Commentary
The Next Generation of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in the Treatment of Lung Cancer Conor E. Steuer, MD1; Fadlo R. Khuri, MD1,2; and Suresh S. Ramalingam, MD1
The discovery of “driver” genomic alterations in patients with non-small cell lung cancer (NSCLC) has dramatically changed the field of thoracic oncology in recent years. The best understood of these molecular drivers are those involving the epidermal growth factor receptor (EGFR), which when aberrantly activated are integral to the development of a subset of NSCLC tumors. First-generation and second-generation tyrosine kinase inhibitors (TKIs) specific to the activated EGFR have shown significant efficacy and have brought about the era of targeted therapy for NSCLC. The most common resistance mechanism is a threonine-to-methionine substitution (T790M) in exon 20 of the EGFR gene. Although the previous standard of care in patients with EGFR-mutated NSCLC that progressed on initial TKI therapy was chemotherapy, third-generation EGFR TKIs have now been developed and have yielded promising results for this population of patients with NSCLC. This article reviews the emerging data regarding third-generation agents in the C 2014 American Cancer Society. treatment of patients with advanced NSCLC. Cancer 2014;000:000-000. V KEYWORDS: non-small cell lung cancer, epidermal growth factor receptor (EGFR), targeted therapy, AZD9291, rociletinib (CO-1686), HM61713.
INTRODUCTION The understanding and treatment of non-small cell lung cancer (NSCLC) has evolved dramatically over the last decade. This is largely due to a better understanding of the driver genomic alterations that can lead to the development of oncogene-dependent NSCLC. The best described of these molecular drivers are those involving the epidermal growth factor receptor (EGFR). First described in 2004, activating mutations in EGFR were shown to be integral to the development of a subset of NSCLC tumors, representing 10% to 30% of NSCLCs.1,2 These early studies demonstrated that the most common mutations occurred in the tyrosine kinase domain of the EGFR gene, more specifically deletions in exon 19 and the L858R point mutation on exon 21. In addition, these mutations were shown to be a predictive biomarker of efficacy for EGFR-specific tyrosine kinase inhibitors (TKIs).3,4 These findings revolutionized the way in which targeted agents were developed for and used in patients with NSCLC. Although now commonly used in the first-line treatment of EGFRmutant (EGFRm) NSCLC, the EGFR TKI erlotinib was originally approved in the United States for second-line use in nonselected patients with metastatic NSCLC based on an overall survival benefit compared with placebo.5 However, subsequent clinical trials of EGFR TKIs, including the first-generation EGFR TKI gefitinib and the second-generation TKI afatinib, focused on patients with NSCLC with EGFRm treated in the frontline setting.6-8 These studies demonstrated significant improvements in overall response rates (ORR) ranging from 55% to 85% and median progression-free survival (PFS) ranging from 9 months to 13 months, which led to their approval and widespread use for the treatment of patients with EGFRm NSCLC.6-12 Unfortunately, despite these impressive results, patients with EGFRm NSCLC eventually develop resistance to TKI therapy.7,8 This is consistent with results observed with TKI therapy for other malignancies, most notably chronic myeloid leukemia and anaplastic lymphoma kinase (ALK)-positive NSCLC.13,14 The median time to disease progression among patients receiving erlotinib and gefitinib is approximately 10 months.15 The mechanisms behind this eventual resistance to TKI therapy have been well described. The most common resistance mechanism, observed in approximately 50% of patients with EGFRm disease, is a threonine-to-methionine substitution (T790M) in exon 20 of the EGFR gene.16 This gatekeeper mutation increases the receptor’s affinity for adenosine triphosphate and decreases the effectiveness of first-generation TKIs.17,18 EGFR gene amplification, bypass signaling pathways (such as MET, HER2, and PIK3CA),
Corresponding author: Suresh S. Ramalingam, MD, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 1365 Clifton Rd NE, Rm C-3090, Atlanta, GA 30322; Fax: (404) 778-5520; [email protected] 1
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia; 2Editor-in-Chief, Cancer.
DOI: 10.1002/cncr.29139, Received: August 7, 2014; Revised: October 5, 2014; Accepted: October 7, 2014, Published online Month 00, 2014 in Wiley Online Library (wileyonlinelibrary.com)
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1
Commentary TABLE 1. Efficacy of the Third-Generation TKIs Overall Response Rate Drug AZD929126 Rociletinib27 HM6171328
Clinical Benefit Rate
Preliminary Median PFS
Total
T790M1
T790M-
Total
T790M1
T790M-
Total
T790M1
T790M-
51% (N5239) NR 21.7% (N583)
61% (N5127) 58% (N540) 29.2% (N548)
21% (N561) NR 11.8% (N534)
84% NR 67.5%
95% NR 75%
61% NR 55.9%
NR NR NR
9.6 mo NR NR
2.8 mo NR NR
Abbreviations: 1, positive; -, negative; NR, not reported; PFS, progression-free survival; T790M, threonine-to-methionine substitution; TKI, tyrosine kinase inhibitor.
epithelial-to-mesenchymal transformation, and histological changes in the tumor also have been implicated as resistance mechanisms to EGFR TKIs.16,19 In the recent past, disease progression occurring among patients treated with erlotinib, gefitinib, or afatinib left chemotherapy as the only treatment option. Initial drugs studied for this EGFRm TKI-resistant population, such as afatinib, the irreversible EGFR inhibitors dacomitinib and neratinib, and the multikinase inhibitor vandetanib, yielded unimpressive results.20-23 The combination of afatinib and cetuximab was also studied in a phase 1b clinical trial, and demonstrated modest efficacy (ORR, 29%), with a median PFS of 4.7 months. Toxicity was observed in a high percentage of patients treated with this combination regimen (46% rate of grade 3/4 toxicities and 2 treatmentrelated deaths).24 Recently, third-generation EGFR TKIs have yielded promising results for these first-generation and second-generation TKI-resistant patients with EGFRm NSCLC. The data for these trials were recently presented at the American Society for Clinical Oncology and European Society for Medical Oncology annual meetings and demonstrate exciting prospects for the care of this patient population. AZD9291
AZD9291 (AstraZeneca, Macclesfield, UK) is an irreversible, selective compound that was designed to target both the activating EGFRm in patients with NSCLC as well as the T790M resistance mutation. In preclinical modeling, AZD9291 was shown to be 200 times more potent against the L858R/T790M-mutant than against the wild-type EGFR.25 In addition, in vivo experiments using mouse xenograft models demonstrated that AZD9291 produced more durable and more profound responses in EGFRm NSCLC tumors compared with the first-generation EGFR TKIs.25 Based on these preclinical data, the compound was taken into phase 1 trials that included both Asian and Western patients with EGFRm lung adenocarcinoma, exclusively those who had developed disease pro2
gression while receiving prior TKI therapy. The primary endpoint was safety and tolerability, but preliminary efficacy was included as a secondary endpoint. The trial design was a “rolling” escalation and expansion cohort. The escalation cohort started at a dose of 20 mg/day and if no dose-limiting toxicities (DLTs) were noted, then the higher-dose cohort would open in doses of 20 mg, 40 mg, 80 mg, 160 mg, and 240 mg. T790M status was not required for the escalation cohort. However, if clinical activity was observed, then an expansion cohort would open and patients would be required to have their T790M status determined. The study rapidly enrolled 253 patients, 222 of whom were in the expansion cohort. Overall, 62% of patients were female and approximately 67% were Asian. In patients in the expansion cohort, for whom T790M status was known, 138 patients were T790M positive. In addition, patients had received a median of 3 prior systemic therapies before enrollment, and at least one prior EGFR TKI. The investigators found that AZD9291 was well tolerated, with no DLT noted at any dose level. The most common side effects were those in line with TKI therapy in general, including diarrhea, rash, pruritus, and nausea, although at a lesser frequency and severity. At the 160-mg and 240-mg doses, hyperglycemia, interstitial lung disease-like symptoms, and QT prolongation were noted in a minority of patients. An ORR of 51% was observed, with an 84% clinical benefit rate (complete response plus partial response plus stable disease). However, the drug was more beneficial in patients with T790M-positive disease, with an ORR of 61% and a clinical benefit rate of 95% versus patients with T790Mnegative disease, who had an ORR of 21% and a clinical benefit rate of 61%. The preliminary median PFS for patients with T790M-positive disease was 9.6 months and was 2.8 months for those with T790M-negative disease (Table 1).26 Based on these results, AZD9291 has been granted breakthrough therapy designation by the US Food and Drug Administration. Both an expansion and separate phase 2 study have opened for patients who have Cancer
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Next Generation of EGFR TKIs in NSCLC/Steuer et al
TABLE 2. Clinical Trials With Third-Generation EGFR TKIs Drug AZD9291
Trial Identifier NCT01802632
NCT02094261
NCT02151981
NCT02143466
Rociletinib
NCT01526928
NCT02147990
NCT02186301
Not yet registered
HM61713
NCT01588145
Status of Trial
T790M Status
Estimated Enrollment
Name of Trial
Phase
Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of AZD9291 in Patients With Advanced Non Small Cell Lung Cancer Who Progressed on Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent (AURA) Phase II, Open Label, Single-arm Study to Assess Safety and Efficacy of AZD9291 in Patients With Locally Advanced/Metastatic NSCLC Whose Disease Has Progressed With Previous EGFR TKI and Whose Tumours Are EGFR and T790M Mutation Positive (AURA2) AZD9291 Versus Platinum-Based Doublet-Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (AURA3) A Multi-arm, Phase Ib, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of AZD9291 in Combination With Ascending Doses of Novel Therapeutics in Patients With EGFRm1 Advanced NSCLC Who Have Progressed Following Therapy With an EGFR TKI (TATTON) A Phase 1/2, Open-Label, Safety, Pharmacokinetic and Preliminary Efficacy Study of Oral Rociletinib in Patients With Previously Treated Mutant EGFR Non-Small Cell Lung Cancer (NSCLC) (TIGERX) TIGER-2: A Phase 2, Open-Label, Multicenter, Safety and Efficacy Study of Oral CO-1686 as 2nd Line EGFR-Directed TKI in Patients With Mutant EGFR Non-Small Cell Lung Cancer (NSCLC) With the T790M Resistance Mutation TIGER 1: A Randomized, Open-Label, Phase 2 Study of CO-1686 or Erlotinib as First-Line Treatment of Patients With EGFR-Mutant Advanced NSCLC A Randomized Phase III Study of CO-1686 vs. Chemotherapy in patients with EGFR-Mutant Advanced NSCLC That Progress on First Line TKI treatment and are T790M Positive (TIGER3) Phase I Study to Assess the Safety, Tolerability and Pharmacokinetic Profile of HM61713 Tablet in NSCLC Patients With EGFR Mutation
1/2
Recruiting
Positive or negative
498
2
Recruiting
Positive
442
3
Not yet recruiting
Positive
1540
1B
Recruiting
Positive or negative
300
1/2
Recruiting
Positive for phase 2 cohort
600
2
Recruiting
Positive
125
Not yet recruiting
Positive or negative
200
3
Planned
Positive
1
Recruiting
Positive or negative
2/3
?
30
Abbreviations: 1, positive; EGFR, epidermal growth factor receptor; EGFRm, EGFR-mutant; NSCLC, non-small cell lung cancer; T790M, threonine-tomethionine substitution; TKIs, tyrosine kinase inhibitors.
EGFRm lung adenocarcinoma and are T790M positive as well as a phase 3 study comparing AZD9291 in the second-line treatment of patients with EGFRm, T790MCancer
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positive NSCLC versus standard platinum doublet chemotherapy (Table 2). These trials will be moving forward with the dose of 80 mg/day. 3
Commentary Rociletinib
Rociletinib (CO-1686; Clovis Oncology, Boulder, Colo) is another third-generation EGFR TKI that has demonstrated promising efficacy data in early trials. Rociletinib was also designed to inhibit the activating EGFRm and the T790M resistance mutation, with a focus on sparing the wild-type EGFR. This design was shown to be effective in preclinical models in which rociletinib was found to have significantly less activity against wild-type EGFR than the early-generation TKIs currently being used clinically, as well as AZD9291. Furthermore, in transgenic mouse models using L858R/T790M, rociletinib was clearly superior to the second-generation TKI afatanib.29 Accrual has been completed to the phase 1 study and the phase 2 expansion is rapidly enrolling patients. The phase 1 trial accrued patients with EGFRm NSCLC who had received prior treatment with EGFR-directed therapy. The phase 2 expansion cohort stratifies patients into 2 groups: those who had received one TKI before enrollment and those who had received 2 TKIs or chemotherapy. In addition, T790M-positive status was a requirement for the phase 2 cohort. The trial enrollment included 75% females and 14% Asian subjects. As with AZD9291, no maximum tolerated dose was identified. Initially, a freebase capsule formulation was used, but this was reformulated with a hydrogen bromide salt tablet in subsequent development to improve the pharmacokinetic profile of the drug. It is interesting to note that the 500mg, 625-mg, 750-mg, and 1000-mg doses of the tablet used were all administered twice daily. The most common adverse event (AE) noted was hyperglycemia, with 22% of cases being grade 3. Once this AE was identified, patients were proactively placed on metformin therapy. Skin rash was observed in only 4% of the patients, much less frequently than the standard TKI AE, and likely due to the selective nature of rociletinib for the EGFRm. In terms of efficacy, among the 40 patients with confirmed T790M positivity, the ORR was 58%. The PFS, although not yet reached at the time of last follow-up, is estimated to be >12 months.27 Rociletinib has recently also been given breakthrough therapy status by the US Food and Drug Administration. Currently, a single-arm phase 2 trial is recruiting patients with the EGFRm who have progressed on a first-line EGFR TKI and are T790M positive on biopsy (TIGER2). The dose of rociletinib in this trial is 625 mg administered twice daily. In addition, a randomized phase 2/3 clinical trial is soon to open, and will be comparing rociletinib versus erlotinib in the first-line setting for patients with EGFRm disease, regardless of T790M status (TIGER1). Finally, a phase 3 trial is planned of roci4
letinib versus platinum doublet chemotherapy in patients with EGFRm lung cancer who develop disease progression while receiving first-line EGFR TKIs and are T790M positive as demonstrated on biopsy (TIGER3). HM61713
Another third-generation EGFR TKI, HM61713 (Hanmi Pharmaceutical Company Ltd, Seoul, South Korea), is also highly selective for the EGFRm. It demonstrated good efficacy in in vivo models, especially those with concurrent T790M mutations. HM61713 was studied in a phase 1 trial enrolling patients from 7 centers in Korea with EGFRm NSCLC that had progressed on prior TKI therapy. In the escalation phase, doses were increased from 75 mg to 800 mg daily. No maximum tolerated dose was found, but 2 DLTs were reported. One was an idiosyncratic drug reaction leading to shortness of breath and rash at a dose of 100 mg twice daily, whereas the other DLT was increased amylase and lipase levels. They included an expansion phase at the 300-mg daily dose, at which T790M testing was performed on the tumor tissues of study participants. A total of 35 patients were enrolled in the dose escalation phase, and 83 patients were enrolled in the expansion arm. The most common AEs noted were nausea, rash, headaches, and diarrhea. It is interesting to note that 3 patients developed grade 3 dyspnea. In the expansion cohort, in which 58% of patients were positive for T790M, the ORR was 21.7% with a clinical benefit rate of 67.5% reported in 83 evaluable patients. In a subset analysis, patients with T790M fared better than those without, with ORR rates of 29% and 12%, respectively.28 Conclusions
Targeted therapy against EGFRm-driven NSCLC is currently at the forefront in the new era of personalized medicine. The current treatment paradigm for patients with EGFRm NSCLC is shown in Figure 1. The development and adaption into the clinic of the first-generation TKIs, erlotinib and gefitinib, has revolutionized the care that oncologists can provide to this subgroup of patients with NSCLC. However, the duration of responses has been limited secondary to the resistance that inevitably develops. Fortunately, new drug development has given hope to this patient population. AZD9291, rociletinib, and HM61713 have all shown preliminary significant efficacy in this population, and appear to be well tolerated. Although these early data demonstrate similar ORR rates between AZD9291 and rociletinib, HM61713 has not shown the same level of effectiveness. Currently, the reason for this disparity is unclear, but could potentially be Cancer
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Next Generation of EGFR TKIs in NSCLC/Steuer et al
Figure 1. The current treatment paradigm for patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer is shown. TKI indicates tyrosine kinase inhibitor.
due to issues with drug dosing or population differences, because to the best of our knowledge HM61713 has only been studied in Korea. The currently available data are not mature enough to determine which agent is the best in its class, with the notable differences primarily related to toxicity and the frequency of administration. Several other EGFR-specific TKIs are currently being investigated in patients with NSCLC with an EGFR-sensitizing mutation and T790M positivity (ie, ASP8273 [Astellas Pharma Inc, Tokyo, Japan] and EGF816 [Novartis Pharmaceuticals, Basel, Switzerland]) but it is too early in their development to know what their clinical role will be for these patients.30,31 Despite the considerable promise of these medications, there are still questions that remain to be addressed. For example, the treatment of patients with EGFRm disease who develop disease progression while receiving first-line treatment with TKIs but are negative for T790M is currently unclear. Combination therapy has demonstrated promise in the treatment of this patient population. In addition, understanding how EGFRm tumors respond to the selective inhibition of third-generation EGFR TKIs will Cancer
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be essential moving forward, and further highlights the importance of obtaining biopsies of these tumors at the time of disease progression. The development of the thirdgeneration agents as the first-line therapy for patients with EGFRm disease has already started and it is hoped that the T790M-mediated resistance can be delayed or prevented. However, it is possible that other less well known escape mechanisms might emerge. Finally, although responses are only anecdotal at this time, the potential activity of the third-generation agents against brain metastasis appears promising and is worthy of further study. In summary, EGFR inhibition in patients with NSCLC has entered the next exciting phase, which is bound to benefit patients. FUNDING SUPPORT No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES Dr. Ramalingam has served as a paid member of the advisory boards of Lilly, Genentech, Clovis, AstraZeneca, and Boehringer Ingelheim and has received research support from AstraZeneca for work performed outside of the current study. 5
Commentary
REFERENCES 1. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350: 2129-2139. 2. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004; 304:1497-1500. 3. Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and final overall survival results from a phase III, randomized, openlabel, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011;29:2866-2874. 4. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004;101:13306-13311. 5. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353: 123-132. 6. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013; 31:3327-3334. 7. Rosell R, Carcereny E, Gervais R, et al; Spanish Lung Cancer Group in collaboration with Groupe Francais de Pneumo-Cancerologie and Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13:239-246. 8. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361: 947-957. 9. Mitsudomi T, Morita S, Yatabe Y, et al; West Japan Oncology Group. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11:121-128. 10. Maemondo M, Inoue A, Kobayashi K, et al; North-East Japan Study Group. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380-2388. 11. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutationpositive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12:735-742. 12. Sequist LV, Martins RG, Spigel D, et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol. 2008;26:2442-2449. 13. Choi YL, Soda M, Yamashita Y, et al; ALK Lung Cancer Study Group. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med. 2010;363:1734-1739. 14. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344:1038-1042. 15. Morita S, Okamoto I, Kobayashi K, et al. Combined survival analysis of prospective clinical trials of gefitinib for non-small cell lung cancer with EGFR mutations. Clin Cancer Res. 2009;15:4493-4498. 16. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3:75ra26.
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17. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2:e73. 18. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352:786-792. 19. Takezawa K, Pirazzoli V, Arcila ME, et al. HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFR T790M mutation. Cancer Discov. 2012;2:922-933. 20. Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012;13:528-538. 21. Reckamp KL, Giaccone G, Camidge DR, et al. A phase 2 trial of dacomitinib (PF-00299804), an oral, irreversible pan-HER (human epidermal growth factor receptor) inhibitor, in patients with advanced non-small cell lung cancer after failure of prior chemotherapy and erlotinib. Cancer. 2014;120:1145-1154. 22. Lee JS, Hirsh V, Park K, et al. Vandetanib versus placebo in patients with advanced non-small-cell lung cancer after prior therapy with an epidermal growth factor receptor tyrosine kinase inhibitor: a randomized, double-blind phase III trial (ZEPHYR). J Clin Oncol. 2012;30:1114-1121. 23. Sequist LV, Besse B, Lynch TJ, et al. Neratinib, an irreversible panErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2010;28:3076-3083. 24. Janjigian YY, Smit EF, Groen HJ, et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov. 2014;4:1036-1045. 25. Cross DA, Ashton SE, Ghiorghiu S, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4:1046-1061. 26. Yang CH, Kim DW, Plachard D, et al. Updated safety and efficacy from a phase I study of AZD9291 in patients with EGFR-TKIresistant non-small cell lung cancer (NSCLC). Presented at: European Society for Medical Oncology (ESMO) Congress; September 26-30, 2014; Madrid, Spain. 27. Sequist LV, Soria J-C, Gadgeel S, et al. First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M). Presented at: 2014 American Society of Clinical Oncology Annual Meeting; May 30June 3, 2014; Chicago, IL. 28. Kim DW, Lee DH, Kang J, et al. Clinical activity and safety of HM61713, an EGFR-mutant selective inhibitor, in advanced nonsmall cell lung cancer (NSCLC) patients (pts) with EGFR mutations who had received EGFR tyrosine kinase inhibitors (TKIs). Presented at: American Society of Clinical Oncology Annual Meeting; May 30-June 3, 2014; Chicago, IL. 29. Walter AO, Sjin RT, Haringsma HJ, et al. Discovery of a mutantselective covalent inhibitor of EGFR that overcomes T790Mmediated resistance in NSCLC. Cancer Discov. 2013;3:1404-1415. 30. .ClinicalTrials.gov. A Dose Escalation Study of ASP8273 in Subjects With Non-Small-Cell Lung Cancer (NSCLC) Who Have Epidermal Growth Factor Receptor (EGFR) Mutations. clinicaltrials.gov/show/ NCT02113813. Accessed September 11, 2014. 31. .ClinicalTrials.gov. A Phase I/II, Multicenter, Open-label Study of EGFRmut-TKI EGF816, Administered Orally in Adult Patients With EGFRmut Solid Malignancies. clinicaltrials.gov/ct2/show/ NCT02108964?term5EGF816&rank51. Accessed September 11, 2014.
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The Next Generation of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in the Treatment of Lung Cancer Conor E. Steuer, MD1; Fadlo R. Khuri, MD1,2; and Suresh S. Ramalingam, MD1
The discovery of “driver” genomic alterations in patients with non-small cell lung cancer (NSCLC) has dramatically changed the field of thoracic oncology in recent years. The best understood of these molecular drivers are those involving the epidermal growth factor receptor (EGFR), which when aberrantly activated are integral to the development of a subset of NSCLC tumors. First-generation and second-generation tyrosine kinase inhibitors (TKIs) specific to the activated EGFR have shown significant efficacy and have brought about the era of targeted therapy for NSCLC. The most common resistance mechanism is a threonine-to-methionine substitution (T790M) in exon 20 of the EGFR gene. Although the previous standard of care in patients with EGFR-mutated NSCLC that progressed on initial TKI therapy was chemotherapy, third-generation EGFR TKIs have now been developed and have yielded promising results for this population of patients with NSCLC. This article reviews the emerging data regarding third-generation agents in the C 2014 American Cancer Society. treatment of patients with advanced NSCLC. Cancer 2014;000:000-000. V KEYWORDS: non-small cell lung cancer, epidermal growth factor receptor (EGFR), targeted therapy, AZD9291, rociletinib (CO-1686), HM61713.
INTRODUCTION The understanding and treatment of non-small cell lung cancer (NSCLC) has evolved dramatically over the last decade. This is largely due to a better understanding of the driver genomic alterations that can lead to the development of oncogene-dependent NSCLC. The best described of these molecular drivers are those involving the epidermal growth factor receptor (EGFR). First described in 2004, activating mutations in EGFR were shown to be integral to the development of a subset of NSCLC tumors, representing 10% to 30% of NSCLCs.1,2 These early studies demonstrated that the most common mutations occurred in the tyrosine kinase domain of the EGFR gene, more specifically deletions in exon 19 and the L858R point mutation on exon 21. In addition, these mutations were shown to be a predictive biomarker of efficacy for EGFR-specific tyrosine kinase inhibitors (TKIs).3,4 These findings revolutionized the way in which targeted agents were developed for and used in patients with NSCLC. Although now commonly used in the first-line treatment of EGFRmutant (EGFRm) NSCLC, the EGFR TKI erlotinib was originally approved in the United States for second-line use in nonselected patients with metastatic NSCLC based on an overall survival benefit compared with placebo.5 However, subsequent clinical trials of EGFR TKIs, including the first-generation EGFR TKI gefitinib and the second-generation TKI afatinib, focused on patients with NSCLC with EGFRm treated in the frontline setting.6-8 These studies demonstrated significant improvements in overall response rates (ORR) ranging from 55% to 85% and median progression-free survival (PFS) ranging from 9 months to 13 months, which led to their approval and widespread use for the treatment of patients with EGFRm NSCLC.6-12 Unfortunately, despite these impressive results, patients with EGFRm NSCLC eventually develop resistance to TKI therapy.7,8 This is consistent with results observed with TKI therapy for other malignancies, most notably chronic myeloid leukemia and anaplastic lymphoma kinase (ALK)-positive NSCLC.13,14 The median time to disease progression among patients receiving erlotinib and gefitinib is approximately 10 months.15 The mechanisms behind this eventual resistance to TKI therapy have been well described. The most common resistance mechanism, observed in approximately 50% of patients with EGFRm disease, is a threonine-to-methionine substitution (T790M) in exon 20 of the EGFR gene.16 This gatekeeper mutation increases the receptor’s affinity for adenosine triphosphate and decreases the effectiveness of first-generation TKIs.17,18 EGFR gene amplification, bypass signaling pathways (such as MET, HER2, and PIK3CA),
Corresponding author: Suresh S. Ramalingam, MD, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 1365 Clifton Rd NE, Rm C-3090, Atlanta, GA 30322; Fax: (404) 778-5520; [email protected] 1
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia; 2Editor-in-Chief, Cancer.
DOI: 10.1002/cncr.29139, Received: August 7, 2014; Revised: October 5, 2014; Accepted: October 7, 2014, Published online Month 00, 2014 in Wiley Online Library (wileyonlinelibrary.com)
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1
Commentary TABLE 1. Efficacy of the Third-Generation TKIs Overall Response Rate Drug AZD929126 Rociletinib27 HM6171328
Clinical Benefit Rate
Preliminary Median PFS
Total
T790M1
T790M-
Total
T790M1
T790M-
Total
T790M1
T790M-
51% (N5239) NR 21.7% (N583)
61% (N5127) 58% (N540) 29.2% (N548)
21% (N561) NR 11.8% (N534)
84% NR 67.5%
95% NR 75%
61% NR 55.9%
NR NR NR
9.6 mo NR NR
2.8 mo NR NR
Abbreviations: 1, positive; -, negative; NR, not reported; PFS, progression-free survival; T790M, threonine-to-methionine substitution; TKI, tyrosine kinase inhibitor.
epithelial-to-mesenchymal transformation, and histological changes in the tumor also have been implicated as resistance mechanisms to EGFR TKIs.16,19 In the recent past, disease progression occurring among patients treated with erlotinib, gefitinib, or afatinib left chemotherapy as the only treatment option. Initial drugs studied for this EGFRm TKI-resistant population, such as afatinib, the irreversible EGFR inhibitors dacomitinib and neratinib, and the multikinase inhibitor vandetanib, yielded unimpressive results.20-23 The combination of afatinib and cetuximab was also studied in a phase 1b clinical trial, and demonstrated modest efficacy (ORR, 29%), with a median PFS of 4.7 months. Toxicity was observed in a high percentage of patients treated with this combination regimen (46% rate of grade 3/4 toxicities and 2 treatmentrelated deaths).24 Recently, third-generation EGFR TKIs have yielded promising results for these first-generation and second-generation TKI-resistant patients with EGFRm NSCLC. The data for these trials were recently presented at the American Society for Clinical Oncology and European Society for Medical Oncology annual meetings and demonstrate exciting prospects for the care of this patient population. AZD9291
AZD9291 (AstraZeneca, Macclesfield, UK) is an irreversible, selective compound that was designed to target both the activating EGFRm in patients with NSCLC as well as the T790M resistance mutation. In preclinical modeling, AZD9291 was shown to be 200 times more potent against the L858R/T790M-mutant than against the wild-type EGFR.25 In addition, in vivo experiments using mouse xenograft models demonstrated that AZD9291 produced more durable and more profound responses in EGFRm NSCLC tumors compared with the first-generation EGFR TKIs.25 Based on these preclinical data, the compound was taken into phase 1 trials that included both Asian and Western patients with EGFRm lung adenocarcinoma, exclusively those who had developed disease pro2
gression while receiving prior TKI therapy. The primary endpoint was safety and tolerability, but preliminary efficacy was included as a secondary endpoint. The trial design was a “rolling” escalation and expansion cohort. The escalation cohort started at a dose of 20 mg/day and if no dose-limiting toxicities (DLTs) were noted, then the higher-dose cohort would open in doses of 20 mg, 40 mg, 80 mg, 160 mg, and 240 mg. T790M status was not required for the escalation cohort. However, if clinical activity was observed, then an expansion cohort would open and patients would be required to have their T790M status determined. The study rapidly enrolled 253 patients, 222 of whom were in the expansion cohort. Overall, 62% of patients were female and approximately 67% were Asian. In patients in the expansion cohort, for whom T790M status was known, 138 patients were T790M positive. In addition, patients had received a median of 3 prior systemic therapies before enrollment, and at least one prior EGFR TKI. The investigators found that AZD9291 was well tolerated, with no DLT noted at any dose level. The most common side effects were those in line with TKI therapy in general, including diarrhea, rash, pruritus, and nausea, although at a lesser frequency and severity. At the 160-mg and 240-mg doses, hyperglycemia, interstitial lung disease-like symptoms, and QT prolongation were noted in a minority of patients. An ORR of 51% was observed, with an 84% clinical benefit rate (complete response plus partial response plus stable disease). However, the drug was more beneficial in patients with T790M-positive disease, with an ORR of 61% and a clinical benefit rate of 95% versus patients with T790Mnegative disease, who had an ORR of 21% and a clinical benefit rate of 61%. The preliminary median PFS for patients with T790M-positive disease was 9.6 months and was 2.8 months for those with T790M-negative disease (Table 1).26 Based on these results, AZD9291 has been granted breakthrough therapy designation by the US Food and Drug Administration. Both an expansion and separate phase 2 study have opened for patients who have Cancer
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Next Generation of EGFR TKIs in NSCLC/Steuer et al
TABLE 2. Clinical Trials With Third-Generation EGFR TKIs Drug AZD9291
Trial Identifier NCT01802632
NCT02094261
NCT02151981
NCT02143466
Rociletinib
NCT01526928
NCT02147990
NCT02186301
Not yet registered
HM61713
NCT01588145
Status of Trial
T790M Status
Estimated Enrollment
Name of Trial
Phase
Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of AZD9291 in Patients With Advanced Non Small Cell Lung Cancer Who Progressed on Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent (AURA) Phase II, Open Label, Single-arm Study to Assess Safety and Efficacy of AZD9291 in Patients With Locally Advanced/Metastatic NSCLC Whose Disease Has Progressed With Previous EGFR TKI and Whose Tumours Are EGFR and T790M Mutation Positive (AURA2) AZD9291 Versus Platinum-Based Doublet-Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (AURA3) A Multi-arm, Phase Ib, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of AZD9291 in Combination With Ascending Doses of Novel Therapeutics in Patients With EGFRm1 Advanced NSCLC Who Have Progressed Following Therapy With an EGFR TKI (TATTON) A Phase 1/2, Open-Label, Safety, Pharmacokinetic and Preliminary Efficacy Study of Oral Rociletinib in Patients With Previously Treated Mutant EGFR Non-Small Cell Lung Cancer (NSCLC) (TIGERX) TIGER-2: A Phase 2, Open-Label, Multicenter, Safety and Efficacy Study of Oral CO-1686 as 2nd Line EGFR-Directed TKI in Patients With Mutant EGFR Non-Small Cell Lung Cancer (NSCLC) With the T790M Resistance Mutation TIGER 1: A Randomized, Open-Label, Phase 2 Study of CO-1686 or Erlotinib as First-Line Treatment of Patients With EGFR-Mutant Advanced NSCLC A Randomized Phase III Study of CO-1686 vs. Chemotherapy in patients with EGFR-Mutant Advanced NSCLC That Progress on First Line TKI treatment and are T790M Positive (TIGER3) Phase I Study to Assess the Safety, Tolerability and Pharmacokinetic Profile of HM61713 Tablet in NSCLC Patients With EGFR Mutation
1/2
Recruiting
Positive or negative
498
2
Recruiting
Positive
442
3
Not yet recruiting
Positive
1540
1B
Recruiting
Positive or negative
300
1/2
Recruiting
Positive for phase 2 cohort
600
2
Recruiting
Positive
125
Not yet recruiting
Positive or negative
200
3
Planned
Positive
1
Recruiting
Positive or negative
2/3
?
30
Abbreviations: 1, positive; EGFR, epidermal growth factor receptor; EGFRm, EGFR-mutant; NSCLC, non-small cell lung cancer; T790M, threonine-tomethionine substitution; TKIs, tyrosine kinase inhibitors.
EGFRm lung adenocarcinoma and are T790M positive as well as a phase 3 study comparing AZD9291 in the second-line treatment of patients with EGFRm, T790MCancer
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positive NSCLC versus standard platinum doublet chemotherapy (Table 2). These trials will be moving forward with the dose of 80 mg/day. 3
Commentary Rociletinib
Rociletinib (CO-1686; Clovis Oncology, Boulder, Colo) is another third-generation EGFR TKI that has demonstrated promising efficacy data in early trials. Rociletinib was also designed to inhibit the activating EGFRm and the T790M resistance mutation, with a focus on sparing the wild-type EGFR. This design was shown to be effective in preclinical models in which rociletinib was found to have significantly less activity against wild-type EGFR than the early-generation TKIs currently being used clinically, as well as AZD9291. Furthermore, in transgenic mouse models using L858R/T790M, rociletinib was clearly superior to the second-generation TKI afatanib.29 Accrual has been completed to the phase 1 study and the phase 2 expansion is rapidly enrolling patients. The phase 1 trial accrued patients with EGFRm NSCLC who had received prior treatment with EGFR-directed therapy. The phase 2 expansion cohort stratifies patients into 2 groups: those who had received one TKI before enrollment and those who had received 2 TKIs or chemotherapy. In addition, T790M-positive status was a requirement for the phase 2 cohort. The trial enrollment included 75% females and 14% Asian subjects. As with AZD9291, no maximum tolerated dose was identified. Initially, a freebase capsule formulation was used, but this was reformulated with a hydrogen bromide salt tablet in subsequent development to improve the pharmacokinetic profile of the drug. It is interesting to note that the 500mg, 625-mg, 750-mg, and 1000-mg doses of the tablet used were all administered twice daily. The most common adverse event (AE) noted was hyperglycemia, with 22% of cases being grade 3. Once this AE was identified, patients were proactively placed on metformin therapy. Skin rash was observed in only 4% of the patients, much less frequently than the standard TKI AE, and likely due to the selective nature of rociletinib for the EGFRm. In terms of efficacy, among the 40 patients with confirmed T790M positivity, the ORR was 58%. The PFS, although not yet reached at the time of last follow-up, is estimated to be >12 months.27 Rociletinib has recently also been given breakthrough therapy status by the US Food and Drug Administration. Currently, a single-arm phase 2 trial is recruiting patients with the EGFRm who have progressed on a first-line EGFR TKI and are T790M positive on biopsy (TIGER2). The dose of rociletinib in this trial is 625 mg administered twice daily. In addition, a randomized phase 2/3 clinical trial is soon to open, and will be comparing rociletinib versus erlotinib in the first-line setting for patients with EGFRm disease, regardless of T790M status (TIGER1). Finally, a phase 3 trial is planned of roci4
letinib versus platinum doublet chemotherapy in patients with EGFRm lung cancer who develop disease progression while receiving first-line EGFR TKIs and are T790M positive as demonstrated on biopsy (TIGER3). HM61713
Another third-generation EGFR TKI, HM61713 (Hanmi Pharmaceutical Company Ltd, Seoul, South Korea), is also highly selective for the EGFRm. It demonstrated good efficacy in in vivo models, especially those with concurrent T790M mutations. HM61713 was studied in a phase 1 trial enrolling patients from 7 centers in Korea with EGFRm NSCLC that had progressed on prior TKI therapy. In the escalation phase, doses were increased from 75 mg to 800 mg daily. No maximum tolerated dose was found, but 2 DLTs were reported. One was an idiosyncratic drug reaction leading to shortness of breath and rash at a dose of 100 mg twice daily, whereas the other DLT was increased amylase and lipase levels. They included an expansion phase at the 300-mg daily dose, at which T790M testing was performed on the tumor tissues of study participants. A total of 35 patients were enrolled in the dose escalation phase, and 83 patients were enrolled in the expansion arm. The most common AEs noted were nausea, rash, headaches, and diarrhea. It is interesting to note that 3 patients developed grade 3 dyspnea. In the expansion cohort, in which 58% of patients were positive for T790M, the ORR was 21.7% with a clinical benefit rate of 67.5% reported in 83 evaluable patients. In a subset analysis, patients with T790M fared better than those without, with ORR rates of 29% and 12%, respectively.28 Conclusions
Targeted therapy against EGFRm-driven NSCLC is currently at the forefront in the new era of personalized medicine. The current treatment paradigm for patients with EGFRm NSCLC is shown in Figure 1. The development and adaption into the clinic of the first-generation TKIs, erlotinib and gefitinib, has revolutionized the care that oncologists can provide to this subgroup of patients with NSCLC. However, the duration of responses has been limited secondary to the resistance that inevitably develops. Fortunately, new drug development has given hope to this patient population. AZD9291, rociletinib, and HM61713 have all shown preliminary significant efficacy in this population, and appear to be well tolerated. Although these early data demonstrate similar ORR rates between AZD9291 and rociletinib, HM61713 has not shown the same level of effectiveness. Currently, the reason for this disparity is unclear, but could potentially be Cancer
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Next Generation of EGFR TKIs in NSCLC/Steuer et al
Figure 1. The current treatment paradigm for patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer is shown. TKI indicates tyrosine kinase inhibitor.
due to issues with drug dosing or population differences, because to the best of our knowledge HM61713 has only been studied in Korea. The currently available data are not mature enough to determine which agent is the best in its class, with the notable differences primarily related to toxicity and the frequency of administration. Several other EGFR-specific TKIs are currently being investigated in patients with NSCLC with an EGFR-sensitizing mutation and T790M positivity (ie, ASP8273 [Astellas Pharma Inc, Tokyo, Japan] and EGF816 [Novartis Pharmaceuticals, Basel, Switzerland]) but it is too early in their development to know what their clinical role will be for these patients.30,31 Despite the considerable promise of these medications, there are still questions that remain to be addressed. For example, the treatment of patients with EGFRm disease who develop disease progression while receiving first-line treatment with TKIs but are negative for T790M is currently unclear. Combination therapy has demonstrated promise in the treatment of this patient population. In addition, understanding how EGFRm tumors respond to the selective inhibition of third-generation EGFR TKIs will Cancer
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be essential moving forward, and further highlights the importance of obtaining biopsies of these tumors at the time of disease progression. The development of the thirdgeneration agents as the first-line therapy for patients with EGFRm disease has already started and it is hoped that the T790M-mediated resistance can be delayed or prevented. However, it is possible that other less well known escape mechanisms might emerge. Finally, although responses are only anecdotal at this time, the potential activity of the third-generation agents against brain metastasis appears promising and is worthy of further study. In summary, EGFR inhibition in patients with NSCLC has entered the next exciting phase, which is bound to benefit patients. FUNDING SUPPORT No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES Dr. Ramalingam has served as a paid member of the advisory boards of Lilly, Genentech, Clovis, AstraZeneca, and Boehringer Ingelheim and has received research support from AstraZeneca for work performed outside of the current study. 5
Commentary
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