Clinical Factors Predicting Detection of T790M Mutation in Rebiopsy for EGFR-Mutant Non–small-cell Lung Cancer

e20603 Background: EGFR-mutant non-small-cell lung cancer (NSCLC) patients inevitably develop drug resistance when treated with EGFR tyrosine kinase inhibitors (TKIs). Clonal and clinical analyses of genetic alterations at baseline and progressive disease (PD), as well as differences between acquired T790M and T790M-negative patients in drug-resistant mechanisms, have not been systematically studied. Methods: We performed targeted sequencing of pre-treatment and PD tumor samples from 54 EGFR-mutant NSCLC patients. Correlation between genomic features and patients’ progression-free survival (PFS) was evaluated. Ten additional patients were sequenced using whole exome sequencing to infer the clonal evolution patterns. Results: We observed new pathways limiting EGFR-inhibitor response, including NOTCH1/ STK11 co-deletion, and TGF-beta alterations. Besides acquired T790M mutation, chromosomal instability (CIN) related genes including AURKA and TP53 alterations were the most frequently acquired events. CIN significantly increased with TKI treatment in T790M-negative patients. Transcriptional regulators including HNF1A, ATRX and NKX2-1 acquired alterations were enriched in T790M-positive patients, and diverse oncogenic pathway alterations were more common in T790M-negative patients. T790M-positive patients had improved PFS compared to T790M-negative patients. We identified subgroups within T790M-positive or T790M-negative patients with distinct PFS. Interestingly, we observed a death-and-birth process of RTK-RAS mutations during TKI treatment, and baseline and acquired RTK-RAS mutations had opposite effects on PFS. Clonal evolution analysis indicated progression of T790M-positive patients depends on competition between T790M and non-T790M resistant subclones. Conclusions: T790M-positive and T790M-negative patients display divergent landscape of acquired somatic events. Subgroups of patients were identified within T790M-positive and T790M-negative patients with distinct survival. Our results point the importance of clonal competition between T790M and non-T790M resistant subclones.

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The continued osimertinib plus chemotherapy overcoming resistance after histologic transformation in EGFR-mutant lung adenocarcinoma treated with osimertinib.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e20615 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e20615-e20615 ◽

Cited By ~ 1

Author(s):

Jin Kang ◽

Xiang-Meng Li ◽

Jia-Tao Cheng ◽

Huajun Chen ◽

Xuchao Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Mouse Model ◽

Lung Adenocarcinoma ◽

Small Cell Lung Cancer ◽

Neuroendocrine Carcinoma ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

T790m Mutation ◽

Egfr Mutant

e20615 Background: Although the third-generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is more potent, histologic transformation from lung adenocarcinoma to other histological types is still a mechanism of resistance in EGFR-mutant adenocarcinoma. Those with histologic transformation usually have poor prognosis. Hence, we focused on the unique molecular mechanism of histologic transformation after osimertinib and explore the strategy of treatment. Methods: Pathology was confirmed in 55 EGFR-mutant patients treated with osimertinib at baseline and disease progression. They were all lung adenocarcinoma at baseline. We established the patient-derived xenograft (PDX) mouse model from an EGFR-mutant adenocarcinoma transforming to neuroendocrine carcinoma. Preclinical efficacy of erlotinib versus osimertinib was evaluated in vivo. All the clinical data of these patients were analyzed. Results: The frequency of histologic transformation after resistance to osimertinib was 14.5% (8/55). Three of them were transformed to small-cell lung cancer totally, two transformed to complex small-cell lung cancer, two transformed to adenosquamous cell carcinoma and one transformed to neuroendocrine carcinoma without T790M mutation in which an PDX mouse model was successfully established. The genetic profiles of those transformed to small-cell lung cancer were characterized by Rb1, TP53 mutations, and PI3K/AKT/MTOR aberrances. Those transformed to adenosquamous carcinoma were characterized by KRAS amplification and EGFR amplification. The median progression-free survival (PFS) was not significantly different between the patients with histologic transformation and those without during the treatment of osimertinib (7.7 VS. 5.7 months, P = 0.763). One went on first-line osimertinib, added etoposide/ cisplatin (EP) chemotherapy meanwhile after progressive disease, and achieved minor response after 2 cycles. The other one received the treatment of EP + osimertinib + erlotinib, and acheived partial response with a PFS of 7 months without obvious toxicities. The PDX model showed more sensitivity to erlotinib than osimertinib. Conclusions: Continued osimertinib plus chemotherapy might be effective in overcoming the resistance. Particularly, the first-generation EGFR-TKI seems to be efficacious in histologically-transformed EGFR-mutant patients without T790M mutation. Further investigations of these patients and PDXs are warranted.

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Comparison of the outcome between immunotherapy alone or in combination with chemotherapy in EGFR-mutant non-small cell lung cancer

Scientific Reports ◽

10.1038/s41598-021-95628-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Chia-I Shen ◽

Heng-Sheng Chao ◽

Tsu-Hui Shiao ◽

Chi-Lu Chiang ◽

Hsu-Ching Huang ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Progression Free Survival ◽

Small Cell ◽

Small Cell Lung ◽

T790m Mutation ◽

Free Survival ◽

Potential Biomarker ◽

Egfr Mutant

AbstractWhether ICIs combined with chemotherapy can improve outcomes in EGFR-mutant non-small cell lung cancer (NSCLC) remains uncertain. Patients with EGFR-mutant NSCLC and who progressed on first-line EGFR-TKIs treatment were retrospectively collected. We reviewed the outcome of these patients treated with ICIs or ICIs combined chemotherapy (ICI + C). Total 30 patients were included. The ORR were 9.1% and 25.0% for the ICI and ICI + C groups. The ICI + C group showed the trend of longer progression-free survival and overall survival periods. Patients without the T790M mutation had a significantly longer PFS than did those without this mutation (4.23 [95% CI: 2.75–5.72] vs. 1.70 [95% CI: 0.00–3.51] months, HR:4.45, p = 0.019). ICIs combined with chemotherapy tended to be more effective than ICIs alone in pretreated EGFR-mutant NSCLC. The T790M mutation may be a potential biomarker.

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Faculty Opinions recommendation of RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725386175.793510338 ◽

2015 ◽

Author(s):

Elaine Mardis

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

Egfr Mutant ◽

Lung Adenocarcinomas

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BEBT-109, a pan-mutant-selective EGFR inhibitor with potent antitumor activity in EGFR-mutant non-small cell lung cancer

Translational Oncology ◽

10.1016/j.tranon.2020.100961 ◽

2021 ◽

Vol 14 (2) ◽

pp. 100961

Author(s):

Fushun Fan ◽

Minhua Zhou ◽

Xiaolan Ye ◽

Zhenxian Mo ◽

Yaru Ma ◽

...

Keyword(s):

Lung Cancer ◽

Antitumor Activity ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Egfr Inhibitor ◽

Small Cell Lung ◽

Egfr Mutant

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Predictive value of pretreatment PD-L1 expression in EGFR-mutant non-small cell lung cancer: a meta-analysis

World Journal of Surgical Oncology ◽

10.1186/s12957-021-02254-x ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Zhiyu Peng ◽

Huahang Lin ◽

Ke Zhou ◽

Senyi Deng ◽

Jiandong Mei

Keyword(s):

Lung Cancer ◽

Sensitivity Analysis ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Predictive Value ◽

Meta Analysis ◽

Small Cell ◽

Small Cell Lung ◽

Egfr Mutant ◽

Egfr Tkis

Abstract Objective To investigate the predictive value of programmed death-ligand 1 (PD-L1) expression in non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Methods We conducted a systemic search of PubMed, EMBASE, and the Cochrane Library from 1 January 2000 to 30 August 2020, to identify related studies. We combined the hazard ratio (HR) and 95% confidence interval (CI) to assess the correlation of PD-L1 expression with progression-free survival (PFS) and overall survival (OS). We assessed the quality of the included studies by the Newcastle–Ottawa Scale (NOS). We performed subgroup analyses based on immunohistochemistry (IHC) scoring system, IHC antibodies, sample size, countries, and survival analysis mode. Sensitivity analysis and evaluation of publication bias were also performed. Results Twelve studies including 991 patients met the criteria. The mean NOS score was 7.42 ± 1.19. Patients with high PD-L1 expression was associated with poorer PFS (HR = 1.90; 95% CI = 1.16–3.10; P = 0.011), while there was no association between PD-L1 expression and OS (HR = 1.19; 95% CI = 0.99–1.43; P = 0.070). Subgroup analysis prompted IHC scoring systems, IHC antibodies, and sample size have important effects on heterogeneity. The pooled results were robust according to the sensitivity analysis. Conclusions The result of this meta-analysis suggested that PD-L1 expression might be a predictive biomarker for EGFR-mutant non-small cell lung cancer treated with EGFR-TKIs.

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CARDIOVASCULAR EVENTS IN PATIENTS WITH EGFR-MUTANT NON-SMALL CELL LUNG CANCER ON OSIMERTINIB

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(21)04642-8 ◽

2021 ◽

Vol 77 (18) ◽

pp. 3288

Author(s):

Ariel Peleg ◽

Ishmam Ibtida ◽

Jennifer Liu ◽

Richard Steingart ◽

Anthony Yu

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Cardiovascular Events ◽

Small Cell ◽

Small Cell Lung ◽

Egfr Mutant

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Utility of Cerebrospinal Fluid Cell-Free DNA in Patients with EGFR-Mutant Non-Small-Cell Lung Cancer with Leptomeningeal Metastasis

Targeted Oncology ◽

10.1007/s11523-021-00791-9 ◽

2021 ◽

Vol 16 (2) ◽

pp. 207-214

Author(s):

Chi-Lu Chiang ◽

Cheng-Chia Lee ◽

Hsu-Ching Huang ◽

Chia-Hung Wu ◽

Yi-Chen Yeh ◽

...

Keyword(s):

Lung Cancer ◽

Cerebrospinal Fluid ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Leptomeningeal Metastasis ◽

Small Cell ◽

Small Cell Lung ◽

Free Dna ◽

Egfr Mutant ◽

Fluid Cell

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Real-world osimertinib for EGFR mutation-positive non-small-cell lung cancer with acquired T790M mutation

Future Oncology ◽

10.2217/fon-2020-0203 ◽

2020 ◽

Vol 16 (21) ◽

pp. 1537-1547

Author(s):

Fumio Imamura ◽

Madoka Kimura ◽

Yukihiro Yano ◽

Masahide Mori ◽

Hidekazu Suzuki ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Kinase Inhibitors ◽

Egfr Mutation ◽

Acquired Resistance ◽

Small Cell ◽

Small Cell Lung ◽

T790m Mutation ◽

Clinical Trial Registration

Aim: Osimertinib is a key drug for EGFR mutation-positive non-small-cell lung cancer (NSCLC). As the hazards ratio of overall survival in comparison with first-generation EGFR-tyrosine kinase inhibitors was almost similar between FLAURA and ARCHER 1050, salvage use of osimertinib is still a treatment option. Patients & methods: We retrospectively analyzed the clinical courses of EGFR mutation-positive NSCLC patients who were potential candidates for salvage osimertinib. Results: Among 524 patients enrolled from five hospitals, 302 patients underwent biopsy, with 52.6% detection rate of T790M. Osimertinib was administered in 93.6% of the T790M-positive patients. The overall response rate and median progression-free survival time of osimertinib were calculated with 147 patients, to be 55.6% and 17.2 months, respectively. Conclusion: Osimertinib is active for T790M-driven acquired resistance in EGFR-mutant NSCLC, but the detection of T790M was unsatisfactory. Clinical Trial Registration: UMIN000028989 (UMIN Clinical Trials Registry)

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