Squamous cell histological transformation beyond EGFR TKI treatment against EGFR-mutant lung adenocarcinoma

e20545 Background: EGFR tyrosine kinase inhibitors (EGFR-TKIs) improve progression-free survival (PFS) in patients with EGFR-mutant NSCLC, but disease progression limits efficacy. Retrospective studies show a survival benefit to LAT in patients with oligoprogressive disease (progression at a limited number of anatomic sites). Methods: This is a prospective study of LAT in patients with oligoprogressive EGFR-mutant NSCLC. Patients with no prior EGFR-TKI therapy (cohort 1) or progression after 1st/2ndgeneration EGFR-TKIs with acquired T790M mutation (cohort 2) receive osimertinib. Upon progression, eligible patients with < = 5 progressing sites undergo LAT and resume osimertinib until disease progression. Patients previously treated with osimertinib qualifying for LAT upon disease progression are also eligible for treatment (cohort 3). Primary endpoint: evaluation of safety and efficacy of reinitiation of osimertinib after LAT (assessed by PFS). Additional goals are assessment of mechanisms of resistance to osimertinib by multi-omics analyses of tumor, blood, and saliva. Results: Between 04/2016 and 01/2017, 15 patients were enrolled (cohort 1: 9, cohort 2: 3, cohort 3: 3). Median age was 57 (range 36-71). Treatment was well tolerated. The most common adverse events (AEs) were rash, diarrhea, thrombocytopenia, and alanine transaminase elevation. Grade 3/4 AEs were observed in 4 (27%) patients. Among evaluable patients, objective response rates prior to LAT in cohorts 1 and 2 were 71% (5/7) and 100% (2/2), respectively, with 6.8 months median PFS (95% CI: 3.4 months-undefined) in cohort 1 and no progressions in cohort 2. To date, 5 patients (33%; cohort 1: 2; cohort 3: 3) had LAT. Two patients with 3 progressing sites underwent a combination of surgery and radiation. Three patients with 1 progressing site underwent surgery alone. Post-LAT PFS and results of molecular analyses will be presented. Conclusions: Patients with EGFR-mutant NSCLC and oligoprogression after EGFR-TKI therapy can be safely treated with LAT. In selected patients, this approach could potentially maximize duration of EGFR-TKI treatment and prevent premature switching to other systemic therapies. Clinical trial information: NCT02759835.

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Impact of HER2 aberrations on EGFR-TKI treatment outcomes in lung tumors harboring EGFR mutations: A HER2-CS STUDY subset analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.9056 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 9056-9056 ◽

Cited By ~ 1

Author(s):

Hiroe Kayatani ◽

Keisuke Aoe ◽

Kadoaki Ohashi ◽

Hiroshige Yoshioka ◽

Akihiro Bessho ◽

...

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor Receptor ◽

Egfr Mutations ◽

Her2 Protein ◽

Epidermal Growth ◽

Tki Treatment ◽

Egfr Mutant ◽

Egfr Mutated ◽

Egfr Tki ◽

Egfr Tkis

9056 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a key treatment for EGFR-mutated non-small-cell lung carcinoma (NSCLC). To date, a biomarker to predict whether NSCLC will exhibit a short- or long-term response to first- or second-generation EGFR-TKIs has not been established for clinical use. Human epidermal growth factor receptor-2 (HER2) aberrations are mechanisms for acquired resistance to EGFR-TKIs; however, their impact on EGFR-TKI therapy outcomes in EGFR-mutant NSCLC has not yet been systematically evaluated. Methods: Patients with advanced NSCLC were prospectively registered from more than 35 institutes (HER2-CS STUDY UMIN 000017003). EGFR mutations or anaplastic lymphoma kinase gene translocations were assessed at each institution using a commercially approved test. HER2 protein expression levels were determined by immunohistochemistry (IHC) using the Ventana I-VIEW PATHWAY anti-HER-2/neu (4B5). The IHC status scoring system applied to gastric cancer was used. Results: Of 1,126 screened patients with NSCLC, 354 (31.8%) had EGFR-mutated tumors, and the HER2 protein statuses were as follows: IHC0 (n = 71, 26%), IHC1+ (n = 148, 53%), IHC2+ (n = 51, 18%), and IHC3+ (n = 7, 3%). The patients’ demographics were almost identical in those with lung tumors harboring EGFR mutations and HER2-IHC2+/3+ (group P) or EGFR mutations and HER2-IHC0/1 (group N). The EGFR-TKI response rates were not different between these groups (Table). However, group P showed significantly shorter time to EGFR-TKI treatment failure than group N (median 19.1 vs. 13.3 months; log rank p = 0.038). Conclusions: These data from a large prospective cohort show that HER2 protein expression in EGFR-mutant NSCLC may have a negative impact on the effect of EGFR-TKIs. A clinical trial of EGFR/HER2-TKIs (e.g., afatinib) is warranted for this population. [Table: see text]

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Management of medical inoperable and tyrosine kinase inhibitor-naive early-stage lung adenocarcinoma with epidermal growth factor receptor mutations: A retrospective multi-institutional analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e21082 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e21082-e21082

Author(s):

Yue Mei Sun ◽

Ming Xiu Zhou ◽

Ming Zeng

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Lung Adenocarcinoma ◽

Kinase Inhibitor ◽

Early Stage ◽

Growth Factor Receptor ◽

Epidermal Growth ◽

Egfr Mutant ◽

Egfr Tki

e21082 Background: The clinical value of combined local radiation and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) and for medical inoperable and TKI-naïve early-stage lung adenocarcinoma patients with EGFR mutations is not yet determined. In this study, we aimed to pool multi-institutional data to compare the therapeutic effect of EGFR-TKI alone and combined radiation and TKI on the survival outcomes in this patient subgroup. Methods: 132 cases of medical non-operable stage I to III EGFR mutant lung adenocarcinoma were retrospectively reviewed based on data from 5 centers. Among the patients, 65 cases received combined radiation and EGFR-TKI therapy (R+TKI) (49.2%), while 67 cases had EGFR-TKI (50.8%) treatment alone. All patients were followed until death. Results: For R+TKI group, the median overall survival (OS) after primary therapy was 42.6 months, while that of the TKI alone group was 29.4 months (log-rank p < .001). In terms of progression-free survival (PFS), the median PFS in these two treatment groups were 24 months and 14.7 months respectively (log-rank p < .001). Multivariate analysis showed that R+TKI was independently associated with improved OS (adjusted HR: 0.420; 95% CI, 0.287 to 0.614; p < .001) and PFS (adjusted HR: 0.420; 95% CI, 0.291 to 0.605; p < .001) compared to TKI alone. Subgroup analysis confirmed the significant OS benefits in stage III patients and RFS benefits in stage II/III patients. Conclusions: Upfront radiation to primary sites with TKI to follow was a feasible option for patients with EGFR-mutant medical inoperable non-small-cell lung carcinoma (NSCLC) during first-line EGFR-TKI treatment, with significantly improved PFS and OS compared with TKI alone

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Efficacy of EGFR-TKI Plus Chemotherapy or Monotherapy as First-Line Treatment for Advanced EGFR-Mutant Lung Adenocarcinoma Patients With Co-Mutations

Frontiers in Oncology ◽

10.3389/fonc.2021.681429 ◽

2021 ◽

Vol 11 ◽

Author(s):

Zhengyu Yang ◽

Ya Chen ◽

Yanan Wang ◽

Shuyuan Wang ◽

Minjuan Hu ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

First Generation ◽

Progression Free Survival ◽

Poor Response ◽

Time To Progression ◽

Free Survival ◽

Egfr Mutant ◽

Egfr Tki ◽

Generation Sequencing ◽

Egfr Tkis

BackgroundCo-mutations was associated with poor response to EGFR-TKIs. First-generation EGFR-TKIs combined with chemotherapy was reported to be more effective than TKIs alone in advanced lung adenocarcinoma patients.ObjectiveThis retrospective study aimed to explore whether EGFR-mutant patients with co-mutations can benefit from EGFR-TKIs plus chemotherapy.Patients and MethodsWe retrospectively collected data of 137 EGFR-mutant patients with advanced lung adenocarcinoma who underwent next-generation sequencing in our hospital in 2018. Among them, 96 were treated with EGFR–TKIs alone and 41 received EGFR–TKIs plus chemotherapy. We analyzed the progression-free survival (PFS) of patients with co-mutations using different treatments.ResultsConcurrent TP53 mutations, especially exon 4 and 6, were associated with a markedly shorter time to progression on EGFR-TKI monotherapy (11.4 months vs. 16.6 months, P=0.003), while EGFR–TKIs plus chemotherapy would benefit those patients more (with TP53: 11.4 months vs. 19.1 months, P=0.001, HR=0.407; without TP53: 16.6 months vs. 18.9 months, P=0.379, HR=0.706). The incidence of T790M after resistance was equal in patients treated with different treatments (53% vs. 53%, P=0.985).ConclusionsIn our study, concurrent TP53 mutations were found to be risk factors for EGFR-TKI monotherapy, but TKI combined with chemotherapy could eliminate this heterogeneity.

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Detailed Analysis and Radiomic Prediction of First Progression Sites of First-Line Targeted Therapy for EGFR-Mutant Lung Adenocarcinoma Patients With Systemic Metastasis

Frontiers in Oncology ◽

10.3389/fonc.2021.757892 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xiaoyang Li ◽

Runping Hou ◽

Wen Yu ◽

Xueru Zhu ◽

Hongwei Li ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Kinase Inhibitor ◽

Stage Iv ◽

Clinical Information ◽

Ct Images ◽

First Line ◽

Systemic Metastasis ◽

Pre Treatment ◽

Tki Treatment ◽

Egfr Mutant

BackgroundWe aimed to analyze the first progression sites of first-line tyrosine kinase inhibitor (TKI) treatment for EGFR-mutant lung adenocarcinoma patients with systemic metastasis to recognize the potential candidates who might benefit from radiotherapy and establish a radiomic-based model to predict the first progression sites.Materials and MethodsWe retrospectively collected the clinical information and pre-treatment chest CT images of patients in Shanghai Chest Hospital from 2013 to 2017. All patients were diagnosed with stage IV EGFR-mutant lung adenocarcinoma and received TKI as first-line treatment. The first progression sites and survival were analyzed. The pre-treatment chest non-contrast CT images were utilized to establish a radiomic-based model to predict the first progression sites.ResultsWe totally collected 233 patients with systemic metastasis, among whom, there were 84 (36.1%) and 149 (63.9%) patients developing first progression in original lesions (OP) and new lesions (NP), respectively. The PFS and OS of patients with OP were longer than those with NP (PFS 11 months vs. 8 months, p = 0.03, OS 50 months vs. 35 months, p = 0.046). For 67.9% of the patients with OF, disease progressed within five sites (oligoprogression). The radiomic-based model could predict the progression sites with an AUC value of 0.736, a specificity of 0.60, and a sensitivity of 0.750 in the independent validation set.ConclusionAmong patients with systemic metastasis, there were 36.1% of patients developing OP at first progression who had a better prognosis than those developing NP. Patients with OP may be potential candidates who might benefit from radiotherapy. Radiomics is a useful method to distinguish patients developing OP and could provide some indications for radiotherapy.

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Inactivation of RB1 and histological transformation in EGFR-mutant lung adenocarcinoma

Annals of Oncology ◽

10.1016/j.annonc.2019.12.004 ◽

2020 ◽

Vol 31 (2) ◽

pp. 169-170

Author(s):

H. Zhai ◽

D. Moore ◽

M. Jamal-Hanjani

Keyword(s):

Lung Adenocarcinoma ◽

Histological Transformation ◽

Egfr Mutant

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Osimertinib in previously EGFR-TKI treated non-small cell lung cancer (NSCLC) patients without T790M mutation: Real-world evidence.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e21631 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e21631-e21631

Author(s):

Yung-Hung Luo ◽

Han Liu ◽

Jason A. Wampfler ◽

Henry D. Tazelaar ◽

Yalun Li ◽

...

Keyword(s):

Treatment Failure ◽

Real World ◽

Survival Benefit ◽

T790m Mutation ◽

Risk Of Death ◽

Tki Treatment ◽

Egfr Mutant ◽

Nsclc Patients ◽

Risk Of Treatment ◽

Egfr Tki

e21631 Background: The efficacy of osimertinib in previously EGFR-TKI treated NSCLC patients without T790M mutation remains unclear in real-world practice. We investigated whether osimertinib can provide survival benefit in EGFR-mutant patients without T790M mutation after 1st/2nd generation TKI treatment. Methods: Between January 1, 2009, and March 31, 2019, 417 patients had stage III-IV NSCLC harboring EGFR mutation and 154 out of 417 patients receiving osimertinib as≥2nd-line EGFR-TKI treatment were identified at Mayo Clinic. The time to treatment failure of osimertinib was analyzed by the Kaplan-Meier (KM) estimates. The risk of death post diagnosis was analyzed by Cox proportional hazard models. Results: Among 417 EGFR-mutant patients, higher risk of death was found in patients with age above 65 years, non-adenocarcinoma, no surgery treatment, no radiation treatment, non-exon 19 deletion/exon 21 L858R mutation, higher ECOG PS (2-4), PD-L1 expression of 50% or more, bone metastasis, live metastasis, and adrenal metastasis (all p < 0.05). Moreover, osimertinib as ≥2nd-line TKI treatment in patients with or without T790M revealed lower risk of death compared to 1st/2nd generation TKI treatment without subsequent osimertinib (HR = 0.33; 0.46, and p = 0.0002; 0.0232, respectively). However, among patients receiving osimertinib as ≥2nd-line TKI treatment, patients with T790M did not have superior survival than those without (p = 0.2803). Among 154 patients receiving osimertinib, a higher risk of treatment failure for osimertinib was found in male (HR = 1.72; p = 0.0327), patients with 1st-line TKI duration ≤12 months (HR = 2.16; p = 0.0019), BMI drop > 10% (HR = 1.85; p = 0.0207), PD-L1 levels of 50% or more (HR = 4.28; p = 0.0008), and 1st-line TKI with afatinib (HR = 2.19; p = 0.0136). Nonetheless, osimertinib as ≥2nd-line TKI in patients without 790M mutation did not have higher risk of treatment failure than those with T790M (p = 0.1236). Conclusions: This is the first study to demonstrate that osimertinib can provide similar survival benefit in previously EGFR-TKI treated NSCLC patients without T790M mutation as those with T790M in real-world practice. Additionally, EGFR-mutant patients with PD-L1 expression ≥50% had a higher risk of treatment failure for osimertinib and worse overall survival than those with PD-L1 expression < 50% and may potentially gain benefit from optimizing treatment strategies including immunotherapy.

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