Resected Epidermal Growth Factor Receptor Research Articles

NOTCH1 and CREBBP co-mutations negatively affect the benefit of adjuvant therapy in completely resected EGFR-mutated NSCLC: translational research of phase III IMPACT study.

The phase III IMPACT study (UMIN000044738) compared adjuvant gefitinib with cisplatin plus vinorelbine (cis/vin) in completely resected epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Although the primary endpoint of disease-free survival (DFS) was not met, we searched for molecular predictors of adjuvant gefitinib efficacy. Of 234 patients enrolled in the IMPACT study, 202 patients were analyzed for 409 cancer-related gene mutations and tumor mutation burden using resected lung cancer specimens. Frequent somatic mutations included tumor protein p53 (TP53; 58.4%), CUB and Sushi multiple domains 3 (CSMD3; 11.8%), and NOTCH1 (9.9%). Multivariate analysis showed that NOTCH1 co-mutation was a significant poor prognostic factor for overall survival (OS) in the gefitinib group and cAMP response element binding protein (CREBBP) co-mutation for DFS and OS in the cis/vin group. In patients with NOTCH1 co-mutations, gefitinib group had a shorter OS than cis/vin group (Hazard ratio 5.49, 95% CI 1.07-28.00), with a significant interaction (P for interaction = 0.039). In patients with CREBBP co-mutations, the gefitinib group had a longer DFS than the cis/vin group, with a significant interaction (P for interaction = 0.058). In completely resected EGFR-mutated NSCLC, NOTCH1 and CREBBP mutations might predict poor outcome in patients treated with gefitinib and cis/vin, respectively.

Evaluation of Cost-Effectiveness of Adjuvant Osimertinib in Patients with Resected EGFR Mutation-Positive Non-small Cell Lung Cancer.

For many patients with resected epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC), current standard of care (SoC) is adjuvant chemotherapy; however, disease recurrence remains high. Based on positive results from ADAURA (NCT02511106), adjuvant osimertinib was approved for treatment of resected stage IB‒IIIA EGFRm NSCLC. The aim was to assess the cost-effectiveness of adjuvant osimertinib in patients with resected EGFRm NSCLC. A five-health-state, state-transition model with time dependency was developed to estimate lifetime (38 years) costs and survival of resected EGFRm patients treated with adjuvant osimertinib or placebo (active surveillance), with/without prior adjuvant chemotherapy, using a Canadian Public Healthcare perspective. Transitions between health states were modeled using ADAURA and FLAURA (NCT02296125) data, Canadian life tables, and real-world data (CancerLinQ Discovery®). The model used a 'cure' assumption: patients remaining disease free for 5 years after treatment completion for resectable disease were deemed 'cured.' Health state utility values and healthcare resource usage estimates were derived from Canadian real-world evidence. In the reference case, adjuvant osimertinib treatment led to a mean 3.20 additional quality-adjusted life-years (QALYs; (11.77 vs 8.57) per patient, versus active surveillance. The modeled median percentage of patients alive at 10 years was 62.5% versus 39.3%, respectively. Osimertinib was associated with mean added costs of Canadian dollars (C$)114,513 per patient and a cost/QALY (incremental cost-effectiveness ratio) of C$35,811 versus active surveillance. Model robustness was demonstrated by scenario analyses. In this cost-effectiveness assessment, adjuvant osimertinib was cost-effective compared with active surveillance for patients with completely resected stage IB‒IIIA EGFRm NSCLC after SoC.

Economic evaluations of adjunctive osimertinib treatment in surgically resected epidermal growth factor receptor positive (EGFR+) non-small cell lung cancer (NSCLC): Analysis for stage 3A disease.

e20505 Background: Patients with surgically resected EGFR+ NSCLC remain at risk of recurrence after surgery. Osimertinib, a tyrosine kinase inhibitor, had been assessed clinically as adjunctive therapy in surgically resected EGFR+ NSCLC including stage 3A. We conducted a cost effectiveness/utility analysis of adjunctive osimertinib therapy in stage 3A surgically resected EGFR+ NSCLC. Methods: We specified a two state partitioned survival model of disease free survival (DFS) versus disease recurrence and death in a), with a 5 year time horizon (US payer perspective). DFS and overall survival curves were extrapolated per parametric functions. A 3% discount rate was utilized to costs and utilities beyond year 1. Costs of therapies (wholesale acquisition cost), adverse events (AE; grade 3/4; all grades for immunotherapy related AEs), and monitoring costs were based on Redbook, publications, and Physician Fee Schedules, respectively (US $2021). Costs, DFS life years (DFSLY) and DFS quality adjusted life years (DFSQALY) were used to determine the incremental cost effectiveness/utility ratios (ICER/ICUR) of the additional cost needed to gain (g) a DFSLY and DFSQALY in base case (BSA) and probabilistic sensitivity analyses (PSA). Results: Exponential regression was used to extrapolate the Kaplan-Meier curves of osimertinib and placebo,. As shown in the table, the BCA (PSA) estimated the incremental cost at $669,369 ($670,274). The incremental DFSLY was 1.895 (1.899), yielding ICER of $353,125/DFSLYg ($352,963/DFSLYg). The incremental DFS QALY was 1.35, yielding an ICUR of $497,905/DFSQALYg ($497,676/DFSQALYg). Conclusions: In stage 3A surgically resected EGFR+ NSCLC, adjunctive osimertinib therapy showed incremental benefits of 1.895 (1.899) DSFLYg and 1.344 (1.349) QALYg compared to placebo, however at marked incremental cost. As adjunctive osimertinib treatment is indicated in EGFR+ NSCLC disease stages1B and 2, the present stage 3A cost effectiveness/utility results should be compared to those for stages 1B and 2.[Table: see text]

Economic evaluations of adjunctive osimertinib treatment in surgically resected epidermal growth factor receptor positive (EGFR+) non-small cell lung cancer (NSCLC): Analysis for stage 1B disease.

e20502 Background: Patients with stage 1B non-small cell lung cancer (NSCLC) who receive surgical resection are at continued risk of disease recurrence and death after the surgery. Osimertinib, a tyrosine kinase inhibitor indicated for epidermal growth factor receptor positive (EGFR+) NSCLC, has been used post-operatively as adjunctive therapy to improve clinical outcomes in surgically resected EGFR+ stage 1B NSCLC. We evaluated the cost effectiveness/utility of adjunctive osimertinib treatment post-surgically in stage 1B. Methods: A two state partitioned survival model with disease free survival (DFS) and disease recurrence or death was specified (US payer perspective). Kaplan-Meier DFS curves were fitted to parametric functions. A 5 year time horizon was adopted and a 3% discount rate was applied to costs and utilities after year 1. Wholesale acquisition costs for treatments were sourced from Redbook, adverse event costs (grade 3/4; all grades for immunotherapy related AEs) utilized published data, and monitoring costs were based on Physician Fee Schedules (US $2021). We estimated incremental costs, DFS life years (DFSLY), and DFS quality adjusted life years (DFSQALY). Based on DFSLY and DFSQALY gained (g), incremental cost effectiveness/utility ratios (ICER/ICUR) were determined in base case analyses (BCA) and probabilistic sensitivity analyses (PSA). Results: Exponential regression was utilized to extrapolate the osimertinib DFS Kaplan-Meier curve, while Weibull regression was applied for extrapolation of the placebo DFS curve. Shown in the table below, the BCA (PSA) revealed incremental cost of $774,710 ($775,941) and ncremental DFSLY of 0.813 (0.954), yielding an ICER of $952,797/DFSLYg ($813,162/DFSLYg); and incremental DFSQALY of 0.576 (0.676), yielding an ICUR of $1,345,340/DFSQALYg (1,147,793/DFSQALYg). Conclusions: In surgically resected stage 1B EGFR+ NSCLC, the model estimated incremental benefits of 0.813 (0.954) LYg and 0.576 (0.676) QALYg, however at marked incremental cost. As adjunctive osimertinib treatment is indicated in EGFR+ NSCLC disease stages 2 and 3A, the present stage 1B cost effectiveness/utility results should be compared to those for stages 2 and 3A.[Table: see text]

Deconstructing ADAURA: It is Time to Forgo Adjuvant Platinum-Based Chemotherapy in Resected IB-IIIA EGFR+ NSCLC (Except with RB Alterations?) When Adopting Adjuvant Osimertinib.

Adjuvant cisplatin-based chemotherapy is considered the standard of care for resected stage IB (tumor ≥ 4m)–IIIA non-small cell lung cancer (NSCLC). The ADAURA trial is a randomized placebo-controlled Phase III trial that demonstrated statistically significant improved disease-free survival (DFS) with the use of 3-years of adjuvant osimertinib in resected stage IB–IIIA NSCLC harboring epidermal growth factor receptor (EGFR) del 19 or L858R mutations. Subgroup analysis revealed that the DFS improvement with adjuvant osimertinib is independent of adjuvant chemotherapy in the primary analysis. A recent follow-up report suggested that adjuvant cisplatin-based chemotherapy provided no additional 2-year DFS improvement on top of adjuvant osimertinib regardless of stage (IB, II, or IIIA) and minimal numerical DFS benefit in stage II or IIIA resected EGFR+ NSCLC for those patients who did not receive adjuvant osimertinib. Here, we argue that if clinicians adopt the use of 3 years of adjuvant osimertinib in resected early-stage EGFR+ NSCLC, there is no role for adjuvant platinum-based chemotherapy. The use of adjuvant chemotherapy was balanced between the osimertinib and the placebo arms by stage even though adjuvant chemotherapy was not one of the three stratification factors (del 19 vs L858R; Stage IA vs II vs III; Asians versus non-Asian) in ADAURA. There may be a potential role of adjuvant cisplatin/vinorelbine in a small subgroup of EGFR+ NSCLC patients whose tumor harbors retinoblastoma (RB) gene alterations but requires further investigation.

Efficacy and safety of adjuvant EGFR-TKIs for resected non-small cell lung cancer: a systematic review and meta-analysis based on randomized control trials

BackgroundPostoperative adjuvant cisplatin-based chemotherapy had been the standard care in patients with completely resected high-risk stage IB to IIIA non-small cell lung cancer (NSCLC) for decades. However, the survival benefits were far from satisfactory in clinical practice. Thus, this meta-analysis was performed to compare the efficacy and safety of adjuvant epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with resected NSCLC based on updated literature and research.MethodsA systematic literature search based on random control trials (RCTs) was conducted with keywords on PubMed, Embase and the Cochrane library databases. All articles compared EGFR-TKIs to placebo or chemotherapy as adjuvant therapies for early-stage resected NSCLC. A meta-analysis was performed to generate combined hazard ratio (HR) with 95% confidence intervals (CI) for disease-free survival (DFS), overall survival (OS), and risk ratio (RR) with 95% CI for disease recurrence and adverse events (AEs). The Stata statistical software (version 14.0) was used to synthesis the data.ResultsA total of 9 RCTs comprising 3098 patients were included. Adjuvant EGFR-TKIs could significantly prolong DFS in patient with resected NSCLC harboring epidermal growth factor receptor (EGFR) mutations (HR 0.46, 95% CI 0.29–0.72), but had no impact on OS (HR 0.87, 95% CI 0.69–1.11). The subgroup analyses indicated that adjuvant EGFR-TKIs were superior in regard to DFS in most subgroups, including varied smoking status, EGFR mutations type, gender, age, Eastern Cooperative Oncology Group performance status and adenocarcinoma. Osimertinib resulted in decreased brain recurrence than first generation of EGFR-TKIs (RR 0.12, 95% CI 0.04–0.34 vs. RR 1.07, 95% CI 0.64–1.78, respectively). The AEs were generally manageable and tolerable. The incidence of high-grade (≥ 3) AEs including diarrhea (RR 5.68, 95% CI 2.94–10.98) and rash (RR 27.74, 95% CI 11.43–67.30) increased after adjuvant EGFR-TKIs treatment.ConclusionsAdjuvant EGFR-TKIs therapy could significantly prolong DFS in patients with completely resected early-stage EGFR mutation-positive NSCLC, but had no impact on OS. Adjuvant EGFR-TKIs could be an important treatment option in patients with resected early-stage EGFR-mutant NSCLC.

Treatment Effectiveness and Tolerability of Long-term Adjuvant First- and Second-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor at Different Doses in Patients With Stage IIA-IIIB Epidermal Growth Factor Receptor-Mutated Lung Adenocarcinoma: A Retrospective Study.

IntroductionFor patients with epidermal growth factor receptor (EGFR)-mutated lung cancer who undergo surgery, adjuvant tyrosine kinase inhibitor (TKI) therapy other than osimertinib is an alternative option. We aimed to discuss the long-term safety and efficacy of TKI treatment in real-world data.MethodsFrom January 2011 to May 2020, patients with stage II–III EGFR-mutated adenocarcinoma who underwent cancer resection surgery at a single center were enrolled. The primary endpoint was disease relapse, and the secondary endpoint was overall survival. In total, 30 patients were included in the study. In our study, all patients underwent complete resection using video-assisted thoracoscopic surgery. The patients were divided into a dose interruption (prolonged interval use) group and non-dose adjustment group.ResultsThe patients' pathological stages were II–III. The initial EGFR TKIs were mostly gefitinib (n = 25, 83%), and others were erlotinib (n = 3, 10%) and afatinib (n = 2, 6%). The mean disease-free survival (DFS) was 53.3 months. The 2- and 5-year DFS rate was 90.0 and 73.3%, respectively. The median TKI treatment duration in this study was 44.5 months (range, 6–133 months), which was the longest in the literature review. Of these patients, nine had dose interruption. We compared the two groups and found no treatment differences between them. There were no significant side effect potentials between both groups.ConclusionTo our knowledge, this study provides the longest experience of TKI in patients with resected EGFR mutations and also provided a dose reduction strategy (prolonged medication interval) for patients who had intolerable side effects.

Does the Adjuvant Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor Change the Natural History of Resected EGFR Mutation-Positive Non-Small Cell Lung Cancer? Is it for Prime Time?

Does the Adjuvant Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor Change the Natural History of Resected EGFR Mutation-Positive Non-Small Cell Lung Cancer? Is it for Prime Time?

Osimertinib in Resected EGFR-Mutated Non–Small-Cell Lung Cancer

BackgroundOsimertinib is standard-of-care therapy for previously untreated epidermal growth factor receptor (EGFR) mutation–positive advanced non–small-cell lung cancer (NSCLC). The efficacy and safety of osimertinib as adjuvant therapy are unknown.MethodsIn this double-blind, phase 3 trial, we randomly assigned patients with completely resected EGFR mutation–positive NSCLC in a 1:1 ratio to receive either osimertinib (80 mg once daily) or placebo for 3 years. The primary end point was disease-free survival among patients with stage II to IIIA disease (according to investigator assessment). The secondary end points included disease-free survival in the overall population of patients with stage IB to IIIA disease, overall survival, and safety.ResultsA total of 682 patients underwent randomization (339 to the osimertinib group and 343 to the placebo group). At 24 months, 90% of the patients with stage II to IIIA disease in the osimertinib group (95% confidence interval [CI], 84 to 93) and 44% of those in the placebo group (95% CI, 37 to 51) were alive and disease-free (overall hazard ratio for disease recurrence or death, 0.17; 99.06% CI, 0.11 to 0.26; P<0.001). In the overall population, 89% of the patients in the osimertinib group (95% CI, 85 to 92) and 52% of those in the placebo group (95% CI, 46 to 58) were alive and disease-free at 24 months (overall hazard ratio for disease recurrence or death, 0.20; 99.12% CI, 0.14 to 0.30; P<0.001). At 24 months, 98% of the patients in the osimertinib group (95% CI, 95 to 99) and 85% of those in the placebo group (95% CI, 80 to 89) were alive and did not have central nervous system disease (overall hazard ratio for disease recurrence or death, 0.18; 95% CI, 0.10 to 0.33). Overall survival data were immature; 29 patients died (9 in the osimertinib group and 20 in the placebo group). No new safety concerns were noted.ConclusionsIn patients with stage IB to IIIA EGFR mutation–positive NSCLC, disease-free survival was significantly longer among those who received osimertinib than among those who received placebo. (Funded by AstraZeneca; ADAURA ClinicalTrials.gov number, NCT02511106.)

SRC-homology 2 domain-containing phosphatase 2 (SHP2) in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD).

9540 Background: Epidermal growth factor (EGFR)-mutant lung adenocarcinomas (LUADs) display impaired phosphorylation of extracellular signal-regulated kinase (ERK) and SRC-homology 2 domain-containing phosphatase 2 (SHP2) in comparison with EGFR wild-type LUADs. However, the function of SHP2 in early EGFR-mutant LUADs and EGFR wild-type LUADs has not been reported. We posit that SHP2 mRNA expression could be a predictive marker in resected EGFR-mutant LUADs versus EGFR wild-type patients (pts). Methods: We examined 267 resected LUADs from Japan and Spain. mRNA expression levels of AXL, MET, CDCP1, STAT3, YAP1 and SHP2 were analyzed by quantitative reverse transcriptase polymerase chain reaction (PCR). EGFR mutant cell lines were investigated for their activity of SHP2. Results: Among the 267 enrolled pts, 100 (37.3%) were EGFR-mutant LUADs. Five-year recurrence-free survival (RFS) and overall survival (OS) were lower for EGFR-mutant LUADs with high SHP2 mRNA levels (hazard ratio = 1.83 and 2.28, respectively. p = 0.03 and p = 0.04). However, SHP2 was not associated with RFS nor OS in the 167 wild-type EGFR LUADs. In EGFR-mutant cells, RMC-4550 (SHP2 inhibitor) plus erlotinib showed synergism via inhibition of AKT (S473) and ERK1/2 (T202/Y204). While erlotinib translocates SHP2 (Y542) into the nucleus, either RMC-4550 alone, or in combination with erlotinib, relocalizes SHP2 into the cytoplasm membrane, limiting AKT and ERK activation. Conclusions: High SHP2 mRNA is related to shorter RFS and OS in EGFR-mutant LUADs, but not in EGFR wild-type LUADs. The findings indicate that the addition of SHP2 inhibitors could improve adjuvant therapy in EGFR-mutant LUADs.

Genetic alteration profile of EGFR-mutant resected IIB-IIIA stage NSCLC and correlation to clinical outcomes.

Genetic alteration profile of epidermal growth factor receptor (EGFR) mutant resected non-small cell lung cancer (NSCLC) and its relationship with clinical outcomes remains to be illustrated and genetic biomarkers that can predict recurrence need to be figured out. Clinicopathological and follow-up information were collected for 99 EGFR-mutant resected NSCLC. Tumor sections were collected for genetic alteration detection. Targeted next-generation sequencing (NGS) was performed to detect somatic mutations within each sample using a 285-gene panel on the Ion Torrent platform. Concurrent driver gene mutations were detected in 86 participants. Adjuvant therapy was a positive factor in disease-free survival (DFS) period, and patients receiving tyrosine kinase inhibitors (TKIs) gained the longest DFS. A total of 34 concurrent mutant driver genes were found. The median number of mutated driver genes for each sample was 2 (range, 0-12). TP53 and NOTCH1 were the most frequent concurrent mutant driver genes with rates of 53.54% and 25.25% respectively. The number of concurrent mutant genes did not have a significant effect on recurrence. Multivariable analysis found that mutations of ATM (P=0.021), KIT (P=0.002), FGFR2 (P<0.001), MET (P=0.015), PDGFRA (P=0.042), RB1 (P=0.006), and wildtype NOTCH1 (P=0.032), ERBB4 (P=0.012), FGFR3 (P=0.035) were independent risk factors for the recurrence of resected EGFR mutant NSCLC. TP53 and NOTCH1 was the most common concurrent mutant driver gene. Mutations of ATM, KIT, FGFR2, MET, PDGFRA, RB1, and wildtype NOTCH1, ERBB4, FGFR3 were independent risk factors for the recurrence of resected EGFR mutant NSCLC.

Mutation Profile of Resected EGFR-Mutated Lung Adenocarcinoma by Next-Generation Sequencing.

The efficacy of adjuvant targeted therapy for operable lung cancer is still under debate. Comprehensive genetic profiling is needed for detecting co-mutations in resected epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma (ADC), which may interfere the efficacy of adjuvant tyrosine kinase inhibitor (TKI) treatment. Mutation profiling of 416 cancer-relevant genes was conducted for 139 resected stage I-IIIa lung ADCs with EGFR mutations using targeted next-generation sequencing. Co-mutation profiles were systematically analyzed. Rare EGFR alterations other than exon 19 deletion and L858R, such as L861Q (∼3%) and G719A (∼2%), were identified at low frequencies. Approximately 10% of patients had mutations in EGFR exon 20 that could confer resistance to first-generation TKIs. Ninety-one percent of patients harbored at least one co-mutation in addition to the major EGFR mutation. TP53 was the top mutated gene and was found more frequently mutated at later stage. Markedly, NF1 mutations were found only in stage II-III ADCs. Conversely, RB1 mutations were more frequent in stage I ADCs, whereas APC mutations were observed exclusively in this group. Thirty-four percent of patients with EGFR TKI-sensitizing mutations had genetic alterations involving EGFR downstream effectors or bypass pathways that could affect the response to EGFR TKIs, such as PIK3CA, BRCA1, and NOTCH1. Operable lung ADCs with EGFR TKI-sensitizing mutations are associated with a high proportion of co-mutations. Mutation profiling of these resected tumors could facilitate in determining the applicability and efficacy of adjuvant EGFR TKI therapeutic strategy. The efficacy of adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy for lung cancer harboring EGFR mutation after surgical resection is still under debate. Next-generation sequencing of 416 cancer-relevant genes in 139 resected lung cancers revealed the co-mutational landscape with background EGFR mutation. Notably, the study identified potential EGFR TKI-resistant mutations in 34.71% of patients with a drug-sensitizing EGFR mutation and who were naive in terms of targeted therapy. A comprehensive mutation profiling of these resected tumors could facilitate in determining the applicability and efficacy of adjuvant EGFR TKI therapeutic strategy for these patients.

PC04.03 Adjuvant Targeted Therapy for PTS with Genomic Alterations - Yes

PC04.03 Adjuvant Targeted Therapy for PTS with Genomic Alterations - Yes

PD-L1 expression and its effect on clinical outcomes of EGFR-mutant NSCLC patients treated with EGFR-TKIs.

Objective:Epidermal growth factor receptor (EGFR) activation was reported to upregulate programmed death-ligand 1 (PD-L1) expression in lung cancer cells and subsequently contribute to immune escape, indicating its critical role in EGFR-driven lung tumors. This study characterized PD-L1 expression in patients with surgically resected EGFR-mutant non-small cell lung cancer (NSCLC). The effect of PD-L1 expression on clinical outcomes was also investigated in advanced EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors (TKIs).Methods:In total, 73 patients with surgically resected NSCLC and EGFR mutations were identified. PD-L1 expression and CD8+ tumor-infiltrating lymphocyte (TIL) density were assessed by immunohistochemistry. A literature review of publications that assessed the predictive and prognostic value of PD-L1 expression in advanced EGFR-mutant NSCLC patients treated with EGFR-TKIs was performed.Results:Nineteen (26.0%) patients were positive for PD-L1 expression, which was significantly associated with concomitant KRAS mutation (P = 0.020) and marginally associated with higher CD8+ TILs density (P = 0.056). Positive PD-L1 expression was associated with markedly inferior overall survival (OS) in multivariate analysis (P = 0.032). The combination of PD-L1 and CD8+ TILs expression could be used to stratify the population into three groups with distinct prognoses. A meta-analysis of six publications showed that positive PD-L1 expression was not associated with OS [hazard ratio (HR) = 0.90; 95% confidence interval (CI), 0.42–1.38] or progression-free survival (HR = 1.03; 95 CI, 0.73–1.33) in advanced EGFR-mutant NSCLC patients receiving EGFR-TKIs. Conclusions:PD-L1 expression tended to correlate with CD8+ TIL expression, concomitant KRAS mutation, and poor survival in surgically resected EGFR-mutant NSCLC. PD-L1 expression was neither the predictive nor the prognostic factor in advanced EGFR-mutant NSCLC patients treated with EGFR-TKIs.

67 Aggressive and unusual metastatic relapses in resected epidermal growth factor receptor (EGFR) mutant adenocarcinoma of lung: biology or chance occurrence?

67 Aggressive and unusual metastatic relapses in resected epidermal growth factor receptor (EGFR) mutant adenocarcinoma of lung: biology or chance occurrence?

Distinct Clinical Course of EGFR-Mutant Resected Lung Cancers: Results of Testing of 1118 Surgical Specimens and Effects of Adjuvant Gefitinib and Erlotinib

EGFR and KRAS mutations are mutually exclusive and predict outcomes with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment in patients with stage IV lung cancers. The clinical significance of these mutations in patients with resected stage I-III lung cancers is unclear. At our institution, resection specimens from patients with stage I-III lung adenocarcinomas are tested for the presence of EGFR or KRAS mutations during routine pathology analysis such that the results are available before consideration of adjuvant therapy. In a cohort of 1118 patients tested over 8 years, overall survival was analyzed using multivariate analysis to control for potential confounders, including age, sex, stage, and smoking history. The impact of adjuvant erlotinib or gefitinib was examined in an independent data set of patients exclusively with EGFR mutation, in which date of recurrence was recorded. In the overall population, we identified 227 KRAS (25%) and 222 EGFR (20%) mutations. Patients with EGFR-mutant lung cancers had a lower risk of death compared with those without EGFR mutations, overall survival (OS) HR 0.51 (95% confidence interval [CI]: 0.34-0.76, p < 0.001). Patients with KRAS-mutant lung cancers had similar outcomes compared with individuals with KRAS wild-type tumors, OS HR 1.17 (95% CI: 0.87-1.57, p = 0.30). A separate data set includes only patients with EGFR-mutant lung cancers identified over 10 years (n = 286). In patients with resected lung cancers and EGFR mutation, treatment with adjuvant erlotinib or gefitinib was associated with a lower risk of recurrence or death, disease-free survival HR 0.43 (95% CI: 0.26-0.72, p = 0.001), and a trend toward improved OS. Patients with resected stage I-III lung cancers and EGFR mutation have a lower risk of death compared with patients without EGFR mutation. This may be because of treatment with EGFR TKIs. Patients with, and without KRAS mutation have similar OS. These data support reflex testing of resected lung adenocarcinomas for EGFR mutation to provide prognostic information and identify patients for enrollment on prospective clinical trials of adjuvant EGFR TKIs.

The SELECT study: A multicenter phase II trial of adjuvant erlotinib in resected epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC).

7010 Background: Cancers with activating EGFR mutations are exquisitely sensitive to EGFR tyrosine kinase inhibitors (TKIs) and retrospective data suggests adjuvant TKIs may improve outcomes in EGFR mutants. This prospective trial investigates the safety and efficacy of adjuvant erlotinib in EGFR mutation-positive NSCLC. Methods: Patients (pts) with surgically resected stage IA-IIIA NSCLC harboring activating EGFR mutations were treated with 150 mg/day of erlotinib for 2 years (y) after completion of any standard adjuvant chemotherapy and/or radiotherapy. The trial was designed to enroll 36 patients, and powered to demonstrate a primary endpoint of 2 y disease free survival (DFS) exceeding 85%, which would suggest improvement over the historically expected 70% 2 y DFS in early stage EGFR-mutant NSCLC (J Thorac Oncol 6:569). Results: Thirty-six pts were enrolled at five sites between 1/08 and 11/09; 53% stage I; 19% stage II; 28% stage IIIA. Toxicities were typical of erlotinib; no grade 4 or 5 events or pneumonitis occurred. 8 pts (22%) required one dose reduction to 100 mg/day and 5 (14%) two reductions to 50 mg/day for grade 3 or persistent grade 2 toxicities. 11 pts discontinued before 2 full years (&lt;1 month (mo) [4], 1-12 mo [2] and 12-23 mo [5]) for toxicities [6], patient preference [3], prostate cancer [1] and recurrence [1]. After a median follow-up of 2.5 y, the 2 y DFS from enrollment is 94% (95% CI 80%, 99%). 10 patients have recurred, 1 during erlotinib treatment and the others after stopping erlotinib (interval before recurrence 2 mo [1], 6-12 mo [4], &gt;12 mo [4]). Genotyping on repeat biopsies from seven of the recurrent cases is underway, as is assessment of response to subsequent erlotinib therapy. Two pts have died of recurrence: one at 1.5 y who stopped erlotinib after 1 mo for toxicity, and one at 2 y who progressed while on erlotinib. Conclusions: This is the first prospective study to report the efficacy of adjuvant erlotinib in NSCLC pts with EGFR mutations. This approach is feasible and yields excellent 2y DFS compared to historical genotype-matched controls. This trial was subsequently expanded to 100 pts to permit subgroup analysis by stage.

Impact of KRAS and EGFR Gene Mutations on Recurrence and Survival in Patients with Surgically Resected Lung Adenocarcinomas

Oncogenic gene mutations observed in lung adenocarcinomas, such as epidermal growth factor receptor (EGFR) and KRAS, have some predictive value for chemotherapeutic drugs or EGFR-tyrosine kinase inhibitors. However, the influence of these gene alterations on patients' prognosis remains controversial. We retrospectively analyzed the tumors of 180 patients with completely resected pathological stage I-III lung adenocarcinoma which harbored either KRAS codon 12 mutation or EGFR gene mutations within exons 18-21 to investigate the impact of these gene mutations on the patients' survival. Gene mutations were detected by established methods. Of 180 patients, 32 had KRAS codon 12 mutations (KRAS group), 148 had EGFR mutations within exon 18-21 (EGFR group). Pathological stage and operation mode were independent factors for disease-free survival. However, the EGFR group had better overall survival than the KRAS group (P = 0.0271). Cox proportional hazard model revealed pathological stage (P = 0.0001) and presence of EGFR gene mutations (P = 0.0408) were independent factors for overall survival. In survival after tumor recurrence, the EGFR group had a better median survival time (46.7 months) after recurrence than the KRAS group (26.0 months). In patients with completely resected lung adenocarcinomas, KRAS and EGFR gene mutation status of tumors was not associated with disease-free survival. However, the presence of an EGFR gene mutation boded well for the patient's overall survival, and thus patients with EGFR mutations have a better prognosis than those with KRAS mutations.

Impact on Disease-Free Survival of Adjuvant Erlotinib or Gefitinib in Patients with Resected Lung Adenocarcinomas that Harbor EGFR Mutations

Patients with stage IV lung adenocarcinoma and epidermal growth factor receptor (EGFR) mutation derive clinical benefit from treatment with EGFR tyrosine kinase inhibitors (TKIs). Whether treatment with TKI improves outcomes in patients with resected lung adenocarcinoma and EGFR mutation is unknown.Data were analyzed from a surgical database of patients with resected lung adenocarcinoma harboring EGFR exon 19 or 21 mutations. In a multivariate analysis, we evaluated the impact of treatment with adjuvant TKI.The cohort consists of 167 patients with completely resected stages I to III lung adenocarcinoma. Ninety-three patients (56%) had exon 19 del, 74 patients (44%) had exon 21 mutations, and 56 patients (33%) received perioperative TKI. In a multivariate analysis controlling for sex, stage, type of surgery, and adjuvant platinum chemotherapy, the 2-year disease-free survival (DFS) was 89% for patients treated with adjuvant TKI compared with 72% in control group (hazard ratio = 0.53; 95% confidence interval: 0.28-1.03; p = 0.06). The 2-year overall survival was 96% with adjuvant EGFR TKI and 90% in the group that did not receive TKI (hazard ratio: 0.62; 95% confidence interval: 0.26-1.51; p = 0.296).Compared with patients who did not receive adjuvant TKI, we observed a trend toward improvement in DFS among individuals with resected stages I to III lung adenocarcinomas harboring mutations in EGFR exon 19 or 21 who received these agents as adjuvant therapy. Based on these data, 320 patients are needed for a randomized trial to prospectively validate this DFS benefit.

Abstract 4114: IGF-1R and EGFR expression and IGF-1R mutational status in non-small cell lung cancer (NSCLC)

Abstract Background: Lung cancer is the commonest cause of cancer related deaths worldwide and has a very poor prognosis Recent evidence indicates that epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor 1 (IGF-1R) interact in the pathogenesis of malignant epithelial tumours including lung cancer. IGF-1R suppresses apoptosis primarily through the phosphoinositide 3-kinase (PI3K) pathway. Currently, several different approaches are being investigated for targeting the IGF-1R. EGFR targeted therapies are now established in the first and second line treatment of NSCLC. Somatic mutations in the tyrosine kinase domain of a receptor can alter its activity and impact on the ability of an inhibitor to bind efficiently. To date there is limited knowledge of mutations in the IGF-1R tyrosine kinase domain. The aims of this study are (i)to examine EGFR and IGF-1R expression and (ii)to screen for mutations in the tyrosine kinase domain of the IGF-1R in a cohort of 184 NSCLC patients and to correlate the results to patient survival/pathological data. Methods: The expression of IGF-1R and EGFR were examined in a panel of cell lines and 20 resected normal/tumour matched NSCLC patient tissues(10 Adenocarcinomas (ADC) and 10 Squamous (SCC)) using Western Blot analysis. IGF-1R and EGFR expression was evaluated in 184 patients using immunohistochemistry analysis and the results were scored by a pathologist. The DNA from the same cohort of patients is being examined for mutations in the tyrosine kinase domain of the IGF1R using sequencing analysis. Results: A panel of NSCLC cell lines showed differences in IGF1R expression. In the fresh frozen resected NSCLC tumours IGF-1R and EGFR were overexpressed relative to matched normal tissues. SCC had higher levels of expression than ADC. IGF-1R 3+/2+ expression was observed in 53.8% of NSCLC with SCC having higher expression than non-SCC(62.6% versus 37.3%,p=0.0004).EGFR 3+ expression was detected in 51% of NSCLC and SCC had higher EGFR expression than non-SCC (57.4% versus 42.5%,p=0.028).A significant association was shown between IGF-1R 3+/2+ and EGFR 3+ protein expression(p &amp;lt;0.005). Patients with EGFR and IGF-1R overexpression had a poorer overall survival(p=0.04). To date 100 patients have been screened for mutations and we have detected a polymorphism(3129A &amp;gt;G) in exon 16 of IGF1R in a significantly higher proportion of NSCLC patients and than in an age/race/gender-matched disease-free control population. Conclusions: Our findings indicate a close inter-relationship between IGFR and EGFR. EGFR and IGF-1R expression alone are not independent prognostic markers in NSCLC. In contrast co-expression correlates with a poor survival. This subset of patients may benefit from treatments co-targeting IGF-1R and EGFR. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4114.