The Challenges of Third-Generation EGFR Tyrosine Kinase Inhibitors in the Therapy of Advanced NSCLC

Abstract

The EGFR tyrosine kinase inhibitors (TKIs) have initiated the era of precision medicine in lung cancer. In the past two decades, EGFR TKIs have dramatically extended the overall survival (OS) of patients with advanced NSCLC with EGFR-activating mutations from less than 12 months in the chemotherapy era1Schiller J.H. Harrington D. Belani C.P. et al.Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.N Engl J Med. 2002; 346: 92-98Google Scholar to 3 years or more in the targeted therapy era.2Popat S. Osimertinib as first-line treatment in EGFR-mutated non-small-cell lung cancer.N Engl J Med. 2018; 378: 192-193Google Scholar From quinazoline-based reversible inhibitors to irreversible pan-HER inhibitors then to pyrimidine-based irreversible inhibitor, the third-generation (3G) EGFR TKIs target Thr790Met (T790M) “gatekeeper” mutation, a first-generation (1G)/second-generation (2G) TKI-resistance mutation, by a strong covalent binding to cysteine 797 residue in the adenosine triphosphate binding site of the EGFR kinase domain.3Cross D.A. Ashton S.E. Ghiorghiu S. et al.AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer.Cancer Discov. 2014; 4: 1046-1061Google Scholar So far, more than four 3G TKIs have striking clinical efficacy. Osimertinib is the first and the only 3G TKI approved by the Food and Drug Administration, European Medicines Agency, and Chinese National Medical Products Administration based on its impressive survival benefit found both in the later-line setting in patients harboring the T790M mutation4Goss G. Tsai C.M. Shepherd F.A. et al.Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study.Lancet Oncol. 2016; 17: 1643-1652Google Scholar, 5Jänne P.A. Yang J.C. Kim D.W. et al.AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer.N Engl J Med. 2015; 372: 1689-1699Google Scholar, 6Mok T.S. Wu Y.L. Ahn M.J. et al.Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.N Engl J Med. 2017; 376: 629-640Google Scholar, 7Goss G. Tsai C.M. Shepherd F.A. et al.CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials.Ann Oncol. 2018; 29: 687-693Google Scholar, 8Wu Y.L. Ahn M.J. Garassino M.C. et al.CNS efficacy of osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: data from a randomized phase III trial (AURA3).J Clin Oncol. 2018; 36: 2702-2709Google Scholar, 9Ahn M.J. Tsai C.M. Shepherd F.A. et al.Osimertinib in patients with T790M mutation-positive, advanced non-small cell lung cancer: long-term follow-up from a pooled analysis of 2 phase 2 studies.Cancer. 2019; 125: 892-901Google Scholar, 10Zhou C. Cheng Y. Lu Y. et al.CNS response to osimertinib in Asian-Pacific patients (pts) with T790M-positive advanced NSCLC: data from an open-label phase II trial (AURA17).Ann Oncol. 2017; 28: V484Google Scholar, 11Zhou C. Wang M. Cheng Y. et al.AURA17 study of osimertinib in Asia-Pacific patients (pts) with EGFR T790M-positive advanced non-small cell lung cancer (NSCLC): updated phase II results including overall survival (OS).Ann Oncol. 2018; 29: IX157Google Scholar and in treatment-naive patients.2Popat S. Osimertinib as first-line treatment in EGFR-mutated non-small-cell lung cancer.N Engl J Med. 2018; 378: 192-193Google Scholar Other 3G TKIs including almonertinib (HS-10296)12Lu S. Wang Q. Zhang G. et al.Efficacy of aumolertinib (HS-10296) in patients with advanced EGFR T790M+ NSCLC: updated post-national medical products administration approval results from the APOLLO registrational trial.J Thorac Oncol. 2022; 17: 411-422Google Scholar and furmonertinib (alflutinib/AST2818)13Shi Y. Hu X. Zhang S. et al.Efficacy, safety, and genetic analysis of furmonertinib (AST2818) in patients with EGFR T790M mutated non-small-cell lung cancer: a phase 2b, multicentre, single-arm, open-label study.Lancet Respir Med. 2021; 9: 829-839Google Scholar have been approved by the Chinese National Medical Products Administration recently for previously treated, metastatic EGFR T790M-positive NSCLC. Nevertheless, not all 3G TKIs have been successfully developed. For example, the development of rociletinib (CO-1686), olmutinib (HM61713/BI 1482694), maverlertinib (PF06747775), and naquotinib (ASP8273) has been discontinued owing to off-target toxicity and modest efficacy. Against this backdrop, Cho et al.14Cho B.C. Han J.Y. Kim S.W. et al.A phase 1/2 study of lazertinib 240 mg in patients with advanced EGFR T790M-positive non-small cell lung cancer after prior EGFR tyrosine kinase inhibitors.J Thorac Oncol. 2022; 17: 558-567Google Scholar report a phase 1/2 study of another 3G EGFR TKI lazertinib 240 mg in T790M-mutant advanced NSCLC after previous 1/2G TKI therapy in this issue of Journal of Thoracic Oncology. Lazertinib (YH25448) is a novel irreversible inhibitor selectively targeting EGFR single (exon 19 deletion [ex19del], L858R, T790M) and double (ex19del/T790M and L858R/T790M) mutations.15Yun J. Hong M.H. Kim S.Y. et al.YH25448, an irreversible EGFR-TKI with potent intracranial activity in EGFR mutant non-small cell lung cancer.Clin Cancer Res. 2019; 25: 2575-2587Google Scholar Preclinical data support the ability of lazertinib to penetrate the blood–brain barrier. In this study, lazertinib 240 mg maintained its promising clinical performance after 2 years of follow-up, exhibiting comparable efficacy with the other 3G TKIs, osimertinib, almonertinib, and alflutinib, in a similar population (Fig. 1 and Supplementary Table 1). In terms of intracranial control, lazertinib had excellent results as well with the objective response rate of 86% (6 of 7) and intracranial progression-free survival (PFS) of 26 months, which is superior to the data currently released by the other 3G TKIs. If these observations can be repeated in larger studies or in the real world in the future, lazertinib may be the drug of choice for patients with brain metastasis. The adverse event spectrum of lazertinib was comparable with that of osimertinib, with the exception that the incidence of cardiac toxicity and interstitial lung disease seemed to be less. Nevertheless, the proportions of treatment adjustments owing to adverse event were higher than that reported for the other 3G TKIs (Table 1).Table 1Comparison of the Safety of the Current 3G EGFR TKIs in Active Phase 2 to 3 Clinical DevelopmentCharacteristic (%)Osimertinib (AZD 92921)AlmonertinibFurmonertinibLazertinibAbivertinibDose80 mg once a d110 mg once a d80 mg once a d240 mg once a d300 mg twice a dStudyAURA Pooled9Ahn M.J. Tsai C.M. Shepherd F.A. et al.Osimertinib in patients with T790M mutation-positive, advanced non-small cell lung cancer: long-term follow-up from a pooled analysis of 2 phase 2 studies.Cancer. 2019; 125: 892-901Google ScholarAURA 36Mok T.S. Wu Y.L. Ahn M.J. et al.Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.N Engl J Med. 2017; 376: 629-640Google ScholarAURA 1711Zhou C. Wang M. Cheng Y. et al.AURA17 study of osimertinib in Asia-Pacific patients (pts) with EGFR T790M-positive advanced non-small cell lung cancer (NSCLC): updated phase II results including overall survival (OS).Ann Oncol. 2018; 29: IX157Google ScholarAPOLLO12Lu S. Wang Q. Zhang G. et al.Efficacy of aumolertinib (HS-10296) in patients with advanced EGFR T790M+ NSCLC: updated post-national medical products administration approval results from the APOLLO registrational trial.J Thorac Oncol. 2022; 17: 411-422Google ScholarALSC00313Shi Y. Hu X. Zhang S. et al.Efficacy, safety, and genetic analysis of furmonertinib (AST2818) in patients with EGFR T790M mutated non-small-cell lung cancer: a phase 2b, multicentre, single-arm, open-label study.Lancet Respir Med. 2021; 9: 829-839Google ScholarPhase 214Cho B.C. Han J.Y. Kim S.W. et al.A phase 1/2 study of lazertinib 240 mg in patients with advanced EGFR T790M-positive non-small cell lung cancer after prior EGFR tyrosine kinase inhibitors.J Thorac Oncol. 2022; 17: 558-567Google ScholarPhase 238Zhou Q. Wu L. Hu P. et al.A novel third generation EGFR tyrosine kinase inhibitor abivertinib for EGFR T790M mutant non-small cell lung cancer: a multicenter phase1/2 study.Clin Cancer Res. 2022; (https://doi.org/10.1158/1078-0432.CCR-21-2595. Accessed November 4, 2021)Google ScholarSample size (n)41127917124422078227Grade ≥3 AE (all/causally related)46/1623/625/1133.6/16.426/1134.6/14.155.9/32.6Serious AE (all/causally related)39/718/316/421.3/6.124/524.4/3.833.9/13.7Discontinuation owing to AE9746.147.77.5Dose reduction owing to AE4312.0216.76.2Dose interruption owing to AE2814613.11121.829.5Rash (all/grade ≥3)42/134/127/016.4/08/037.2/1.337.0/2.2Diarrhea (all/grade ≥3)39/<141/135/111.5/0.49/026.9/1.361.2/4.4ALT elevation (all/grade ≥3)10/36/1NA13.1/1.215/112.8/064.8/7.5AST elevation (all/grade ≥3)10/15/1NA14.3/0.416/114.1/057.3/5.7CPK elevation (all/grade ≥3)NANANA20.9/7NANANAQT prolongation (all/grade ≥3)5/1.23/0NA6.1/015/03.8/019.4/1.3ILD (all/grade ≥3)3/1.93/<1<1/NA0/0<1/00/05.3/4.03G, three-generation; AE, adverse event; ALT, alanine transaminase; AST, aspartate transaminase; CPK, creatine phosphokinase; ILD, interstitial lung disease; NA, not available; TKI, tyrosine kinase inhibitor. Open table in a new tab 3G, three-generation; AE, adverse event; ALT, alanine transaminase; AST, aspartate transaminase; CPK, creatine phosphokinase; ILD, interstitial lung disease; NA, not available; TKI, tyrosine kinase inhibitor. Several favorable properties of lazertinib ensure its comparable potency and intracranial activity to osimertinib, including lower specific off-target toxicity. First, lazertinib exhibited higher selectivity against various mutant EGFRs, including T790M, and lower activity against wild-type EGFR than did osimertinib.15Yun J. Hong M.H. Kim S.Y. et al.YH25448, an irreversible EGFR-TKI with potent intracranial activity in EGFR mutant non-small cell lung cancer.Clin Cancer Res. 2019; 25: 2575-2587Google Scholar The inhibition of downstream EGFR signaling pathways by lazertinib was similarly effective and more pronounced compared with osimertinib in vitro. Second, unlike osimertinib, lazertinib is not a substrate for BCRP and only a weak substrate of MDR1 (P-glycoprotein),15Yun J. Hong M.H. Kim S.Y. et al.YH25448, an irreversible EGFR-TKI with potent intracranial activity in EGFR mutant non-small cell lung cancer.Clin Cancer Res. 2019; 25: 2575-2587Google Scholar suggesting lazertinib may be less affected by efflux transporters. Consistent with this hypothesis, lazertinib had superior tumor-shrinking efficacy to osimertinib in a murine brain metastasis model, with a high blood–brain barrier penetration profile. Third, owing to lack of inhibition of HER2 and type 1 insulin-like growth factor receptor,15Yun J. Hong M.H. Kim S.Y. et al.YH25448, an irreversible EGFR-TKI with potent intracranial activity in EGFR mutant non-small cell lung cancer.Clin Cancer Res. 2019; 25: 2575-2587Google Scholar lazertinib exhibited less cardiac toxicity and hyperglycemia compared with osimertinib and rociletinib, respectively. This safety profile may allow the conduct of high-dose studies or combinations with agents such as antiangiogenics aimed at specific populations such as those with leptomeningeal metastases and atypical mutations in the future. As a mono-anilino–pyrimidine compound, lazertinib has a similar binding mode to osimertinib, resulting in generally similar acquired resistance mechanisms. Nevertheless, incidence of resistance occurred in different proportions in the current study compared with other 3G TKIs in the second-line setting.16He J. Huang Z. Han L. Gong Y. Xie C. Mechanisms and management of 3rdgeneration EGFRTKI resistance in advanced nonsmall cell lung cancer (review).Int J Oncol. 2021; 59: 90Google Scholar Of note, the resistance mechanisms of 3G TKIs in the first-line and later-line settings are distinct. We look forward to the results of LASER301 to provide more information. The development pattern of EGFR TKIs in lung cancer has been the model for tumors with oncogene drivers, changing multiple paradigms in practice.17Murtuza A. Bulbul A. Shen J.P. et al.Novel third-generation EGFR tyrosine kinase inhibitors and strategies to overcome therapeutic resistance in lung cancer.Cancer Res. 2019; 79: 689-698Google Scholar Nevertheless, there are many challenges to maximizing the efficacy of 3G TKIs. First, what is the optimal order to sequence EGFR TKIs with “three” generations under one roof? Osimertinib was found to have superiority in treatment-naive patients with EGFR-sensitizing mutations compared with 1G EGFR TKIs in the FLAURA study. Aumolertinib, another 3G TKI from People’s Republic of China, was found to have prolonged PFS compared with gefitinib in a similar population although the OS data are immature.18Shun L. Dong X. Jian H. et al.Randomized phase III trial of aumolertinib (HS-10296, Au) versus gefitinib (G) as first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) and EGFR exon 19 del or L858R mutations (EGFRm).J Clin Oncol. 2021; 39 (9013–9013)Google Scholar Clinical trials of other 3G TKIs including lazertinib for first-line treatment are currently in progress. Nevertheless, despite this, in the context of less than convincing OS data for osimertinib in specific populations (Asian, L858R mutation) and more complicated resistance mechanisms, the optimal sequencing of different generations of EGFR TKIs remains controversial. Indeed, in real-world studies of EGFR-mutant advanced NSCLC, initial therapy with 1/2G TKIs followed by osimertinib when there is an acquired T790M mutation achieved a remarkable OS of more than 40 months.19Hochmair M.J. Morabito A. Hao D. et al.Sequential treatment with afatinib and osimertinib in patients with EGFR mutation-positive non-small-cell lung cancer: an observational study.Future Oncol. 2018; 14: 2861-2874Google Scholar Therefore, the value of treatment becomes the key to determine the most suitable treatment strategy. Unlike those from the American Society of Clinical Oncology20Schnipper L.E. Davidson N.E. Wollins D.S. et al.American Society of Clinical Oncology statement: a conceptual framework to assess the value of cancer treatment options.J Clin Oncol. 2015; 33: 2563-2577Google Scholar and the European Society for Medical Oncology,21Cherny N.I. Sullivan R. Dafni U. et al.A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS).Ann Oncol. 2015; 26: 1547-1573Google Scholar the approach to value the anticancer therapies of the Chinese Thoracic Oncology Group has taken the subsequent treatment into account and distributed different weights to the four aspects, including efficacy (PFS/OS and sequential treatment), safety (treatment-related severe adverse events and dose adjustment), quality of life, and compensation.22Cui J.W. Zhou Q. Lu S. et al.The Chinese Thoracic Oncology Group (CTONG) therapeutic option scoring system: a multiple-parameter framework to assess the value of lung cancer treatment options.Transl Lung Cancer Res. 2021; 10: 3594-3607Google Scholar According to the Chinese Thoracic Oncology Group scoring system, osimertinib is only preferred for untreated patients with EGFR ex19del mutation and brain metastases. Taking into account the differences in ethnicity and affordability, more studies with large sample sizes are needed to delineate optimal treatment patterns. Second, how can the efficacy of 3G TKIs be better predicted? EGFR-mutant lung cancer has evolved along different trajectories and ended up with the heterogeneity in clinical outcomes in individual patients with different genomic characteristics.23Tan A.C. Teh Y.L. Lai G.G.Y. Tan D.S.W. Third generation EGFR TKI landscape for metastatic EGFR mutant non-small cell lung cancer (NSCLC).Expert Rev Anticancer Ther. 2019; 19: 431-435Google Scholar EGFR comutations,24Kim Y. Lee B. Shim J.H. et al.Concurrent genetic alterations predict the progression to target therapy in EGFR-mutated advanced NSCLC.J Thorac Oncol. 2019; 14: 193-202Google Scholar low-sensitizing variant allele frequency,25Li Y. Zhang F. Yuan P. Guo L. Jianming Y. He J. High MAF of EGFR mutations and high ratio of T790M sensitizing mutations in ctDNA predict better third-generation TKI outcomes.Thorac Cancer. 2020; 11: 1503-1511Google Scholar,26Gieszer B. Megyesfalvi Z. Dulai V. et al.EGFR variant allele frequency predicts EGFR-TKI efficacy in lung adenocarcinoma: a multicenter study.Transl Lung Cancer Res. 2021; 10: 662-674Google Scholar and specific atypical EGFR-mutant types27Cho J.H. Lim S.H. An H.J. et al.Osimertinib for patients with non-small-cell lung cancer harboring uncommon EGFR mutations: a multicenter, open-label, phase II trial (KCSG-LU15-09).J Clin Oncol. 2020; 38: 488-495Google Scholar have been identified as negative predictors of osimertinib efficacy. A structure-based approach was described recently to divide EGFR mutations into four functional groups for a more personalized EGFR TKI choice.28Robichaux J.P. Le X. Vijayan R.S.K. et al.Structure-based classification predicts drug response in EGFR-mutant NSCLC.Nature. 2021; 597: 732-737Google Scholar Furthermore, although applied in the adjuvant setting and aimed at 1G TKI, the recently proposed MINERVA score on the basis of genomic signatures provided a more precise framework for guiding adjuvant TKI therapy.29Liu S.Y. Bao H. Wang Q. et al.Genomic signatures define three subtypes of EGFR-mutant stage II–III non-small-cell lung cancer with distinct adjuvant therapy outcomes.Nat Commun. 2021; 12: 6450Google Scholar It may be worth applying this score to 3G TKIs. Third, how do we overcome the primary and acquired resistance to 3G TKIs? The factors that drive primary resistance to 3G TKIs are poorly understood. EGFR exon 20 insertion30Robichaux J.P. Elamin Y.Y. Tan Z. et al.Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer.Nat Med. 2018; 24: 638-646Google Scholar and B-cell lymphoma-2–like 11 deletion polymorphism31Tanimoto A. Takeuchi S. Arai S. et al.Histone deacetylase 3 inhibition overcomes BIM deletion polymorphism-mediated osimertinib resistance in EGFR-mutant lung cancer.Clin Cancer Res. 2017; 23: 3139-3149Google Scholar could be potential contributors. Acquired resistance is essentially a tumor clonal evolution under drug pressure, resulting in selective dominance of subclonal cells lacking the original sensitizing mutations, including EGFR-dependent and -independent resistance mechanisms. The resistance patterns for osimertinib are different in different lines of treatment. There are more unknown mechanisms and earlier presence of EGFR-independent mechanisms in the first-line setting, suggesting a complex resistance landscape and altered tumor biology. This difference in resistance mechanisms may extend to the adjuvant setting, given that osimertinib has obtained adjuvant therapy indications from the Food and Drug Administration after the results of the ADAURA study.32Wu Y.L. Tsuboi M. He J. et al.Osimertinib in resected EGFR-mutated non-small-cell lung cancer.N Engl J Med. 2020; 383: 1711-1723Google Scholar A variety of strategies are being explored to overcome different types of resistance, including the development of next-generation TKIs, combination of 3G TKIs with other targeted or conventional therapies, combined immunotherapy strategies, and dose escalation in specific populations. Next-generation EGFR inhibitors (EI045,33Wang S. Song Y. Liu D. EAI045: the fourth-generation EGFR inhibitor overcoming T790M and C797S resistance.Cancer Lett. 2017; 385: 51-54Google Scholar JBJ-04-125-02,34To C. Jang J. Chen T. et al.Single and dual targeting of mutant EGFR with an allosteric inhibitor.Cancer Discov. 2019; 9: 926-943Google Scholar BLU-94535Schalm S.S. Dineen T. Lim S.M. et al.1296PBLU-945, a highly potent and selective 4th generation EGFR TKI for the treatment of EGFR T790M/C797S resistant NSCLC.Ann Oncol. 2020; 31: S839Google Scholar) are still in the early stages of development but found to have great potential. The promising combinations with 3G TKIs include agents targeting distinct alternative bypass pathways, such as MET, HER2, ALK, RET, MEK, and BRAF gene aberrations. Of interest, the combination of lazertinib and an EGFR-MET bispecific antibody amivantamab had promising efficacy with an objective response rate of 36% in osimertinib-relapsed, chemotherapy-naive patients in the phase 1 CHRYSALIS study,36Cho B. Lee K. Cho E. et al.1258O Amivantamab (JNJ-61186372), an EGFR-MET bispecific antibody, in combination with lazertinib, a 3rd-generation tyrosine kinase inhibitor (TKI), in advanced EGFR NSCLC.Ann Oncol. 2020; 31: S813Google Scholar suggesting switching to another 3G TKI combined with different targeted drugs may overcome the resistance to osimertinib. The combinations of chemotherapy or antiangiogenic drugs have been broadly investigated with 1G TKIs in the first-line setting, and the survival benefits remain controversial. First, the combination with chemotherapy was at the expense of more adverse effects although OS advantage was considerable, and it is not a typically adopted strategy in clinical practice. Second, the PFS advantage observed in the combination with antiangiogenic therapies failed to translate into an OS benefit. Third, osimertinib plus bevacizumab failed to improve the survival of patients with EGFR T790M mutation compared with osimertinib alone in the second-line setting.37Akamatsu H. Teraoka S. Morita S. et al.Phase I/II study of osimertinib with bevacizumab in EGFR-mutated, T790M-positive patients with progressed EGFR-TKIs: West Japan Oncology Group 8715L (WJOG8715L).Clin Lung Cancer. 2019; 20: e492-e494Google Scholar Therefore, it is unclear whether the impressive efficacy of the 3G TKIs can be further improved by the combination with antiangiogenic therapy or chemotherapy. The dominance of osimertinib in the landscape of 3G TKIs has been changing with more and more novel compounds emerging. In the heyday of 3G TKIs, a more precise predictive model for guiding personalized treatment selection and novel combinations based on improved knowledge of resistance mechanisms are the direction of future efforts. Fen Wang: Conceptualization, Data curation, Writing - original draft preparation, Visualization. Qing Zhou: Writing - review & editing. Download .docx (.03 MB) Help with docx files Supplementary Table 1 A Phase 1/2 Study of Lazertinib 240 mg in Patients With Advanced EGFR T790M-Positive NSCLC After Previous EGFR Tyrosine Kinase InhibitorsJournal of Thoracic OncologyVol. 17Issue 4PreviewThis integrated analysis of a phase 1/2 study (NCT03046992) evaluated the efficacy and safety of lazertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), in patients with advanced EGFR T790M-positive NSCLC after previous EGFR TKI therapy. Full-Text PDF Open Access