Osimertinib treatment for patients with EGFR exon 20 mutation positive non-small cell lung cancer

doi:10.1016/j.lungcan.2019.12.013

Lung Cancer

Volume 141, March 2020, Pages 9-13

https://doi.org/10.1016/j.lungcan.2019.12.013 Get rights and content

Highlights

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Limited antitumor activity of osimertinib in EGFR exon 20 mutated lung cancer.
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Objective response rate was 5 %.
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Median progression free survival was 3.6 months.
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A subgroup derived durable disease stabilization of five months and beyond.

Abstract

Objectives

Epidermal growth factor receptor (EGFR) exon 20 insertions comprise 4–10 % of EGFR mutations in non-small cell lung cancer (NSCLC) and are associated with primary resistance to first and second generation EGFR tyrosine kinase inhibitors (TKIs). In vitro and preclinical animal studies have shown that osimertinib exerts antitumor activity against EGFR exon 20 mutation positive NSCLC. We report on a cohort of advanced stage NSCLC patients who harbor an EGFR exon 20 mutation and received osimertinib treatment.

Material and methods

Twenty-one patients were treated with osimertinib 80 or 160 mg once daily from April 2016 to June 2018, in four institutions in the Netherlands. Data were obtained retrospectively. Progression free survival (PFS), disease control rate (DCR), overall survival (OS) and objective response rate (ORR) were assessed using RECIST v1.1.

Results

Thirteen patients received prior platinum-based chemotherapy, and three patients a first – or second generation EGFR TKI. We observed 1 partial response, 17 patients with stable disease and 3 with progressive disease as best response to osimertinib (ORR 5 %). Median PFS was 3.6 (95 % CI, 2.6–4.5) months. PFS did not differ for patients with co-occurring TP53 mutations (p = 0.937). The DCR at three months was 71 %. Median OS was 8.7 (95 % CI, 1.1–16.4) months.

Conclusion

Osimertinib has limited antitumor activity in patients with EGFR exon 20 mutated NSCLC, with an ORR of 5 %.

Introduction

Epidermal growth factor receptor (EGFR) exon 20 insertion mutations are identified as a subset (4–12 %) of EGFR mutation-positive non-small cell lung cancer (NSCLC) and are the third most common category of EGFR activating mutations [[1], [2], [3]]. EGFR exon 20 insertion mutations are heterogeneous at the molecular level but can be characterized as in-frame duplications (dup) or insertions (ins), or deletion/insertion (delins) mutations. EGFR exon 20 insertions are EGFR driver mutations that exhibit intrinsic resistance to first and second generation EGFR tyrosine kinase inhibitors (TKIs) with overall response rates of only 3–8 % [1,3]. In contrast to the common EGFR exon-19 deletion and L858R point mutations, EGFR exon 20 insertion mutations alter the α-C helix resulting in steric hindrance of the drug-binding pocket, that prevents binding of first and second generation EGFR TKIs [3,4]. Given the limited activity of first and second generation EGFR TKIs, new treatment options are needed to overcome primary resistance of EGFR directed treatment for tumors harboring an EGFR exon 20 insertion. Data about effectiveness of third generation EGFR TKIs are conflicting in pre-clinical studies. In vivo, in vitro and 3D modeling by Robichaux et al. showed that osimertinib lacks activity against cell lines harboring an EGFR exon 20 insertion, due to steric hindrance as a result of significant changes within the drug-binding pocket [4]. In contrast, a study by Floc’h et al. described anti-tumor activity of osimertinib across xenograft models, representing a variety of EGFR exon 20 insertions [5], in line with a previous report presenting in vitro activity of osimertinib in exon 20 insertion mutant cell lines [6]. Limited clinical data are available. Two cases with a clinical response to osimertinib have been published [7,8]. Recently, Fang et al. treated six Chinese patients with an EGFR exon 20 insertion mutation with osimertinib. This resulted in a median progression free survival (PFS) of 6.2 months [9]. Here, we report on a cohort of advanced stage EGFR exon 20 mutation positive NSCLC patients that were treated with osimertinib.

Section snippets

Material and methods

Twenty-one patients with advanced stage NSCLC harboring an EGFR exon 20 mutation were treated with osimertinib in four institutions in the Netherlands (Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, University Medical Center Groningen, Amsterdam UMC and Erasmus Medical Center). Data were obtained retrospectively. We started a search by identifying all patients treated with osimertinib from April 2016 to June 2018 in the four institutions. Then we selected the patients with an EGFR

Patient and tumor characteristics

Patient and tumor characteristics are summarized in Table 1. Median age was 63 years (range 38–82), 67 % of patients were female and median number of prior systemic treatments was 1 (range 0–3). Thirteen patients (62 %) received prior platinum-based chemotherapy. Three patients were treated with a first or second generation EGFR TKI, erlotinib (n = 1) or afatinib (n = 2); one patient experienced stable disease (SD) for 11 months after having received afatinib, while the other two patients had

Discussion

EGFR exon 20 insertions represent a heterogeneous group of genomic aberrations with an unmet clinical need in precision oncology. EGFR exon 20 insertions after residue 764 are resistant to first and second generation EGFR TKIs [1]. Data about effectiveness of third generation EGFR TKIs are limited. Our series describes the results of osimertinib treatment, a third generation EGFR TKI, in 21 patients with advanced stage NSCLC harboring an EGFR exon 20 mutation. Despite the low response rate of 5

Conclusion

In conclusion, our study shows that osimertinib 80 mg once daily has limited antitumor activity in patients with EGFR exon 20 mutated NSCLC, with an ORR of 5 %.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CRediT authorship contribution statement

B. van Veggel: Conceptualization, Data curation, Formal analysis, Writing - original draft, Methodology. J.F. Vilacha Madeira R Santos: Writing - review & editing. S.M.S. Hashemi: Data curation, Writing - review & editing. M.S. Paats: Data curation, Writing - review & editing. K. Monkhorst: Writing - review & editing. D.A.M. Heideman: Data curation, Writing - review & editing. M. Groves: Writing - review & editing. T. Radonic: Writing - review & editing. E.F. Smit: Conceptualization,

Declaration of Competing Interest

Dr. de Langen reports grants from Boehringer, grants from AstraZeneca, non-financial support from Roche, grants and personal fees from Merck / MSD, grants and personal fees from BMS, outside the submitted work.

Dr. Heideman is minority shareholder of Self-screen B.V., a spin-off company of VU University Medical Center (currently known as Amsterdam UMC, Vrije Universiteit Amsterdam). She has been on the speakers bureau of QIAGEN and serves occasionally on the scientific advisory boards of Pfizer

Acknowledgements

None.

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The purpose of the manuscript is to provide a comprehensive overview of literature about molecular resistance mechanisms to first-line osimertinib, from a clinical perspective and therefore in relationship to emerging therapeutic approaches.
Advances in the Diagnosis and Treatment of Advanced Non–Small-Cell Lung Cancer With EGFR Exon 20 Insertion Mutation
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The discovery of epidermal growth factor receptor (EGFR) mutations has greatly changed the clinical outlook for patients with advanced non–small-cell lung cancer (NSCLC). Unlike the most common EGFR mutations, such as exon 19 deletion (del19) and exon 21 L858R point mutation, EGFR exon 20 insertion mutation (EGFR ex20ins) is a rare mutation of EGFR. Due to its structural specificity, it exhibits primary resistance to traditional epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), leading to poor overall survival prognosis for patients. In recent years, there has been continuous progress in the development of new drugs targeting EGFR ex20ins, bringing new hope for the treatment of this patient population. In this regard, we conducted a systematic review of the molecular characteristics, diagnostic advances, and treatment status of EGFR ex20ins. We summarized the latest data on relevant drug development and clinical research, aiming to provide reference for clinical diagnosis, treatment, and drug development.
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This study describes treatment patterns and outcomes in patients with NSCLC with EGFR exon 20 insertions (EGFRex20ins) in the United States.
The Flatiron Health electronic health record database was used to select three cohorts among patients diagnosed with NSCLC with EGFRex20ins (January 1, 2011–February 29, 2020): (1) first-line (1L) or patients receiving 1L therapy after documented EGFRex20ins; (2) second or later-line (≥2L) or patients receiving ≥2L therapy after documented EGFRex20ins; and (3) ≥2L postplatinum trial-aligned, or ≥2L patients previously treated with platinum chemotherapy whose baseline characteristics aligned with key eligibility criteria (initiating new treatment after documented EGFRex20ins and ≥1 previous treatment excluding mobocertinib or amivantamab) of the mobocertinib trial NCT02716116. Real-world end points were confirmed overall response rate, overall survival, and progression-free survival.
Of 237 patients with EGFRex20ins-mutated NSCLC, 129 and 114 patients were included in the 1L and ≥2L cohorts, respectively. In 1L patients, platinum chemotherapy plus nonplatinum chemotherapy (31.0%) and EGFR tyrosine kinase inhibitors (28.7%) were the most common regimens. In ≥2L patients, immuno-oncology monotherapy (28.1%) and EGFR tyrosine kinase inhibitors (17.5%) were the most common index treatments. For any 1L, ≥2L, and ≥2L postplatinum trial-aligned patients, the confirmed overall response rate was 18.6%, 9.6%, and 14.0%, respectively; the median overall survival was 17.0, 13.6, and 11.5 months; the median progression-free survival was 5.2, 3.7, and 3.3 months, respectively.
The outcomes for patients with NSCLC with EGFRex20ins were poor. This real-world study provides a benchmark on treatment outcomes in this patient population and highlights the unmet need for improved therapeutic options.
Osimertinib in NSCLC With Atypical EGFR-Activating Mutations: A Retrospective Multicenter Study
2023, JTO Clinical and Research Reports
EGFR mutations drive a subset of NSCLC. Patients harboring the common EGFR mutations, deletion of exon 19 and L858R, respond well to osimertinib, a third-generation tyrosine kinase inhibitor. Nevertheless, the effect of osimertinib on NSCLC with atypical EGFR mutations is not well described. This multicenter retrospective study evaluates the efficacy of osimertinib among patients with NSCLC harboring atypical EGFR mutations.
Patients with metastatic NSCLC treated with osimertinib, harboring at least one atypical EGFR mutation, excluding concurrent deletion of exon 19, L858R, or T790M mutations, from six U.S. academic cancer centers were included. Baseline clinical characteristics were collected. The primary end point was the time to treatment discontinuation (TTD) of osimertinib. Objective response rate by the Response Evaluation Criteria in Solid Tumors version 1.1 was also assessed.
A total of 50 patients with NSCLC with uncommon EGFR mutations were identified. The most frequent EGFR mutations were L861Q (40%, n = 18), G719X (28%, n = 14), and exon 20 insertion (14%, n = 7). The median TTD of osimertinib was 9.7 months (95% confidence interval [CI]: 6.5–12.9 mo) overall and 10.7 months (95% CI: 3.2–18.1 mo) in the first-line setting (n = 20). The objective response rate was 31.7% (95% CI: 18.1%–48.1%) overall and 41.2% (95% CI: 18.4%–67.1%) in the first-line setting. The median TTD varied among patients with L861Q (17.2 mo), G719X (7.8 mo), and exon 20 insertion (1.5 mo) mutations.
Osimertinib has activity in patients with NSCLC harboring atypical EGFR mutations. Osimertinib activity differs by the type of atypical EGFR-activating mutation.
Molecular Epidemiology and Treatment Patterns of Patients With EGFR Exon 20-Mutant NSCLC in the Precision Oncology Era: The European EXOTIC Registry
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Real-world evidence regarding molecular epidemiology and management patterns of patients with EGFR exon-20 mutated, advanced NSCLC outside the context of clinical trials is lacking.
We created a European registry for patients with advanced EGFR exon 20-mutant NSCLC diagnosed from January 2019 to December 2021. Patients enrolled in clinical trials were excluded. Clinicopathologic and molecular epidemiology data were collected, and treatment patterns were recorded. Clinical end points according to treatment assignment were assessed using Kaplan-Meier curves and Cox regression models.
Data on 175 patients from 33 centers across nine countries were included in the final analysis. Median age was 64.0 (range: 29.7–87.8) years. Main features included female sex (56.3%), never or past smokers (76.0%), adenocarcinoma (95.4%), and tropism for bone (47.4%) and brain (32.0%) metastases. Mean programmed death-ligand 1 tumor proportional score was 15.8% (range: 0%–95%) and mean tumor mutational burden was 7.06 (range: 0–18.8) mutations per megabase. Exon 20 was detected in the tissue (90.7%), plasma (8.7%), or both (0.6%), using mostly targeted next-generation sequencing (64.0%) or polymerase chain reaction (26.0%). Mutations were mainly insertions (59.3%), followed by duplications (28.1%), deletions-insertions (7.7%), and the T790M (4.5%). Insertions and duplications were located mainly in the near loop (codons 767–771, 83.1%) and the far loop (codons 771–775, 13%) and only in 3.9% within the C helix (codons 761–766). Main co-alterations included mutations in TP53 (61.8%) and MET amplifications (9.4%). Treatment on mutation identification included chemotherapy (CT) (33.8%), CT-immunotherapy (IO) (18.2%), osimertinib (22.1%), poziotinib (9.1%), mobocertinib (6.5%), mono-IO (3.9%), and amivantamab (1.3%). Disease control rates were 66.2% with CT plus or minus IO, 55.8% with osimertinib, 64.8% with poziotinib, and 76.9% with mobocertinib. Corresponding median overall survival was 19.7, 15.9, 9.2, and 22.4 months, respectively. In multivariate analysis, type of treatment (new targeted agents versus CT ± IO) affected progression-free survival (p = 0.051) and overall survival (p = 0.03).
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^☆: Presented in part at WCLC, September 23–26, 2018 in Toronto and ESMO, October 19–23, 2018 in Munich.

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Osimertinib treatment for patients with EGFR exon 20 mutation positive non-small cell lung cancer☆

Highlights

Abstract

Objectives

Material and methods

Results

Conclusion

Introduction

Section snippets

Material and methods

Patient and tumor characteristics

Discussion

Conclusion

Funding

CRediT authorship contribution statement

Declaration of Competing Interest

Acknowledgements

J. Thorac. Oncol.

J. Thorac. Oncol.

J. Thorac. Oncol.

J. Thorac. Oncol.

EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications

Lancet Oncol.

Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer

Sci. Transl. Med.

Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer

Nat. Med.