Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: Clinical outcomes and response to erlotinib

Naidoo, Jarushka; Sima, Camelia S.; Rodriguez, Katherine; Busby, Natalie; Nafa, Khedoudja; Ladanyi, Marc; Riely, Gregory J.; Kris, Mark G.; Arcila, Maria E.; Yu, Helena A.

doi:10.1002/cncr.29493

Cited by 212Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchLung Cancer Diagnosis and Treatment

Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: Clinical outcomes and response to erlotinib

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Naidoo, Jarushka, Sima, Camelia S., Rodriguez, Katherine, Busby, Natalie, Nafa, Khedoudja, Ladanyi, Marc, Riely, Gregory J., Kris, Mark G. +2 more·2015·Cancer

DOI 10.1002/cncr.29493PMC PMC4807634

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Abstract

BACKGROUND: Epidermal growth factor receptor (EGFR) exon 20 insertions (exon20ins) represent approximately 10% of EGFR-mutant lung adenocarcinomas, and are associated with resistance to EGFR tyrosine kinase inhibitors (TKIs). Clinical outcomes in comparison with patients with sensitizing EGFR mutations are not well established. METHODS: Patients with stage IV lung adenocarcinomas with EGFR exon20ins were identified through routine molecular testing. Clinicopathologic data were collected. Overall survival (OS) was measured from the diagnosis of stage IV disease, and in patients treated with EGFR TKIs, the time to progression (TTP) on erlotinib was measured. RESULTS: One thousand eight hundred and eighty-two patients with stage IV lung adenocarcinomas were identified: 46 patients had EGFR exon20ins (2%), and 258 patients had an EGFR exon 19 deletion (exon19del)/L858R point mutation (14%). Among 11 patients with lung adenocarcinomas with EGFR exon20ins who received erlotinib, 3 patients (27%) had a partial response (FQEA, 1; ASV, 1; and unknown variant, 1). TTP for patients with EGFR exon20ins and patients with EGFR exon19del/L858R on erlotinib were 3 and 12 months, respectively (P < .01). Responses to chemotherapy were similar for patients with lung adenocarcinomas with EGFR exon20ins and patients with lung adenocarcinomas with EGFR exon19del/L858R. Median OS from the diagnosis of stage IV disease for patients with EGFR exon20ins and patients with EGFR exon19del/L858R was 26 months (95% confidence interval, 19 months-not reached n = 46) and 31 months (95% confidence interval, 28-33 months; n = 258), respectively (P = .53). CONCLUSIONS: The majority of patients with advanced lung adenocarcinomas harboring EGFR exon20ins do not respond to EGFR TKI therapy. Standard chemotherapy should be used as first-line therapy. These patients have an OS similar to that of patients with sensitizing EGFR mutations. Individuals with certain variants such as FQEA and ASV may respond to erlotinib.

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Available treatment outcomes demonstrated lack of response to first- and second-generation EGFR TKIs such as erlotinib, gefitinib, and afatinib, consistent with other series.
“Available treatment outcomes demonstrated lack of response to first- and second-generation EGFR TKIs such as erlotinib, gefitinib and afatinib, consistent with other series”
From Diverse EGFR Exon 20 Insertions and Co-Occurring Molecular Alterations Identified by Comprehensive Genomic Profiling of NSCLC (2018) · cites this paper as [19]
In a review of 84 patients with EGFR exon 20 insertions treated with gefitinib or erlotinib, the response rate was 11% and progression-free survival was 2.4 months.
“A review of 84 patients with exon 20 insertions across different series treated with either gefitinib or erlotinib demonstrated a RR of only 11% with a PFS of 2.4 months (12).”
From Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors (2017) · cites this paper as [12]
Most exon 20 insertion mutations, except the rare A763_Y764insFQEA, make tumors resistant to the standard first-line EGFR inhibitors erlotinib, gefitinib, and afatinib.
“EGFR Ex20Ins tumors are generally unresponsive to 1st and 2nd generation EGFR inhibitors”
From Antitumor Activity of Osimertinib, an Irreversible Mutant-Selective EGFR Tyrosine Kinase Inhibitor, in NSCLC Harboring EGFR Exon 20 Insertions (2018) · cites this paper as [6]
Patients with exon 20 insertions may experience a higher ORR (58-63%) and a longer PFS (six months) with platinum-doublet chemotherapy.
“These patients may experience a higher overall response rate (ORR) (58–63%) and a longer PFS (six months) with platinum-doublet chemotherapy, as reported in small retrospective studies [70,71].”
From Heterogeneous Responses to Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) in Patients with Uncommon EGFR Mutations: New Insights and Future Perspectives in this Complex Clinical Scenario (2019) · cites this paper as [70]
Patients harboring exon 20 insertions have an ORR of 0-11% and a median PFS of 2-3 months when treated with first- or second-generation EGFR TKIs.
“Patients harboring exon 20 insertions are associated with an ORR of 0–11% and a median progression-free survival (PFS) of 2–3 months when treated with first- or second-generation EGFR TKIs [19,21,37,44,45,70]”
From Heterogeneous Responses to Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) in Patients with Uncommon EGFR Mutations: New Insights and Future Perspectives in this Complex Clinical Scenario (2019) · cites this paper as [70]

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Authors: Naidoo, J., Sima, C. S., Rodriguez, K., Busby, N., Nafa, K., Ladanyi, M., Riely, G. J., Kris, M. G., Arcila, M. E., & Yu, H. A.
Affiliations: Memorial Sloan Kettering Cancer Center (US)
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine Memorial Sloan Kettering Cancer Center New York New York
Department of Pathology Memorial Sloan Kettering Cancer Center New York New York
Corresponding author: Naidoo, Jarushka
ORCID: Naidoo, Jarushka
Ladanyi, Marc
Riely, Gregory J.
Kris, Mark G.
Arcila, Maria E.
Yu, Helena A.
Venue: Cancer
Publisher: Wiley
Published: 2015-06-10
Volume: 121
Issue: 18
Pages: 3212-3220
ISSN: 0008-543X (ISSN-L)
1097-0142
DOI: 10.1002/cncr.29493
PMC: PMC4807634
OpenAlex: W1566300951
Cited by: 211
References: 37
Citations by year: 2026: 8 · 2025: 19 · 2024: 17 · 2023: 19 · 2022: 29 · 2021: 34 · 2020: 28 · 2019: 13 · 2018: 21 · 2017: 11 · 2016: 10 · 2015: 2
FWCI: 11.60
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Cancer (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Cancer Institute (P01CA129243, P30CA008748, T32CA009207, R25CA020449)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
Keywords: EGFR exon 20 insertion, lung adenocarcinoma, erlotinib, EGFR tyrosine kinase inhibitors, EGFR exon 19 deletion, L858R mutation, EGFR mutation, treatment resistance, overall survival, time to progression, first-line chemotherapy, advanced lung cancer, clinical outcomes, molecular testing, targeted therapy response
MeSH terms: Erlotinib Hydrochloride, Adenocarcinoma of Lung, Adenocarcinoma, Aged, Antineoplastic Agents, Exons, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutagenesis, Insertional, Treatment Outcome, Genes, erbB-1, Drug Resistance, Neoplasm, Protein Kinase Inhibitors, Kaplan-Meier Estimate

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Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: Clinical outcomes and response to erlotinib

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