EGFR Mutation-positive Non-small Cell Research Articles

Dacomitinib versus gefitinib for the first-line treatment of advanced EGFR mutation positive non-small cell lung cancer (ARCHER 1050): A randomized, open-label phase III trial.

The full, final text of this abstract will be available at abstracts.asco.org at 7:30 AM (EDT) on Monday, June 5, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.

Tolerability and antitumor activity of ASP8273 in TKI-naive Japanese subjects with EGFR mutation–positive non-small cell lung cancer.

9037 Background: EGFR-activating mutations (eg, exon 19 deletions [ex19del], L858R) occur in ~50% of East Asian patients with non-small cell lung cancer (NSCLC) and confer sensitivity to tyrosine kinase inhibitor (TKI) treatment. ASP8273, an orally administered EGFR TKI that inhibits EGFR-activating mutations, has demonstrated clinical activity in subjects with EGFR mutation-positive (EGFRmut+) NSCLC. Methods: EGFR TKI-naïve adult subjects (≥20 yr) with EGFRmut+ NSCLC were enrolled in this single arm Phase 2 study conducted in Japan (NCT02500927). Subjects received open-label ASP8273 300 mg once daily until discontinuation criteria were met. Primary endpoint was tolerability; secondary endpoint was antitumor activity defined by RECIST v1.1. Results: A total of 31 Japanese subjects (12 M/19 F; median age 64 years [range: 31–82]) were enrolled. Based on local testing, 27 subjects had an ex19del (n = 13, 42%) or a L858R (n = 14, 45%) EGFR activating mutation; 4 subjects (13%) had other EGFR activating mutations (L861Q [n = 2], G719X [n = 2]). ASP8273 300 mg had tolerable adverse events with diarrhea and peripheral neuropathy being most common; no interstitial lung disease events were reported (Table). Across all 31 subjects, based on investigator assessment, treatment with 300 mg ASP8273 was associated with an overall response rate (ORR) of 52%, disease control rate (DCR) of 94%, and a median duration of progression-free survival (PFS) of 11.3 months (95% CI: 7.2, 15.5). In subjects with ex19del, ASP8273 300 mg was associated with an ORR of 46% and DCR of 85%; median PFS was 8.3 months (95% CI: 2.9, -). In subjects with the L858R, ASP8273 300 mg was associated with an ORR of 57% and DCR of 100%; median PFS was 15.5 months (95% CI: 7.2, 15.5). Conclusions: Once-daily ASP8273 300 mg was tolerable in TKI-naïve Japanese subjects with EGFRmut+ NSCLC and demonstrated antitumor activity. Clinical trial information: NCT02500927. [Table: see text]

OA23.06 Overall Survival (OS) of EGFR Mutation Positive Non-Small Cell Lung Cancer Patients: Real-World Treatment Patterns of 1,660 Japanese Patients

Since the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) was launched in Japan, the survival periods of advanced/recurrent EGFR mutation positive (EGFR m+) non-small cell lung cancer (NSCLC) patients have been getting longer. However, clinical factors which contributed to the extension of survival periods of these patients remain unclear. We investigated overall survival, prognostic factors and treatments patterns of EGFR m+ NSCLC patients in real-world clinical practice. This is a multi-center, observational, retrospective study. Histologically or cytologically diagnosed EGFR m+ NSCLC patients who were started first-line treatment from 1/1/2008 to 31/12/2012 were enrolled. The primary objective was the estimated OS. The secondary objectives were to determine prognostic factors, real-world treatment patterns. 1,660 EGFR m+ NSCLC patients were enrolled from 17 hospitals in Japan (median age 67.0 years, female 64.8%, 38.9% had smoking history, ECOG-performance status 0, 1, 2, 3, 4 were 39.5%, 41.1%, 7.1%, 4.9%, 0.7%, respectively, adenocarcinoma 95.2%, 50.1% exon 19 deletion, 66.7% at stage IV). Median estimated OS was 29.7 months. Cox regression analysis revealed age, smoking history, performance status, histological diagnosis, EGFR mutation type and clinical stage were independently associated with OS. Five year survival rate of stage IV patients was 13.8%. The median number of treatment regimens was two. EGFR-TKI and platinum-doublet chemotherapy were most frequently used as first- and second-line treatments. Real world treatment of the large data-set of 1,660 EGFR m+ NSCLC patients was retrospectively investigated. Median OS was 29.7 months and EGFR-TKIs are major components of the treatment regimens for these patients in Japan. (NCT0247520).

P3.02b-115 Clinical Activity of Osimertinib in EGFR Mutation Positive Non-Small Cell Lung Cancer (NSCLC) Patients (Pts) Previously Treated with Rociletinib: Topic: EGFR RES

P3.02b-115 Clinical Activity of Osimertinib in EGFR Mutation Positive Non-Small Cell Lung Cancer (NSCLC) Patients (Pts) Previously Treated with Rociletinib: Topic: EGFR RES

P3.02b-065 Third Line Therapy in EGFR Positive Advanced Non-Small Cell Lung Cancer: Topic: EGFR Clinical

This study was designed to evaluate the response and outcomes to third line chemotherapy in classic activating EGFR mutation positive non-small cell lung cancer (NSCLC) who had progressed on both TKI and intravenous chemotherapy. 85 EGFR mutation positive NSCLC patients who had received both TKI and intravenous chemotherapy (mainly Pemetrexed and platinum, 80 patients) were selected for this analysis. The treatment regimens, response in accordance with RECIST v1.1 and treatment outcomes were noted. Descriptive statistics was performed. Kaplan Meier survival analysis was used for estimation of PFS and OS. 85 patients received third line therapy of which weekly paclitaxel was given in 43 (50.6%) patients, Docetaxel in 15 (17.6%) patients, Gemcitabine in 6 (7.1%) patients, rechallenged TKI in 11 (13%) patients and other chemotherapy in 10 (11.8%) patients. Out of 85 patients, 67 were evaluable for response; 13(19.4%) patients had partial response, 34 (50.7%) patients had stable disease and 20 (29.9%) patients had progression as best response. In 7 patients chemotherapy had to be stopped. It was because of toxicity in 5 patients and patient preference in 2 patients. The median PFS & OS were 4.2 months (95% CI 3.4-4.9 months) and 8.4 months (95% CI 6.9-9.9 months) respectively. There was no difference in PFS and OS between weekly Paclitaxel and other regimens. Third line therapy in EGFR mutated patients post TKI and Pemetrexed progression is associated with meaningful PFS and OS.

The impact of osimertinib on function and health status for patients with EGFR mutation-positive advanced non-small cell lung cancer.

e20548Background: The impact of osimertinib (AZD9291) on lung cancer symptoms (cough, pain and dyspnea) has been described in phase I and phase II trials (Ryden A et al. Poster P282 European Cancer...

Abstract 3602: Cross-resistance to 1st, 2nd, and 3rd generation EGFR tyrosine kinase inhibitors in vitro is characterized by MET amplification and PTEN loss

Abstract Reversible EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib offer significant clinical benefit to patients with EGFR mutation positive non-small cell lung cancer (NSCLC) compared to chemotherapy alone, but high rates of resistance especially at EGFR T790M (50-60% of resistant cases) underscore the need for better targeted treatments for NSCLC patients. Third generation irreversible TKIs–AZD9291 and CO-1686–were developed for efficacy in the T790M setting. However, resistance to the new class of EGFR TKIs is inevitable, prompting us to investigate the relationship between erlotinib and AZD9291 resistance mechanisms and explore novel ones. NSCLC cell lines harboring activating EGFR mutations with (NCI-H1975) or without T790M (HCC4006, HCC827, and PC-9) were exposed to erlotinib, dacomitnib, or AZD9291 at IC 75 or greater for three months to generate resistance. We observed cross-resistance to other EGFR TKIs in nearly all resistant lines, suggesting that T790M was not the main driver of resistance in the erlotinib-treated lines and that a common mechanism might account for resistance in each cell line set. An epithelial to mesenchymal transition (EMT) was observed and a corresponding increase in vimentin staining was seen in resistant lines, consistent with cross-resistance. Previous studies showed that MET amplification caused erlotinib resistance in HCC827; our data suggest MET amplification also accounted for the AZD9291 and dacomitnib resistance in HCC827. In AZD9291-resistant HCC4006 and H1975 lines, PTEN levels were substantially reduced compared to the parental line, with a corresponding increase in PIK3 pathway markers. Whole exome sequencing data support homozygous deletion of PTEN loss as a mechanism of acquired resistance to AZD9291 in NCI-H1975. The PTEN null line NCI-H1650 was found to be resistant to all three TKIs without long-term drug exposure, implicating PTEN loss as a mechanism of de novo resistance. An analysis of EGFR mutation status, PTEN status, MET expression, and the kinetics of acquired resistance will be presented and clinical implications will be discussed. Citation Format: Sarah M. Paul, Dorothee Nickles, Xioafen Ye, Robert L. Yauch, David S. Shames. Cross-resistance to 1st, 2nd, and 3rd generation EGFR tyrosine kinase inhibitors in vitro is characterized by MET amplification and PTEN loss. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3602. doi:10.1158/1538-7445.AM2015-3602

Updated safety and efficacy results from phase I/II study of HM61713 in patients (pts) with EGFR mutation positive non-small cell lung cancer (NSCLC) who failed previous EGFR-tyrosine kinase inhibitor (TKI).

8084 Background: HM61713 is an orally available EGFR mutation-specific inhibitor with sparing EGFR WT tumors that previously showed promising efficacy in T790M positive tumors at the dose of 300 mg...

O10.2 - HM61713, an EGFR-mutant selective inhibitor

ABSTRACT EGFR tyrosine kinase inhibitors (TKIs) are effective for EGFR mutation positive non-small cell lung cancer (NSCLC) patients. However, acquired resistance occurs in most cases and EGFR T790M mutation is a major (>50%) resistance mechanism of first-generation EGFR TKIs. HM61713 is an orally active, EGFR-mutant selective inhibitor showed strong anti-cancer activity in EGFR mutant lung cancer cell lines including T790M mutation positive one. In addition, lower activity to wild-type EGFR inhibition suggested the possibility of decreased clinical toxicities such as skin rash and diarrhea. A phase 1/2 trial is ongoing to evaluate the safety, pharmacokinetics, and efficacy of HM61713 in patients with advanced EGFR mutation positive NSCLC who had failed to previous EGFR-TKIs (NCT01588145). In dose escalation part, the 3 + 3 dose-escalation scheme was used and the maximum tolerated dose was determined as 800 mg qd. An early expansion cohort was implemented at the dose 300 mg qd (N = 83) and the preliminary result was reported in ASCO 2014; the objective response rate was 29.2% in T790M positive patients (N = 48) and 11.8% in T790M negative population (N = 34). The disease control rate was 75.0% and 55.9%, respectively. Commonly reported adverse events (AEs) included skin exfoliation, nausea, diarrhea, rash, decreased appetite and pruritus. Most AEs were typically Gr 1/2, easily manageable and reversible without interruption of dosing. HM61713 showed good safety profile and promising anti-tumor activity in pts with EGFR mutated NSCLC who failed to EGFR-TKIs, especially in patients with T790M mutation. The phase 2 part is ongoing at the dose of 800 mg qd.

Relationship between tumor response with outcomes in EGFR mutation positive (M+) non-small cell lung cancer (NSCLC) treated with tyrosine-kinase inhibitors (TKI).

e19101 Background: The relationship between RECIST tumour measurements and clinical outcomes in EGFR mutant NSCLC is not well established. We sought to identify tumour response parameters that corr...

1340 - Phase II Study of Erlotinib in Japanese Patients with Pretreated EGFR Mutation Positive Non-Small Cell Lung Cancer: Lung Oncology Group in Kyushu, Japan (LOGIK0803)

ABSTRACT Background Erlotinib has been reported to be useful for treating EGFR mutation-positive (EGFR-mt) non-small cell lung cancer (NSCLC) (OPTIMAL ESMO 2010, EURTAC Lancet Oncol. 2012). However, its usefulness had not been investigated in Japanese patients. Hence, we conducted a multicenter phase II study to investigate the efficacy and safety of erlotinib in Japanese patients with pretreated EGFR-mt NSCLC. Methods Erlotinib, 150 mg/day, was orally administered daily to patients with pretreated EGFR-mt (exon 19/21) NSCLC who had not been treated with EGFR-TKIs. The primary endpoint was objective response rate (ORR), and the secondary endpoints were disease control rate (DCR), progression-free survival (PFS), and safety. Results Between April 2009 and January 2011, 26 patients were enrolled from 15 participating centers. The patient characteristics were as follows: median age, 68 years (51 to 79); men/women, 11/15; adenocarcinoma/others, 24/2; nonsmoking/smoking, 20/6; ECOG PS 0/1/2, 16/8/2; exon 19/21, 19/7; and 2nd/3rd line therapy, 25/1. The antitumor effect was as follows: PR, 14 patients; SD, 7 patients; PD, 4 patients; NE, 1 patient; ORR, 54%; and DCR, 81%. The ORR and DCR according to the EGFR status were 47.4%/71.4% (exon 19/21, p = 0.3913) and 73.7%/100% (p = 0.2782), respectively. The PFS was 9.3 months (range, 0.9 to 19.2 mo). Major adverse drug reactions were rash (96%) and hepatic function disorder (40%); most episodes were grade 2 or less, and all were tolerable. No patients developed interstitial lung disease, and there were no treatment-related deaths. Conclusion In this study, the usefulness of erlotinib was investigated prospectively in Japanese patients with pretreated EGFR-mt NSCLC for the first time, and this drug was shown to be effective and tolerable. At this congress, we will report the study results including the ORR and PFS according to the patient characteristics. Disclosure Y. Nakanishi: From Chugai Pharmaceutical, I received 7500 Euro as honoraria on 2011, and 22000 Euro on 2010 and 70000 Euro on 2011 as research grant. Y. Ichinose: I have research funding with Chugai Pharmaceutical company. All other authors have declared no conflicts of interest.