
1
2
Never
Erlotinib
P.V769_D770INSASV
NE
642
642
D
TRUST
38
Male
Asian
2
2
Never
Erlotinib
P.T790Ma
SD
491
873
D
FASTACT-2
61
Female
Asian
0
1
Never
Carboplatin/
P.S768Ia
SD
225
1084b
D
P.S768I
PR
371
1909b
C
P.S768I
SD
169
939
D
Bevacizumab
P.A763Vb
CR
689
827
D
Bevacizumab +
P. P772S
NE
75
75
C
P.D746Ab
PR
424
435
D
P.V774M
PD
36
82
C
P.K860E
PD
39
127
D
gemcitabine FASTACT-2
62
Male
Asian
0
1
Never
Carboplatin/
erlotinib 56
Female
Asian
1
1
Never
Carboplatin/
M AN U
FASTACT-2
SC
gemcitabine plus
RI PT
TRUST
gemcitabine
ATLAS
57
Male
Caucasian
1
1
Former
ATLAS
71
Male
Caucasian
1
1
Former
ATLAS
33
Female
Black
1
1
TE D
erlotinib
Never
Bevacizumab + erlotinib
61
Male
Male
Asian
Caucasian
BETA
67
Female
Caucasian
BETA
70
Male
Caucasian
1
1
1
Current
EP
BETA
58
2/3
AC C
ATLAS
Former
Bevacizumab + erlotinib
Erlotinib + bevacizumab
1
2/3
Never
Erlotinib + placebo
INS
PD
42
354
D
1
2/3
Former
Erlotinib + placebo
T790M
PR
296
498
D
28
ACCEPTED MANUSCRIPT
69
Male
Caucasian
0
2/3
Never
Erlotinib + placebo
T790Mc
PD
40
665
C
BETA
60
Female
Caucasian
1
2/3
Former
Erlotinib + placebo
T790Mb
NE
27
27
D
BETA
50
Female
Caucasian
1
2/3
Former
Erlotinib +
S768I; V769L
PR
83
125
D
Exon 18 mutation in addition.
b
Exon 19 deletion in addition.
c
Exon 21 mutation in addition.
M AN U
a
SC
bevacizumab
RI PT
BETA
CR, complete response; ECOG PS, Eastern Cooperative Oncology Group performance status; NE, non-evaluable; OS, overall survival; PFS, progression-free survival; PR,
AC C
EP
TE D
partial response; PD, progressive disease; SD, stable disease; Tx, treatment.
29
ACCEPTED MANUSCRIPT
TABLE 4. Efficacy Data for Rare Mutations in Exon 21 of EGFR
ECOG
Tx
Smoking
First Trial
Sex
Race
PS
Line
Status
Medication
TITAN
60
Male
Asian
1
2
Never
Erlotinib
TITAN
51
Male
Caucasian
1
2
Current
TITAN
64
Male
Caucasian
0
2
Current
SATURN
47
Female
Caucasian
0
1
Current
SATURN
63
Male
Caucasian
0
1
TRUST
42
Female
Caucasian
2
2
TRUST
56
Male
Caucasian
2
FASTACT-2
48
Female
Asian
1
63
Female
Caucasian
ATLAS
62
Female
Caucasian
or Censored (C) at Database
PFS, Response
days
OS, days
Closure
P.L861Q
PD
18
18
D
Pemetrexed
P.P848L
PD
50
173
D
Docetaxel
P.L833Fa
PD
25
25
C
Erlotinib
P.P848L
SD
78
655
C
TE D
Placebo
P.H835L; P.L833V
SD
85
308
D
Current
Erlotinib
P.D837N
SD
52
52
D
EP
Former
2
Current
Erlotinib
P.K860N
SD
354
354
D
1
Never
Carboplatin/
P.L861Q
PR
141
175
D
AC C
ATLAS
Actual Mutation Exon 21
M AN U
years
Protocol
SC
Age,
RI PT
Death (D)
gemcitabine
1
1
Former
Bevacizumab
P.L858Q; P.V834A
PD
36
137
C
1
1
Current
Bevacizumab +
P.R841G; P.A859V
PD
39
52
C
30
ACCEPTED MANUSCRIPT
erlotinib 78
Male
Caucasian
1
1
Former
Bevacizumab + erlotinib
ATLAS
52
Female
Caucasian
1
1
Current
Bevacizumab + erlotinib
53
Female
Caucasian
0
1
Former
Bevacizumab + erlotinib
69
Female
Caucasian
1
1
Former
85
691
D
P.L858Rb
SD
126
728
D
P.L858R; L861P
PD
212
348
C
Bevacizumab +
PR
85
407
C
P.A840V; P.A859T
M AN U
ATLAS
SD
SC
ATLAS
P.H870Y
RI PT
ATLAS
erlotinib
ATLAS
23
Male
Caucasian
0
1
Never
ATLAS
72
Female
Caucasian
1
1
Current
Bevacizumab
P.G836S
PD
46
763
D
Bevacizumab +
P.G836S
PR
429
642
D
P.A871V
SD
125
313
D
erlotinib
88
Male
Caucasian
0
1
Former
Bevacizumab +
TE D
ATLAS
erlotinib
Former
Bevacizumab
P.V843Ib
SD
127
511
D
1
Former
Bevacizumab
P.Q849S
NE
78
184
C
1
Current
Bevacizumab
P.G824D; P.V851A
PD
78
293
C
Former
Erlotinib +
Y827C; V845M; H870Yc
NE
85
282
D
P.H835R
PR
417
460
C
43
Female
Caucasian
1
1
ATLAS
70
Male
Caucasian
1
ATLAS
71
Female
Black
0
BETA
58
Male
Caucasian
61
Female
Hispanic
AC C
BETA
EP
ATLAS
1
1
2/3
2/3
bevacizumab Never
Erlotinib + placebo
31
69
Male
Caucasian
0
2/3
Never
Erlotinib + placebo
P.L858Rb
PD
40
665
C
BETA
69
Male
Caucasian
1
2/3
Current
Erlotinib + placebo
P.R831C; P.T854Id
SD
116
116
D
BETA
64
Female
Caucasian
0
2/3
Former
Erlotinib +
P.G874Se
SD
423
444
C
P.L861Q
SD
234
339
C
PD
39
104
D
RI PT
BETA
SC
ACCEPTED MANUSCRIPT
bevacizumab BETA
72
Male
Caucasian
1
2/3
Former
Erlotinib + bevacizumab
47
Female
Black
1
2/3
Former
BETA
67
Female
Caucasian
1
2/3
Former
BETA
64
Female
Caucasian
0
2/3
Former
Erlotinib + placebo
P.T854I
M AN U
BETA
Erlotinib + placebo
P.V851Af
SD
215
329
C
Erlotinib +
P.L838V; P.L858R
SD
211
430
C
P.A859T
NE
36
687
C
P.D855V
SD
173
259
C
bevacizumab
BETA
78
Female
Caucasian
0
2/3
Former
Erlotinib +
BETA
53
Female
Caucasian
0
2/3
TE D
bevacizumab
Former
Erlotinib +
Exon 18 mutation in addition.
b
Exon 20 T790M mutation in addition.
c
Exon 19 K745E in addition.
d
Exon 19 deletion in addition.
e
Exon 18 I706T mutation in addition.
f
Exon 19 A755T mutation in addition.
AC C
a
EP
bevacizumab
32
ACCEPTED MANUSCRIPT
ECOG PS, Eastern Cooperative Oncology Group performance status; NE, non-evaluable; OS, overall survival; PFS, progression-free survival; PR, partial response; PD,
AC C
EP
TE D
M AN U
SC
RI PT
progressive disease; SD, stable disease; Tx, treatment.
33
ACCEPTED MANUSCRIPT
ITT population
Erlotinib: 36.3 weeks
Erlotinib: 19.3 months
Control: 43.0 weeks
Control: Not reached
Erlotinib: 12.0 months
Erlotinib: 44.6 weeks
Erlotinib: Not reached
Control: 11.1weeks
Control: 11.0 months
Control: 13.0 weeks
Control: 23.8 months
MERIT9
Erlotinib: 11.3 weeks
Erlotinib: 7.6 months
Erlotinib: NA
Erlotinib: NA
TRUST10,12
Erlotinib: 3.2 months
Erlotinib: 13.5
Erlotinib: 23.5 months
Erlotinib: 5.3 months
Control: 8.6 weeks
Control: 5.5 months
Erlotinib: 12.3 weeks
Erlotinib: 7.6 months
M AN U
TE D
FASTACT-215
Erlotinib: 6.3 weeks
SC
OS
SATURN2,14
OS
EGFR mutation-positive subgroup PFS
TITAN13
PFS
EP
Study
RI PT
Supplementary Table 1. Efficacy outcomes in ITT and classical EGFR mutation populations of TITAN, SATURN, MERIT, TRUST, FASTACT2, ATLAS and BeTa.
ATLAS17
AC C
Control: 6.0 months
Erlotinib: 7.9 months
Erlotinib: 18.3 months Control: 15.2 months
months Erlotinib: 16.8 months
Erlotinib: 31.4 months Control: 20.6 months
Control: 6.9 months
Erlotinib: 4.8 months
Erlotinib: 14.4 months
Erlotinib: 7.2 months
Erlotinib: 14.5 months
Control:3.7 months
Control: 13.3 months
Control: 2.8 months
Control: 14.3 months 34
ACCEPTED MANUSCRIPT
Erlotinib: 3.4 months
Erlotinib: 9.3 months
Erlotinib: NA
Erlotinib: Not reached
Control: 1.7 months
Control: 9.2 months
Control: NA
Control: 20.2 months
RI PT
BeTa16
AC C
EP
TE D
M AN U
SC
NA, Not applicable
35