1st Generation EGFR Tyrosine Kinase Inhibitors Research Articles

Genomic profiling of resistant tumor samples following progression on EGF816, a third generation, mutant-selective EGFR tyrosine kinase inhibitor (TKI), in advanced non-small cell lung cancer (NSCLC).

11506 Background: Up to 60% of patients (pts) with NSCLC harboring an activating EGFR mutation (mut) and treated with a 1st generation EGFR TKI develop a secondary gatekeeper T790M mut. EGF816 is an irreversible EGFR TKI that is highly potent against activating mut (L858R, ex19del) and T790M mut, while sparing wild-type EGFR. As previously reported, in a Phase I dose escalation study, the overall response rate to EGF816 in pts with advanced EGFR T790M mut NSCLC was 47% and the disease control rate was 87%. However, pts ultimately develop disease progression. Tumor biopsies were obtained from pts who had progressed on EGF816 to identify mechanisms of resistance. Methods: Pts with NSCLC with locally or centrally confirmed T790M status were enrolled in this multicenter, dose escalation study to determine the safety, tolerability and antitumor activity of EGF816 (NCT02108964). EGF816 was administered at 7 dose levels ranging from of 75-350 mg QD. Following disease progression, a tumor sample was obtained and was analyzed by the Foundation Medicine next-generation sequencing (NGS) T7 panel, which interrogates 395 cancer-related genes for base substitutions, insertion-deletions, and copy number changes, as well as introns of 31 genes involved in rearrangements. Results: Tumor samples taken following disease progression on EGF816 were analyzed from 9 pts. Of the 8 pts whose tumors were T790M+ at baseline, this was detected in only 3 pts’ post-EGF816 progression samples. One patient developed an EGFR C797S mut and concurrent deletion in mTOR. Other identified alterations include BRAF fusions (n = 2) and c-MET amplification (n = 1). Only one patient was found to have concurrent TP53 mutation and RB1 truncating mutation. Individual patient response data, including duration of response, will be presented along with detailed genomic parameters. Conclusions: NGS analysis of tumors that developed resistance to EGF816 revealed multiple potential mechanisms of resistance. These data are hypothesis-generating and could lead to rational combination studies with EGF816 to improve the depth and/or duration of response to EGF816. Clinical trial information: NCT02108964.

Mutations in TP53, PIK3CA, PTEN and other genes in EGFR mutated lung cancers: Correlation with clinical outcomes

IntroductionThe degree and duration of response to epidermal growth factor receptor (EGFR) inhibitors in EGFR mutated lung cancer are heterogeneous. We hypothesized that the concurrent genomic landscape of these tumors, which is currently unknown in view of the prevailing single gene assay diagnostic paradigm in clinical practice, could play a role in clinical outcomes and/or mechanisms of resistance. MethodsWe retrospectively probed our institutional lung cancer database for tumors with EGFR kinase domain mutations that were also evaluated by more comprehensive molecular profiling, and evaluated tumor response to EGFR tyrosine kinase inhibitors (TKIs). ResultsOut of 171 EGFR mutated tumor-patient cases, 20 were sequenced using at least a limited comprehensive genomic profiling platform. 50% harbored concurrent TP53 mutation, 10% PIK3CA mutation, 5% PTEN mutation, among others. The response rate to EGFR TKIs, the median progression-free survival (PFS) to TKIs, the percentage of EGFR-T790M TKI resistance and survival had higher trends in EGFR mutant/TP53 wild-type cases when compared to EGFR mutant/TP53 mutant tumors (all p >0.05 without statistical significance); with a significantly longer median PFS in EGFR-exon 19 deletion mutant/TP53 wild-type cancers treated with 1st generation EGFR TKIs (p=0.035). ConclusionsConcurrent mutations, specifically TP53, are common in EGFR mutated lung cancer and may alter clinical outcomes. Additional cohorts will be needed to determine if comprehensive molecular profiling adds clinically relevant information to single gene assay identification in oncogene-driven lung cancers.

P1.02-031 Mutations in TP53, PIK3CA, PTEN and Other Genes in EGFR Mutated Lung Cancers: Correlation with Clinical Outcomes

The degree and duration of response to epidermal growth factor receptor (EGFR) inhibitors in EGFR mutated lung cancer are heterogeneous. We hypothesized that the concurrent genomic landscape of these tumors, which is currently largely unknown in view of the prevailing single gene assay diagnostic paradigm in clinical practice, could play a role in clinical outcomes and/or mechanisms of resistance. We retrospectively probed our institutional lung cancer patient database for tumors harboring EGFR kinase domain mutations that were also evaluated by more comprehensive molecular profiling, and assessed tumor response to EGFR tyrosine kinase inhibitors (TKIs). Out of 171 EGFR mutated tumor-patient cases, 20 were sequenced using at least a limited comprehensive genomic profiling platform. 50% of these harbored concurrent TP53 mutation, 10% PIK3CA mutation, and 5% PTEN mutation, among others. The response rate to EGFR TKIs, the median progression-free survival (PFS) to TKIs, the percentage of EGFR-T790M TKI resistance and survival were higher in EGFR mutant/TP53 wild-type cases when compared to EGFR mutant/TP53 mutant tumors; with a significantly longer median PFS in EGFR-exon 19 deletion mutant/TP53 wild-type cancers treated with 1st generation EGFR TKIs. Concurrent mutations, specifically TP53, are common in EGFR mutated lung cancer and may alter clinical outcomes. Additional cohorts will be needed to determine if comprehensive molecular profiling adds clinically relevant information to single gene assay identification in oncogene-driven lung cancers.

Osimertinib for EGFR T790M mutation-positive non-small cell lung cancer

ABSTRACTIntroduction: Significant advances have been made since the development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) targeting EGFR mutations in non-small-cell lung cancer (NSCLC), however, lung cancer cells eventually acquire resistance to those agents. Osimertinib (AZD9291) has been developed as 3rd generation EGFR-TKI with activities against sensitizing mutations and T790 M resistance mutation, which account for about 50% of the mechanisms of acquired resistance to 1st or 2nd generation EGFR-TKIs. A recent phase I/II clinical trial with osimertinib for advanced NSCLC patients with known sensitizing EGFR mutations and documented disease progression on prior EGFR-TKIs revealed promising effect with acceptable toxicities.Areas covered: This article summarizes current understanding and available preclinical and clinical data on osimertinib and also discusses future directions. The literature search included PubMed and the latest articles from international conferences.Expert commentary: The development of osimertinib has provided new therapeutic options for NSCLC patients harboring T790 M. Compared with other EGFR-TKIs including rociletinib, osimertinib seems to possess an advantage with respect to the effect and safety profile among existing EGFR-TKIs. However, tumor progression still occurs even when treating with osimertinib. A further understanding of the mechanisms of resistance is eagerly anticipated in order to develop next generation EGFR-TKIs.

In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer.

EGFR mutated lung cancer accounts for a significant subgroup of non-small-cell lung cancer (NSCLC). Over the last decade, multiple EGFR tyrosine kinase inhibitors (EGFR-TKIs) have been developed to target mutated EGFR. However, there is little information regarding mutation specific potency of EGFR-TKIs against various types of EGFR mutations. The purpose of this study is to establish an in vitro model to determine the "therapeutic window" of EGFR-TKIs against various types of EGFR mutations, including EGFR exon 20 insertion mutations. The potency of 1st (erlotinib), 2nd (afatinib) and 3rd (osimertinib and rociletinib) generation EGFR-TKIs was compared in vitro for human lung cancer cell lines and Ba/F3 cells, which exogenously express mutated or wild type EGFR. An in vitro model of mutation specificity was created by calculating the ratio of IC50 values between mutated and wild type EGFR. The in vitro model identified a wide therapeutic window of afatinib for exon 19 deletions and L858R and of osimertinib and rociletinib for T790M positive mutations. The results obtained with our models matched well with previously reported preclinical and clinical data. Interestingly, for EGFR exon 20 insertion mutations, most of which are known to be resistant to 1st and 2nd generation EGFR-TKIS, osimertinib was potent and presented a wide therapeutic window. To our knowledge, this is the first report that has identified the therapeutic window of osimertinib for EGFR exon 20 insertion mutations. In conclusion, this model will provide a preclinical rationale for proper selection of EGFR-TKIs against clinically-relevant EGFR mutations.

Abstract B25: A comparison of resistance mechanisms to 1st, 2nd, and 3rd generation EGFR TKIs in NSCLC

Abstract Reversible EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib offer significant clinical benefit to patients with EGFR mutation positive NSCLC compared to chemotherapy alone. In nearly all cases resistance emerges after approximately a year on therapy, often due to the EGFR T790M (50-60% of cases). Irreversible pan-HER TKIs, including dacomitnib and afatinib were developed in part to address the emergence of T790M mutations. Both molecules showed promise, but the T790M mutation is still a dominant resistance mechanism and the number and severity of adverse events in the clinic underscore the unmet need for better targeted treatments for NSCLC patients. Third generation TKIs—AZ9291 and CO-1686—were designed against activating EGFR mutations in order to spare the wild type pathway and developed for efficacy in the T790M setting. However, resistance to the new class of EGFR TKIs is inevitable, prompting us to investigate the impact of erlotinib resistance mechanisms on AZ9291 and ask what new mechanisms are involved. NSCLC cell lines harboring activating EGFR mutations with (H1975) or without T790M (HCC4006 and HCC827) were exposed to erlotinib, dacomitnib, or AZ9291 at IC 75 or greater for three months to generate resistance. The PTEN null line H1650 was found to be resistant to all three TKIs without long-term drug exposure, implicating constitutive PIK3 pathway signaling as one mechanism of resistance. In addition, AZ9291 resistance in H1975 resulted in an epithelial to mesenchymal transition (EMT) at the phenotypic level and a corresponding increase in vimentin staining, with at least a 1000-fold increase in IC 50. Preliminary results indicate both acquired and de novo mechanisms account for AZ9291 resistance in H1975. AZ9291 resistance in HCC827 resulted in resistance to erlotinib and dacomitnib, implicating either additional mutations in EGFR or in downstream genes. Expression of E-cadherin was markedly increased in the AZ9291 resistant HCC827 line. An analysis of EGFR mutation status, PTEN status, Met expression, and EMT gene expression and methylation signatures will be presented, and the possible implications for patients will be discussed. Citation Format: Sarah M. Paul, Xioafen Ye, Zora Modrusan, Somasekar Seshagiri, Robert Yauch, David S. Shames. A comparison of resistance mechanisms to 1st, 2nd, and 3rd generation EGFR TKIs in NSCLC. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B25.