1190 Editorial Overcoming resistance to third-generation epidermal growth factor receptor tyrosine kinase inhibitor in non-small cell lung cancer Shoko Noda-Narita, Shintaro Kanda Department of Thoracic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo Correspondence to: Shintaro Kanda, MD. Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104- 0045, Japan. Email: [email protected]. Comment on: Uchibori K, Inase N, Araki M, et al. Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer. Nat Commun 2017;8:14768. Submitted Aug 31, 2017. Accepted for publication Sep 04, 2017. doi: 10.21037/tcr.2017.09.04 View this article at: http://dx.doi.org/10.21037/tcr.2017.09.04 In the treatment of non-small cell lung cancers (NSCLCs) in vivo studies (1,2). Based on the results of a phase 3 trial, with epidermal growth factor receptor (EGFR) mutations, which showed a response rate (RR) of approximately 71%, and EGFR-tyrosine kinase inhibitor (EGFR-TKI) is a key drug a progression-free survival (PFS) period of 10.1 months (3), that can prolong the survival of patients. However, resistance osimertinib obtained FDA and EMA approval for the treatment to EGFR-TKIs has become a new problem that must be of T790M-positive EGFR mutant NSCLC. solved. All patients with NSCLCs with an EGFR mutation However, third-generation EGFR-TKIs have also who have been treated with first- and second-generation created the next problem: acquired resistance to themselves. EGFR-TKIs eventually exhibit disease progression, even if In this article, we would like to describe this problem they have had a long period of response to the EGFR-TKI in detail and to discuss the promising strategies that are treatment. To overcome this resistance, various mechanisms now being investigated by many researchers, focusing on for the acquisition of the resistance to first- and second- brigatinib, an ALK inhibitor that shows activity toward generation EGFR-TKIs have been identified, including osimertinib-resistant EGFR mutant tumor cells. second site mutation in EGFR, bypass mechanism of other pathways (such as MET amplification, PIK3CA mutation, and Mechanisms of resistance to third-generation BRAF mutation), and transformation to small cell lung cancer. EGFR-TKIs T790M second site mutation is the most frequently detected mechanism in recurrent EGFR mutant NSCLCs after first- Tumors with double mutations consisting of T790M and line EGFR-TKI treatment. This second site mutation is a driver mutation that are treated with a third-generation substitution of threonine to methionine at the 790 site of EGFR-TKI eventually exhibit disease progression, even exon 20, leading structural change in the ATP binding site though they initially responded to the TKI. The mechanism of EGFR. T790M is called a “gate-keeper mutation” and is responsible for this resistance to third-generation EGFR- responsible for approximately 60% of acquired resistance to TKIs is now being investigated, and several mechanisms first- and second-generation EGFR-TKIs. that are similar to the resistance to first- and second- To overcome this most frequent mechanism of resistance, generation EGFR-TKIs conferred by the T790M mutation third-generation EGFR-TKIs have been investigated, and some have been found. The study of cell-free DNA in the AURA of these compounds have now fully conquered this problem. trial detected a C797S substitution in 6 out of 15 specimens Osimertinib, CO-1686 (rociletinib), HM61713 (olmutinib), from AZD9291 (osimertinib)-resistant patients and the loss and other third-generation EGFR-TKIs (EGF816, ASP8273) of the T790M mutation in 4 of the other specimens (4). selectively bind to the ATP binding site of T790M mutant Similar data were reported in an in vitro study investigating EGFR, and their efficacy has been shown in both in vitro and third-generation EGFR-TKI-resistant cell lines (5). © Translational Cancer Research. All rights reserved. tcr.amegroups.com Transl Cancer Res 2017;6(Suppl 7):S1187-S1190 S1188 Noda-Narita and Kanda. Overcoming resistance to 3rd generation EGFR-TKI in NSCLC The study detected 3 major acquired mutations (L718Q, not only ALK, but also other kinases, such as ROS1 and L844, and C797S) that occurred during treatment with FLT3 (8). Brigatinib is also known to show modest activity WZ4002, CO-1686, and AZD9291, although only the toward T790M mutant EGFR, and both in vitro and in vivo C797S mutation led to AZD9291 resistance. Other than data have shown the inhibition of T790M mutant tumor these EGFR point substitutions, HER2 amplification, cMET cells when brigatinib is administered at doses similar to those amplification, and other mechanisms were also detected active against ALK-rearranged NSCLC cells. In s phase 1/2 in osimertinib-resistant tumors (6). As osimertinib is now trial of brigatinib, patients with EGFR mutant NSCLCs used in clinical practice, the mechanisms of resistance are were enrolled, and a limited efficacy was demonstrated expected to become much more heterogeneous. in these patients (9). In this trial, 42 patients with EGFR Similar to the situation surrounding the acquisition of mutant NSCLCs, 39 (93%) of who had previously received the T790M mutation after first- and second-generation first-generation EGFR-TKIs, were enrolled in the phase 1 EGFR-TKI treatment, a strategy to overcome the cohort. Twenty-two of these patients (52%) had a T790M resistance conferred by the C797S mutation, which is mutation. Among the 42 patients, the response to treatment thought to be the most frequently acquired mechanism was assessed in 36 patients, with 2 patients (5.6%) exhibiting of resistance to third-generation EGFR-TKI treatment, a partial response and 14 patients (38.9%) exhibiting stable is now attracting our concerns. The cysteine residue at disease. This RR of 5.6% is quite small, compared with the the 797 site of the ATP binding pocket of EGFR forms a RR of 72% for patients with ALK-rearranged NSCLCs, covalent bond with third-generation EGFR-TKIs, and the even though half of the patients had EGFR mutant NSCLCs substitution of cysteine to serine at the 797 site obstructs that might have had mechanisms of resistance other than the bonding, resulting in resistance to those TKIs. To the T790M mutation. However, this data does confirm the overcome this mechanism of resistance, an EGFR allosteric limited efficacy of brigatinib against EGFR mutant NSCLCs. inhibitor (EAI)-045, which binds to an allosteric pocket of the EGFR structure, has been discovered and the efficacy of Efficacy of brigatinib against C797S triple this inhibitor against C797S/T790M/L858R triple mutant mutation in a preclinical study NSCLC cells when administered in combination with cetuximab has been shown (7). However, the inhibitor was Regarding the problem that EAI-045 is not effective against not effective against C797S/T790M/del19 triple mutant C797S/T790M/del19 triple mutant NSCLC cells, Uchibori NSCLC cells, since C797S/T790M/del19 triple mutant et al. screened 30 drugs to identify agents with activity EGFR has a different structure at the allosteric pocket against C797S/T790M/del19 triple mutant NSCLC cells from that of C797S/T790M/L858R triple mutant EGFR. and discovered that brigatinib, an ALK inhibitor, exhibited A “fourth-generation EGFR-TKI” that is effective against such activity. Though brigatinib was already known to have both C797S/T790M/L858R and C797S/T790M/del19 some efficacy against T790M double mutant NSCLCs, as triple mutant NSCLCs has not yet been discovered, and described above, this was the first report to indicate that further investigation is expected. brigatinib is also active against C797S/T790M/del19 triple mutant NSCLC cells, as well as T790M/del19 double Brigatinib, an ALK inhibitor harboring some mutant NSCLC cells. In the in vitro part of this study, brigatinib showed its activity toward T790M mutant EGFR activity against C797S/T790M/del19 triple mutant NSCLC Brigatinib was first investigated as an ALK inhibitor and is cells, and the growth of C797S/T790M/del19 triple mutant effective against ALK-rearranged NSCLCs that are resistant xenograft tumors in nude mice was also inhibited by to the ALK-TKI, crizotinib (8). This compound exhibited brigatinib. Furthermore, an in silico simulation showed that selectivity for the L1196M substitution in translocated brigatinib binds to the ATP binding pocket of C797S triple ALK, which is known to be a frequent mechanism of mutant EGFR. This result is interesting in that brigatinib resistance to crizotinib, in an in vitro study, and phase is the first TKI to be reported to bind to the ATP binding 1/2 trials have shown a relatively high RR of 50–70% for pocket of C797S triple mutant EGFR and to exert activity patients with ALK-rearranged NSCLC (9). A randomized against both C797S/T790M/del19 triple mutant NSCLC phase 2 trial targeting ALK-rearranged NSCLCs previously cells and C797S/T790M/L858R triple mutant cells. Thus, treated with crizotinib is presently ongoing. brigatinib might be a promising TKI for overcoming the In vitro studies of brigatinib have shown activity against resistance conferred by the C797S mutation, potentially © Translational Cancer Research. All rights reserved. tcr.amegroups.com Transl Cancer Res 2017;6(Suppl 7):S1187-S1190 Translational Cancer Research, Vol 6, Suppl 7 October 2017 S1189 enabling it to be called a “fourth-generation EGFR-TKI”. studies. The phase 1b trial of this combination regimen, However, the activity of brigatinib against C797S/ which enrolled patients who had been previously treated T790M/L858R triple mutation could not be confirmed with first-generation EGFR-TKI, reported a RR of in this preclinical in vitro study. Brigatinib was effective 32% and of 25% against T790M-positive and T790M- against C797S/T790M/L858R triple mutant cell lines to negative NSCLCs, respectively (11).