Comparative Clinical Outcomes for Patients With Advanced NSCLC Harboring EGFR Exon 20 Insertion Mutations and Common EGFR Mutations

Abstract Background: Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for 4%–10% of all EGFR mutations in patients with non-small cell lung cancer (NSCLC). However, data on the differences in clinical characteristics between patients with EGFR exon 20 insertion mutations and major mutations (exon 19 deletion and L858R) are limited. Methods: We retrospectively reviewed advanced NSCLC patients with EGFR mutations, including EGFR exon 20 insertions and major mutations, who were treated with systemic therapy between January 2011 and December 2019.Results: We identified 23 patients with EGFR exon 20 insertions and 534 patients with EGFR mutations. Among patients with exon 20 insertion, the median age was 60 years (range: 27–88 years), and females and never smokers were predominant. The clinical characteristics of patients with exon 20 insertions were similar to those with major EGFR mutations. Regarding the clinical outcomes in patients with exon 20 insertions, 17 patients received platinum doublet as first-line therapy, and the overall response rate (ORR) and median progression-free survival (mPFS) were 11.8% and 8.9%. Additionally, eight patients received anti-PD-1 antibodies and seven patients received EGFR-tyrosine kinase inhibitors (TKIs) in any-line therapy, and their ORR and mPFS were 0%, 25% and 2.2, 3.1 months, respectively. Overall survival was significantly shorter in patients with exon 20 insertions than in those with EGFR major mutations (29.3 vs. 43.4 months, p=0.04). Conclusions: The clinical outcomes in patients with exon 20 insertions were not satisfactory compared to those in patients with major EGFR mutations.

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Real-world response and outcomes in NSCLC patients with EGFR exon 20 insertion mutations.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.9098 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 9098-9098

Author(s):

Sai-Hong Ignatius Ou ◽

Huamao Mark Lin ◽

Jin-Liern Hong ◽

Yu Yin ◽

Shu Jin ◽

...

Keyword(s):

Treatment Outcome ◽

Real World ◽

Index Date ◽

Advanced Nsclc ◽

Eligibility Criteria ◽

Start Date ◽

Platinum Based Chemotherapy ◽

Exon 20 ◽

Egfr Tki ◽

Insertion Mutations

9098 Background: There is currently no targeted therapy approved for patients with EGFR exon 20 insertion mutations (exon20ins) in NSCLC. Real world treatment outcome evidence for this rare population is limited. This study describes treatment patterns and outcomes in US patients with advanced NSCLC with EGFR exon20ins. Methods: The nationwide Flatiron Health electronic health record-derived deidentified database (cut-off 29 Feb 2020) was used to select 4 separate cohorts: (1) first-line (1L): patients receiving 1L therapy after documented exon20ins (1L start date as index date); (2) second or later line (≥2L): patients receiving ≥2L therapy after documented exon20ins (start date of ≥2L as index date); (3) ≥2L trial-aligned: ≥2L patients with baseline characteristics aligned with the key eligibility criteria of mobocertinib Trial NCT02716116 Part 3; and (4) ≥2L post platinum: ≥2L trial-aligned patients previously treated with platinum-based chemotherapy. Real-world endpoints were: confirmed overall response rate (cORR), PFS, and OS. Additional analyses were conducted for patients treated with immune-oncology therapy (IO). Results: Of 237 EGFR exon20ins patients, 129 patients were included in 1L cohort and 114 were in ≥2L cohort, including 63 ≥2L trial-aligned and 50 ≥2L post platinum patients. In 1L patients, EGFR TKI (28.7%) and platinum-based chemotherapy ± IO (56.6%) were the most common 1L regimens. In ≥2L patients, 28.1% received IO monotherapy, 17.5% received EGFR TKI, and 23.7% received platinum-based chemotherapy ± IO as index treatment. In the 1L setting, median PFS (mPFS) was 5.7 months for platinum-based chemotherapy and 4.5 months for IO + platinum-based chemotherapy. In the ≥2L setting, mPFS was 3.7 months for any therapy and 2.3 months for IO monotherapy. Full effectiveness data are provided in the accompanying table. Conclusions: This real world study provided a benchmark on the treatment outcome in patients with advanced NSCLC with EGFR exon20ins. Platinum-based chemotherapy was the most common 1L therapy and provided the longest mPFS. Immunotherapy, either as monotherapy or in combination with chemotherapy, appeared less effective for treatment of NSCLC with EGFR exon20ins. There is an unmet medical need for improved therapeutic options.[Table: see text]

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EGFR exon 20 insertion mutations: Incidence and clinicopathologic characteristics in U.S. patients with lung adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.10560 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 10560-10560

Author(s):

Maria E. Arcila ◽

Khedoudja Nafa ◽

Jamie E. Chaft ◽

Natasha Rekhtman ◽

Maureen Frances Zakowski ◽

...

Keyword(s):

Point Mutations ◽

Genetic Alterations ◽

Egfr Mutations ◽

Small Subset ◽

Clinicopathologic Characteristics ◽

Primary Resistance ◽

Recurrent Point ◽

Exon 2 ◽

Exon 20 ◽

Insertion Mutations

10560 Background: Activating insertion mutations in exon 20 of EGFR are reported in a small subset of lung adenocarcinomas (ADC). In contrast to the classic EGFR mutations, they appear to confer primary resistance to currently approved EGFR tyrosine kinase inhibitors. Their incidence and clinicopathologic features are not well established. Methods: Lung ADCs (n=1500) were screened for major activating mutations in EGFR (exons 19 and 21) and KRAS (exon 2). Negative cases were tested for EGFR exon 20 insertions by a PCR-based sizing assay. Extended testing for additional recurrent point mutations in EGFR, KRAS, BRAF, NRAS, PIK3CA, MEK1 and AKT was performed in all cases by Sequenom mass spectrometry. A subset of cases was also tested for ALK rearrangements by FISH. Results: We identified 32cases withEGFRexon 20 insertions, accounting for 11% of all EGFR mutations. EGFRexon 20 insertions were mutually exclusive with the other genetic alterations tested except for PIK3CA mutations. The incidence was higher among never-smokers (p<0.0001) but there was no association with sex, ethnic origin or stage at diagnosis. Insertions were 3, 6, 9 or 12bp; 9bp insertions were most common (50%, 16/32). Morphologically, 90% of tumors were moderate to poorly differentiated with a predominant mixed ADC phenotype. Conclusions: EGFR exon 20 testing may identify a unique subset of EGFR mutant lung ADCs which is significantly larger than previously reported, making this the third most common type of EGFR mutation after exon 19 deletions and L858R. This population could potentially benefit from alternate targeted therapies, many of which are currently in clinical development.

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Clinical outcomes of EGFR exon 20 insertion in advanced NSCLC in Korea.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.e21136 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. e21136-e21136

Author(s):

Seonggyu Byeon ◽

Youjin Kim ◽

Jiyun Lee ◽

Jong-Mu Sun ◽

Yoon-La Choi ◽

...

Keyword(s):

Clinical Outcomes ◽

Advanced Nsclc ◽

Exon 20

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Clinical Outcomes of EGFR Exon 20 Insertion Mutations in Advanced Non-small Cell Lung Cancer in Korea

Cancer Research and Treatment ◽

10.4143/crt.2018.151 ◽

2019 ◽

Vol 51 (2) ◽

pp. 623-631 ◽

Cited By ~ 8

Author(s):

Seonggyu Byeon ◽

Youjin Kim ◽

Sung Won Lim ◽

Jang Ho Cho ◽

Sehoon Park ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Clinical Outcomes ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

Exon 20 ◽

Insertion Mutations

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HSR19-082: Epidemiological Findings and Outcomes in Non-Small Cell Lung Cancer Patients with Exon 20 Insertion Mutations: A Meta-Analysis

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2018.7199 ◽

2019 ◽

Vol 17 (3.5) ◽

pp. HSR19-082

Author(s):

Victoria Crossland ◽

Aaron Galaznik ◽

Huamao M. Lin ◽

Dimitrios Tomaras ◽

Shan Ashton Garib ◽

...

Keyword(s):

Lung Cancer ◽

Egfr Mutation ◽

Meta Analysis ◽

Small Cell ◽

Egfr Mutations ◽

Small Cell Lung ◽

Exon 20 ◽

Meta Analyses ◽

Nsclc Patients ◽

Insertion Mutations

Background: Epidermal growth factor receptor (EGFR) mutations are frequently found in non-small cell lung cancer (NSCLC) patients. Various EGFR mutations respond differently to EGFR tyrosine kinase inhibitors (TKIs), and several TKIs have been approved for use on common mutations but none have been approved for EGFR exon 20 insertions, indicating a need for targeted therapy for this subpopulation. A systematic literature review (SLR) and meta-analysis were conducted to synthesize epidemiological and outcome data for the uncommon EGFR exon 20 insertion mutation. Methods: An SLR was performed on August 7, 2018 following the Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, using the Population, Intervention Comparators, Outcomes and Study Design (PICOS) criteria. Studies were identified based on a systematic search using key biomedical literature databases: EMBASE, MEDLINE, and Cochrane. Relevant congress abstracts published between 2015–2018 were also identified. Two independent reviewers screened all citations and full-text articles using PICOS-based criteria; any discrepancies were resolved by a third independent reviewer. Data were extracted into a predefined template for meta-analysis and summarized using the PRISMA flow diagram. Results: A total of 61 studies reporting the number of EGFR mutation−positive patients and/or NSCLC patients were identified. A meta-analysis found that 3.7% of EGFR mutation−positive patients and 0.8% of NSCLC patients harbored the EGFR exon 20 insertion, with geographic variations in epidemiology. There were 12, 10, and 12 studies, respectively, that reported overall survival, progression-free survival, and overall response rates in 2 cohorts, patients with EGFR exon 20 insertions and patients without EGFR exon 20 mutations. A Most patient populations in these studies included a mixture of treatment at various lines. A meta-analysis of outcomes across these studies showed that patients with EGFR exon 20 insertions experienced worse outcomes compared with those without the mutation (Table 1). Meta-analyses were weighted based on each study’s relevant population. No economic or quality of life studies were identified. Conclusions: Exon 20 insertion mutations represent an important subgroup of EGFR mutations in patients with NSCLC, and current therapies have limited efficacy. These relatively poor outcomes indicate a need for novel treatment strategies.

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Sensitivity to EGFR inhibitors based on location of EGFR exon 20 insertion mutations within the tyrosine kinase domain of EGFR.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.7523 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 7523-7523 ◽

Cited By ~ 1

Author(s):

Daniel Botelho Costa ◽

Hiroyuki Yasuda ◽

Natasha J Sng ◽

Wee-Lee Yeo ◽

Lorena Lobo de Figueiredo-Pontes ◽

...

Keyword(s):

Tyrosine Kinase ◽

Cell Line ◽

Molecular Mechanisms ◽

Site Directed Mutagenesis ◽

Egfr Mutations ◽

Tyrosine Kinase Domain ◽

Exon 20 ◽

Insertion Mutations ◽

Egfr Tkis

7523 Background: Epidermal growth factor receptor (EGFR) mutations (M) define an important subgroup of non-small-cell lung cancer (NSCLC). Most patients whose tumors harbor exon 19 deletions or L858R EGFR M have responses to reversible ATP-mimetic EGFR tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib. Exon 20 insertion M comprise ~5% of EGFR M, occur at the N-lobe of EGFR after its C-helix (AA M766), and nearly all NSCLCs with EGFR exon 20 insertion M display lack of responses to EGFR TKIs (Yasuda H. Lancet Oncol 2011). Methods: We have 1) compiled genotype-clinical outcomes of EGFR exon 20 insertion M NSCLCs to EGFR TKIs, 2) generated a comprehensive panel of exon 20 EGFR M constructs using site-directed mutagenesis and introduced them into Ba/F3 cells for in vitro analysis, and 3) compared NSCLC cell lines with EGFR M to a novel malignant pleural effusion-derived cell line. Results: The disease control rate of gefitinib or erlotinib was significantly higher in EGFR exon 20 insertion M located within the C-helix (3/3,100%) when compared to M following the C-helix (1/14, 7%; p=0.00059). The NSCLC with EGFR-A763_Y764insFQEA (located within the C-helix of EGFR) achieved a partial response to erlotinib that lasted 18 months. Most other exon 20 insertion M-positive NSCLCs did not respond (p=0.07). Eight representative exon 20 insertion M were studied (including EGFR-A763_Y764insFQEA, Y764_S765insHH, A767_V769dupASV, D770_N771insNPG, H773_V774insH). All, but A763_Y764insFQEA, were resistant to micromolar concentrations (C) of EGFR TKIs. Ba/F3 cells with EGFR-A763_Y764insFQEA underwent apoptosis upon exposure to nanomolar C of erlotinib. A patient-derived cell line with EGFR-A763_Y764insFQEA had phosphorylated EGFR, ERK and AKT inhibited by nanomolar C of erlotinib. Conclusions: Not all EGFR exon 20 insertion mutations are resistant to EGFR TKIs, and in specific EGFR-A763_Y764insFQEA is an EGFR TKI-sensitive M. This finding has clinical implications for the care of the 10,000 cases of EGFR exon 20 insertion M NSCLC diagnosed yearly and points towards the need to define the molecular mechanisms that underlie differential responses to EGFR TKIs.

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Frequency and clinical correlations of epidermal growth factor receptor (EGFR) mutations in a large cohort of Italian non-small cell lung cancer (NSCLC) patients (pts) within the EGFR FASTnet program.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e18021 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e18021-e18021

Author(s):

Nicola Normanno ◽

Carmine Pinto ◽

Gian Luigi Taddei ◽

Giancarlo Troncone ◽

Paolo Graziano ◽

...

Keyword(s):

Real Time ◽

Real Time Pcr ◽

Sanger Sequencing ◽

Advanced Nsclc ◽

Mutational Analysis ◽

Growth Factor Receptor ◽

Smoking History ◽

Egfr Mutations ◽

Medical Oncologists ◽

Exon 20

e18021 Background: Gefitinib was approved in Italy for treatment of pts with advanced NSCLC carrying mutant EGFR in May 2010. Methods: The EGFR FASTnet program was designed to facilitate the exchange of biological material, clinico-pathological data and reports between medical oncologists, primary pathologists and referral laboratories. EGFR mutational analysis was carried by Sanger sequencing, Real Time PCR, Pyrosequencing, Fragment Analysis and High resolution melting. The Italian Association of Medical Oncology (AIOM) and the Italian Society of Surgical Pathology and Cytopathology (SIAPEC-IAP) have full access to the anonymous EGFR FASTnet database. Results: As of December 31, 2011, 503 oncologists, 135 pathologists and 38 referral laboratories joined the EGFR FASTnet program. The enrolled cohort of 3819 pts with advanced NSCLC was significantly enriched for adenocarcinoma histology (3172 [83%]), female sex (1361 [36%]) and smoking history (never smoker 911 [24%], former smoker>15 yrs 880 [23%], light smoker 194 [5%]). Mutational analysis was feasible in 3567 pts (93%). At registration, 72% of the pts had not received yet treatment for advanced disease. Mutational analysis was carried by Sanger sequencing in 2021 cases (57%), Real Time PCR in 174 (5%), Pyrosequencing in 636 (18%) and other techniques in 736 (21%). EGFR mutations were found in 520 cases (14.6%): 334 in exon 19 (9.4%), 163 in exon 21 (4.6%), 7 in exon 18 (0.2%) and 16 in exon 20 (0.4%). Proportion of mutated cases was slightly higher with Real time PCR compared to other techniques: Sanger 14.8%, Real time PCR 21.3%, Pyrosequencing 13.5%, other 13.3% (p = 0.049). A higher mutation rate was found in never smokers (32.0%), light smokers (18.7%) and former smokers >15 yrs (12.4%), as well as in adenocarcinoma (15.7%) and females (25.2%). Conclusions: The pts for EGFR mutational screening are spontaneously selected by medical oncologists according to known predictive factors. The results of the mutational analysis from clinical practice in Italy are consistent with data from literature.

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EGFR-D770>GY and Other Rare EGFR Exon 20 Insertion Mutations with a G770 Equivalence Are Sensitive to Dacomitinib or Afatinib and Responsive to EGFR Exon 20 Insertion Mutant-Active Inhibitors in Preclinical Models and Clinical Scenarios

Cells ◽

10.3390/cells10123561 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3561

Author(s):

Ikei S. Kobayashi ◽

Hollis Viray ◽

Deepa Rangachari ◽

Susumu S. Kobayashi ◽

Daniel B. Costa

Keyword(s):

Clinical Care ◽

Growth Factor Receptor ◽

Egfr Mutations ◽

Insertion Mutant ◽

Preclinical Models ◽

2Nd Generation ◽

Clinical Scenarios ◽

Exon 20 ◽

Insertion Mutations ◽

Egfr Tkis

Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for a tenth of all EGFR mutations in lung cancers. An important unmet clinical need is the identification of EGFR exon 20 insertion mutants that can respond to multiple classes of approved EGFR-TKIs. We sought to characterize variants involving EGFR-D770 to EGFR-G770 position equivalence changes that structurally allow for response to irreversible 2nd generation EGFR-TKIs. Our group used preclinical models of EGFR exon 20 insertion mutations to probe representative 1st (erlotinib), 2nd (afatinib, dacomitinib), 3rd generation (osimertinib) and EGFR exon 20 insertion mutant-active (poziotinib, mobocertinib) TKIs; we also queried the available clinical literature plus our institutional database to enumerate clinical outcomes. EGFR-D770>GY and other EGFR insertions with a G770 equivalence were identified at a frequency of 3.96% in separate cohorts of EGFR exon 20 insertion mutated lung cancer (n = 429). Cells driven by EGFR-D770>GY were insensitive to erlotinib and osimertinib, displayed sensitivity to poziotinib and dacomitinib and were uniquely sensitive to afatinib and dacomitinib in comparison with other more typical EGFR exon 20 insertion mutations using proliferation and biochemical assays. Clinical cases with EGFR-G770 equivalence from the literature and our center mirrored the preclinical data, with radiographic responses and clinical benefits restricted to afatinib, dacomitinib, poziotinib and mobocertinib, but not to erlotinib or osimertinib. Although they are rare, at <4% of all exon 20 insertion mutations, EGFR-G770 equivalence exon 20 insertion mutations are sensitive to approved 2nd generation EGFR TKIs and EGFR exon 20 insertion mutant-active TKIs (mobocertinib and poziotinib). EGFR-D770>GY and other insertions with a G770 equivalence join EGFR-A763_Y764insFQEA as exon 20 insertion mutationsresponsive to approved EGFR TKIs beyond mobocertinib; this data should be considered for clinical care, genomic profiling reports and clinical trial elaboration.

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