Background
Epidermal growth factor receptor exon 20 insertion (EGFRex20ins) mutations represent approximately 4–12% of EGFR mutations and are generally refractory to the 1st and 2nd generation EGFR tyrosine kinase inhibitors (TKIs). Development of effective therapies for patients with EGFRex20ins mutant non-small-cell lung carcinoma (NSCLC) represents a great unmet need. Preclinical models have shown that osimertinib is active in NSCLC harboring EGFRex20ins, while the antitumor activity of osimertinib remains to be evaluated in patients with EGFRex20ins mutations.
Methods
Tumor genotyping was performed in 2316 Chinese NSCLC cases with targeted next generation sequencing (NGS) covering the whole exons of EGFR gene. The frequency and genetic characteristics of EGFRexon20ins mutations were analyzed. Furthermore, six patients with specific EGFRexon20ins mutations and receiving osimertinib 80 mg once daily were retrospectively included to assess the antitumor activity and safety of monotherapy osimertinib.
Results
EGFRex20ins mutations were identified in 4.8% (53/1095) of EGFR mutant NSCLC and 2.3% (53/2316) of all NSCLC cases. The most frequently identified EGFRexon20ins is A767_V769dup (17/53,32.1%). We found that the genetic characteristics of EGFRex20ins mutations in Chinese patients with NSCLC were comparable to those reported in Caucasian patients. Four patients with osimertinib therapy achieved partial response and the rest stable disease. Median progression free survival (PFS) was 6.2 months (95% confidence interval 5.0–12.9 months; range 4.9–14.6 months). The most common adverse events (AEs) were diarrhea (2/6), pruritis (2/6), stomatitis (1/6) and nausea (1/6). No grade 3 or more AEs were documented.
Conclusions
This study revealed that the genetic characteristics of EGFRex20ins mutations in Chinese patients with NSCLC were comparable to those reported in Caucasian patients. Furthermore, our study firstly demonstrated promising antitumor activity of osimertinib in certain EGFRex20ins mutant advanced NSCLC patients, indicating that osimertinib treatment for EGFRex20ins positive patients deserves further study.
Electronic supplementary material
The online version of this article (10.1186/s12885-019-5820-0) contains supplementary material, which is available to authorized users.
Background: Several mechanisms including abnormal activation of PI3K-AKT-mTOR pathway have been proved to generate acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). In this study, we investigated the genomic characteristics of PI3K pathway activated in NSCLC patients after progression on EGFR-TKIs and whether both targeting EGFR and PI3K pathway could overcome resistance.Methods: A total of 605 NSCLC cases with a history of EGFR TKI treatment were reviewed, in which 324 patients harboring EGFR mutations were confirmed progression on at least one EGFR TKI and finally enrolled. Tumor tissues or blood samples were collected at the onset of TKI progression for next generation sequencing (NGS). Six EGFR mutant patients with co-occurring mutations in PI3K pathway were retrospectively collected to assess the effect of EGFR TKI plus everolimus, a mTOR inhibitor.Results: Forty-nine (14.9%) patients resistant to EGFR TKIs have at least one genetic variation in PI3K pathway. PIK3CA, PTEN and AKT1 variations were detected in 31 (9.5%), 18 (5.5%) and 3 (0.9%) of patients, respectively. No significant differences were observed in distribution of PI3K pathway alterations among patients with different EGFR mutations (EGFR exon19 deletion mutations/EGFR L858R/ uncommon EGFR mutations) and among patients resistant to different EGFR TKIs. For patients treated with everolimus and EGFR-TKI, five (5/6, 83.3%) achieved stable disease (SD) and one (1/6, 16.7%) didn't receive disease control. The median progression-free survival (PFS) was 2.1 months (95% confidence interval, 1.35-4.3 months, range, 0.9-4.4 months). The most common adverse events were dental ulcer (6/6), rash (1/6).Conclusions: Our study revealed that PI3K pathway was activated in at least 14.9% in EGFR-TKI resistant patients. EGFR-TKIs plus everolimus showed limited antitumor activity in EGFR mutant NSCLC patients with PI3K pathway aberrations.
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