REVIEW URRENT C OPINION
Second and third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer Bin-Chi Liao a, Chia-Chi Lin a,b, and James Chih-Hsin Yang a,c
Purpose of review The first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, are effective as first-line treatment of advanced nonsmall cell lung cancer (NSCLC) harboring activating EGFR mutations (deletions in exon 19 and exon 21 L858R mutation). EGFR T790 M resistance mutation (EGFRT790M) ultimately emerged in most of these patients. The second and third-generation EGFRTKIs were designed to have more potent inhibition of EGFR and to overcome EGFRT790M. This review describes the recent developments of these novel EGFR-TKIs. Recent findings The second-generation EGFR-TKIs, afatinib and dacomitinib, irreversibly bind to the tyrosine kinase of EGFR and other ErbB-family members. Afatinib has been approved as first-line treatment of advanced NSCLC harboring activating EGFR mutations. Dacomitinib is under development. Third-generation EGFR-TKIs, AZD9291, CO-1686, and HM61713, inhibit both EGFR activating and resistance mutations, while sparing wild-type EGFR. In early-phase studies, these drugs demonstrated promising response rates against tumors with acquired EGFRT790M. Summary Second-generation EGFR-TKI, afatinib, is available as first-line treatment of advanced NSCLC harboring activating EGFR mutations. Third-generation EGFR-TKIs are under development for tumors harboring acquired EGFRT790M. Keywords afatinib, AZD9291, CO-1686, EGFR T790 M mutation, lung cancer
INTRODUCTION
advanced EGFR-mutated lung adenocarcinoma [13 ,14 ]. However, EGFR T790 M resistance mutation (substitution of threonine with methionine at amino acid position 790, EGFRT790M) emerged following EGFR-TKI therapy, and thirdgeneration EGFR-TKIs were designed to overcome this gatekeeper mutation, which accounts for 60% of acquired resistance to EGFR-TKIs [15–18]. In this review, we describe the recent developments of &
The first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, had been extensively studied in treatment of patients with advanced nonsmall cell lung cancer (NSCLC). Tumors harboring an activating EGFR mutation, especially deletions in exon 19 (EGFRdel19) and exon 21 L858R mutation (EGFRL858R), frequently respond to EGFR-TKI therapy. These mutations are predictive of a response to EGFR-TKI treatment [1–3]. Many phase II and III studies have confirmed the role of the first-line EGFR-TKI in patients with advanced EGFR-mutated lung adenocarcinoma [4–12]. Second-generation EGFR-TKIs, afatinib and dacomitinib, are irreversible EGFR-TKIs, which aim to have more potent EGFR tyrosine kinase inhibition and to target other ErbB-family members, including HER2. Recent reports have demonstrated the role of afatinib in first-line treatment of www.co-oncology.com
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a Department of Oncology, bDepartment of Urology and cGraduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
Correspondence to James Chih-Hsin Yang, MD, PhD, Department of Oncology, National Taiwan University Hospital, 7, Chung-Shan South Road, Taipei 100, Taiwan. Tel: +886 2 23123456 ext. 67511; fax: +886 2 23711174; e-mail: [email protected] Curr Opin Oncol 2015, 27:94–101 DOI:10.1097/CCO.0000000000000164 Volume 27 Number 2 March 2015
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Second and third-generation EGFR-TKIs in advanced NSCLC Liao et al.
KEY POINTS The second-generation EGFR-TKIs irreversibly bind to the tyrosine kinase of EGFR and are more potent than the first-generation EGFR-TKIs, which reversibly bind to the targets. Afatinib monotherapy as first-line treatment prolonged PFS and OS in patients with advanced lung adenocarcinoma harboring activating EGFR mutations and EGFR exon 19 deletions, respectively, as compared with pemetrexed plus cisplatin or gemcitabine plus cisplatin chemotherapy. The most common adverse effects of second-generation EGFR-TKIs are diarrhea and skin rash. The third-generation EGFR-TKIs have activities against activating EGFR mutations and EGFRT790M, while sparing wild-type EGFR. The third-generation EGFR-TKIs have less adverse effects of diarrhea and skin rash. The results of early-phase clinical trials, especially in tumors harboring acquired EGFRT790M, are encouraging.
second and third-generation EGFR-TKIs in treatment of selected lung cancer patients. A literature review of clinical studies published between January 2012 and July 2014 was conducted using PubMed and MEDLINE, with the entry keywords ‘nonsmall cell lung cancer,’ ‘epidermal growth factor receptor T790 M mutation,’ ‘afatinib,’ ‘dacomitinib,’ ‘AZD9291,’ and ‘CO-1686.’ We also performed a manual search of abstracts presented at the major oncology meetings.
SECOND-GENERATION EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITOR: AFATINIB Afatinib (BIBW2992), an aniline-quinazoline, is an orally bioavailable, selective, irreversible ErbB family blocker of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4). Afatinib demonstrated activities against cancer cells harboring activating EGFR mutations in preclinical studies, including the most common mutation EGFRL858R, and EGFRL858R/T790M [19,20]. In a phase I study, three patients with NSCLC achieved a durable partial response to afatinib, including two patients with tumors harboring EGFR mutations [21]. In a single arm phase II study (LUX-Lung 4) conducted in Japan, patients with advanced lung adenocarcinoma who progressed after 3 12 weeks of prior gefitinib and/or erlotinib treatment received afatinib therapy at 50 mg/day. Of 61 evaluable patients, five patients (8.2%) had a confirmed objective response [22]. In a phase IIb/III study (LUX-Lung 1), afatinib (50 mg/
day) or placebo was administered as salvage treatment for advanced lung adenocarcinoma after failure of prior cytotoxic chemotherapy and at least 12 weeks of previous EGFR-TKI (gefitinib or erlotinib) therapy. A total of 585 patients were randomized, and the median overall survival (OS) (primary end point) was 10.8 months in the afatinib group and 12.0 months in the placebo group [hazard ratio (HR) 1.08; 95% confidence interval (CI) 0.86–1.35; P ¼ 0.74]. The progression-free survival (PFS) was 3.3 and 1.1 months, respectively (HR 0.38; 95% CI 0.31–0.48; P < 0.0001). Confirmed response rate was 7% in the afatinib group by independent review [23]. The study did not meet its primary end point, and the author attributed it to high proportion of subsequent cancer treatment after progression in both groups. In these two studies, patients were required to have at least 12 weeks of prior treatment with gefitinib and/or erlotinib. This was an enrichment strategy to select patients with possible activating EGFR mutations and subsequent acquired EGFRT790M [24]. However, the low response rates in these two trials made investigators doubt its ability to overcome acquired EGFRT790M. Possible explanation included the presence of multiple resistance mechanisms [22,23,25–28]. A strategy of dual blockade, afatinib plus cetuximab (a chimeric IgG1 monoclonal antibody against EGFR), emerged to overcome acquired EGFRT790M [29]. Regarding the afatinib therapy in first-line setting, in a phase II study (LUX-Lung 2), afatinib as first or second-line therapy (EGFR-TKI naive) demonstrated activity in the treatment of patients with advanced EGFR-mutated lung adenocarcinoma (especially EGFRdel19 and EGFRL858R). The response rate was 61% by independent review, and the median PFS was 10.1 months (95% CI 8.12–13.80) [30]. Around three-fourths of the patients were treated with a starting dose of 50 mg/day and one-fourth of them were treated with a starting dose of 40 mg/day. The response rates were similar in the two groups, but grade 3 diarrhea and rash or acne were less common in patients receiving a 40 mg/day starting dose. This dose level was chosen to compare with chemotherapy in subsequent phase III studies. LUX-Lung 3 is a global phase III study for evaluating the efficacy and safety of afatinib monotherapy compared with pemetrexed plus cisplatin chemotherapy as first-line treatment for patients with EGFR-mutated advanced lung adenocarcinoma [14 ]. Pemetrexed plus cisplatin was regarded as the best regimen of platinum combination for advanced nonsquamous NSCLC when this study was designed [31]. Continuation maintenance therapy with pemetrexed was not standard of care at that time although this treatment strategy was proved to prolong PFS and OS after the
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LUX-Lung 3 study commenced [32,33]. A total of 345 patients were randomized 2 : 1 to daily afatinib at 40 mg/day (n ¼ 230) or intravenous chemotherapy with pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) up to 6 cycles (n ¼ 115). The primary end point was PFS by independent central review. Forty-nine percent of the patients were positive for EGFRdel19, and 40% were positive for EGFRL858R. Based on the intention-to-treat (ITT) population analysis, the afatinib arm had a significantly prolonged PFS as compared with the chemotherapy arm (median PFS 11.1 vs. 6.9 months; HR 0.58; 95% CI 0.43–0.78; P ¼ 0.001). Objective response rate (ORR) was significantly higher with afatinib (56 vs. 23%; P ¼ 0.001). In 308 patients with common mutations (EGFRdel19 and EGFRL858R), median PFS was 13.6 vs. 6.9 months, respectively (HR 0.47; 95% CI 0.34– 0.65; P ¼ 0.001). Most common drug-related grade 3 3 adverse effects were rash/acne (16.2%), diarrhea (14.4%), and paronychia (11.4%) with afatinib. Three patients (1%) developed interstitial lung disease-like events [14 ]. Health-related quality of life by the EORTC QLQ C30 questionnaire favored afatinib treatment. Improvements of pain and dyspnea were more frequently seen in the afatinib group, as determined by the LC13 questionnaire [13 ]. Based on the LUX-Lung 3 study, afatinib was first approved in Taiwan in May 2013 and then in the United States for first-line treatment of patients with metastatic NSCLC whose tumors have EGFRdel19 or EGFRL858R. Afatinib also underwent comparison with gemcitabine plus cisplatin chemotherapy in patients with advanced EGFR-mutated lung adenocarcinoma in the LUX-Lung 6 study. This study was conducted in China, Thailand, and South Korea. A total of 364 patients were randomized 2 : 1 to daily afatinib at 40 mg/day (n ¼ 242) or intravenous chemotherapy with gemcitabine (1000 mg/m2, on days 1 and 8) plus cisplatin (75 mg/m2, on day 1) up to 6 cycles (n ¼ 122). Median PFS was significantly longer in the afatinib group as compared with the chemotherapy group (median PFS 11.0 vs. 5.6 months; HR 0.28; 95% CI 0.20–0.39; P < 0.0001) [34 ]. In a combined OS analysis from the LUX-Lung 3 and LUXLung 6 studies, the OS of the overall populations did not differ (median OS 28.2 vs. 28.2 months in LUXLung 3 and 23.1 vs. 23.5 months in LUX-Lung 6). In preplanned subgroup analysis of patients with EGFRdel19, the OS was significantly longer in the afatinib groups of both studies (median OS 33.3 vs. 21.1 months; HR 0.54; 95% CI 0.36–0.79; P¼0.0015 in LUX-Lung 3 and 31.4 vs. 18.4 months; HR 0.64; 95% CI 0.44–0.94; P¼0.023 in LUX-Lung 6) [35]. This is the first study of first-line EGFR-TKI therapy that showed OS benefit, which was not demonstrated in the first-generation EGFR-TKI, &&
&
&
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gefitinib and erlotinib, studies [5,36–38]. Whether first or second-generation EGFR-TKI is the best firstline therapy will be answered in the LUX-Lung 7 study, a phase IIb study, which compared afatinib with gefitinib in patients with advanced EGFRmutated lung adenocarcinoma (ClinicalTrials.gov, NCT01466660). Phase III clinical trials of afatinib, LUX-Lung 1 [23], LUX-Lung 3 [14 ], LUX-Lung 6 [34 ], and ongoing LUX-Lung 8 are listed in Table 1 [14 ,23,34 ,39,40]. &&
&
&&
&
SECOND-GENERATION EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITOR: DACOMITINIB Dacomitinib (PF-00299804) is an irreversible inhibitor of EGFR, HER2, and HER4. In preclinical cell lines and xenograft studies, dacomitinib demonstrated activities against both activating EGFR mutations and EGFRT790M [41,42]. A phase I study determined the maximum tolerated dose (MTD) of 45 mg/day, and the dose-limiting toxicities (DLTs) included stomatitis and skin toxicities [43]. A phase III study (NCIC CTG BR.26) compared dacomitinib 45 mg/day with placebo in patients with advanced NSCLC pretreated with cytotoxic chemotherapy and an EGFR-TKI [39]. A total of 720 patients were randomized 2 : 1 to dacomitinib or placebo. The PFS was significantly improved in the dacomitinib group (median PFS 2.7 vs. 1.4 months; HR 0.66; 95% CI 0.55–0.79; P < 0.0001), but the OS (primary end point) was not (median OS 6.8 vs. 6.3 months; HR 1.0; 95% CI 0.83–1.21; P ¼ 0.99). The OS was similar regardless of EGFR mutation status, but appeared to differ by KRAS status. Improving OS was observed in patients with wild-type KRAS (median OS 7.0 vs. 5.2 months; HR 0.79; 95% CI 0.61–1.03) [39]. A phase II study compared dacomitinib monotherapy with erlotinib as second or thirdline treatment for unselected patients with advanced NSCLC who had not undergone EGFRdirected therapy [44]. A total of 188 patients were randomly assigned, and the median PFS (primary end point) was 2.86 months in the dacomitinib group and 1.91 months in the erlotinib group (HR 0.66; 95% CI 0.47–0.91; P ¼ 0.012). PFS benefit was observed in patients with the molecular subsets of KRAS wild-type/EGFR any status and KRAS wildtype/EGFR wild-type. Regarding the subgroups of patients with an EGFR mutation, 19 patients received dacomitinib treatment and 11 patients received erlotinib treatment. The median PFS was 7.44 months in both groups (HR 0.46; 95% CI 0.18– 1.18; P ¼ 0.098). The most common treatmentrelated adverse effects in the dacomitinib arm were diarrhea (73.1%) and dermatitis acneiform (64.5%) Volume 27 Number 2 March 2015
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364
NA
LUX-Lung 3 [14 ]
LUX-Lung 6 [34 ]
LUX-Lung 8
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878
NA
BR. 26 [39]
ARCHER 1009 [40]
ARCHER 1050
&
Treatment-naive advanced NSCLC harboring EGFR mutations
Advanced NSCLC pretreated with one or two lines of cytotoxic chemotherapy
Advanced NSCLC pretreated with cytotoxic chemotherapy and EGFR-TKI
Advanced lung squamous cell carcinoma pretreated with platinum-based chemotherapy
Treatment-naive advanced lung adenocarcinoma harboring EGFR mutations
Treatment-naive advanced lung adenocarcinoma harboring EGFR mutations
Advanced lung adenocarcinoma pretreated with cytotoxic chemotherapy and EGFR-TKI
Patient group
Gefitinib
Erlotinib
Placebo
Erlotinib
Gemcitabine plus cisplatin
Pemetrexed plus cisplatin
Placebo
Comparator
NA
11.4 vs. 8.2%
7 vs. 1%
NA
66.9% vs 23.0%
56 vs. 23%
7 vs. 0.5%
ORR
NA
2.6 vs. 2.6 months (HR 0.941; P ¼ 0.229)
2.7 vs. 1.4 months
NA
11.0 vs. 5.6 months (HR 0.28, 95% CI 0.2–0.39; P < 0.0001)
11.1 vs. 6.9 months (HR 0.58, 95% CI 0.43–0.78; P ¼ 0.001)
3.3 vs. 1.1 months
PFS
NA
7.9 vs. 8.4 months
6.8 vs. 6.3 months (HR 1.002, 95% CI 0.828–1.212; P ¼ 0.9873)
NA
23.1 vs. 23.5 months
28.2 vs. 28.2 months
10.8 vs. 12.0 months (HR 1.08, 95% CI 0.86–1.35; P ¼ 0.74)
OS
Ongoing clinical trial
Primary end point: PFS
Primary end point: OS
Ongoing clinical trial
Primary end point: PFS
Primary end point: PFS
Primary end point: OS
Trial outcome and status
CI, confidence interval; EGFR, epidermal growth factor receptor; HR, hazard ratio; NA, not available; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.
Dacomitinib
345
LUX-Lung 1 [23]
Afatinib
&&
585
Study name
Drugs
N
Table 1. Phase III clinical studies of second-generation EGFR-TKIs
Second and third-generation EGFR-TKIs in advanced NSCLC Liao et al.
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[44]. Based on this study’s results, a phase III trial (ARCHER 1009 study) of second or third-line dacomitinib versus erlotinib was conducted. A total of 878 patients were enrolled, and activating EGFR mutation was present in 41 patients in each arm. The PFS (primary end point) was 2.6 months in both arms (HR 0.941; P ¼ 0.229). The author concluded that dacomitinib was not superior to erlotinib in second or third-line therapy for advanced NSCLC [40]. Regarding dacomitinib therapy in the first-line setting, a phase II trial of first-line dacomitinib for advanced lung adenocarcinoma enrolled patient population restricted to nonsmokers (or former light smokers) or patients with known activating EGFR mutations regardless of smoking status [ClinicalTrials.gov, NCT00818441]. The preliminary result reported a response rate of 76% in 46 patients with activating mutations of EGFRdel19 (n ¼ 25) or a mutation in exon 21 (n ¼ 21) [45,46]. A phase III randomized study (ARCHER-1050) is ongoing, which compared first-line dacomitinib or gefitinib in patients with advanced NSCLC harboring activating EGFR mutations (ClinicalTrials.gov, NCT01774721). Phase III trials of dacomitinib, BR. 26 [39], ARCHER 1009 [40], and ARCHER 1050 are listed in Table 1. Dacomitinib was not yet approved by any regulatory agency as of July 2014.
THIRD-GENERATION EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITORS Although afatinib and dacomitinib have activity against EGFRT790M, they also irreversibly inhibit wild-type EGFR. The side-effects, such as diarrhea and skin toxicities, were thus higher. The thirdgeneration EGFR-TKIs were designed to inhibit EGFRT790M while sparing wild-type EGFR [47]. Three drugs, AZD9291 [48], CO-1686 [49], and HM61713 [50], have been evaluated in early-phase clinical trials (Table 2) [48–50]. Other third-generation EGFR-TKIs, such as EGF816 (ClinicalTrials.gov,
NCT02108964) and ASP8273 (ClinicalTrials.gov, NCT02113813), are under development.
AZD9291 AZD9291, a mono-anilino-pyrimidine compound, is an irreversible mutant selective EGFR-TKI [51]. This drug is structurally different from the first and second-generation EGFR-TKIs. In preclinical studies, it potently inhibited phosphorylation of EGFR in cell lines with activating EGFR mutations (EGFRdel19 and EGFRL858R) and EGFRT790M. AZD9291 also caused profound and sustained tumor regression in tumor xenograft and transgenic mouse models harboring activating EGFR mutations and EGFRT790M. AZD9291 was less potent in inhibiting phosphorylation of wild-type EGFR cell lines and had increased selectivity margin against wild-type EGFR [52 ]. In a phase I dose escalation study (AURA; ClinicalTrials.gov, NCT01802632), patients with advanced EGFR-mutated NSCLC who had disease progression following EGFR-TKI therapy (mainly gefitinib or erlotinib) were enrolled. The starting dose was 20 mg/day and administered orally. A total of 31 and 201 patients were enrolled in the escalation and expansion cohort, respectively. The ORR was 53% regardless of tumor T790 M mutation status. In patients with EGFRT790M, the ORR was 64% (69/107; 95% CI 55%, 73%), and the overall disease control rate (DCR, complete response plus partial response plus stable disease) was 94% (101/107; CI: 88%, 98%). The response rates were similarly high across the five tested dose levels. By contrast, in patients without EGFRT790M, the ORR was 22% (11/50; 95% CI 12%, 36%), and the overall DCR was 56% (28/50; 95% CI 41%, 70%) [48]. The most common adverse effects were diarrhea, rash, nausea, and pruritus. These adverse effects were mostly mild. Only three patients developed mild hyperglycemia. Six patients developed interstitial lung disease-like events. Any grade 3 3 adverse effects developed in only 24% of the patients, and these &
Table 2. Phase I clinical studies of third-generation EGFR-TKIs N
Drugs
Patient group
ORR
ORR in EGFRT790M
ORR in non EGFRT790M
Common adverse effects
AZD9291 [48]
232
Advanced EGFR-mutated NSCLC pretreated with EGFR-TKI
53%
64%
22%
Diarrhea, rash, nausea, and pruritus
CO-1686 [49]
72
Advanced EGFR-mutated NSCLC pretreated with EGFR-TKI
NA
58%
NA
Nausea, fatigue, impaired glucose intolerance/hyperglycemia (grade 3 in 22% of the patients), and diarrhea
HM61713 [50]
83
Advanced EGFR-mutated NSCLC pretreated with EGFR-TKI
21.7%
29.2%
NA
Skin exfoliation, nausea, diarrhea, decreased appetite, and pruritus
EGFR, epidermal growth factor receptor; NA, not available; ORR, objective response rate; TKI, tyrosine kinase inhibitor.
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Second and third-generation EGFR-TKIs in advanced NSCLC Liao et al.
adverse effects led to dose reduction and drug discontinuation in only 2 and 4% of patients. There were no DLTs at any dose level. MTD was not defined. For future development of this drug, 80 mg/day was selected based on the activity and toxicity results. A global phase II confirmatory single-arm open-label study (AURA 2; ClinicalTrials.gov, NCT02094261) is ongoing, which administered AZD9291 80 mg/day in patients with advanced NSCLC harboring activating EGFR mutation whose disease progressed after prior EGFR-TKI therapy and harbored EGFRT790M. Another phase III study (AURA 3; ClinicalTrials.gov, NCT0215198) compared AZD9291 80 mg/day with pemetrexed plus platinum chemotherapy in the same population as the AURA 2 study. Trials of AZD9291 in combination with other novel drugs are also ongoing. A phase I study that assesses the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of AZD9291 in combination with MEDI4736 (anti-PD-L1 antibody), selumetinib (MEK inhibitor), or AZD6094 (MET tyrosine kinase inhibitor) is recruiting participants (ClinicalTrials.gov, NCT02143466).
CO-1686 Rociletinib (CO-1686), a 2,4-disubstituted pyrimidine molecule, is an irreversible mutant selective EGFR-TKI. In preclinical studies, CO-1686 led to tumor regression in cell-lines, xenograft models, and transgenic mouse models harboring activating EGFR mutations and EGFRT790M [53 ]. In a phase I study (ClinicalTrials.gov, NCT01526928), patients with advanced EGFR-mutated NSCLC pretreated with EGFR-TKIs were enrolled, and tumor re-biopsy was mandatory. The DLT rates at all dose levels were below 33%. The most common adverse effects were nausea, fatigue, impaired glucose intolerance/ hyperglycemia (grade 3 in 22% of the patients), and diarrhea (grade 1 in 19% and grade 2 in 4% of the patients). Only 4% of the patients developed any form of skin rashes, and all were grade 1. In the 40 patients with centrally confirmed EGFRT790M who had undergone CO-1686 therapy within therapeutic range, the ORR was 58% [49]. The confirmatory phase II trial of second-line CO-1686 (625 mg twice a day) for advanced EGFRmutated NSCLC progressed after previous EGFRTKI therapy is ongoing (TIGER 2; ClinicalTrials.gov, NCT02147990). This trial only enrolled patients with EGFRT790M. A randomized phase II study of first-line CO-1686 or erlotinib monotherapy for advanced EGFR-mutated advanced NSCLC will start soon (TIGER 1; ClinicalTrials.gov, NCT02186301). EGFR T790 M status will not be screened in this trial. &
HM61713 HM61713 is an orally administered, selective inhibitor for activating EGFR mutations and EGFRT790M. It has low activity against wild-type EGFR. In a phase I study (ClinicalTrials.gov, NCT01588145), patients with EGFR-TKI pretreated advanced EGFR-mutated NSCLC were enrolled. MTD has not been reached and an 800 mg cohort is ongoing. The common adverse effects were skin exfoliation, nausea, diarrhea, decreased appetite, and pruritus. Most of the adverse effects were grade 1 and 2. Among the 83 patients in the expansion cohort, the ORR was 21.7% and DCR was 67.5%. The ORR and DCR in the 48 patients with documented EGFRT790M were 29.2 and 75.0%, respectively [50].
CONCLUSION In addition to gefitinib and erlotinib, second-generation EGFR-TKI, afatinib, is available as first-line monotherapy of advanced NSCLC harboring activating EGFR mutations. It prolonged PFS as compared with pemetrexed plus cisplatin or gemcitabine plus cisplatin chemotherapy and improved quality of life. In patients with EGFRdel19, first-line afatinib therapy even prolonged OS. Patient education and management of afatinib-related side-effects, such as diarrhea and skin toxicity, are crucial. Third-generation EGFR-TKIs are under clinical development or tumors harboring acquired EGFRT790M. These drugs reserved activities against activating EGFR mutations while sparing wild-type EGFR, and consequently, the toxicities of these drugs were mild as compared with second-generation EGFR-TKIs. The results of early-phase clinical trials are encouraging, especially in patients with re-biopsy-confirmed acquired EGFRT790M, and the confirmatory phase II trials are ongoing. Trials of first-line treatment with a third-generation EGFR-TKI in patients with activating EGFR mutations are ongoing regardless of EGFR T790 M status given the reserved activities against activating EGFR mutations. Acknowledgements None. Financial support and sponsorship No sources of funding were used to assist with the preparation of this review. Conflicts of interest J.C-H.Y. is a compensated advisor for Boehringer Ingelheim, Eli Lilly, Novartis, Roche Genetech, Astrazeneca, Pfizer, Takeda, Clovis, MSD, and Merck Serono. He received honoraria for advisory role or speaker from
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Astrazeneca, Bayer, and Roche; B-C.L., C-C.L. have no conflicts of interest that are directly relevant to the content of this review.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 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. 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. 4. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive nonsmall-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012; 13:239–246. 5. Han J-Y, Park K, Kim S-W, et al. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol 2012; 30:1122–1128. 6. Zhou C, Wu Y-L, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive nonsmall-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011; 12:735–742. 7. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with nonsmall-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. 8. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non– small-cell lung cancer with mutated EGFR. N Engl J Med 2010; 362:2380– 2388. 9. Mok TS, Wu Y-L, Thongprasert S, et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361:947–957. 10. Yang C-H, Yu C-J, Shih J-Y, et al. Specific EGFR mutations predict treatment outcome of stage IIIB/IV patients with chemotherapy-naive non–small-cell lung cancer receiving first-line gefitinib monotherapy. J Clin Oncol 2008; 26:2745–2753. 11. Yang JC-H, Wu Y-L, Chan V, et al. Epidermal growth factor receptor mutation analysis in previously unanalyzed histology samples and cytology samples from the phase III Iressa Pan-ASia Study (IPASS). Lung Cancer 2014; 83:174–181. 12. Liao B-C, Lin C-C, Yang J-H. First-line management of EGFR-mutated advanced lung adenocarcinoma: recent developments. Drugs 2013; 73:357–369. 13. Yang JC-H, Hirsh V, Schuler M, et al. Symptom control and quality of life in & LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31:3342–3350. Afatinib not only prolonged PFS, but also improved quality of life and lung cancerrelated symptoms. 14. Sequist LV, Yang JC-H, 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. This is the first report that afatinib monotherapy as first-line treatment prolonged PFS in patients with advanced lung adenocarcinoma harboring activating EGFR mutations as compared with pemetrexed plus cisplatin chemotherapy. 15. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFRmutant lung cancers. Clin Cancer Res 2013; 19:2240–2247. 16. 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. 17. 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. 18. Bell DW, Gore I, Okimoto RA, et al. Inherited susceptibility to lung cancer may be associated with the T790 M drug resistance mutation in EGFR. Nat Genet 2005; 37:1315–1316. 19. Li D, Ambrogio L, Shimamura T, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008; 27:4702–4711.
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20. Solca F, Dahl G, Zoephel A, et al. Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther 2012; 343:342–350. 21. Yap TA, Vidal L, Adam J, et al. Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors. J Clin Oncol 2010; 28:3965–3972. 22. Katakami N, Atagi S, Goto K, et al. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non–small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol 2013; 31:3335–3341. 23. Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic nonsmall-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. 24. Jackman D, Pao W, Riely GJ, et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non–small-cell lung cancer. J Clin Oncol 2010; 28:357–360. 25. 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 EGFRT790 M mutation. Cancer Discov 2012; 2:922–933. 26. Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007; 316:1039–1043. 27. Bean J, Brennan C, Shih J-Y, et al. MET amplification occurs with or without T790 M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A 2007; 104:20932–20937. 28. Sacher AG, Ja¨nne PA, Oxnard GR. Management of acquired resistance to epidermal growth factor receptor kinase inhibitors in patients with advanced nonsmall cell lung cancer. Cancer 2014; 120:2289–2298. 29. Janjigian YY, Smit EF, Groen HJM, et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790 M mutations. Cancer Discov 2014; 4:1036–1045. 30. Yang JC-H, Shih J-Y, Su W-C, et al. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol 2012; 13:539–548. 31. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non–small-cell lung cancer. J Clin Oncol 2008; 26:3543–3551. 32. Paz-Ares LG, de Marinis F, Dediu M, et al. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non–small-cell lung cancer. J Clin Oncol 2013; 31:2895–2902. 33. Paz-Ares L, de Marinis F, Dediu M, et al. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced nonsquamous nonsmall-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol 2012; 13:247–255. 34. Wu Y-L, Zhou C, Hu C-P, et al. Afatinib versus cisplatin plus gemcitabine for & first-line treatment of Asian patients with advanced nonsmall-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol 2014; 15:213–222. This study concluded that afatinib prolonged PFS in patients with advanced lung adenocarcinoma harboring activating EGFR mutations as compared with gemcitabine plus cisplatin chemotherapy. 35. Yang JC-H, Wu Y-L, Schuler M, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol 2015. [Epub ahead of print] 36. Zhou C, Wu YL, Liu X, et al. Overall survival (OS) results from OPTIMAL (CTONG0802), a phase III trial of erlotinib (E) versus carboplatin plus gemcitabine (GC) as first-line treatment for Chinese patients with EGFR mutation-positive advanced nonsmall cell lung cancer (NSCLC). ASCO Meeting Abstracts 2012; 30:7520. 37. Fukuoka M, Wu Y-L, Thongprasert S, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, 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. 38. Inoue A, Kobayashi K, Maemondo M, et al. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin–paclitaxel for chemo-naive nonsmall cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol 2013; 24:54–59. 39. Ellis PM, Liu G, Millward M, et al. NCIC CTG BR.26: A phase III randomized, double blind, placebo controlled trial of dacomitinib versus placebo in patients with advanced/metastatic nonsmall cell lung cancer (NSCLC) who received prior chemotherapy and an EGFR TKI. ASCO Meeting Abstracts 2014; 32:8036. 40. Ramalingam SS, Janne PA, Mok T, et al. Randomized, double-blinded study of dacomitinib, an irreversible pan-human epidermal growth factor receptor (HER) inhibitor, versus erlotinib for second-line/third-line therapy of locally advanced/metastatic nonsmall cell lung cancer (ARCHER 1009). ASCO Meeting Abstracts 2014; 32:8018.
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Second and third-generation EGFR-TKIs in advanced NSCLC Liao et al. 41. Gonzales AJ, Hook KE, Althaus IW, et al. Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible panerbB receptor tyrosine kinase inhibitor. Mol Cancer Ther 2008; 7:1880– 1889. 42. Engelman JA, Zejnullahu K, Gale C-M, et al. PF00299804, an irreversible PanERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res 2007; 67:11924– 11932. 43. Ja¨nne PA, Boss DS, Camidge DR, et al. Phase I dose-escalation study of the Pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors. Clin Cancer Res 2011; 17:1131–1139. 44. Ramalingam SS, Blackhall F, Krzakowski M, et al. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan–human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non–smallcell lung cancer. J Clin Oncol 2012; 30:3337–3344. 45. Kris M, Goldberg Z, Janne PA, et al. Dacomitinib (PF-00299804), an irreversible pan-Her tyrosine kinase inhibitor (TKI), for first-line treatment of EGFR-mutant or Her2-mutant or -amplified lung cancers. Ann Oncol 2012; 23:ix400–ix446. 46. Mok T, Lee K, Tang M, Leung L. Dacomitinib for the treatment of advanced or metastatic nonsmall-cell lung cancer. Future Oncol 2014; 10:813–822. 47. Zhou W, Ercan D, Chen L, et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790 M. Nature 2009; 462:1070–1074.
48. Janne PA, Ramalingam SS, Yang JC-H, et al. Clinical activity of the mutantselective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitorresistant nonsmall cell lung cancer (NSCLC). ASCO Meeting Abstracts 2014; 32:8009. 49. Sequist LV, Soria J-C, Gadgeel SM, et al. First-in-human evaluation of CO1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790 M). ASCO Meeting Abstracts 2014; 32:8010. 50. Kim D-W, Lee DH, Kang JH, 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). ASCO Meeting Abstracts 2014; 32:8011. 51. Ward RA, Anderton MJ, Ashton S, et al. Structure- and reactivity-based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor (EGFR). J Med Chem 2013; 56:7025–7048. 52. Cross DAE, 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. This is the preclinical data of antitumor activity of AZD9291. 53. Walter AO, Sjin RTT, Haringsma HJ, et al. Discovery of a mutant-selective & covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer Discov 2013; 3:1404–1415. This is the preclinical data of antitumor activity of CO-1686.
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Second and third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer Bin-Chi Liao a, Chia-Chi Lin a,b, and James Chih-Hsin Yang a,c
Purpose of review The first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, are effective as first-line treatment of advanced nonsmall cell lung cancer (NSCLC) harboring activating EGFR mutations (deletions in exon 19 and exon 21 L858R mutation). EGFR T790 M resistance mutation (EGFRT790M) ultimately emerged in most of these patients. The second and third-generation EGFRTKIs were designed to have more potent inhibition of EGFR and to overcome EGFRT790M. This review describes the recent developments of these novel EGFR-TKIs. Recent findings The second-generation EGFR-TKIs, afatinib and dacomitinib, irreversibly bind to the tyrosine kinase of EGFR and other ErbB-family members. Afatinib has been approved as first-line treatment of advanced NSCLC harboring activating EGFR mutations. Dacomitinib is under development. Third-generation EGFR-TKIs, AZD9291, CO-1686, and HM61713, inhibit both EGFR activating and resistance mutations, while sparing wild-type EGFR. In early-phase studies, these drugs demonstrated promising response rates against tumors with acquired EGFRT790M. Summary Second-generation EGFR-TKI, afatinib, is available as first-line treatment of advanced NSCLC harboring activating EGFR mutations. Third-generation EGFR-TKIs are under development for tumors harboring acquired EGFRT790M. Keywords afatinib, AZD9291, CO-1686, EGFR T790 M mutation, lung cancer
INTRODUCTION
advanced EGFR-mutated lung adenocarcinoma [13 ,14 ]. However, EGFR T790 M resistance mutation (substitution of threonine with methionine at amino acid position 790, EGFRT790M) emerged following EGFR-TKI therapy, and thirdgeneration EGFR-TKIs were designed to overcome this gatekeeper mutation, which accounts for 60% of acquired resistance to EGFR-TKIs [15–18]. In this review, we describe the recent developments of &
The first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, had been extensively studied in treatment of patients with advanced nonsmall cell lung cancer (NSCLC). Tumors harboring an activating EGFR mutation, especially deletions in exon 19 (EGFRdel19) and exon 21 L858R mutation (EGFRL858R), frequently respond to EGFR-TKI therapy. These mutations are predictive of a response to EGFR-TKI treatment [1–3]. Many phase II and III studies have confirmed the role of the first-line EGFR-TKI in patients with advanced EGFR-mutated lung adenocarcinoma [4–12]. Second-generation EGFR-TKIs, afatinib and dacomitinib, are irreversible EGFR-TKIs, which aim to have more potent EGFR tyrosine kinase inhibition and to target other ErbB-family members, including HER2. Recent reports have demonstrated the role of afatinib in first-line treatment of www.co-oncology.com
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a Department of Oncology, bDepartment of Urology and cGraduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
Correspondence to James Chih-Hsin Yang, MD, PhD, Department of Oncology, National Taiwan University Hospital, 7, Chung-Shan South Road, Taipei 100, Taiwan. Tel: +886 2 23123456 ext. 67511; fax: +886 2 23711174; e-mail: [email protected] Curr Opin Oncol 2015, 27:94–101 DOI:10.1097/CCO.0000000000000164 Volume 27 Number 2 March 2015
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Second and third-generation EGFR-TKIs in advanced NSCLC Liao et al.
KEY POINTS The second-generation EGFR-TKIs irreversibly bind to the tyrosine kinase of EGFR and are more potent than the first-generation EGFR-TKIs, which reversibly bind to the targets. Afatinib monotherapy as first-line treatment prolonged PFS and OS in patients with advanced lung adenocarcinoma harboring activating EGFR mutations and EGFR exon 19 deletions, respectively, as compared with pemetrexed plus cisplatin or gemcitabine plus cisplatin chemotherapy. The most common adverse effects of second-generation EGFR-TKIs are diarrhea and skin rash. The third-generation EGFR-TKIs have activities against activating EGFR mutations and EGFRT790M, while sparing wild-type EGFR. The third-generation EGFR-TKIs have less adverse effects of diarrhea and skin rash. The results of early-phase clinical trials, especially in tumors harboring acquired EGFRT790M, are encouraging.
second and third-generation EGFR-TKIs in treatment of selected lung cancer patients. A literature review of clinical studies published between January 2012 and July 2014 was conducted using PubMed and MEDLINE, with the entry keywords ‘nonsmall cell lung cancer,’ ‘epidermal growth factor receptor T790 M mutation,’ ‘afatinib,’ ‘dacomitinib,’ ‘AZD9291,’ and ‘CO-1686.’ We also performed a manual search of abstracts presented at the major oncology meetings.
SECOND-GENERATION EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITOR: AFATINIB Afatinib (BIBW2992), an aniline-quinazoline, is an orally bioavailable, selective, irreversible ErbB family blocker of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4). Afatinib demonstrated activities against cancer cells harboring activating EGFR mutations in preclinical studies, including the most common mutation EGFRL858R, and EGFRL858R/T790M [19,20]. In a phase I study, three patients with NSCLC achieved a durable partial response to afatinib, including two patients with tumors harboring EGFR mutations [21]. In a single arm phase II study (LUX-Lung 4) conducted in Japan, patients with advanced lung adenocarcinoma who progressed after 3 12 weeks of prior gefitinib and/or erlotinib treatment received afatinib therapy at 50 mg/day. Of 61 evaluable patients, five patients (8.2%) had a confirmed objective response [22]. In a phase IIb/III study (LUX-Lung 1), afatinib (50 mg/
day) or placebo was administered as salvage treatment for advanced lung adenocarcinoma after failure of prior cytotoxic chemotherapy and at least 12 weeks of previous EGFR-TKI (gefitinib or erlotinib) therapy. A total of 585 patients were randomized, and the median overall survival (OS) (primary end point) was 10.8 months in the afatinib group and 12.0 months in the placebo group [hazard ratio (HR) 1.08; 95% confidence interval (CI) 0.86–1.35; P ¼ 0.74]. The progression-free survival (PFS) was 3.3 and 1.1 months, respectively (HR 0.38; 95% CI 0.31–0.48; P < 0.0001). Confirmed response rate was 7% in the afatinib group by independent review [23]. The study did not meet its primary end point, and the author attributed it to high proportion of subsequent cancer treatment after progression in both groups. In these two studies, patients were required to have at least 12 weeks of prior treatment with gefitinib and/or erlotinib. This was an enrichment strategy to select patients with possible activating EGFR mutations and subsequent acquired EGFRT790M [24]. However, the low response rates in these two trials made investigators doubt its ability to overcome acquired EGFRT790M. Possible explanation included the presence of multiple resistance mechanisms [22,23,25–28]. A strategy of dual blockade, afatinib plus cetuximab (a chimeric IgG1 monoclonal antibody against EGFR), emerged to overcome acquired EGFRT790M [29]. Regarding the afatinib therapy in first-line setting, in a phase II study (LUX-Lung 2), afatinib as first or second-line therapy (EGFR-TKI naive) demonstrated activity in the treatment of patients with advanced EGFR-mutated lung adenocarcinoma (especially EGFRdel19 and EGFRL858R). The response rate was 61% by independent review, and the median PFS was 10.1 months (95% CI 8.12–13.80) [30]. Around three-fourths of the patients were treated with a starting dose of 50 mg/day and one-fourth of them were treated with a starting dose of 40 mg/day. The response rates were similar in the two groups, but grade 3 diarrhea and rash or acne were less common in patients receiving a 40 mg/day starting dose. This dose level was chosen to compare with chemotherapy in subsequent phase III studies. LUX-Lung 3 is a global phase III study for evaluating the efficacy and safety of afatinib monotherapy compared with pemetrexed plus cisplatin chemotherapy as first-line treatment for patients with EGFR-mutated advanced lung adenocarcinoma [14 ]. Pemetrexed plus cisplatin was regarded as the best regimen of platinum combination for advanced nonsquamous NSCLC when this study was designed [31]. Continuation maintenance therapy with pemetrexed was not standard of care at that time although this treatment strategy was proved to prolong PFS and OS after the
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LUX-Lung 3 study commenced [32,33]. A total of 345 patients were randomized 2 : 1 to daily afatinib at 40 mg/day (n ¼ 230) or intravenous chemotherapy with pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) up to 6 cycles (n ¼ 115). The primary end point was PFS by independent central review. Forty-nine percent of the patients were positive for EGFRdel19, and 40% were positive for EGFRL858R. Based on the intention-to-treat (ITT) population analysis, the afatinib arm had a significantly prolonged PFS as compared with the chemotherapy arm (median PFS 11.1 vs. 6.9 months; HR 0.58; 95% CI 0.43–0.78; P ¼ 0.001). Objective response rate (ORR) was significantly higher with afatinib (56 vs. 23%; P ¼ 0.001). In 308 patients with common mutations (EGFRdel19 and EGFRL858R), median PFS was 13.6 vs. 6.9 months, respectively (HR 0.47; 95% CI 0.34– 0.65; P ¼ 0.001). Most common drug-related grade 3 3 adverse effects were rash/acne (16.2%), diarrhea (14.4%), and paronychia (11.4%) with afatinib. Three patients (1%) developed interstitial lung disease-like events [14 ]. Health-related quality of life by the EORTC QLQ C30 questionnaire favored afatinib treatment. Improvements of pain and dyspnea were more frequently seen in the afatinib group, as determined by the LC13 questionnaire [13 ]. Based on the LUX-Lung 3 study, afatinib was first approved in Taiwan in May 2013 and then in the United States for first-line treatment of patients with metastatic NSCLC whose tumors have EGFRdel19 or EGFRL858R. Afatinib also underwent comparison with gemcitabine plus cisplatin chemotherapy in patients with advanced EGFR-mutated lung adenocarcinoma in the LUX-Lung 6 study. This study was conducted in China, Thailand, and South Korea. A total of 364 patients were randomized 2 : 1 to daily afatinib at 40 mg/day (n ¼ 242) or intravenous chemotherapy with gemcitabine (1000 mg/m2, on days 1 and 8) plus cisplatin (75 mg/m2, on day 1) up to 6 cycles (n ¼ 122). Median PFS was significantly longer in the afatinib group as compared with the chemotherapy group (median PFS 11.0 vs. 5.6 months; HR 0.28; 95% CI 0.20–0.39; P < 0.0001) [34 ]. In a combined OS analysis from the LUX-Lung 3 and LUXLung 6 studies, the OS of the overall populations did not differ (median OS 28.2 vs. 28.2 months in LUXLung 3 and 23.1 vs. 23.5 months in LUX-Lung 6). In preplanned subgroup analysis of patients with EGFRdel19, the OS was significantly longer in the afatinib groups of both studies (median OS 33.3 vs. 21.1 months; HR 0.54; 95% CI 0.36–0.79; P¼0.0015 in LUX-Lung 3 and 31.4 vs. 18.4 months; HR 0.64; 95% CI 0.44–0.94; P¼0.023 in LUX-Lung 6) [35]. This is the first study of first-line EGFR-TKI therapy that showed OS benefit, which was not demonstrated in the first-generation EGFR-TKI, &&
&
&
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gefitinib and erlotinib, studies [5,36–38]. Whether first or second-generation EGFR-TKI is the best firstline therapy will be answered in the LUX-Lung 7 study, a phase IIb study, which compared afatinib with gefitinib in patients with advanced EGFRmutated lung adenocarcinoma (ClinicalTrials.gov, NCT01466660). Phase III clinical trials of afatinib, LUX-Lung 1 [23], LUX-Lung 3 [14 ], LUX-Lung 6 [34 ], and ongoing LUX-Lung 8 are listed in Table 1 [14 ,23,34 ,39,40]. &&
&
&&
&
SECOND-GENERATION EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITOR: DACOMITINIB Dacomitinib (PF-00299804) is an irreversible inhibitor of EGFR, HER2, and HER4. In preclinical cell lines and xenograft studies, dacomitinib demonstrated activities against both activating EGFR mutations and EGFRT790M [41,42]. A phase I study determined the maximum tolerated dose (MTD) of 45 mg/day, and the dose-limiting toxicities (DLTs) included stomatitis and skin toxicities [43]. A phase III study (NCIC CTG BR.26) compared dacomitinib 45 mg/day with placebo in patients with advanced NSCLC pretreated with cytotoxic chemotherapy and an EGFR-TKI [39]. A total of 720 patients were randomized 2 : 1 to dacomitinib or placebo. The PFS was significantly improved in the dacomitinib group (median PFS 2.7 vs. 1.4 months; HR 0.66; 95% CI 0.55–0.79; P < 0.0001), but the OS (primary end point) was not (median OS 6.8 vs. 6.3 months; HR 1.0; 95% CI 0.83–1.21; P ¼ 0.99). The OS was similar regardless of EGFR mutation status, but appeared to differ by KRAS status. Improving OS was observed in patients with wild-type KRAS (median OS 7.0 vs. 5.2 months; HR 0.79; 95% CI 0.61–1.03) [39]. A phase II study compared dacomitinib monotherapy with erlotinib as second or thirdline treatment for unselected patients with advanced NSCLC who had not undergone EGFRdirected therapy [44]. A total of 188 patients were randomly assigned, and the median PFS (primary end point) was 2.86 months in the dacomitinib group and 1.91 months in the erlotinib group (HR 0.66; 95% CI 0.47–0.91; P ¼ 0.012). PFS benefit was observed in patients with the molecular subsets of KRAS wild-type/EGFR any status and KRAS wildtype/EGFR wild-type. Regarding the subgroups of patients with an EGFR mutation, 19 patients received dacomitinib treatment and 11 patients received erlotinib treatment. The median PFS was 7.44 months in both groups (HR 0.46; 95% CI 0.18– 1.18; P ¼ 0.098). The most common treatmentrelated adverse effects in the dacomitinib arm were diarrhea (73.1%) and dermatitis acneiform (64.5%) Volume 27 Number 2 March 2015
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364
NA
LUX-Lung 3 [14 ]
LUX-Lung 6 [34 ]
LUX-Lung 8
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878
NA
BR. 26 [39]
ARCHER 1009 [40]
ARCHER 1050
&
Treatment-naive advanced NSCLC harboring EGFR mutations
Advanced NSCLC pretreated with one or two lines of cytotoxic chemotherapy
Advanced NSCLC pretreated with cytotoxic chemotherapy and EGFR-TKI
Advanced lung squamous cell carcinoma pretreated with platinum-based chemotherapy
Treatment-naive advanced lung adenocarcinoma harboring EGFR mutations
Treatment-naive advanced lung adenocarcinoma harboring EGFR mutations
Advanced lung adenocarcinoma pretreated with cytotoxic chemotherapy and EGFR-TKI
Patient group
Gefitinib
Erlotinib
Placebo
Erlotinib
Gemcitabine plus cisplatin
Pemetrexed plus cisplatin
Placebo
Comparator
NA
11.4 vs. 8.2%
7 vs. 1%
NA
66.9% vs 23.0%
56 vs. 23%
7 vs. 0.5%
ORR
NA
2.6 vs. 2.6 months (HR 0.941; P ¼ 0.229)
2.7 vs. 1.4 months
NA
11.0 vs. 5.6 months (HR 0.28, 95% CI 0.2–0.39; P < 0.0001)
11.1 vs. 6.9 months (HR 0.58, 95% CI 0.43–0.78; P ¼ 0.001)
3.3 vs. 1.1 months
PFS
NA
7.9 vs. 8.4 months
6.8 vs. 6.3 months (HR 1.002, 95% CI 0.828–1.212; P ¼ 0.9873)
NA
23.1 vs. 23.5 months
28.2 vs. 28.2 months
10.8 vs. 12.0 months (HR 1.08, 95% CI 0.86–1.35; P ¼ 0.74)
OS
Ongoing clinical trial
Primary end point: PFS
Primary end point: OS
Ongoing clinical trial
Primary end point: PFS
Primary end point: PFS
Primary end point: OS
Trial outcome and status
CI, confidence interval; EGFR, epidermal growth factor receptor; HR, hazard ratio; NA, not available; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.
Dacomitinib
345
LUX-Lung 1 [23]
Afatinib
&&
585
Study name
Drugs
N
Table 1. Phase III clinical studies of second-generation EGFR-TKIs
Second and third-generation EGFR-TKIs in advanced NSCLC Liao et al.
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[44]. Based on this study’s results, a phase III trial (ARCHER 1009 study) of second or third-line dacomitinib versus erlotinib was conducted. A total of 878 patients were enrolled, and activating EGFR mutation was present in 41 patients in each arm. The PFS (primary end point) was 2.6 months in both arms (HR 0.941; P ¼ 0.229). The author concluded that dacomitinib was not superior to erlotinib in second or third-line therapy for advanced NSCLC [40]. Regarding dacomitinib therapy in the first-line setting, a phase II trial of first-line dacomitinib for advanced lung adenocarcinoma enrolled patient population restricted to nonsmokers (or former light smokers) or patients with known activating EGFR mutations regardless of smoking status [ClinicalTrials.gov, NCT00818441]. The preliminary result reported a response rate of 76% in 46 patients with activating mutations of EGFRdel19 (n ¼ 25) or a mutation in exon 21 (n ¼ 21) [45,46]. A phase III randomized study (ARCHER-1050) is ongoing, which compared first-line dacomitinib or gefitinib in patients with advanced NSCLC harboring activating EGFR mutations (ClinicalTrials.gov, NCT01774721). Phase III trials of dacomitinib, BR. 26 [39], ARCHER 1009 [40], and ARCHER 1050 are listed in Table 1. Dacomitinib was not yet approved by any regulatory agency as of July 2014.
THIRD-GENERATION EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITORS Although afatinib and dacomitinib have activity against EGFRT790M, they also irreversibly inhibit wild-type EGFR. The side-effects, such as diarrhea and skin toxicities, were thus higher. The thirdgeneration EGFR-TKIs were designed to inhibit EGFRT790M while sparing wild-type EGFR [47]. Three drugs, AZD9291 [48], CO-1686 [49], and HM61713 [50], have been evaluated in early-phase clinical trials (Table 2) [48–50]. Other third-generation EGFR-TKIs, such as EGF816 (ClinicalTrials.gov,
NCT02108964) and ASP8273 (ClinicalTrials.gov, NCT02113813), are under development.
AZD9291 AZD9291, a mono-anilino-pyrimidine compound, is an irreversible mutant selective EGFR-TKI [51]. This drug is structurally different from the first and second-generation EGFR-TKIs. In preclinical studies, it potently inhibited phosphorylation of EGFR in cell lines with activating EGFR mutations (EGFRdel19 and EGFRL858R) and EGFRT790M. AZD9291 also caused profound and sustained tumor regression in tumor xenograft and transgenic mouse models harboring activating EGFR mutations and EGFRT790M. AZD9291 was less potent in inhibiting phosphorylation of wild-type EGFR cell lines and had increased selectivity margin against wild-type EGFR [52 ]. In a phase I dose escalation study (AURA; ClinicalTrials.gov, NCT01802632), patients with advanced EGFR-mutated NSCLC who had disease progression following EGFR-TKI therapy (mainly gefitinib or erlotinib) were enrolled. The starting dose was 20 mg/day and administered orally. A total of 31 and 201 patients were enrolled in the escalation and expansion cohort, respectively. The ORR was 53% regardless of tumor T790 M mutation status. In patients with EGFRT790M, the ORR was 64% (69/107; 95% CI 55%, 73%), and the overall disease control rate (DCR, complete response plus partial response plus stable disease) was 94% (101/107; CI: 88%, 98%). The response rates were similarly high across the five tested dose levels. By contrast, in patients without EGFRT790M, the ORR was 22% (11/50; 95% CI 12%, 36%), and the overall DCR was 56% (28/50; 95% CI 41%, 70%) [48]. The most common adverse effects were diarrhea, rash, nausea, and pruritus. These adverse effects were mostly mild. Only three patients developed mild hyperglycemia. Six patients developed interstitial lung disease-like events. Any grade 3 3 adverse effects developed in only 24% of the patients, and these &
Table 2. Phase I clinical studies of third-generation EGFR-TKIs N
Drugs
Patient group
ORR
ORR in EGFRT790M
ORR in non EGFRT790M
Common adverse effects
AZD9291 [48]
232
Advanced EGFR-mutated NSCLC pretreated with EGFR-TKI
53%
64%
22%
Diarrhea, rash, nausea, and pruritus
CO-1686 [49]
72
Advanced EGFR-mutated NSCLC pretreated with EGFR-TKI
NA
58%
NA
Nausea, fatigue, impaired glucose intolerance/hyperglycemia (grade 3 in 22% of the patients), and diarrhea
HM61713 [50]
83
Advanced EGFR-mutated NSCLC pretreated with EGFR-TKI
21.7%
29.2%
NA
Skin exfoliation, nausea, diarrhea, decreased appetite, and pruritus
EGFR, epidermal growth factor receptor; NA, not available; ORR, objective response rate; TKI, tyrosine kinase inhibitor.
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Second and third-generation EGFR-TKIs in advanced NSCLC Liao et al.
adverse effects led to dose reduction and drug discontinuation in only 2 and 4% of patients. There were no DLTs at any dose level. MTD was not defined. For future development of this drug, 80 mg/day was selected based on the activity and toxicity results. A global phase II confirmatory single-arm open-label study (AURA 2; ClinicalTrials.gov, NCT02094261) is ongoing, which administered AZD9291 80 mg/day in patients with advanced NSCLC harboring activating EGFR mutation whose disease progressed after prior EGFR-TKI therapy and harbored EGFRT790M. Another phase III study (AURA 3; ClinicalTrials.gov, NCT0215198) compared AZD9291 80 mg/day with pemetrexed plus platinum chemotherapy in the same population as the AURA 2 study. Trials of AZD9291 in combination with other novel drugs are also ongoing. A phase I study that assesses the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of AZD9291 in combination with MEDI4736 (anti-PD-L1 antibody), selumetinib (MEK inhibitor), or AZD6094 (MET tyrosine kinase inhibitor) is recruiting participants (ClinicalTrials.gov, NCT02143466).
CO-1686 Rociletinib (CO-1686), a 2,4-disubstituted pyrimidine molecule, is an irreversible mutant selective EGFR-TKI. In preclinical studies, CO-1686 led to tumor regression in cell-lines, xenograft models, and transgenic mouse models harboring activating EGFR mutations and EGFRT790M [53 ]. In a phase I study (ClinicalTrials.gov, NCT01526928), patients with advanced EGFR-mutated NSCLC pretreated with EGFR-TKIs were enrolled, and tumor re-biopsy was mandatory. The DLT rates at all dose levels were below 33%. The most common adverse effects were nausea, fatigue, impaired glucose intolerance/ hyperglycemia (grade 3 in 22% of the patients), and diarrhea (grade 1 in 19% and grade 2 in 4% of the patients). Only 4% of the patients developed any form of skin rashes, and all were grade 1. In the 40 patients with centrally confirmed EGFRT790M who had undergone CO-1686 therapy within therapeutic range, the ORR was 58% [49]. The confirmatory phase II trial of second-line CO-1686 (625 mg twice a day) for advanced EGFRmutated NSCLC progressed after previous EGFRTKI therapy is ongoing (TIGER 2; ClinicalTrials.gov, NCT02147990). This trial only enrolled patients with EGFRT790M. A randomized phase II study of first-line CO-1686 or erlotinib monotherapy for advanced EGFR-mutated advanced NSCLC will start soon (TIGER 1; ClinicalTrials.gov, NCT02186301). EGFR T790 M status will not be screened in this trial. &
HM61713 HM61713 is an orally administered, selective inhibitor for activating EGFR mutations and EGFRT790M. It has low activity against wild-type EGFR. In a phase I study (ClinicalTrials.gov, NCT01588145), patients with EGFR-TKI pretreated advanced EGFR-mutated NSCLC were enrolled. MTD has not been reached and an 800 mg cohort is ongoing. The common adverse effects were skin exfoliation, nausea, diarrhea, decreased appetite, and pruritus. Most of the adverse effects were grade 1 and 2. Among the 83 patients in the expansion cohort, the ORR was 21.7% and DCR was 67.5%. The ORR and DCR in the 48 patients with documented EGFRT790M were 29.2 and 75.0%, respectively [50].
CONCLUSION In addition to gefitinib and erlotinib, second-generation EGFR-TKI, afatinib, is available as first-line monotherapy of advanced NSCLC harboring activating EGFR mutations. It prolonged PFS as compared with pemetrexed plus cisplatin or gemcitabine plus cisplatin chemotherapy and improved quality of life. In patients with EGFRdel19, first-line afatinib therapy even prolonged OS. Patient education and management of afatinib-related side-effects, such as diarrhea and skin toxicity, are crucial. Third-generation EGFR-TKIs are under clinical development or tumors harboring acquired EGFRT790M. These drugs reserved activities against activating EGFR mutations while sparing wild-type EGFR, and consequently, the toxicities of these drugs were mild as compared with second-generation EGFR-TKIs. The results of early-phase clinical trials are encouraging, especially in patients with re-biopsy-confirmed acquired EGFRT790M, and the confirmatory phase II trials are ongoing. Trials of first-line treatment with a third-generation EGFR-TKI in patients with activating EGFR mutations are ongoing regardless of EGFR T790 M status given the reserved activities against activating EGFR mutations. Acknowledgements None. Financial support and sponsorship No sources of funding were used to assist with the preparation of this review. Conflicts of interest J.C-H.Y. is a compensated advisor for Boehringer Ingelheim, Eli Lilly, Novartis, Roche Genetech, Astrazeneca, Pfizer, Takeda, Clovis, MSD, and Merck Serono. He received honoraria for advisory role or speaker from
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Astrazeneca, Bayer, and Roche; B-C.L., C-C.L. have no conflicts of interest that are directly relevant to the content of this review.
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