Non-small Cell Lung Cancer Harboring EGFR Mutations Research Articles

PC03.01 Adjuvant Therapy for Resected NSCLC Harboring EGFR Mutation, Chemotherapy or Targeted Therapy - PROs

Lung cancer is so far the leading cause of cancer death worldwide. Complete surgical resection remains the most effective approach for patients with early-stage non-small cell lung cancer (NSCLC). Patients with completely resected stage I NSCLC could have a 5-year survival of ∼80%, whereas it fails to ∼30%. Since 2003, adjuvant chemotherapy became the standard of care showing 4% absolute 5-year survival benefit compared to surgery alone [1]. Following randomized control trials revealed similar results [2-4], yet limited survival benefit, low therapeutic completed rate plus high toxicities rate may somehow hinder its clinical applicability. In the past decade, targeted therapies had achieved tremendous success in oncogene-driven advanced NSCLC showing both high efficacy and low toxicities [5]. As a matter of course, targeted therapy had its baby steps in early-stage NSCLC. However, no positive results were found in these trials which should probably be blame for large proportion of stage IB patients and incorrect detection methods for EGFR mutation. Besides, conservative trial design without head to head comparison could not fully address toxicities issues caused by chemotherapy. Precise target population seemed to be an essential key point to adjuvant targeted therapies and ADJUVANT as well as EVAN trial came into being [6, 7]. Although overall survival (OS) was not mature enough to measure, significantly prolonged disease-free survival (DFS) was observed in both trials along with better tolerability. Indeed, questioning around adjuvant targeted therapy has never been adjourned such as the optimal duration of targeted therapies, study design and lack of OS data. Ross et al brought up with an informative comment for ADJUVANT trial bringing the concept of MRD (molecular residual disease) into adjuvant treatment [8]. Based on the ctDNA testing after standard of care adjuvant chemotherapy, patients of high risk of recurrence will be given further treatments while observation for the others. It highlighted the significant role of discriminating beneficiaries from adjuvant targeted therapies instead of simply providing more efficient treatment modalities. Previous biomarker-based studies regarding adjuvant treatment among different tumor types [9, 10] had provided inspirational examples, and as well shown clinical feasibility and urgent need for personalized adjuvant treatment after complete surgical resection. For ADJUVANT trial, we established a comprehensive signature of genetic-features (MEDUSA) to guide personalized adjuvant treatment in EGFR-mutant stage II-III NSCLC. Results would be unleashed in upcoming ESMO meeting. Through utilizing multi-omics data, we could predict whether additional treatments, adjuvant chemotherapy only or observation would be adequate for each individual and provide optimal sequential treatments. Further translational researches and corresponding trials regarding resectable NSCLC should decipher the issues. Fortunately, several trials regarding dynamic monitoring postoperative ctDNA or genomic profile of primary cancer to guide sequential treatments are ongoing and the results should be expected. 1. Arriagada R, Bergman B, Dunant A et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004; 350: 351-360. 2. Winton T, Livingston R, Johnson D et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005; 352: 2589-2597. 3. Strauss GM, Herndon JE, 2nd, Maddaus MA et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008; 26: 5043-5051. 4. Douillard JY, Rosell R, De Lena M et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 2006; 7: 719-727. 5. Hirsch FR, Scagliotti GV, Mulshine JL et al. Lung cancer: current therapies and new targeted treatments. Lancet 2017; 389: 299-311. 6. Zhong WZ, Wang Q, Mao WM et al. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study. Lancet Oncol 2018; 19: 139-148. 7. Yue D, Xu S, Wang Q et al. Erlotinib versus vinorelbine plus cisplatin as adjuvant therapy in Chinese patients with stage IIIA EGFR mutation-positive non-small-cell lung cancer (EVAN): a randomised, open-label, phase 2 trial. Lancet Respir Med 2018; 6: 863-873. 8. Ng TL, Camidge DR. Lung cancer's real adjuvant EGFR targeted therapy questions. Lancet Oncol 2018; 19: 15-17. 9. Sparano JA, Gray RJ, Makower DF et al. Prospective Validation of a 21-Gene Expression Assay in Breast Cancer. N Engl J Med 2015; 373: 2005-2014. 10. Dienstmann R, Salazar R, Tabernero J. Personalizing colon cancer adjuvant therapy: selecting optimal treatments for individual patients. J Clin Oncol 2015; 33: 1787-1796. Adjuvant therapy, EGFR-TKI, Lung cancer

A meta-analysis of adjuvant EGFR-TKIs for patients with resected non-small cell lung cancer

ObjectivesWe performed this meta-analysis to compare adjuvant EGFR-TKIs with a placebo or adjuvant chemotherapy among patients with resected non-small cell lung cancer (NSCLC). Materials and MethodsA literature search was performed using relevant keywords. All randomized controlled trials (RCTs) that compared the survival benefits of adjuvant EGFR-TKIs with those of placebo or adjuvant chemotherapy for resected NSCLC were eligible for inclusion. ResultsThe literature search yielded five eligible RCTs including three RCTs that compared adjuvant EGFR-TKIs with a placebo, and two RCTs that compared adjuvant EGFR-TKIs with chemotherapy. For unselected intent-to-treat patients who received adjuvant EGFR-TKIs versus a placebo, the hazard ratio (HR) of disease-free survival (DFS) was 0.88 (95% confidence interval (CI): 0.59–1.32; P = 0.54). For patients with an EGFR mutation, the DFS after adjuvant EGFR-TKIs was superior to that after a placebo, with a HR of 0.59 (95% CI: 0.40–0.88; P = 0.009). For patients with an EGFR mutation, the DFS after EGFR-TKIs was greater than that after chemotherapy, with a HR of 0.42 (95% CI: 0.19–0.93; P = 0.03). For patients with wild-type EGFR, the DFS of adjuvant EGFR-TKIs was similar to the placebo, with a RR of 1.00 (95% CI: 0.62–1.60; P = 0.99). Treatment with EGFR-TKIs resulted in more adverse events compared with the placebo, with a risk ratio (RR) of 2.72, (95% CI: 2.23–3.33; P < 0.00001), but fewer adverse events compared with chemotherapy, with an RR of 0.26 (95% CI: 0.18–0.38; P < 0.00001). ConclusionsFor patients with resected NSCLC harboring EGFR mutations, treatment with an adjuvant EGFR-TKI was superior to that of a placebo or chemotherapy in terms of DFS. Treatment with adjuvant EGFR-TKIs were not effective among patients with wild type EGFR NSCLC.

Comparing the efficacy of concurrent EGFR-TKI and whole-brain radiotherapy vs EGFR-TKI alone as a first-line therapy for advanced EGFR-mutated non-small-cell lung cancer with brain metastases: a retrospective cohort study.

BackgroundNon-small-cell lung cancer (NSCLC) is a global public health problem, and brain is a common metastatic site in advanced NSCLC. Currently, whole-brain radiotherapy (WBRT) remains a major treatment for brain metastases, while EGFR-tyrosine kinase inhibitor (TKI) is the standard treatment for advanced NSCLC harboring EGFR mutations, which is also effective for brain metastases. However, whether EGFR-TKIs plus radiotherapy is superior to EGFR-TKIs alone for the treatment of advanced EGFR-mutant NSCLS with brain metastases remains controversial. This study aimed to compare the efficacy of concurrent EGFR-TKIs and WBRT vs EGFR-TKI alone in a retrospective cohort of advanced EGFR-mutant NSCLS with brain metastases.Patients and methodsThe medical records of 104 treatment-naïve, advanced EGFR-mutant NSCLC patients with brain metastases were retrospectively reviewed, and there were 56 patients undergoing concurrent EGFR-TKI and WBRT, and 48 patients given EGFR-TKI alone, including 20 cases with salvage WBRT upon brain metastasis progression. The survival prognosis was compared between the two cohorts.ResultsThe baseline clinicopathologic factors were balanced between the two cohorts. After a median follow-up of 23 months, 35.6% of the study subjects survived. Concurrent EGFR-TKI and WBRT significantly improved the median intracranial PFS (iPFS) compared with EGFR-TKI alone (17.7 vs 11.0 months, P=0.015); however, no significant difference was seen in median overall survival between the two cohorts (28.1 vs 24.0 months, P=0.756). In addition, the median iPFS was found to significantly vary in the number of brain metastases (≤3 vs>3 metastases: 18.0 vs 12.5 months, P=0.044). Subgroup analysis showed that concurrent EGFR-TKI and WBRT improved median iPFS compared with EGFR-TKI alone in patients with more than three brain metastases (P=0.001); however, no significant difference was observed between the two regimens in patients with three or less brain metastases (P=0.526).ConclusionOur data demonstrate that concurrent EGFR-TKI and WBRT achieves longer iPFS than EGFR-TKI alone in advanced EGFR-mutant NSCLC with brain metastases. In advanced EGFR-mutant NSCLC with three or less brain metastases, EGFR-TKI alone may be an option as a first-line therapy.

Comparison of the efficacies of first-generation epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in patients with advanced non-small-cell lung cancer harboring EGFR mutations

BackgroundCompared with standard chemotherapy, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are more effective in patients with advanced non-small-cell lung cancer (NSCLC) harboring EGFR mutations. However, data comparing the efficacies of different EGFR−TKIs, especially regarding the presence of brain metastasis, are lacking.MethodsEGFR-TKI naive patients with recurrent or stage IIIB/IV NSCLC harboring EGFR mutations, excluding resistance mutations, were enrolled in this study. We retrospectively determined progression-free survival (PFS) using the Kaplan−Meier method with log-rank test in patients treated with either gefitinib or erlotinib, cumulative incidence of central nervous system (CNS) progression using the Fine and Gray competing risk regression model, and favorable prognostic factors for CNS progression by multivariate analysis.ResultsSeventy-seven EGFR-TKI-naive patients were started on either gefitinib (n = 55) or erlotinib (n = 22) in our hospital from April 2010 to April 2016. Among the patients with brain metastasis, PFS tended to be longer in the erlotinib than in the gefitinib group. In the analysis of cumulative incidence, the probability of CNS progression was lower in the erlotinib group than in the gefitinib group. Particularly, in a subgroup analysis of the patients with brain metastasis, there was a significant difference between the erlotinib and gefitinib groups (hazard ratio 0.25; 95% confidence interval, 0.08–0.81; p = 0.021). Of the prognostic factors for CNS progression evaluated, the absence of brain metastasis before EGFR-TKI therapy and receiving erlotinib (vs gefitinib) had a significantly favorable effect on patient prognosis.ConclusionAlthough this was a retrospective analysis involving a small sample size, erlotinib is potentially more promising than gefitinib for treatment of brain metastasis in patients with EGFR-mutant NSCLC.

PL03.06 The Future of Targeted Therapy

PL03.06 The Future of Targeted Therapy

P3.01-80 Retrospective Analysis of the Impact of EGFR T790M Mutation Detection by Re-Biopsy in Patients with NSCLC Harboring EGFR Mutations.

EGFR-TKIs show a good response to most of patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR activating mutations. However, it ultimately becomes the acquired resistance to EGFR-TKIs after various periods. We currently attempt to detect EGFR-T790M mutation by re-biopsy that induced a half of acquired resistances to them, because the third generation EGFR-TKI osimertinib had an effective response against the refractory tumors with EGFR-T790M mutations. However, the re-biopsy from tumors is relatively invasive and some cases are impossible to perform them. Therefore, it is a critical issue to select the population with EGFR-T790M mutations. In this study, we analyzed the refractory cases to initial EGFR-TKIs with successful re-biopsy samples to disclose these clinical questions. 78 advanced NSCLC patients with EGFR mutations who had successful re-biopsy samples after the resistance to initial EGFR-TKI treatment are enrolled at five institutions in Japan. We validated for the association between the emergence of EGFR-T790M mutation and their profiles, such as clinical outcomes with EGFR-TKI treatment and EGFR activating mutation status. s Of 78 advanced NSCLC patients with EGFR mutations, 39 cases were EGFR-T790M positive and 39 were negative in the re-biopsy samples. Of EGFR-T790M positive patients, 2 cases achieved a complete response (CR), 33 a partial response (PR), and 4 stable disease (SD). In contrast, 1 patient experienced a CR, 19 a PR, 18 SD, and 1 progressive disease (PD) in T790M negative patients. The objective response rate was higher in patients with T790M positive mutations than in those with T790M negative mutations (89.7% versus 51.2%, p< 0.01). There were no differences between each patients in progression free survival and time to failure treated with initial EGFR-TKIs. The response to initial EGFR TKI treatment might be one of good predictors for emerging of refractory tumors with EGFR-T790M mutations. Further experiments are needed to identify them.

EGFR-TKI-based vs non-EGFR-TKI-based adjuvant therapy in resected non-small-cell lung cancer with EGFR mutations: a meta-analysis of randomized controlled trials.

PurposeThe great efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) has been identified in patients with advanced non-small-cell lung cancer (NSCLC) who harbor EGFR mutations. However, it has not yet been established in postoperative adjuvant therapy.Patients and methodsTo compare the prognosis and toxicity of EGFR-TKI-based adjuvant therapy and non-EGFR-TKI-based adjuvant therapy in resected NSCLC with sensitive EGFR mutations, we performed this meta-analysis of all eligible randomized controlled trials (RCTs).ResultsA comprehensive literature search of electronic databases (from inception to December 31, 2017) was performed. Additionally, abstracts presented at the American Society of Clinical Oncology conferences and World Conference on Lung Cancer held between January 2000 and November 2017 were searched to identify relevant trials. Disease-free survival (DFS), overall survival (OS), and grade 3 or 4 toxicities were analyzed. Five RCTs were selected, and 560 participants were included. This meta-analysis demonstrated that EGFR-TKI-based adjuvant therapy was associated with better DFS compared with non-EGFR-TKI-based therapy (HR =0.52, 95% CI 0.34–0.78, P=0.002). Pooled estimate has showed the trend of superiority of EGFR-TKI-based therapy in the aspect of OS (HR =0.65, 95% CI 0.22–1.91, P=0.43); however, the difference was not significant. The incidence rate of grade 3–4 toxicities of EGFR-TKI-based regimens was significantly higher for rash (OR =10.17, 95% CI 2.37–43.63, P=0.002) but lower for vomiting (OR =0.08, 95% CI 0.01–0.61, P=0.02).ConclusionEGFR-TKI-based therapy was associated with better DFS compared with non-EGFR-TKI-based adjuvant therapy in patients with NSCLC harboring EGFR mutations. A trend was found that EGFR-TKI-based regimen improved the OS, though the difference was not significant. Although more OS data are needed, EGFR-TKI-based treatment has the potential to be an alternative of adjuvant therapy for NSCLC with a sensitive EGFR mutation.

Association between PD-L1 expression and driver gene status in non-small-cell lung cancer: a meta-analysis.

ObjectiveTo assess the association between PD-L1 expression and driver gene mutations in patients with non-small-cell lung cancer (NSCLC).MethodWe performed a meta-analysis of 26 studies (7541 patients) which were published from 2015 to 2017. Pooled odds ratios (ORs) with 95% confidence intervals (CI) were calculated to describe the correlation. Subgroup analysis was performed based on population characteristics, types of PD-L1 antibodies and quality of individual studies.ResultsA lower frequency of PD-L1 positivity was observed in NSCLCs harboring EGFR mutation (OR: 0.64, 95% CI, 0.45–0.91, p = 0.014). A negative correlation was also found at 1% (OR: 0.35, 95% CI, 0.22–0.55, p = 0.000) and 50% (OR: 0.33, 95% CI, 0.14–0.81, p = 0.015) cutoff for PD-L1 positive, elderly age group (OR: 0.56, 95% CI, 0.35–0.89, p = 0.013), female dominant group (OR: 0.55, 95% CI, 0.29–0.94, p = 0.030) and smoker dominant group (OR: 0.52, 95% CI, 0.29–0.96, p = 0.035). No significant differences in PD-L1 expression were observed among patients with different ALK, BRAF, HER2, PIK3CA status and MET expression level. Higher level of PD-L1 was found in tumors with KRAS mutation (OR: 1.45, 95% CI, 1.18–1.80, p = 0.001). PD-L1 expression level was not significantly different between triple (EGFR/ALK/KRAS) wild type NSCLCs and those with EGFR/ALK/KRAS mutation.ConclusionsPD-L1 expression in EGFR mutated NSCLCs were lower than those in EGFR wild type NSCLCs, while tumors with KRAS mutation showed higher levels of PD-L1.

P2.03-014 A Phase I Study of Afatinib for Patients Aged 75 or Older with Advanced NSCLC Harboring EGFR Mutations

The efficacy and safety of afatinib therapy among elderly (aged 75 or older) populations diagnosed with EGFR-mutated non-small cell lung cancer (NSCLC) has not been evaluated yet. This phase I trial was conducted to determine the maximum tolerated dose (MTD), recommended phase II dose of afatinib in elderly patients with advanced NSCLC harboring EGFR mutations.

Impact of EGFR mutation status on clinical outcome of nintedanib plus docetaxel in patients with previously treated non-small cell lung cancer (NSCLC): Retrospective analysis of Korean nintedanib named-patient usage (NPU) program in NSCLC (KCSG LU14-2).

e20638 Background: Anti-angiogenic agents have been reported to have clinical activity for NSCLC harboring EGFR mutation (mutEGFR) with/without EGFR Tyrosine kinase inhibitor (TKI). We report clinical outcomes of nintedanib plus docetaxel for refractory NSCLC patients conducted by virtue of Korean NPU program. Methods: Patients with NSCLC were eligible if they failed at least one prior systemic treatment. Docetaxel was administered with 75 or 60mg/m2 on D1 or 37.5mg/m2 on D1, D8 every 3 weeks plus nintedanib 200mg orally twice daily. Nintedanib treatment was continued until disease progression or unacceptable toxicity after 4-6 cycles of combination therapy. Results: Of 62 patients enrolled, 23 patients had activating EGFR mutations (14 in exon19 deletion, 7 exon21 L858R/L861Q, 1 exon20 duplication, and 1 in both exon19 deletion and exon20 T790M) and progressed during prior EGFR-TKI treatment. Of 23 patients, 22 had progressed during or after platinum doublet chemotherapy. Only for 2 patients, EGFR mutation status was unknown. The majority of patients were heavily pretreated, with 43.7% received nintedanib plus docetaxel as ≥ 4th line therapy. 4 patients had prior bevacizumab treatment. Objective response rate (ORR) was 22.9%. Median PFS and OS were 3.9 months (95% CI 3.1-4.6) and 9.5 months (95% CI 5.3-13.7), respectively. Depending on EGFR mutation status, ORR in mutEGFR group was higher than wtEGFR group (30.4% vs 20%, p= 0.50) and median PFS in mutEGFR group was significantly longer than wtEGFR group (6.1 vs 3.3 months, p= 0.008). No treatment related death was reported. Common grade 3/4 adverse events were neutropenia (58.3%) and reversible elevated liver enzyme (18.8%). Conclusions: Taken together, nintedanib plus docetaxel showed meaningful clinical activity with good tolerability for refractory NSCLC patients. Our data suggest that this combination may be a recommendable regimen for EGFR-TKI-resistant mutEGFR NSCLC.

MTE26.02 EGFR Targeted Therapies: Lessons Learned

MTE26.02 EGFR Targeted Therapies: Lessons Learned

P3.02b-063 Analysis of Survival in EGFR-Mutation-Positive Advanced Non-Small-Cell Lung Cancer Patients with Miliary Pulmonary Metastasis: Topic: EGFR Clinical

Miliary pulmonary metastasis of non-small-cell lung cancer (NSCLC) indicates hematogenous dissemination and is more frequent in patients harboring EGFR mutations, and dramatic responses are often observed after treatment with EGFR-tyrosine kinase inhibitors (TKI). The relevance between miliary pulmonary metastasis and EGFR mutation has been suggested; therefore, we analyzed the survival in patients with miliary pulmonary metastasis harboring EGFR mutations treated with EGFR-TKI. We retrospectively analyzed 269 patients diagnosed with advanced or recurrent NSCLC treated with EGFR-TKI between 2005 and 2015 identified from the electronic database at our hospital. OS and PFS were estimated using the Kaplan–Meier method. We analyzed the survival in all eligible patients and performed propensity score matching based on clinical characteristics. A total of 215 NSCLC patients harboring EGFR mutations and treated with EGFR-TKIs were included in the study. Patients had a median age of 61 years (38–88 years). With regard to EGFR-TKIs, gefitinib was administered in 167 patients (77.7%), erlotinib in 30 (14.0%), and afatinib in 1 (0.5%). PFS for EGFR-TKI was 12.5 months [95% confidence interval (CI) 9.6–13.8 months) and OS was 23.7 months (95% CI: 20.3–27.2). A total of 31 patients with miliary pulmonary metastasis were identified; propensity matching identified 29 patients from each group with similar clinical characteristics. PFS between miliary pulmonary metastasis and matched control groups was 8.2 months (95% CI, 5.2–5.0) vs. 14.3 months (95% CI, 9.6–30.0) (p = 0.02), and OS was 15.3 months (95% CI, 11.0–20.3 months) vs. 27.9 months (95% CI, 22.0–33.0 months) (p = 0.003). The response rates did not show any significant difference between the two groups. The prognosis of patients with advanced NSCLC harboring EGFR mutations with miliary pulmonary metastasis demonstrated significantly worse outcome compared with those without miliary pulmonary metastasis.

EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small Cell Lung Cancer: A Retrospective Analysis.

PD-1 inhibitors are established agents in the management of non-small cell lung cancer (NSCLC); however, only a subset of patients derives clinical benefit. To determine the activity of PD-1/PD-L1 inhibitors within clinically relevant molecular subgroups, we retrospectively evaluated response patterns among EGFR-mutant, anaplastic lymphoma kinase (ALK)-positive, and EGFR wild-type/ALK-negative patients. We identified 58 patients treated with PD-1/PD-L1 inhibitors. Objective response rates (ORR) were assessed using RECIST v1.1. PD-L1 expression and CD8(+) tumor-infiltrating lymphocytes (TIL) were evaluated by IHC. Objective responses were observed in 1 of 28 (3.6%) EGFR-mutant or ALK-positive patients versus 7 of 30 (23.3%) EGFR wild-type and ALK-negative/unknown patients (P = 0.053). The ORR among never- or light- (≤10 pack years) smokers was 4.2% versus 20.6% among heavy smokers (P = 0.123). In an independent cohort of advanced EGFR-mutant (N = 68) and ALK-positive (N = 27) patients, PD-L1 expression was observed in 24%/16%/11% and 63%/47%/26% of pre-tyrosine kinase inhibitor (TKI) biopsies using cutoffs of ≥1%, ≥5%, and ≥50% tumor cell staining, respectively. Among EGFR-mutant patients with paired, pre- and post-TKI-resistant biopsies (N = 57), PD-L1 expression levels changed after resistance in 16 (28%) patients. Concurrent PD-L1 expression (≥5%) and high levels of CD8(+) TILs (grade ≥2) were observed in only 1 pretreatment (2.1%) and 5 resistant (11.6%) EGFR-mutant specimens and was not observed in any ALK-positive, pre- or post-TKI specimens. NSCLCs harboring EGFR mutations or ALK rearrangements are associated with low ORRs to PD-1/PD-L1 inhibitors. Low rates of concurrent PD-L1 expression and CD8(+) TILs within the tumor microenvironment may underlie these clinical observations. Clin Cancer Res; 22(18); 4585-93. ©2016 AACRSee related commentary by Gettinger and Politi, p. 4539.

Next-generation EGFR/HER tyrosine kinase inhibitors for the treatment of patients with non-small-cell lung cancer harboring &lt;em&gt;EGFR&lt;/em&gt; mutations: a review of the evidence

Tyrosine kinase inhibitors (TKIs) against human epidermal growth factor receptor (EGFR/HER) family have been introduced into the clinic to treat cancers, particularly non-small-cell lung cancer (NSCLC). There have been three generations of the EGFR/HER-TKIs. First-generation EGFR/HER-TKIs, binding competitively and reversibly to the ATP-binding site of the EGFR TK domain, show a significant breakthrough treatment in selected NSCLC patients with activating EGFR mutations (actEGFRm) EGFRL858R and EGFRDel19, in terms of safety, efficacy, and quality of life. However, all those responders inevitably develop acquired resistance within 12 months, because of the EGFRT790M mutation, which prevents TKI binding to ATP-pocket of EGFR by steric hindrance. The second-generation EGFR/HER-TKIs were developed to prolong and maintain more potent response as well as overcome the resistance to the first-generation EGFR/HER-TKIs. They are different from the first-generation EGFR/HER-TKIs by covalently binding to the ATP-binding site, irreversibly blocking enzymatic activation, and targeting EGFR/HER family members, including EGFR, HER2, and HER4. Preclinically, these compounds inhibit the enzymatic activation for actEGFRm, EGFRT790M, and wtEGFR. The second-generation EGFR/HER-TKIs improve overall survival in cancer patients with actEGFRm in a modest way. However, they are not clinically active in overcoming EGFRT790M resistance, mainly because of dose-limiting toxicity due to simultaneous inhibition against wtEGFR. The third-generation EGFR/HER-TKIs selectively and irreversibly target EGFRT790M and actEGFRm while sparing wtEGFR. They yield promising efficacy in NSCLC patients with actEGFRm as well as EGFRT790M resistant to the first- and second-generation EGFR-TKIs. They also appear to have a lower incidence of toxicity due to the reduced inhibitory effect on wtEGFR. Currently, the first-generation EGFR/HER-TKIs gefitinib and erlotinib and second-generation EGFR/HER-TKI afatinib have been approved for use as the first-line treatment of metastatic NSCLC with actEGFRm. This review will summarize and evaluate a broad range of evidence of recent development of EGFR/HER-TKIs, with a focus on the second- and third-generation EGFR/HER-TKIs, in the treatment of patients with NSCLC harboring EGFR mutations.

Gli1-Mediated Regulation of Sox2 Facilitates Self-Renewal of Stem-Like Cells and Confers Resistance to EGFR Inhibitors in Non–Small Cell Lung Cancer

Non–small cell lung cancer (NSCLC) patients have very low survival rates because the current therapeutic strategies are not fully effective. Although EGFR tyrosine kinase inhibitors are effective for NSCLC patients harboring EGFR mutations, patients invariably develop resistance to these agents. Alterations in multiple signaling cascades have been associated with the development of resistance to EGFR inhibitors. Sonic Hedgehog and associated Gli transcription factors play a major role in embryonic development and have recently been found to be reactivated in NSCLC, and elevated Gli1 levels correlate with poor prognosis. The Hedgehog pathway has been implicated in the functions of cancer stem cells, although the underlying molecular mechanisms are not clear. In this context, we demonstrate that Gli1 is a strong regulator of embryonic stem cell transcription factor Sox2. Depletion of Gli1 or inhibition of the Hedgehog signaling significantly abrogated the self-renewal of stem-like side-population cells from NSCLCs as well as vascular mimicry of such cells. Gli1 was found to transcriptionally regulate Sox2 through its promoter region, and Gli1 could be detected on the Sox2 promoter. Inhibition of Hedgehog signaling appeared to work cooperatively with EGFR inhibitors in markedly reducing the viability of NSCLC cells as well as the self-renewal of stem-like cells. Thus, our study demonstrates a cooperative functioning of the EGFR signaling and Hedgehog pathways in governing the stem-like functions of NSCLC cancer stem cells and presents a novel therapeutic strategy to combat NSCLC harboring EGFR mutations.

P2-17-4 - The Relationships of pfs, pps and Tumor Response with Os in Patients with Nsclc Treated with Gefitinib as First-Line

Background: The effects of first-line chemotherapy on overall survival(OS) might be confounded by subsequent therapies in patients with non-small cell lung cancer(NSCLC) harboring EGFR mutation. We retrospectively examined whether progression-free survival(PFS), post-progression survival(PPS), or tumor response could be valid surrogate endpoints for OS after first-line chemotherapy with gefitinib in advanced NSCLC harboring EGFR mutation in our institute.Patients and methods: Between January 2006 and June 2012, 35 patients with advanced NSCLC treated with gefitinib as first-line chemotherapy were analyzed. The relationships of PFS, PPS, and tumor response with OS were analyzed at the individual level. Male/female = 11/24; Median age was 67 years(range: 45 to 88); adenocarcinoma/others = 35/0; stageIIIB/IV = 3/32; ECOG PS0/1/ ≥ 2 = 15/17/3; EGFR mutation ex19del/ex21L858R/others = 20/15/0; Number of regimens after progression 0/1/2/3/4/5/ ≥ 6 = 11/6/6/3/5/1/3.Results: Spearman rank correlation analysis and linear regression analysis showed that PPS was strongly correlated with OS(r = 0.85, P < 0.05, (R2 = 0.86), PFS was not correlated with OS(r = 0.13, P < 0.05, (R2 = 0.001). tumor shrinkage was not also correlated with OS(r = 0.08, P < 0.05, (R2 = 0.01). Performance status at the end of first-line treatment, the best response to second-line treatment, and number of regimens used after progression following first-line chemotherapy were significantly associated with PPS(P < 0.05).Conclusions: Analysis of individual-level date suggested that PPS could be used as a surrogate for OS in patients with advanced NSCLC with EGFR mutation.Our findings suggest that subsequent treatment after disease progression following first-line chemotherapy with gefitinib for the patients with advanced NSCLC harboring EGFR mutation may greatly influence OS.

Abstract 1050: Alvespimycin (17-DMAG) blocks TGFβ-induced EMT and migration in A549 lung cancer cells

Abstract Background: Transforming Growth Factor β (TGFβ) can induce Epithelial-to-Messenchymal Transition (EMT) in Non-Small Cell Lung Cancer (NSCLC) leading to increased potential to migrate and metastasize. A unique Tumor Promoting signature (TGFβ-TP97) with genes highly associated with TGFβ-induced EMT was derived from human lung cancer cell line microarray experiments. The TGFβ-TP97 EMT signature was then searched against the Connectivity Map (CMAP) dataset for drugs that induce gene expression changes opposite to those of the TGFβ-TP97 signature, and identified 17-DMAG as a compound that could potentially inhibit EMT in NSCLC cells. 17-DMAG is an Hsp90 inhibitor recently described to have a stronger antiproliferative effect in NSCLC harboring EGFR mutations over EGFR wild type lung cancers cells. Furthermore, 17-DMAG has been recently shown to prevent TGFβ induced fibrosis. Methods: A549 and A549T (A549 cells grown in the presence of TGFβ for over two weeks, that have acquired a mesenchymal/fibroblast-like phenotype) were treated with increasing concentrations of 17-DMAG, both in the absence and presence of 5ng/mL TGFβ, and proliferation was measured through GLO assay after 72 hours. The effects of 17-DMAG on TGFβ signaling was tested by Western Blotting for phosphorylated Smads and markers of TGFβ-induced EMT. 17-DMAG effects on morphology and migration were also determined through wound healing and invasion assays. Results: 1) A549T cells grown in TGFβ are more sensitive to the effects of 17-DMAG than cells grown without TGFβ; 2) Pre-treatment of A549 cells with 17-DMAG blocks the induction of EMT markers such as Snail and the downregulation of Ecadherin; 3) 17-DMAG blocks TGFβ-induced phosphorylation of SMAD2, SMAD3; and 4) 17-DMAG inhibits migration and decreases motility of A549 cells in the presence of TGFβ. Conclusion: These results show that 17-DMAG is a potent inhibitor of the effects of TGFβ-induced EMT in A549 cells. It interferes with the regulated process of TGFβ signaling by its ability to block Smad activation and induction of EMT proteins. These findings suggest that 17-DMAG can potentially be used in the treatment of NSCLC cells to prevent disease dissemination and invasion. Citation Format: Edna Gordian, Eric Welsh, Teresita Muñoz-Antonia. Alvespimycin (17-DMAG) blocks TGFβ-induced EMT and migration in A549 lung cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1050. doi:10.1158/1538-7445.AM2014-1050

TPCA-1 Is a Direct Dual Inhibitor of STAT3 and NF-κB and Regresses Mutant EGFR-Associated Human Non–Small Cell Lung Cancers

Epidermal growth factor receptor (EGFR) is a clinical therapeutic target to treat a subset of non-small cell lung cancer (NSCLC) harboring EGFR mutants. However, some patients with a similar kind of EGFR mutation show intrinsic resistance to tyrosine kinase inhibitors (TKI). It indicates that other key molecules are involved in the survival of these cancer cells. We showed here that 2-[(aminocarbonyl)amino]-5 -(4-fluorophenyl)-3- thiophenecarboxamide (TPCA-1), a previously reported inhibitor of IκB kinases (IKK), blocked STAT3 recruitment to upstream kinases by docking into SH2 domain of STAT3 and attenuated STAT3 activity induced by cytokines and cytoplasmic tyrosine kinases. TPCA-1 is an effective inhibitor of STAT3 phosphorylation, DNA binding, and transactivation in vivo. It selectively repressed proliferation of NSCLC cells with constitutive STAT3 activation. In addition, using pharmacologic and genetic approaches, we found that both NF-κB and STAT3 could regulate the transcripts of interleukin (IL)-6 and COX-2 in NSCLC harboring EGFR mutations. Moreover, gefitinib treatment only did not efficiently suppress NF-κB and STAT3 activity. In contrast, we found that treatment with TKIs increased phosho-STAT3 level in target cells. Inhibiting EGFR, STAT3, and NF-κB by combination of TKIs with TPCA-1 showed increased sensitivity and enhanced apoptosis induced by gefitinib. Collectively, in this work, we identified TPCA-1 as a direct dual inhibitor for both IKKs and STAT3, whereas treatment targeting EGFR only could not sufficiently repress NF-κB and STAT3 pathways for lung cancers harboring mutant EGFR. Therefore, synergistic treatment of TPCA-1 with TKIs has potential to be a more effective strategy for cancers.

First-Line Gefitinib in Patients Aged 75 or Older With Advanced Non–Small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Mutations: NEJ 003 Study

Recent studies have demonstrated that first-line treatment with gefitinib, an epidermal growth factor receptor (EFGR)-targeted tyrosine kinase inhibitor, is significantly superior to standard chemotherapy for advanced non-small-cell lung cancer (NSCLC) harboring EGFR sensitive mutations. Meanwhile, the efficacy of gefitinib therapy among elderly populations diagnosed with EGFR-mutated NSCLC has not yet been elucidated. The purpose of this study was to investigate the efficacy and feasibility of gefitinib for chemotherapy-naive patients aged 75 or older with NSCLC harboring EGFR mutations; generally, these patients have no indication for treatment with platinum doublets. Chemotherapy-naive patients aged 75 years or older with performance status 0 to 1 and advanced NSCLC harboring EGFR mutations, as determined by the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method, were enrolled. The enrolled patients received 250 mg/day of gefitinib orally. Between January 2008 and May 2009, 31 patients were enrolled, all of whom were eligible. The median age was 80 (range, 75-87) years. Twenty-five patients (81%) were women, and 30 patients (97%) had adenocarcinoma. The overall response rate was 74% (95% confidence interval, 58%-91%), and the disease control rate was 90%. The median progression-free survival was 12.3 months. The common adverse events were rash, diarrhea, and liver dysfunction. One treatment-related death because of interstitial lung disease occurred. This is the first study that verified safety and efficacy of first-line treatment with gefitinib in elderly patients having advanced NSCLC with EGFR mutation. Considering its strong antitumor activity and mild toxicity, first-line gefitinib may be preferable to standard chemotherapy for this population.

First-line gefitinib for elderly patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations: A combined analysis of NEJ studies.

7563 Background: The first-line treatment with gefitinib has been established as a standard of care for advanced NSCLC patients with EGFR mutation by previous studies including NEJ002. Since the percentage of elderly population in those studies was lower than that of real situation, further validation of its usefulness for elderly patients with EGFR-mutated NSCLC is warranted. Methods: The efficacy and safety data of fit elderly patients (70 years or older with PS 0-2) with EGFR-mutated NSCLC who received the first-line gefitinib in NEJ001 (phase 2), NEJ002 (phase 3), and NEJ003 (phase 2) were combined. Same population treated with the first-line carboplatin plus paclitaxel in NEJ002 (n=34) were also examined their efficacy and safety for reference. Regarding the toxicity and quality of life (QOL), the comparison between elderly patients and younger patients (&lt; 70 years old) both treated with first-line gefitinib in NEJ002 was also performed. Results: Data from 71 patients (7 from NEJ001, 33 from NEJ002, 31 from NEJ003) treated with first-line gefitinib were combined. Patients’ characteristics were as follows; mean age: 76.8 years (range 70-89), female: 73%, never smoker: 75%, PS 0-1: 92%. Overall response rate (73.2%) and median progression-free survival (14.3 months) in this group were significantly better than those in the reference group (26.5% and 5.7 months, respectively). Despite fewer patients received second-line chemotherapy in the first-line gefitinib group, its median overall survival (30.8 months) was not inferior to that of reference group (26.4 months). Regarding toxicities such as liver dysfunction, rash, diarrhea, and pneumonitis, and QOL examined by self questionnaires, there were no difference between the elderly patients and younger patients in NEJ002. Conclusions: First-line gefitinib still achieved high efficacy with acceptable toxicity in fit elderly patients with advanced NSCLC harboring EGFR mutation. Considering that elderly patients tend to receive fewer treatment lines compared with younger patients, first-line gefitinib would be strongly recommended for this population to avoid the risk of missing its administration.