Use of adjuvant EGFR tyrosine kinase inhibitors in early stage EGFR-mutant non-small cell lung cancer: is the evidence strong enough?
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ABSTRACT:
SUBMITTER: Lemmon C
PROVIDER: S-EPMC7578493 | biostudies-literature | 2020 Sep
REPOSITORIES: biostudies-literature
Publications
Use of adjuvant EGFR tyrosine kinase inhibitors in early stage <i>EGFR</i>-mutant non-small cell lung cancer: is the evidence strong enough?
Lemmon Christopher C Pennell Nathan A NA
Journal of thoracic disease 20200901 9
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Project description: Not available
| S-EPMC6987370 | biostudies-literature
Project description:Given the unprecedented efficacy of EGFR tyrosine kinase inhibitors (TKI) in advanced EGFR-mutant lung cancer, adjuvant TKI therapy is an appealing strategy. However, there are conflicting findings regarding the potential benefit of adjuvant EGFR-TKI in patients with lung cancer harboring EGFR mutations. To better understand these results, we studied the natural history of lung cancers which recurred despite adjuvant TKI.Patients with recurrent EGFR-mutant lung cancer following adjuvant TKI were identified using an Institutional Review Board-approved mechanism. Recurrent cancer specimens were tested for resistance mutations. Sensitivity to retreatment with EGFR-TKI was evaluated.Twenty-two patients with cancers harboring an EGFR sensitizing mutation received adjuvant erlotinib or gefitinib for a median of 17 months (range 1-37 months). T790M was more common in cancers which recurred while receiving TKI than in those which recurred after stopping TKI (67% vs. 0%, P = 0.011). Fourteen patients who developed recurrence after stopping EGFR-TKI were retreated, with a median time to progression of 10 months and radiographic response seen in 8 of 11 patients with evaluable disease (73%).Recurrence of EGFR-mutant lung cancer after stopping adjuvant TKI should not preclude a trial of TKI retreatment; a phase II trial of erlotinib in this setting is underway. Studies of adjuvant EGFR-TKI will underestimate the potential survival benefit of adjuvant TKI for patients with EGFR-mutant lung cancers if retreatment at recurrence is not given.
| S-EPMC3186869 | biostudies-literature
Project description:BackgroundAlthough epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have been the standard treatment for advanced EGFR-mutant adenocarcinoma, the effects of upfront EGFR-TKI use in unresectable stage III EGFR-mutant adenocarcinoma remain unexplored. Here, we conducted a retrospective study to compare different treatment strategies in these patients.MethodsFrom October 2010 to June 2019, patients with unresectable stage III adenocarcinoma who received treatment at a tertiary referral center were enrolled. Patients were classified into three groups: EGFR-mutant adenocarcinoma treated with concurrent chemoradiotherapy (group 1) or EGFR-TKI (group 2) and EGFR wild-type adenocarcinoma treated with concurrent chemoradiotherapy (group 3). Progression-free survival, progression-free survival-2, and overall survival were estimated and compared using Kaplan-Meier and log-rank tests.ResultsA total of 92 patients were enrolled; 10, 40, and 42 patients were assigned to groups 1, 2, and 3, respectively. Patients with EGFR mutations who received upfront EGFR-TKIs had significantly longer progression-free and overall survival than those who received upfront concurrent chemoradiotherapy (hazard ratio 0.33 vs. 0.34, p = 0.006 vs. 0.031) according to a Cox model adjusted for possible confounders. Moreover, upfront concurrent chemoradiotherapy did not lead to higher survival rates in patients with EGFR mutations than in those with EGFR wild-type adenocarcinoma (progression-free survival; hazard ratio 0.37, p = 0.036; overall survival; hazard ratio 0.35, p = 0.080) by Cox regression analysis.ConclusionThis current study suggests that EGFR-TKIs is a better choice for patients with unresectable stage III EGFR-mutant adenocarcinoma. However, further randomized studies are required to validate the results.
| S-EPMC8758433 | biostudies-literature
Project description:Lung adenocarcinomas with mutant epidermal growth factor receptor (EGFR) respond to EGFR-targeted tyrosine kinase inhibitors (TKIs), but resistance invariably occurs. We found that the Janus kinase (JAK)/signal transduction and activator of transcription 3 (STAT3) signaling pathway was aberrantly increased in TKI-resistant EGFR-mutant non-small cell lung cancer (NSCLC) cells. JAK2 inhibition restored sensitivity to the EGFR inhibitor erlotinib in TKI-resistant cell lines and xenograft models of EGFR-mutant TKI-resistant lung cancer. JAK2 inhibition uncoupled EGFR from its negative regulator, suppressor of cytokine signaling 5 (SOCS5), consequently increasing EGFR abundance and restoring the tumor cells' dependence on EGFR signaling. Furthermore, JAK2 inhibition led to heterodimerization of mutant and wild-type EGFR subunits, the activity of which was then blocked by TKIs. Our results reveal a mechanism whereby JAK2 inhibition overcomes acquired resistance to EGFR inhibitors and support the use of combination therapy with JAK and EGFR inhibitors for the treatment of EGFR-dependent NSCLC.
| S-EPMC4950506 | biostudies-literature
Project description:BackgroundThe standard of care for fit locally advanced non-small cell lung cancer (NSCLC) patients is concurrent chemoradiotherapy (CCRT). However, in a subset of patients with lung adenocarcinoma with mutant EGFR (LA-mEGFR), the role of EGFR-tyrosine kinase inhibitors (TKIs) is not clear. We compared CCRT versus TKIs for the treatment of stage IIIb LA-mEGFR in a Taiwanese population.MethodsWe identified patients from the Taiwan Cancer Registry with good performance status at clinical stage IIIb LA-mEGFR, diagnosed from June 2011 to December 2015 and treated with either TKIs or CCRT. Clinical covariables and survival status were also collected. The Cox regression method was used in the primary analyses and several propensity score methods and alternative study cohort definitions were used in additional analyses.ResultsWe compared the data of 177 TKI and 22 CCRT patients and found no statistically significant difference in overall (adjusted hazard ratio of death 0.71, 95% confidence interval 0.34-1.47) or lung cancer-specific survival (hazard ratio 0.65, 95% confidence interval 0.31-1.35). The results of most additional analyses were insignificant.ConclusionIn this population-based study from Taiwan with limited case numbers, no statistical difference in the survival outcomes of patients with clinical stage IIIb LA-mEGFR treated with either EGFR-TKIs or CCRT was determined. Further prospective studies are needed to clarify our findings.
| S-EPMC6209772 | biostudies-literature
Project description:Small molecule tyrosine kinase inhibitors (TKIs) have transformed the management of advanced non-small-cell lung cancer (NSCLC) harboring activating epithelial growth factor receptor (EGFR) mutations, while the efficacy of TKIs in the adjuvant setting remains unclear. We collected the data of 209 EGFR-mutant NSCLC patients receiving complete resection from 2010 to 2013. Study end points were disease-free survival (DFS) and overall survival (OS). Among the eligible patients, 41 (19.6%) received EGFR TKIs in the adjuvant treatment. The 3-year DFS of adjuvant EGFR TKIs treatment group (70.5%, 95% CI, 54.6-86.4%) was significantly superior that control group (50.2%, 95% CI, 40-60.4%; log-rank P = 0.014). TKIs treatment (HR, 0.51; 95% CI, 0.29-0.97; P = 0.04) was significantly associated with improved DFS in multivariate Cox analysis. No significant difference was observed in 3-year OS between two groups (73.1% [58.0-88.2%] vs 61.8% [52.2-71.4%], log-rank P = 0.21). Propensity-score matching further confirmed that adjuvant TKIs treatment extended the DFS (log-rank P = 0.024), but did not improve OS (log-rank P = 0.40). Our analysis revealed that adjuvant EGFR TKIs treatment was beneficial for early-stage NSCLC patients harboring activating EGFR mutations after complete resection.
| S-EPMC5599620 | biostudies-literature
Project description: Not available
| S-EPMC7653125 | biostudies-literature
Project description:PurposeIn patients with advanced non-small cell lung cancer (NSCLC) and oncogenic driver mutations treated with effective targeted therapy, a characteristic pattern of tumor volume dynamics with an initial regression, nadir, and subsequent regrowth is observed on serial computed tomography (CT) scans. We developed and validated a linear model to predict the tumor volume nadir in EGFR -mutant advanced NSCLC patients treated with EGFR tyrosine kinase inhibitors (TKI).Materials and methodsPatients with EGFR -mutant advanced NSCLC treated with EGFR-TKI as their first EGFR-directed therapy were studied for CT tumor volume kinetics during therapy, using a previously validated CT tumor measurement technique. A linear regression model was built to predict tumor volume nadir in a training cohort of 34 patients, and then was validated in an independent cohort of 84 patients.ResultsThe linear model for tumor nadir prediction was obtained in the training cohort of 34 patients, which utilizes the baseline tumor volume before initiating therapy (V 0 ) to predict the volume decrease (mm 3 ) when the nadir volume (V p ) was reached: V 0 -V p =0.717×V 0 -1347 ( P =2×10 -16 ; R2 =0.916). The model was tested in the validation cohort, resulting in the R2 value of 0.953, indicating that the prediction model generalizes well to another cohort of EGFR -mutant patients treated with EGFR-TKI. Clinical variables were not significant predictors of tumor volume nadir.ConclusionThe linear model was built to predict the tumor volume nadir in EGFR -mutant advanced NSCLC patients treated with EGFR-TKIs, which provide an important metrics in treatment monitoring and therapeutic decisions at nadir such as additional local abrasive therapy.
| S-EPMC8920948 | biostudies-literature
Project description:Although tyrosine kinase inhibitors (TKIs) targeting Epidermal Growth Factor Receptor (EGFR) activating mutations have significantly improved outcomes in EGFR-mutant non-small cell lung cancer, resistance inevitably develops. Despite the heterogeneity of resistance mechanisms, many induce activation of MAPK signaling in the presence of EGFR-TKIs. ARAF gene amplification is identified as one such mechanism that activates MAPK signaling by directly interacting with RAS, yet its clinicopathologic characteristics remain poorly understood. We characterized five cases with ARAF amplification resistant to first- or second-generation EGFR-TKIs and screened an additional 48 re-biopsied specimens following resistance to Osimertinib. Among Osimertinib-resistant tumors, we identified four cases with ARAF amplification. Overall, these nine ARAF-amplified resistant tumors retained their original founder EGFR mutation and lacked secondary alterations. Furthermore, we identified two cases showing histologic transformation from lung adenocarcinoma to small cell lung cancer (SCLC). SCLC can be classified into four subtypes defined by transcriptional signatures driven by specific transcription factors. To estimate the subtypes of these resistant tumors, RNA sequencing analysis was performed in paired samples before and after treatment with EGFR-TKIs.
2024-10-30 | GSE274293 | GEO
Project description:Advanced NSCLC harboring epidermal growth factor receptor (EGFR) mutations treated with EGFR tyrosine kinase inhibitors (TKIs) typically progresses after initial response due to acquired resistance. TKIs are often continued beyond progressive disease by RECIST. We investigated the practice of continuing EGFR-TKIs after RECIST-PD via CT findings.Among 101 advanced NSCLC patients with sensitizing EGFR mutations treated with first-line EGFR-TKIs, 70 patients had baseline and at least one follow-up CT for retrospective radiographic assessments using RECIST1.1; 56 patients had experienced PD by the data closure date of June 2011.Among 56 patients experiencing PD, 82% were female, median age was 63 years, 50% were never-smokers, 57% had distant metastasis, 57% had exon 19 deletion, and 89% were treated with erlotinib. 49 patients (88%) continued TKI therapy beyond retrospectively assessed PD. 31/32 (97%) patients who progressed by an increase in their target lesions continued TKI. 13/16 (81%) patients who progressed by appearance of a new lesion remained on TKI. 5/6 (83%) patients with both increase of target lesions and new lesion at PD continued TKI. Two patients with PD in non-target lesions discontinued therapy at PD. In 49 continuing patients, the median time from retrospectively assessed RECIST-PD to termination of TKI was 10.1 months.88% of EFGR-mutant NSCLC patients who progressed on first-line TKI continued therapy beyond RECIST-PD, which is not the single determining factor for terminating TKI in EGFR-mutant NSCLC patients. Additional radiographically defined progression criteria are needed for this population.
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