Third generation EGFR TKIs: current data and future directions

Tan et al. Molecular Cancer (2018) 17:29 https://doi.org/10.1186/s12943-018-0778-0 REVIEW Open Access Third generation EGFR TKIs: current data and future directions Chee-Seng Tan 1, Nesaretnam Barr Kumarakulasinghe1, Yi-Qing Huang1, Yvonne Li En Ang1, Joan Rou-En Choo1, Boon-Cher Goh1,2,3 and Ross A. Soo1,2,4* Abstract Acquired T790 M mutation is the commonest cause of resistance for advanced non-small cell lung cancer (NSCLC) epidermal growth factor receptor (EGFR) mutant patients who had progressed after first line EGFR TKI (tyrosine kinase inhibitor). Several third generation EGFR TKIs which are EGFR mutant selective and wild-type (WT) sparing were developed to treat these patients with T790 M acquired resistant mutation. Osimertinib is one of the third generation EGFR TKIs and is currently the most advanced in clinical development. Unfortunately, despite good initial response, patients who was treated with third generation EGFR TKI would develop acquired resistance and several mechanisms had been identified and the commonest being C797S mutation at exon 20. Several novel treatment options were being developed for patients who had progressed on third generation EGFR TKI but they are still in the early phase of development. Osimertinib under FLAURA study had been shown to have better progression-free survival over first generation EGFR TKI in the first line setting and likely will become the new standard of care. Keywords: Third generation EGFR TKI, T790 M, Osimertinib, Resistance mechanism, FLAURA, Sequencing Background In 2009, the IPASS study established the superiority of gefitinib over chemotherapy for metastatic non-small cell lung cancer (NSCLC) patients with sensitizing epidermal growth factor receptor (EGFR) mutations [1]. Several first line phase III studies on first (gefitinib, erlotinib) and second (afatinib, dacomitinib) generation EGFR TKIs showed objective response rate and progression free survival (PFS) of patients with sensitizing EGFR to be 60–70% and 9 to 15 months, respectively [1–8]. Despite the initial high response rates, patients on EGFR TKIs will inevitably become resistant to treatment. Various mechanisms of acquired resistance have been identified and these can be divided into secondary mutations in EGFR, the activation of alternative signaling pathways, and phenotypic or histologic transformation [9–11]. The commonest mechanism of acquired * Correspondence: 1 Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, 1E Kent Ridge Road, NUHS Tower Block, Level 7, Singapore 119228, Singapore 2 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore Full list of author information is available at the end of the article resistance is T790 M mutation accounting for 50–60% of secondary resistance to primary EGFR TKI therapy [12]. This is also the basis for the development of third generation EGFR TKIs. The full discussion on the acquired mechanisms of resistance to first and second generation EGFR TKIs is beyond the scope of this article. Please refer to the following articles for a comprehensive review on this topic [9, 13]. Third generation TKIs Given the limited efficacy of second generation TKIs in circumventing T790 M resistance to first generation TKIs, third generation TKIs were developed. These include osimertinib, EGF816, olmutinib, PF-06747775, YH5448, avitinib and rociletinib. The defining characteristic of these third generation agents is that they have significantly greater activity in EGFR mutant cells than in EGFR WT cells, making them mutant-selective [14]. The only approved third generation TKI is osimertinib. In the rest of this article, we will review the preclinical and clinical data surrounding osimertinib and other third generation EGFR TKIs, as well as future challenges © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Tan et al. Molecular Cancer (2018) 17:29 on the evaluation and treatment of resistance that arises from these third generation EGFR TKIs. Osimertinib: pre-clinical and clinical data Osimertinib, an oral third-generation EGFR TKI selectively and irreversibly targets both sensitizing EGFR mutations as well as T790 M while sparing the wild-type EGFR tyrosine kinase [15]. Osimertinib, a mono-anilinopyrimidine compound is less potent at inhibiting phosphorylation of EGFR in wild-type cell lines with close to 200 times greater potency against L858R/T790 M than wild-type EGFR [15]. In preclinical studies, osimertinib demonstrated impressive activity in xenograft and transgenic murine tumor models with both profound and sustained tumor regression [15]. In addition, osimertinib also induced sustained tumor regression in an EGFRmutated mouse brain metastases model [16]. The Phase I/II AURA trial was conducted to determine the safety and efficacy of osimertinib in patients (n = 252) who progressed on initial EGFR TKIs [17]. Diarrhea was the most frequent toxicity (47%), followed by rash (40%), nausea and decreased appetite (21%). Despite G3 or higher toxicities noted in 32% of patients, only 7% and 6% of patients required a dose reduction or drug discontinuation. Of interest, 6 cases of potential pneumonitis-like events were reported. All 6 patients discontinued osimertinib. With regards to efficacy, the ORR was 51% and an impressive disease control rate (DCR) of 84%. And the median PFS was 8.2 months. As expected, the subgroup of T790 M-positive patients (N = 127) had an excellent DCR of 95%, ORR of 61% and median PFS of 9.6 months. Activity was lower in patients (n = 61) without EGFR T790 M mutations with an ORR and PFS of 21% and 2.8 months (95% confidence interval (CI) 2.1–4.3) respectively. Following the encouraging efficacy and safety date from the initial AURA Phase I/II study, the single arm, multi-center phase II Aura 2 study was conducted with osimertinib at 80 mg orally daily [18]. All patients (n = 210) had advanced NSCLC harboring EGFR T790 M mutations that was centrally confirmed and had progressed on prior EGFR TKI therapy. The ORR was 70% with 3% complete responses and a DCR of 92%. The median PFS was 9.9 months (95% CI 8.5–12.3) with a median duration of response of 11.4 months. Overall, toxicities were manageable with the most common possibly treatment-related grade 3 or 4 AEs were prolonged electrocardiogram QT (2%), neutropenia (1%) an (...truncated)