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687262 TAM0010.1177/1758834016687262Therapeutic Advances in Medical OncologyO. Juan and S. Popat review-article2017 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Treatment choice in epidermal growth factor 2017, Vol. 9(3) 201 –216 DOI: 10.1177/ receptor mutation-positive non-small cell © The Author(s), 2017. Reprints and permissions: lung carcinoma: latest evidence and clinical http://www.sagepub.co.uk/ journalsPermissions.nav implications Oscar Juan and Sanjay Popat Abstract: Discovery of sensitizing mutations in epidermal growth factor receptor (EGFR) and the subsequent development of EGFR tyrosine kinase inhibitors (TKIs) have substantially changed the treatment of lung cancer. First-line treatment with EGFR TKIs (gefitinib, erlotinib and afatinib) has demonstrated a superior response rate and progression-free survival (PFS) compared with chemotherapy in EGFR-mutation positive patients. However, a number of open questions remain, such as choice between the three EGFR TKIs licensed, treatment of patients unsuitable for chemotherapy due to morbidity or advanced age, management of acquired resistance and optimal biological sample to determine EGFR status. Recently the first head- to-head trial comparing gefitinib and afatinib (LUX-Lung 7) has been reported. Moreover, third-generation EGFR TKIs such as osimertinib, rociletinib, olmutinib and ASP8273, with preferential activity against T790M mutant tumours, the commonest resistance mechanism to EGFR TKIs, have shown promising results in early clinical trials, with osimertinib now licensed. In this review, we summarize latest advances in the treatment of EGFR-mutation positive patients focusing on controversial areas and emerging challenges to optimally treat these patients in the future. Keywords: EGFR, mutation, non-small cell lung carcinoma, tyrosine kinase inhibitors Received: 30 August 2016; accepted: 9 November 2016. Introduction constitute approximately 80–90% of EGFR muta- Correspondence to: Sanjay Popat, PhD, FRCP In the last decade, the identification of epidermal tions in adenocarcinomas [Lynch et al. 2004]. Royal Marsden Hospital, growth factor receptor (EGFR) mutations and the Sensitizing mutations in exon 18 (G719C, G719S, London SW3 6JJ, UK. email@example.com development of molecular targeted therapies have G719A and S720F) and others in exon 21 (L861Q Oscar Juan launched the era of precision medicine in non- and L861R) are less common. Other mutations Department of Medical Oncology, University small cell lung cancer (NSCLC). EGFR mutations include exon 20 insertions and point mutations, Hospital La Fe, Valencia, have been described in up to 17% of White patients which are associated to primary TKI resistance. Spain with nonsquamous NSCLC, mostly adenocarci- Identification of these EGFR-activating mutations nomas and never-smokers [Rosell et al. 2009; Kris in NSCLC is the single most important predictor et al. 2014], and is three times more common in of response and outcome to EGFR TKIs. Asians for reasons still unknown. These somatic However, despite 10 years of using TKIs, a num- mutations mainly target exons 18–21 of EGFR, ber of open questions remain about the manage- which encodes part of the tyrosine kinase (TK) ment of such patients. Here, we review areas of domain of the gene and are clustered around the controversy with the latest evidence. adenosine triphosphate (ATP)-binding pocket. The most common EGFR mutations are exon 19 deletions (del19) and exon 21 L858R substitutions Is overall survival a useful endpoint in first- (45–82% and 30%, respectively), that are com- line EGFR TKI trials? monly referred to as ‘sensitizing mutations’ as they Nowadays it is well established that TKIs are a confer sensitivity to TK inhibitors (TKIs), and standard first-line treatment for patients with journals.sagepub.com/home/tam 201 Therapeutic Advances in Medical Oncology 9(3) NSCLC harbouring EGFR mutations; the first- [Booth and Eisenhauer, 2012]. In trials where generation TKIs gefitinib and erlotinib, and the both the activity of the investigational drug and second-generation TKI afatinib have both been crossover on progression is high, PFS may be a licensed for this indication since 2009. In phase better endpoint. In the phase III trials comparing III trials of first-line chemotherapy or EGFR EGFR TKI with chemotherapy, crossover is a TKI in NSCLC patients with EGFR mutations, huge confounder for OS due to 57–98% of gefitinib and erlotinib show significant improve- patients assigned to the chemotherapy arm receiv- ments in overall response rate (ORR) and pro- ing second- or third-line therapy with EGFR gression-free survival (PFS), but not in overall TKIs (Table 1). survival (OS) [Mok et al. 2009; Maemondo et al. 2010; Mitsudomi et al. 2010; Zhou et al. 2011; Han et al. 2012; Rosell et al. 2012] (Table 1). All Is there evidence of different efficacy of these trials except EURTAC [Rosell et al. between EGFR TKIs for first-line therapy? 2012] exclusively enrolled Asian patients. Regarding direct comparisons, a head-to-head EURTAC, an open label study comparing plati- comparison of gefitinib and erlotinib has not been num-gemcitabine/docetaxel doublet chemother- carried in the first-line setting of EGFR-mutated apy to erlotinib, showed an increase in ORR NSCLC patients. There have been two studies from 15–58% and a median PFS from 5.2–9.7 conducted in Asian patients which directly com- months [Rosell et al. 2012]. However, as with pared erlotinib and gefitinib, but were based on other gefitinib and erlotinib trials, no significant previously treated patients [Yang et al. 2015c; difference in OS was observed between treat- Urata et al. 2016]. Neither of these studies showed ment arms. differences in PFS and OS between TKIs. Additionally, a retrospective matched-pair case- More recently, afatinib showed a clear benefit control study compared 121 patients treated with for ORR and PFS compared with cisplatin/ gefitinib with 121 patients treated with erlotinib pemetrexed (LUX-Lung 3) or cisplatin/gemcit- [Lim et al. 2014]. Of the 242 patients, 63 (26%) abine (LUX-Lung 6) [Sequist et al. 2013; received EGFR TKI as first-line therapy. There Wu et al. 2014] in EGFR-mutant NSCLC. were no statistically significant differences with Although these results are similar to those of regard to PFS (median, 11.7 versus 9.6 months, first-generation TKIs, these trials are distin- p = 0.056) or ORR (76.9% versus 74.4% p = guished by several factors: LUX-lung trials are 0.575) in the whole population or for patients the largest phase III trials to date of first-line receiving erlotinib or gefitinib as first-line treat- EGFR TKI with chemotherapy; PFS and ORR ment (median PFS, 11.7 versus 14.5 months, were assessed by independent radiology review; p = 0.507; and ORR, 76.7% versus 90.0%, p = both common sensitizing mutations (del19/ 0.431). Both gefitinib and erlotinib are anilino- L858R) and uncommon mutation patients were quinazolines with a similar molecular structure enrolled; and LUX-Lung 3 recruited both and similar mechanism of action in binding to the Asian and non-Asian patients using a modern EGFR ATP pocket, so it seems biologically chemotherapy comparator (cisplatin/peme- unlikely that large differences in efficacy may be trexed). Although OS between afatinib and observed. Therefore, a specific trial to directly chemotherapy was not statistically significant compare gefitinib and erlotinib in the first-line different in each trial, in a prespecified com- treatment for EGFR-mutant patients may be clin- bined analysis of individual patient data from ically unjustified. both trials for common mutation, afatinib demonstrated a statistically significant OS Recently, the first direct comparison between improvement compared with chemotherapy EGFR TKIs in the first-line setting has been [27.3 versus 23.5 months, hazard ratio (HR) = reported (LUX-Lung 7) [Park et al. 2016]. In 0.81, 95% confidence interval (CI): 0.66–0.99, this exploratory phase IIb trial, 319 patients with p = 0.037] [Yang et al. 2015a]. NSCLC and common mutations (del19/L858R) were randomized to receive afatinib or gefitinib. Whilst OS has been traditionally considered the Three co-primary endpoints were selected: PFS strongest endpoint for clinical research in oncol- by independent central review, time-to-treat- ogy, one of the commonest reasons for failure to ment failure (TTF) and OS. Unlike a classical observe a survival gain after a PFS improvement superiority-testing trial, no formal hypotheses is the influence of post-progression therapy were defined and the sample size was based on 202 journals.sagepub.com/home/tam O Juan and S Popat Table 1. Phase III trials comparing EGFR TKIs with chemotherapy in first-line EGFR-mutation positive NSCLC patients. Author Study Agent N ORR Median PFS HR OS (months) OS HR Crossover EGFR + PFS % (PS2) (months) Mok et al. IPASS Gefitinib 261 71.2% versus 9.8 versus 0.48 21.6 versus 1.00 39.5 2009 (10%) 47.3% 6.4 (0.36–0.64) 21.9 (0.76–1.33) Han et al. First-SIGNAL Gefitinib 42 84.6% versus 8.0 versus 0.54 27.2 versus 1.04 75 2012 (9%) 37.5% 6.3 (0.27–1.1) 25.6 (0.50–2.18) Mitsudomi WJTOG 3405 Gefitinib 172 62.1% versus 9.2 versus 0.49 30.9 versus 1.25 59.3 et al. 2010 (0%) 32.2% 6.3 (0.34–0.71) NR (0.88–1.78) Maemondo NEJGSG002 Gefitinib 230 73.7% versus 10.8 versus 0.30 30.5 versus 0.89 94.6 et al. 2010 (1%) 30.7% 5.4 (0.22–0.41) 23.6 (0.63–1.24) Zhou et al. OPTIMAL Erlotinib 154 83% versus 13.7 versus 0.16 22.7 versus 1.04 NA 2011 (6%) 36% 4.6 (0.10–0.26) 28.9 (0.69–1.58) Rosell EURTAC Erlotinib 174 58% versus 9.7 versus 0.47 19.3 versus 0.93 76 et al. 2012 (14%) 15% 5.2 (0.28–0.78) 19.5 (0.64–1.35) Sequist LUX-Lung 3 Afatinib 345 56% versus 13.6 versus 0.47 31.6 versus 0.78 75 et al. 2013 (0%) 23% 6.9 (0.34–0.65) 28.2 (0.58–1.06) Wu et al. LUX-Lung 6 Afatinib 364 67% versus 11.0 versus 0.28 23.6 versus 0.83 56 2014 (0%) 23% 5.6 (0.20–0.39) 23.5 (0.62–1.09) EGFR, epidermal growth factor receptor; HR, hazard ratio; NA, not applicable; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase. controlling the half-width of the 95% CI for the respectively [Mazieres et al. 2013]. However, due logged HR to 0.25 in both directions of PFS. to its pan-HER2 inhibitor activity, this mecha- Afatinib significantly prolonged median PFS nism has not been reported with afatinib to date. (11.0 versus 10.9 months, HR = 0.73, 95% CI: In a small study with 42 patients with acquired 0.57–0.95, p = 0.017), median TTF (13.7 versus resistance to afatinib, neither small-cell or squa- 11.5 months, HR = 0.73, 95% CI: 0.58–0.92, p mous-cell lung cancer transformation was = 0.0073) and ORR (70% versus 56%, p = observed, nor were other somatic mutations in 0.0083) compared with gefitinib. For the third PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, co-primary endpoint, OS, data were immature AKT2, LKB1 and JAK2 identified after treat- but median OS was not statistically different ment with first-generation TKIs [Wu et al. 2016]. between treatment arms (27.9 and 25 months). However, T790M mutation, the major mecha- Interestingly, although median PFS was almost nism of acquired resistance to first-generation identical in both arms, after this point a separa- TKIs, is also detected in half of the patients with tion of the curves were observed and exploratory acquired afatinib resistance, being not dissimilar Kaplan–Meier estimates of PFS were consist- to that proportion observed with first-generation ently markedly higher for afatinib compared EGFR TKI-treated patients [Wu et al. 2016]. with gefitinib at the 18 month (27.3% versus Albeit with limitations of scarce data, these 15.2%) and 24 month (17.6% versus 7.6%) potentially different mechanisms of acquired landmarks. resistance during afatinib treatment may explain the separation between PFS curves with time in The superiority of afatinib versus gefitinib may be the LUX-Lung 7 trial. To date, a head-to-head explained by the different mechanism of action comparison of afatinib versus erlotinib in first- between the first-generation TKI gefitinib, which line EGFR-mutated NSCLC patients has not reversibly binds to, and inhibits EGFR signalling, been performed. and the second-generation irreversible TKI afatinib, which irreversibly binds to and blocks Dacomitinib is another pan-HER inhibitor that signalling from all relevant HER family receptor irreversibly binds to HER1/EGFR, HER2 and homo- and heterodimers (including EGFR, HER4 TKs. In a pooled subset analysis of EGFR- HER2, HER3 and HER4) [Li et al. 2008; Solca mutated patients from two randomized trials et al. 2012]. Amongst the mechanisms of acquired comparing dacomitinib with erlotinib in previ- resistance to TKIs, HER2 amplification and ously treated molecularly unselected NSCLC mutations have been observed in 10% and 2% of (ARCHER 1009 [ClinicalTrials.gov identifier: patients treated with erlotinib or gefitinib, NCT01360554] and A7471028 [ClinicalTrials. journals.sagepub.com/home/tam 203 Therapeutic Advances in Medical Oncology 9(3) gov identifier: NCT00769067]), no statistically (2.2%), whilst ALT/AST elevation was more differences in median PFS (14.6 versus 9.6, p = common for gefitinib (6.2/13% for gefitinib versus 0.146) or OS were observed (26.6 versus 23.2 2.2/3.3% for erlotinib). months, p = 0.265) for dacomitinib versus erlo- tinib, respectively [Ramalingam et al. 2016b]. Icotinib, a novel first-generation EGFR TKI cur- Results from ARCHER 1050, a phase III trial rently only available in China, was compared with comparing dacomitinib with gefitinib as first-line gefitinib in NSCLC patients after one or two failed therapy in EGFR-mutated patients is awaited to chemotherapy regimens [Shi et al. 2013]. The trial replicate findings from LUX-Lung 7 that irre- revealed that icotinib had equivalent efficacy and versible TKIs are potentially superior to first- better tolerability than gefitinib: drug-related AEs generation TKIs. were 61% and 70% for patients receiving icotinib and gefitinib, respectively (p = 0.04). Are adverse events different according to Recently, the results of a pooled analysis of the the type of TKI? occurrence of severe AEs according to the type of Besides efficacy, toxicity is the other cornerstone EGFR TKI based on data extracted from 21 upon which the choice of TKI should be based. phase II and III trials published between 2006 Trials results suggest that toxicity profiles of and 2014 and including more than 1400 patients TKIs are different. In the direct comparison of with EGFR-mutated NSCLC has been reported afatinib and gefitinib (LUX-Lung 7), the num- [Takeda et al. 2015]. The treatment discontinua- ber of patients discontinuing treatment due to tion rate due to AEs was significantly more fre- adverse events (AEs) was similar in each group. quent for afatinib than for erlotinib (7.2% versus However, the most frequent drug-related AEs 4.1%, p = 0.04), as well as for gefitinib than for leading to discontinuation differed between the erlotinib (7.6% versus 4.1%, p = 0.032). However, two groups: diarrhoea (3%) was the commonest these data may be biased by the inability to dose reason for afatinib, whilst increased alanine ami- attenuate gefitinib. The commonest AEs for dis- notransferase (ALT)/aspartate aminotransferase continuation for each TKI were: skin toxicity and (AST) levels (3%) and interstitial lung disease diarrhoea for afatinib, hepatotoxicity for gefitinib (ILD) (3%) were the commonest for gefitinib. and ILD for erlotinib. Grade ⩾3 rash and diar- Moreover, grade ⩾3 AEs were markedly more rhoea were significantly more frequent with frequent for afatinib (31%) than gefitinib (18%). afatinib than with erlotinib or gefitinib. The fre- quency of grade ⩾3 ILD was low and similar Although a direct comparison of erlotinib with between all three EGFR TKIs (0.6–2.2%). afatinib has not been performed in first-line Gefitinib was associated with significantly higher EGFR-mutated patients, data from toxicity com- grade ⩾3 hepatotoxicity compared with erlotinib parisons may be implied from the head-to-head or afatinib. study for second-line patients with squamous sub-type NSCLC (LUX-Lung 8) [Soria et al. In conclusion, physicians should fully consider 2015]. Here, drug discontinuations because of the efficacy–toxicity balance for individual AEs were similar in each group, and grade 3–4 patients to select the appropriate TKI. Gefitinib, drug-related AEs were 25% for afatinib versus erlotinib and afatinib have different toxicity pro- 17% for erlotinib. Furthermore, the toxicity pro- files and possibly differences in efficacy. Afatinib file was again different: grade 3–4 diarrhoea might be superior to first-generation TKIs but (11%) and stomatitis (4%) were more frequent with slightly more rash and diarrhoea. for afatinib and rash or acne (10%) more frequent for erlotinib. Which is the TKI of choice in unfit and In the randomized phase III trial of Urata and elderly patients? colleagues comparing gefitinib and erlotinib in Phase III trials that led to the approval of gefi- previously treated adenocarcinoma, the number tinib, erlotinib and afatinib as first-line treatment of patients who discontinued treatment due to were conducted in patients suitable for platinum- toxicity was similar (33 and 32 patients, respec- doublet chemotherapy [Mok et al. 2009; tively) [Urata et al. 2016]. As reported in previous Maemondo et al. 2010; Mitsudomi et al. 2010; trials, grade 3–4 rash toxicities were more fre- Zhou et al. 2011; Han et al. 2012; Rosell et al. quent for erlotinib (18.1%) than for gefitinib 2012; Sequist et al. 2013; Wu et al. 2014]. Patients 204 journals.sagepub.com/home/tam O Juan and S Popat medically unfit to receive standard first-line plati- placebo [Lee et al. 2012]. Median OS was similar num-doublet chemotherapy owing to poor per- in both groups (3.7 versus 3.6 months for erlotinib formance status (PS) or comorbidities were not and placebo, respectively). Although, a statisti- represented in these trials. However, although cally significant improvement in median PFS data are scarce, unfit patients account for about was identified for erlotinib (2.8 versus 2.6 months, 30% of newly diagnosed patients with advanced p = 0.019), this was not clinically significant. NSCLC [Davidoff et al. 2010]. So, special analy- Nonetheless, population characteristics, demon- sis for these populations underrepresented in strating 40% of patients with squamous histology these first-line trials is warranted. and 37% of smokers made the presence of EGFR mutations unlikely. Whilst LUX-Lung 3 and LUX-Lung 6 were restricted to patients with PS0–1 [Sequist et al. To date, no data from prospective studies of 2013; Wu et al. 2014], all of the gefitinib and erlo- afatinib in patients with comorbidities unsuita- tinib trials [Mok et al. 2009; Maemondo et al. ble for chemotherapy are available. Evidence on 2010; Mitsudomi et al. 2010; Zhou et al. 2011; the safety and efficacy of afatinib in medically Han et al. 2012; Rosell et al. 2012] except one unfit patients who have either suspected or con- [Mitsudomi et al. 2010] also allowed enrolment firmed EGFR mutation will come from the UK of PS2 patients. However, the proportion of PS2 TIMELY trial [ClinicalTrials.gov identifier: patients enrolled was small, only EURTAC NCT01415011]. included >10% PS2 patients [Rosell et al. 2012] (Table 1). Hence, the evidence for using TKIs Elderly patients were also underrepresented in from these studies is limited. the phase III clinical trials of first-line TKI. Whilst, approximately two-thirds of lung cancer There has only been one small prospective phase cases are diagnosed in people aged ⩾65 years, II study of gefitinib that recruited 30 patients and almost half of cases are diagnosed in patients ineligible for chemotherapy according to PS or aged >70 years [Owonikoko et al. 2007], fewer advanced age with EGFR mutations [Inoue et al. than 30% of patients enrolled into these trials 2009]. A total of 22 patients had PS ⩾ 3, 68% of were ⩾65 years of age [Mok et al. 2009; these showed a rapid improvement in PS at 1 Maemondo et al. 2010; Mitsudomi et al. 2010; month. ORR, PFS and OS were 66%, 6.5 Zhou et al. 2011; Han et al. 2012; Rosell et al. months and 18.8 months, respectively. These 2012; Sequist et al. 2013; Wu et al. 2014]. Aging results are much better than that observed in a may be associated with lower body mass index, retrospective analysis of 74 PS3–4 patients with decreased physiologic reserve, polymorbidity and advanced NSCLC who were treated with first- concomitant medications that might affect either line gefitinib without EGFR mutational analysis. TKI clearance or their efficacy and safety. Studies ORR, median PFS and median OS were 27%, specifically evaluating TKIs in EGFR-mutated 32 days and 61 days, respectively. Never smok- patients aged >70 years are therefore needed to ing and adenocarcinoma were independent pre- better quantify and evaluate the TKI toxicity/effi- dictors of better PFS [Lee et al. 2010]. Toxicity cacy balance. for gefitinib in both studies was comparable with that observed in patients with good PS. Despite Several observational studies and trials support the difference in the results between these stud- the safety and efficacy of erlotinib in elderly ies, TKI treatment in patients with poor PS and patients, albeit in molecular unselected popula- high suspicion of EGFR mutation according to tions [Kurishima et al. 2013; Yoshioka et al. clinical characteristics may be clinically justified, 2014], mainly informing the toxicity profile. especially if there are no other therapeutic Erlotinib was compared with oral vinorelbine options suitable, as a randomized blinded trial prospectively in a randomized phase II trial in versus placebo in this clinical setting would likely 113 advanced NSCLC patients aged ⩾70 years be difficult to recruit to. [Chen et al. 2012]. The most frequent treatment- related toxicities for erlotinib were no different to TOPICAL, a randomized phase III trial in molec- that observed in the phase III trial in general pop- ularly unselected advanced NSCLC patients ulation: rash (64.9%), diarrhoea (29.8%), and unsuitable for chemotherapy due to PS ⩾ 2, pres- mouth ulceration (14.0%). Median PFS and OS ence of comorbidities or both, specifically for EGFR-mutated patients treated with erlotinib addressed the efficacy of erlotinib compared with were 8.4 months and 22.7 months, respectively. journals.sagepub.com/home/tam 205 Therapeutic Advances in Medical Oncology 9(3) Whereas safety and efficacy of gefitinib in EGFR- tested [Rosell et al. 2012]. Similarly, both LUX- mutated patients aged ⩾70 years have been also Lung 3 and LUX-Lung 6 trials demonstrated confirmed for by several reports [Maemondo et al. PFS differences with afatinib on the basis of 2012; Morikawa et al. 2015], studies specifically EGFR mutation type; PFS was most improved in evaluating afatinib in elderly patients are limited del19 patients compared with L858R [Sequist [Rossi et al. 2016]. However, pharmacokinetic et al. 2013; Wu et al. 2014] (Figure 1). characteristics of afatinib are different from the first-generation TKIs. Whilst, gefitinib and erlo- There are three meta-analyses that have exam- tinib undergo extensive hepatic metabolism pre- ined the impact of different EGFR mutations on dominantly by cytochrome P450-dependent PFS in the first-line setting [Wang et al. 2014; enzymes, in contrast, afatinib undergoes minimal Zhang et al. 2014b; Lee et al. 2015a]. In all, biotransformation and oxidative cytochrome- patients with del19 had longer PFS with first-line mediated metabolism is of negligible importance. EGFR TKIs compared with those with L858R. Thus, gefitinib and erlotinib have an important The results were similar through subgroup analy- potential for interaction with other agents metab- ses stratified by the type of TKI [Zhang et al. olized by, or are inhibitors/inducers of cytochrome- 2014b]. However, afatinib showed the highest related enzymes. In a retrospective analysis of 49 efficacy in patients harbouring del19 than those patients with advanced NSCLC and EGFR muta- with L858R mutation (HR = 0.49, 95% CI: 19/21 tions, median PFS was significantly longer in 0.21–1.17, p = 0.108), compared with gefitinib elderly patients treated with both gefitinib and HR = 0.76, 95% CI: 0.47–1.21, p = 0.244) 19/21 afatinib in comparison with younger patients (12.6 and erlotinib (HR = 0.53, 95% CI: 0.18– 19/21 and 5.6 months, respectively; p = 0.008). Median 1.61, p = 0.264) [Zhang et al. 2014b] (Figure 1). PFS was statistically superior in elderly patients treated with gefitinib compared with those receiv- The LUX-Lung 3 and 6 trials are the only studies ing afatinib, although the small number of patients that demonstrated a differential OS difference precludes any conclusion. This potentially supe- between genotype. Here, an exploratory sub- rior activity of TKIs in elderly patients compared group analyses by mutation genotype showed a with young patients might be explained by the statistically significant OS improvement at 12.2 higher number of medications related to concomi- and 13 months for afatinib in LUX-Lung 3 and tant comorbidities that cause an increased plasma LUX-Lung 6, respectively for del19, whereas no level of TKIs [Rossi et al. 2016]. OS difference was observed in L858R patients [Yang et al. 2015a]. Pooled analysis of these trials was consistent the individual studies demonstrat- Should we choose a different TKI depending ing an OS benefit in del19 patients only (HR = on the type of EGFR mutation? 0.59, 95% CI: 0.45–0.77, p = 0.0001; L858R It has been extensively proved that EGFR sensi- HR = 1.25, 95% CI: 0.92–1.71, p = 0.16) [Yang tizing mutations (del19/L858R) predict the ben- et al. 2015a]. efit of EGFR TKIs. However, whether the efficacy of TKIs varies between del19 and L858R The mechanisms for these differences are cur- mutations is still controversial. Several studies rently unknown and several hypotheses might be reported that advanced NSCLC patients with considered: first, del19 might be more efficiently EGFR del19 had a higher benefit following treat- inhibited by EGFR TKIs due to an increased ment with gefitinib and erlotinib than those with affinity for these than L858R mutations; second, L858R [Jackman, 2006; Riely, 2006; Rosell et al. T790M mutation (associated with acquired TKI 2012; Sequist et al. 2013], whilst others did not resistance), might occur more frequently for demonstrate this difference [Sequist et al. 2008; L858R; and third, L858R could more frequently Mitsudomi et al. 2010; Fukuoka et al. 2011]. For coexist with other uncommon EGFR mutations instance, subgroup analysis of EURTAC showed thereby affecting the EGFR kinase sensitivity to that median PFS for both erlotinib and chemo- TKIs [Zhang et al. 2014b]. In summary, these therapy were superior for del19 than for L858R results confirmed that del19 is a distinct disease (del19: 11 versus 4.6 months for erlotinib/chemo- form compared with L858R, implying that future therapy, HR = 0.30, 95% CI: 0.18–0.50, p < studies should be stratified for mutation type. 0.00; L858R: 8.4 versus 6 months for erlotinib/ chemotherapy, HR = 0.55, 95% CI: 0.29–1.02, Another related question is whether different p = 0.0539), although this has not formally been EGFR TKIs should be used contingent on 206 journals.sagepub.com/home/tam O Juan and S Popat Figure 1. Median PFS and HR of EGFR TKIs versus chemotherapy according to the mutation type (del19 or L858R). EGFR, epidermal growth factor receptor; HR, hazard ratio; PFS, progression-free survival; TKI, tyrosine kinase inhibitor. mutation type. In the head-to-head LUX-Lung 7 categorized as: point mutations or duplications in trial, afatinib resulted in a longer median PFS exon 18–21 (group 1); de novo T790M mutations than gefitinib in both L858R (HR = 0.71, 95% alone or in combination with others (group 2); or CI: 0.47–1.06, p = 0.086) and del19 patients exon 20 insertions (group 3). ORR was 71.1%, (HR = 0.76, 95% CI: 0.55–1.06, p = 0.107). 14.3% and 8.3 % for group 1, 2 and 3, respec- Similarly, the ORR for L858R was 66% versus tively. Median PFS and OS were 10.7 and 19.4 42%, and in del19 73% versus 66% for afatinib months for group 1, 2.9 and 14.9 months for versus gefitinib, respectively [Park et al. 2016]. group 2, and 2.7 and 9.2 months for group 3. For Thus currently, tailoring treatment with afatinib the most frequent uncommon mutations, the or gefitinib on the basis of mutation subtype ORR for G719X was 77.8%, 56.3% for L861Q, (del19 or L858R) is not indicated. and 100% with S768I. Data regarding sensitivity of tumours harbour- Afatinib is therefore unique in showing activity in ing uncommon EGFR mutations such as E709X, NSCLC patients with uncommon EGFR muta- G719X, L861Q, S768I and others to TKI are tions, especially G719X, L861Q, and S768I from limited. Most phase III trials comparing first- trial data. line TKIs with chemotherapy were restricted to common mutations (del19/L858R). Only NEJ002 [Maemondo et al. 2010] and the LUX- Can we delay the development of acquired Lung 3/6 [Sequist et al. 2013; Wu et al. 2014] resistance to first-line TKIs? included patients with uncommon mutations. In Unfortunately, despite initial benefit, virtually all a post hoc analysis of NEJ002, gefitinib-treated patients ultimately progress due to acquired patients with G719X or L861Q had a signifi- resistance. Intra-tumour heterogeneity is particu- cantly shorter OS (11.9 versus 29.3 months; p < larly relevant for NSCLC, and it has been postu- 0.001) than those with common mutations. lated as one of the main reasons for the incomplete However, the small number of uncommon disease response and acquired resistance mutations (4.4%) precludes establishing solid observed, with the influence of drug therapy in conclusions [Watanabe et al. 2014]. the selection of cell clones demonstrated [Bai et al. 2012]. In a recent study, clones with EGFR The largest dataset for uncommon mutations mutations, wild-type EGFR clones and even cells comes from post hoc analyses of pooled afatinib with ALK translocations can be found in the same outcomes from LUX-Lung 3/6, where 11% of tumour [Cai et al. 2015]. The most common patients recruited had uncommon mutations, and mechanism (60%) [Yu et al. 2013] of acquired LUX-Lung 2 (a single-arm phase II afatinib trial) resistance to first-generation EGFR TKIs is by [Yang et al. 2015b]. Here, patients were clonal selection of the T790M allele. There are journals.sagepub.com/home/tam 207 Therapeutic Advances in Medical Oncology 9(3) two theories that have been suggested regarding intercalated erlotinib–chemotherapy compared the appearance of the T790M mutation: ‘acquire- with EGFR TKI monotherapy followed by chem- ment’ and ‘selection’ [Nguyen et al. 2009]. otherapy alone remains unknown. Initially it was described that patients with EGFR sensitizing mutations did not exhibit T790M Bevacizumab, a recombinant humanized mono- mutation and only acquired this mutation after clonal antibody, binds to vascular endothelial exposure to gefitinib or erlotinib [Pao et al. 2005]. growth factor A (VEGF-A), causing inhibition of However, in some cases, T790M mutation has tumour-induced angiogenesis. This different tar- been found in patients not treated with TKIs get might be synergistic with EGFR TKIs, espe- [Toyooka et al. 2005]. De novo T790M mutations cially through inhibiting EGFR TKI resistance detected by conventional methods are rare (1– [Naumov et al. 2009]. Following on the subset 8%) [Yu et al. 2013] and are more often associ- analysis of EGFR-mutant patients recruited to ated with the L858R mutation and imply poorer the BETA trial of erlotinib with/without bevaci- prognosis [Toyooka et al. 2005], supporting the zumab demonstrating a higher median PFS with tumour heterogeneity theory of different cell pop- the combination of erlotinib and bevacizumab ulations and of TKI therapy positively selecting (17.1 months) compared with erlotinib alone (9.7 T790M clones. A recent study has also now con- months) [Herbst et al. 2011], a Japanese rand- firmed both clonal selection and the de novo omized phase II study evaluated this combina- somatic acquisition of T790M as a new acquired tion. Here, an impressive 16 months median PFS resistance event [Hata et al. 2016]. for the combination versus 9.7 months for erlo- tinib monotherapy (HR = 0.54, p = 0.0015) was Combination therapy with TKI and chemother- demonstrated [Seto et al. 2014]. Discontinuation apy may therefore be an approach to attack het- of treatment because of AEs occurred at similar erogeneous cellular clones. However, a combined frequency in both groups. Grade 3–4 AEs were analysis of INTACT1 and INTACT2 trials more frequent in the erlotinib plus bevacizumab (combination gefitinib–chemotherapy in molecu- group (91%) than the in the erlotinib group larly unselected NSCLC patients) showed no OS (53%). The most common grade ⩾3 AEs were improvement for additional gefitinib in a post hoc rash (25% in the combination versus 19% mono- EGFR-mutant subset [Bell et al. 2005]. This lack therapy), hypertension (60% versus 10%), and of benefit could be explained by pharmacological proteinuria (8% versus none), with no new safety antagonism when TKI and chemotherapy are signals for bevacizumab observed. administered concomitantly: gefitinib and erlo- tinib may arrest the cell cycle in the G1 phase and A European single-arm phase II trial of bevaci- interfere with the cell cycle phase-related cyto- zumab-erlotinib (BELIEF; ETOP 2–11) in EGFR toxic effects of chemotherapy. Hence, separating common mutations demonstrated a less impres- chemotherapy and erlotinib administration might sive median PFS of 13.8 months, with no differ- avoid this [Davies et al. 2011]. This rationale was ence in outcome between del19 or L858R, but tested in the FASTACT 2 trial. In this phase III more prolonged PFS in those with T790M trial, 451 molecularly unselected NSCLC patients detected at baseline by an ultrasensitive method were randomized to chemotherapy [gemcitabine/ (PCR-PNA) than without (16 versus 10.5 months, platinum with intercalated erlotinib (d15–28) or respectively) [Stahel et al. 2015]. The European placebo 4-weekly]. PFS was significantly pro- Medicines Agency (EMA) has recently approved longed for erlotinib combination therapy versus this combination and a confirmatory randomized chemotherapy alone (PFS 7.6 versus 6 months, European trial is recruiting (BEVERLY HR = 0.57, p < 0.0001). Analysis by EGFR [ClinicalTrials.gov identifier: NCT02633189]). mutation status identified that treatment benefit Another recently published single-arm phase II was noted only in EGFR-mutant patients both for study tested the combination of gefitinib plus bev- PFS (16.8 versus 6.9 months, HR = 0.25, p < acizumab in EGFR-mutant all-comers [Ichihara 0.0001) and OS (31.4 versus 20.6 months, HR = et al. 2015]. Median PFS was 14.4 months, with a 0.48, p = 0.0092). Although small (n = 97), this significant difference between del19 and L858R is the only trial reporting a statistically significant genotypes (18.0 versus 9.4 months; p = 0.006). OS gain for patients treated with combination erlotinib–chemotherapy versus chemotherapy In addition to bevacizumab, ramucirumab, alone [Wu et al. 2013]. However, the magnitude another anti-angiogenic monoclonal antibody of the PFS and OS advantage contributed by targeted against VEGF receptor 2, is being 208 journals.sagepub.com/home/tam O Juan and S Popat evaluated in a phase III trial in combination with first-generation EGFR TKIs not selected by erlotinib to evaluate its efficacy and safety in T790M status and 222 additional patients were patients with common EGFR mutations (RELAY included in the expansion cohorts according to [ClinicalTrials.gov identifier: NCT02411448]). prospective T790M status (re-biopsy at enrol- ment was required). The maximal tolerated dose Other mechanisms of resistance, such as HER2 was not reached at any dose level and 80 mg daily and MET amplification, and PIK3CA mutations, was the recommended dose to maximize efficacy were also reported [Sequist et al. 2011; Yu et al. and minimize skin and gastrointestinal toxicity. 2013]. Targeting cMET receptor in combination In the entire 239 evaluable patients, an ORR of with EGFR TKI is likely to predict better sur- 51% was observed, with a median PFS of 8.4 vival. However, trials combining MET inhibitors months [Jänne et al. 2015]. In T790M-positive such as tivantinib or onartuzumab have been neg- patients, a 61% ORR and 9.6 month PFS was ative [Lin et al. 2014]. Nowadays, trials with new observed. In contrast, in T790M negative MET inhibitors are recruiting. Similarly, the patients, ORR was 21% and PFS was 2.8 months. rationale of combining EGFR and ERBB2 inhibi- As observed in first- and second-generation TKIs tors is via various molecular interactions across ORR was higher in del19/T790M-positive their downstream signalling pathways. Afatinib, tumours than in L858R/T790M-positive tumours as irreversible ErbB family blocker may play a role (64% versus 57%, respectively). No dose-limiting in the delay of the development of resistance by toxicities were reported at any dose level. The this mechanism [De Grève et al. 2015]. commonest AEs were mainly grade 1–2: diar- rhoea (47% all grade), rash (40%), nausea (22%) and poor appetite (21%). Grade ⩾3 AEs were What is the role of third-generation TKIs? 32%. Therefore, data from this study suggest that Present and future T790M is not only prognostic but also a predic- The most frequent molecular mechanism of tive biomarker, and hence osimertinib was further acquired resistance observed is the development developed in this group only. of the gatekeeper T790M point mutation (observed in up to 60% of cases) [Yu et al. 2013]. A recent report of data from the phase I dose expansion cohort (AURA P1 [ClinicalTrials.gov Although total EGFR blockade by the combina- identifier: NCT01802632]) and a pre-planned tion of afatinib and cetuximab showed a 29% pooled analysis of two phase II studies ORR in a phase Ib trial for patients with acquired (AURA extension [ClinicalTrials.gov identifier: resistance to erlotinib, this combination had sub- NCT01802632] and AURA2 [ClinicalTrials.gov stantial toxicity with grade ⩾3 AEs observed in identifier: NCT02094261]), investigating osimer- >20% of patients [Janjigian et al. 2014]. tinib at 80 mg, confirmed the previous efficacy findings. In the AURA pooled phase II, by inde- Third-generation mutation-specific EGFR TKIs, pendent central review, an ORR of 66% and a such as rociletinib, osimertinib (AZD9291), median PFS of 11.0 months were observed in 411 olmutinib (BI1482694/HM61713) and ASP8273, T790M-positive patients progressing following were specifically designed to inhibit EGFR in a EGFR TKI therapy, leading to EMA and FDA covalent irreversible manner, with preferential approvals. Again, most toxicities were grade 1–2, activity against both T790M and classical sensi- with rash grouped terms [41% (⩾G3 1%)] and tizing EGFR mutations, but with minimal activity diarrhoea [38% (⩾G3 1%)] [Yang et al. 2016a]. against the EGFR wild-type allele. Rociletinib is no longer being developed after the United States In addition, osimertinib has greater central nerv- Food and Drug Administration (FDA) consid- ous system penetration than first-generation TKIs ered the data from the phase I–II TIGER-X and [Ballard et al. 2016]. BLOOM [ClinicalTrials.gov TIGER-2 trials insufficient to recommend accel- identifier: NCT02228369] is a phase I multicen- erated approval. tre trial to assess the safety and preliminary activ- ity of osimertinib in patients with NSCLC with Osimertinib was tested in the phase I dose escala- EGFR mutations who failed standard treatment tion trial (AURA [ClinicalTrials.gov identifier: and developed brain and leptomeningeal disease. NCT01802632]) at doses of 20–240 mg once Here, 11 out of 21 patients (52%), with leptome- daily in 31 patients with EGFR-mutated NSCLC ningeal disease and stable extracranial disease with disease progression following treatment with treated with osimertinib showed shrinkage of journals.sagepub.com/home/tam 209 Therapeutic Advances in Medical Oncology 9(3) brain lesions, with 7 (33%) confirmed partial increased with the higher efficacy observed with responses [Yang et al. 2016b]. third-generation EGFR TKIs in patients har- bouring T790M. Although re-biopsy is techni- Similarly, olmutinib is approved in South Korea cally feasible in 50–90% of patients [Chouaid based on the result of the phase I/II HM-EMSI-101 et al. 2014; Bosc et al. 2015; Hasegawa et al. 2015; trial showing an ORR of 62% in similarly pre- Kawamura et al. 2016], this remains a challenging treated patients [Lee et al. 2015b], with the con- task in some cases because of the localization of firmatory ELUXA2 phase II trial completed and lesions and patient comorbidities. Moreover, results awaited. some patients refuse the procedure and up to 25% of the re-biopsies are non-informative as the The impressive results obtained with osimertinib sample provides no, or too few cells for pathologi- have led to its evaluation in the first-line setting in cal or molecular diagnosis [Chouaid et al. 2014]. an expansion cohort of AURA trial, at 80 mg (n = Furthermore, biopsy results may be affected by 30) or 160 mg (n = 30). EGFR mutation subtypes spatial heterogeneity of the tumour [Zhang et al. included del19 (37%) and L858R (40%); five 2014a; Cai et al. 2015]. Analysis of circulating patients were T790M positive. With median follow tumour DNA (ctDNA), colloquially termed up of 16.6 months the confirmed ORR was 77% ‘liquid biopsies’, may be a feasible and suitable and median PFS 19.3 months [Ramalingam et al. alternative for the identification of molecular 2016a]. These results appear to be promising but alterations such as EGFR mutations. The use of preliminary. The ongoing confirmatory rand- ctDNA for the detection of EGFR mutations has omized phase III trial FLAURA [ClinicalTrials.gov been investigated in multiple studies demonstrat- identifier: NCT02296125] is assessing the efficacy ing high specificity but low sensitivity compared of osimertinib in first-line therapy in advanced with tissue EGFR status [Qiu et al. 2015]. NSCLC with EGFR common mutations com- pared with gefitinib or erlotinib. Moreover, the effi- Oxnard and colleagues performed analysis of cacy of osimertinib in patients with EGFR plasma ctDNA of patients included in the AURA mutations and the EGFR T790M mutation at phase I trial using BEAMing technology. Both diagnosis will be evaluated in the AZENT trial central tumour and plasma samples for diagnos- [ClinicalTrials.gov identifier: NCT02841579]. tic comparison were available in 216 patients. Sensitivity was 82–86% for sensitizing mutations Head-to-head comparison studies between a and 70% for T790M mutation. ORR to treat- third-generation and first-generation TKIs will ment with osimertinib in patients with tumour likely help determine the role of T790M-specific and plasma T790M positive was 62% and 63%, TKIs in the first-line setting, potentially as a way respectively. However, ORR in T790M-negative to attack tumour heterogeneity. Currently, sev- tumours was 26%, whilst in patients with eral questions remain open such as whether T790M-negative plasma was 46%, implying sequencing first/second-generation TKIs fol- false-negative results. Similarly, tumour T790M lowed by osimertinib may be superior for OS positivity predicts benefit form osimertinib com- compared with commencing with first-line osi- pared with tumour T790M-negative patients mertinib. Moreover, which patients may get (PFS 9.7 versus 3.4 months, p < 0.001). T790M- greater benefit of osimetinib in the first-line set- positive plasma also predicts for a prolonged PFS ting; whether this is independent of baseline of 9.7 months. However, median PFS in plasma T790M status. Ultrasensitive methodologies for T790M-negative patients was longer than detecting and quantification T790M might expected (8.2 months) again due to T790M potentially be useful to determine over what abso- plasma false negatives. Therefore, plasma lute level T790M mutant alleles benefit from osi- T790M-negative status cannot replace tumour mertinib [Watanabe et al. 2015]. biopsy [Oxnard et al. 2016]. In another analysis of plasma T790M from Is tissue necessary to treat patients with patients enrolled in the AURA phase II studies EGFR mutations or are liquid biopsies (AURA extension and AURA 2) by using the adequate? COBAS test. Plasma and tissue-based COBAS The study of resistance mechanisms to optimize testing were similarly sensitive and specific com- acquired resistance management has provided a pared with a next-generation sequencing (NGS) clinical rationale for re-biopsy. This impetus has reference method. Sensitivity was 75–85% for 210 journals.sagepub.com/home/tam O Juan and S Popat sensitizing mutations and 61% for T790M mutation. ORR to osimertinib was similar in ctDNA T790M-positive patients and tissue pos- itive patients (64% and 66%, respectively) [Jenkins et al. 2016]. Recently, Wakelee and col- leagues reported EGFR genotyping analysis of matched urine, plasma and tissue form patients treated with rociletinib. Therascreen, BEAMing and Trovera quantitative NGS assays were used for tissue, plasma and urine analysis. Both plasma and urine sensitivity was 81%. From 181 samples matched for T790M result in plasma, urine and tissue, 104 (57%) were positive in all samples types. In T790M-positive patients, ORR and median PFS were similar independent of sample type (plasma, urine or tissue) from which T790M status was identified [Wakelee et al. 2016]. Indeed, plasma ctDNA analysis to determine T790M status is a minimally invasive effective Figure 2. Algorithm to test T790M mutation method that may potentially avoid tumour biop- integrating ctDNA in patients progressing to first- or sies. However, given the limited sensitivity, fail- second-generation EGFR TKIs. ctDNA, circulating tumour DNA; EGFR, epidermal growth ure to identify T790M should be followed up factor receptor; TKI, tyrosine kinase. with tissue verification. Moreover, given the molecular heterogeneity identified in tissue, ctDNA may potentially detect T790M missed on standard tumour biopsies [Tan et al. 2016]. Based of the head-to-head dacomitinib versus gefitinib in these results a new paradigm for use of plasma trial are awaited. diagnostics can be proposed (Figure 2). Moreover, result of the combination of erlotinib– bevacizumab is promising and may be a strategy Conclusion to prolong PFS delaying the development of Gefitinib, erlotinib and afatinib have dramatically acquired resistance, especially in patients with changed the prognosis of EGFR-mutant NSCLC, T790M mutation. However, resistance mecha- showing significant improvements in ORR from nisms after progression to the combination are 23–47% to 58–85% and PFS from 4.6–6.4 to not known. 8–13.7 months compared with chemotherapy [Mok et al. 2009; Maemondo et al. 2010; The emergence of third-generation TKIs has Mitsudomi et al. 2010; Zhou et al. 2011; Han changed the whole treatment paradigm. et al. 2012; Rosell et al. 2012; Sequist et al. 2013; Osimertinib has demonstrated an ORR of 66% Wu et al. 2014]. Despite these promising results, and a median PFS of 11.0 months in patients who tumours invariably develop acquired resistance to had progressed following EGFR TKI therapy EGFR TKIs. In addition, approximately 20% of through the T790M mutation. These impressive patients with EGFR mutations exhibit de novo results have led to evaluating the efficacy of third- resistance and do not respond to EGFR TKI generation TKIs in first-line therapy (FLAURA therapy. Although several mechanisms of acquired study ongoing). Nevertheless, despite the positive resistance have been reported, the most common results, acquired resistance to osimertinib type is T790M (observed in up to 60% of cases) emerges. The most frequent mechanism is the [Yu et al. 2013]. presence of a novel EGFR C797S gatekeeper mutation [Thress et al. 2015]. Moreover, it was Efforts have been made to answer what is the best recently reported that if C797S develops in EGFR TKIs to use first-line. LUX-Lung 7 has T790M wild-type cells, the cells are resistant to potentially shown superior efficacy for afatinib third-generation TKIs, but retain sensitivity to over gefitinib but at the cost of toxicity and results first-generation TKIs [Niederst et al. 2015]. journals.sagepub.com/home/tam 211 Therapeutic Advances in Medical Oncology 9(3) Therefore, it is unknown whether upfront osimer- References Bai, H., Wang, Z., Chen, K., Zhao, J., Lee, J., Wang, tinib will be more effective than, in sequence, fol- S. et al. (2012) Influence of chemotherapy on EGFR lowing first-generation TKI use and will delay the mutation status among patients with non-small-cell emergence of T790M mutations or, conversely, lung cancer. J Clin Oncol 30: 3077–3083. sequential TKI treatment will be superior to target different cell populations. Furthermore, Ballard, P., Yates, J., Yang, Z., Kim, D., Yang, J., patients who develop acquired resistance to osi- Cantarini, M. et al. 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Therapeutic Advances in Medical Oncology – SAGE
Published: Mar 1, 2017
Keywords: EGFR; mutation; non-small cell lung carcinoma; tyrosine kinase inhibitors
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