Review
Protein kinase inhibitors to treat non-small-cell lung cancer Gabriele Minuti, Armida D’Incecco, Lorenza Landi & Federico Cappuzzo† 1.
Introduction
Istituto Toscano Tumori, Ospedale Civile, Oncologia Medica, Livorno, Italy
2.
EGFR protein kinase inhibitors
3.
Crizotinib in ALK-positive
Introduction: Activating mutations of the EGFR and rearrangement of anaplastic lymphoma kinase (ALK) best illustrate the therapeutic relevance of molecular characterization in NSCLC patients. Areas covered: For this review article, all published data on the most relevant Phase III trials with tyrosine kinase inhibitors (TKIs) for the treatment of NSCLC were collected and analyzed. Expert opinion: Eight Phase III trials clearly established EGFR TKIs as the best therapeutic option for front-line therapy in EGFR-mutated patients. In pretreated NSCLC, EGFR TKIs are considered more effective than standard monotherapy with cytotoxics in presence of classical EGFR mutations, whereas in the EGFR wild-type population, a similar efficacy to docetaxel or pemetrexed in term of survival has been demonstrated. In ALK-translocated NSCLC, a Phase III trial demonstrated the superiority of a multi-target TKI, including ALK, in terms of progression-free survival, response rate and toxicity profile when compared to standard second-line chemotherapy. New agents targeting EGFR or ALK are under evaluation particularly in individuals with acquired resistance to EGFR TKIs or crizotinib.
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NSCLC 4.
Discussion
5.
Expert opinion
Keywords: afatinib, crizotinib, erlotinib, gefitinib, NSCLC Expert Opin. Pharmacother. (2014) 15(9):1203-1213
1.
Introduction
Lung cancer is the leading cause of cancer-related mortality worldwide in men and is secondary only to breast cancer in women [1]. NSCLC accounts for 75% of all lung cancers and includes different subtypes, underlying relevant biological differences. The most part of patients with NSCLC are diagnosed in advanced stage, with a 5-year survival rate of < 5% [2]. In the past years progresses conducted in the field of cancer biology have significantly impacted on NSCLC treatment, mainly in adenocarcinoma histology, and, today, the old ‘one size fit all’ chemotherapeutic approach has been substitute by a novel approach, where treatment selection is based on biological characteristics (Figure 1). Alterations in gene sequence or expression can occur in the cell-signaling and regulatory pathways involved in cell cycle control, apoptosis, proteasome regulation and angiogenesis. As a consequence of genetic alterations, tumor can become highly dependent for proliferation and survival on the function of a single oncogene, defined as ‘driver oncogene’ (Figure 2) [3]. The demonstration of cells with genetic abnormalities that become addicted to oncogenes [4] is a rational basis for the development of targeted therapies. Specifically, the treatment of NSCLC has dramatically changed since the discovery of the biological and therapeutic importance of acquired genetic alterations in two genes that encode pharmacologically targetable tyrosine kinases (TK), EGFR [5-7] and Anaplastic lymphoma kinase (ALK) [8]. Drugs targeting the TK domain of EGFR, such as gefitinib, erlotinib or afatinib, demonstrated superiority over standard chemotherapy in patients harboring activating EGFR mutations (Table 1) [9-16] and crizotinib is now approved by the FDA for patients with ALK translocation [17]. 10.1517/14656566.2014.909412 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
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In the past years, progresses conducted in the field of cancer biology have significantly impacted on NSCLC treatment, mainly in adenocarcinoma histology, with the opportunity to identify molecularly defined subgroup of patients. Tailored approach with targeted agents, such as gefitinib, erlotinib or afatinib, demonstrated superiority versus standard chemotherapy in patients harboring activating EGFR mutations, and crizotinib is now approved for patients with anaplastic lymphoma kinase (ALK) translocation. An important option for patients not progressing after standard first-line chemotherapy is represented by maintenance therapy. Several studies investigated the role of erlotinib or gefitinib in this setting. Unfortunately, after an initial response, a consistent proportion of EGFR-mutant and ALK-positive patients inevitably progress. Several approaches are under clinical evaluation to overcome acquired resistance, including the use of novel and more selective tyrosine kinase inhibitors or combined strategies with inhibitors of multiple pathways. The possibility to obtain additional tumor tissue at progression or to explore biomarkers in plasma will represent the backbone of clinical trials evaluating novel targeted agents, aiming to offer newer tailored treatments for the cure of NSCLC patients.
This box summarizes key points contained in the article.
Aim of the present paper is to review the available data from Phase III trials with protein kinase inhibitors in advanced NSCLC. 2.
EGFR protein kinase inhibitors
The first successful example of targeted therapy based on driver mutations in lung cancer involved EGFR that encodes for one of the four receptor of the ErbB family, including EGFR (ErbB-1; HER1), HER2 (c-ErbB-2), HER3 (c-ErbB- 3) and HER4 (c-ErbB-4). EGFR gene mutations were first identified in 2004 and classical activating EGFR mutations are localized in exon 19, mainly consisting of an in-frame deletion (45 -50%), and in exon 21, with a L858R point mutation (40 -45%). Preclinical models demonstrated that EGFR mutations increase sensitivity to TK inhibitors (TKIs), most likely through induction of critical structural modifications of the ATPbinding site in the TK domain [6,7]. Additional mutations have been characterized, including mutations in exon 20, classically associated with EGFR TKIs resistance, and other uncommon mutations with an undefined predictive role [18]. Since their identification, it was clear that EGFR mutations, predominantly discovered in adenocarcinoma histology, in Asian race, in never-smokers and in female [5], outlined a distinct subgroup of NSCLC patients. In the past years, eight Phase III trials [9-16] had clearly established that EGFR-mutated 1204
patients benefit more from first-line treatment with EGFR TKIs than from standard chemotherapy with platinum doublet, at least in terms of response rate (RR), progression-free survival (PFS), toxicity profile and quality of life (QoL), with no differences in overall survival (OS), most likely because of crossover effect (Table 1). Gefitinib (ZD 1839, IressaÒ, AstraZeneca) and erlotinib (OSI 774, TarcevaÒ, Genentech) are orally bioavailable synthetic anilinoquinazoline compounds that selectively bind to the ATP-binding site of EGFR TK intracellular domain, blocking EGFR autophosphorylation. Afatinib (GilotrifÒ, Boehringer Ingelheim) is a highly selective anilinoquinazoline that irreversibly binds directly to the ATP site in the kinase domain of both EGFR and human epidermal growth factor receptor 2 (HER2). In European countries, gefitinib and afatinib are approved for patients with EGFR mutations only, whereas erlotinib is also approved in second or third line for EGFR wild-type patients. Several and large Phase III trials evaluated the efficacy of reversible EGFR TKIs both in unselected and selected NSCLC population as front-line therapy.
EGFR TKIs front line in unselected NSCLC The two large randomized Phase III trials (INTACT 1 and INTACT 2), evaluating the role of gefitinib in combination with standard chemotherapy in first-line setting, failed to demonstrate any benefit in terms of survival for patients receiving gefitinib, even when the analysis was restricted to patients harboring EGFR mutation [19,20]. As observed for gefitinib, the combination of erlotinib with platinum-based chemotherapy (carboplatin and paclitaxel in TRIBUTE, cisplatin and gemcitabine in TALENT) did not demonstrate any gain in term of OS over chemotherapy alone [21,22]. Gridelli et al. explored the possibility of giving erlotinib as front-line treatment in unselected NSCLC in a randomized Phase III trial. The TORCH study [23] was conducted in a cohort of 760 NSCLC patients to evaluate whether first-line erlotinib followed at progression by cisplatin plus gemcitabine was not inferior in term of OS to the reverse standard sequence. As expected, median PFS was significantly in favor of standard arm, and, most importantly for clinical practice, survival was statistically longer for patients treated with chemotherapy first. Therefore, the TORCH trial confirmed that upfront chemotherapy is the gold standard for unselected population and that EGFR TKIs can be offered as front-line only in patients harboring activating EGFR mutations. An important clinical question is whether erlotinib could be indicated as front-line treatment in EGFR-unselected NSCLC unfit for chemotherapy. In the TOPICAL study, erlotinib was compared to placebo in patients with a poor performance status or unsuitable for chemotherapy [24]. No difference in OS was observed, confirming that front-line erlotinib is not beneficial in EGFR undefined patients. 2.1
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TKIs to treat NSCLC
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Stratification for EGFR, ALK and histolory
EGFR Mut+
ALK+
EGFR TKI
Crizotinib
EGFR WT/ALKnon-squamous
EGFR WT/ALKsquamous
Platinum doublet + bevacizumab OR platinum + pemetrexed +/- bevacizumab
Platinum-based doublet
Figure 1. This figure illustrates an algorithm for first-line treatment in metastatic NSCLC based on biological information. ALK: Anaplastic lymphoma kinase; Mut: Mutated; TKI: Tyrosine kinase inhibitor; WT: Wild-type.
UNKNOWN ≈ 50% KRAS 26.9% EGFR 9.4% ALK 4% MET 4% RET 1.9% ROS 11.7% BRAF 1.6% HER 20.9% PIK3CA 2.6%
Figure 2. This figure illustrates targetable oncogenic drivers in lung adenocarcinoma. Data taken from [3,72,73]. ALK: Anaplastic lymphoma kinase; HER2: Human epidermal growth factor receptor 2; MET: Mesenchymal-epithelial transition; PIK3CA: Phosphatidylinositol 3 kinase.
EGFR TKIs front line in selected NSCLC The IPASS trial was the first Phase III trial conducted in a NSCLC population selected for clinical characteristics predictive for presence of EGFR mutations. In this study, untreated Asiatic patients with advanced lung adenocarcinoma, non- or former/light smokers were randomized to receive gefitinib or carboplatin-paclitaxel [9]. The primary objective was to assess the noninferiority of gefitinib versus carboplatin-paclitaxel in terms of PFS. The study exceeded the primary objective and demonstrated superiority of gefitinib relative to chemotherapy in terms of PFS in the intent-to-treat (ITT) population. Patients assigned to the gefitinib arm had a significant reduction in the risk of progression (hazard ratio [HR] = 0.78, p < 0.001), with no difference in OS probably because of the confounding effect of post-study treatments. Importantly, the PFS 2.2
benefit observed in this trial was confined to patients harboring EGFR mutations, with a clear detrimental effect of gefitinib in individuals with EGFR wild-type. In the First-SIGNAL trial [10], another Asian study conducted in a clinically selected population, gefitinib significantly improved PFS (HR = 0.81, p = 0.044) and offered better QoL when compared to chemotherapy, with a similar OS for the two arms of treatment. Similar to the IPASS study, the benefit in PFS favored the gefitinib arm only in patients with EGFR mutations. Therefore, both the IPASS and the First-SIGNAL trials demonstrated that EGFR TKI can be offered as front-line therapy only in EGFR-mutated patients and clinical characteristics are not sufficient for a proper patient selection. Two randomized Phase III studies have been performed in Japanese patients to compare the efficacy of gefitinib versus chemotherapy in the first-line setting. Both trials, the WJTOG3405 [11] and the NEJ002 [12], confirmed that in NSCLC patients with EGFR mutations, gefitinib produces higher RR and longer PFS than platinum-doublet chemotherapy. In 2011, Zhou et al. published the results of the OPTIMAL trial, a Phase III study comparing erlotinib with carboplatin and gemcitabine in Chinese patients harboring EGFR mutations [13]. A striking HR of 0.16 for PFS (13.1 vs 4.6 months, p < 0.0001) was reported for subjects receiving the experimental treatment with erlotinib. The possibility of translating these findings to Western populations was a major theme of discussion. Rosell et al. duplicated the results of erlotinib over standard first-line chemotherapy in European EGFR-mutated population in a large Phase III trial (EURTAC) [14]. In this study, patients receiving erlotinib had a 63% relative reduction in risk of progression compared to chemotherapy (9.7 vs 5.2 months; HR = 0.37, p < 0.0001), leading to the approval of the drug in firstline setting only in EGFR-mutated patients.
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Table 1. First-line Phase III trials comparing standard chemotherapy with platinum doublet versus EGFR TKIs in EGFR-mutated population. Study
EGFR-TKI versus Chemotherapy
Patients (n)
RR (%)
PFS (months)
HR p value
OS (months)
HR p value
IPASS* [9]
Gefitinib versus CBDCA + TXL Gefitinib versus CDDP + GEM Gefitinib versus CDDP + TXT Gefitinib versus CBDCA + TXL Erlotinib versus CBDCA + GEM Erlotinib versus Platinum-doublet Afatinib versus CDDP + PEM Afatinib versus CDDP + GEM
97 versus 111 159 versus 150 88 versus 89 114 versus 114 82 versus 72 77 versus 76 230 versus 115 242 versus 122
71.2 versus 47.3 84.6 versus 37.5 62.1 versus 32.2 73.7 versus 30.7 83.0 versus 36.0 54.5 versus 10.5 56.0 versus 23.0 66.9 versus 23.0
9.5 versus NR 8.0 versus 6.3 9.2 versus 6.3 10.4 versus 5.5 13.1 versus 4.6 NR
0.48
21.6 versus 21.9 27.2 versus 25.6 36.0 versus 39.0 27.7 versus 26.6 NR
1.00
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FIRST SIGNAL* [10] WJTOG 3405 [11] NEJ 002 [12]
OPTIMAL [13]
EURTAC [14]
LUX LUNG 3 [15] LUX LUNG 6 [16]
11.1 versus 6.9 11.0 versus 5.6
< 0.0001 0.54 0.008 0.48 < 0.001 0.36 < 0.001 0.16 < 0.0001 0.34 < 0.0001 0.58 0.0004 0.28 < 0.0001
0.99 1.04 NR 1.18 NR 0.89 0.48 1.06 0.06
22.9 versus 20.8
NR
NR
NR
NR
0.95 0.75
*Shown data are restricted to EGFR-mutant population. CBDCA: Carboplatin; CDDP: Cisplatin; GEM: Gemcitabine; HR: Hazard ratio; NR: Not reported; OS: Overall survival; PEM: Pemetrexed; PFS: Progression-free survival; RR: Response rate; TKI: Tyrosine kinase inhibitor; TXL: Paclitaxel; TXT: Docetaxel.
The role of afatinib in first-line setting has been investigated in two Phase III studies. The LUX-LUNG 3 trial [15] compared afatinib with cisplatin plus pemetrexed in patients with advanced lung adenocarcinoma harboring EGFR mutations. The primary end point, PFS, assessed by independent review has been significantly prolonged (11.1 vs 6.9 months) in the afatinib arm compared to chemotherapy arm (HR = 0.58; p = 0.001) and particularly in patients with classical EGFR mutations (HR = 0.47; p = 0.001). Recently, Wu et al. published the results of the LUX-LUNG 6 trial [16], conducted in Asian patients harboring EGFR mutations and randomized to afatinib or cisplatin plus gemcitabine. The study showed that patients treated with afatinib had a significantly longer PFS than individuals receiving chemotherapy (median PFS = 11.0 vs 5.6 months, HR = 0.28, p < 0.0001), as well as higher RR (66.9 vs 23.0%, p < 0.0001). Therefore, in clinical practice, we have three EGFR TKIs available for EGFR-mutated patients, two reversible (gefitinib and erlotinib) and one irreversible (afatinib). At the present time, no study directly compared these three agents in patients with EGFR mutations. Nevertheless, indirect comparisons suggested that the three agents are equally effective with higher toxicity, particularly skin rash and diarrhea, reported in the afatinib studies. Recently, Pfizer announced that the 1206
ARCHER 1009 study [25], a Phase III, multicenter, double-blinded trial comparing dacomitinib (PF00299804, Pfizer, USA), an irreversible EGFR, HER2 and HER4 inhibitor, with erlotinib in pretreated NSCLC, did not met its primary end point, reinforcing the hypothesis that efficacy differences among currently available EGFR TKIs are minimal, if any. Resistance to EGFR TKIs and new generation EGFR TKIs
2.3
In the vast majority of patients with EGFR-activating mutations, an EGFR TKI treatment induces a dramatic tumor shrinkage with a median PFS ranging from 8 to 13 months. Unfortunately, after an initial response, all patients inevitably progress. Several mechanisms responsible for acquired resistance have been described, including the T790M missense mutation in exon 20 of EGFR [26], additional secondary EGFR mutations [27], MET amplification [28], HER2 amplification [26], small cell transformation [26], BRAF mutations [29] or combined events (Figure 3) [26]. One of the possible strategies to overcome resistance is to intensify EGFR inhibition through the use of compounds with additional activity against other ERBB family receptors. Second-generation EGFR TKIs, such as neratinib, dacomitinib and afatinib, showed promising activity in preclinical models [30-32]. Nevertheless,
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TKIs to treat NSCLC
EGFR TKIs in maintenance or as second-line therapy
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2.4
T790M 60% MET amplification ≈ 4% HER2 amplification 8% Small cell transformation 1% Concomitant mecanisms of resistance 10% UNKNOWN ≈ 18%
Figure 3. This figure illustrates the principal events responsible for acquired resistance in EGFR-mutant patient treated with EGFR TKIs. Data taken from [26,28]. HER2: Human epidermal growth factor receptor 2; MET: Mesenchymal-epithelial transition; TKIs: Tyrosine kinase inhibitors.
afatinib and neratinib demonstrated only a modest efficacy in clinical trials [33-35]. This lack of clinical activity in EGFR TKIs refractory patients is probably due to the high concentrations required to inhibit the T790M-mutated form of EGFR and the dose-related toxicity limitations derived from the concurrent inhibition of the wild-type form. Finally, as previously reported, an intensified strategy with irreversible EGFR TKIs, such as dacomitinib, failed to demonstrate a better outcome in pretreated NSCLC when compared to erlotinib [25]. Alternative strategies to overcome EGFR TKIs resistance, currently under clinical evaluation in Phase III trial, include the continuation of EGFR inhibition along with chemotherapy at the time of progression (the IMPRESS trial, NCT01544179) or the ‘re-challenge’ with EGFR TKIs after chemotherapy (the ICARUS trial, NCT01530334). Therefore, the ideal inhibitor should be more active and less toxic than older compounds. Covalent pyrimidine EGFR inhibitors seem to be good candidate to test in clinical, considering their ability to simultaneously inhibit EGFR mutant clone, including T790M, and spare EGFR wild-type. Preliminary results of a Phase I/II study with CO-1686, an oral covalent TKI, suggested a relevant activity in T790M-mutated NSCLC patients previously exposed to first-generation EGFR TKIs with a good tolerability, lacking the typical class adverse events [36]. Similarly, the ongoing Phase I trial with AZD9291, an oral and irreversible third-generation selective inhibitor of both EGFR-activating mutation and T790M, showed tumor shrinkage in a promising percentage of EGFR TKIs refractory patients, especially in those with T790M-positive NSCLC [37].
In clinical practice, not all EGFR-mutated NSCLC patients receive EGFR TKIs as front-line therapy, which is related to several factors, including the small amount of tumor tissue, facilities available or simply the time necessary for obtaining the results of the test. In a consistent proportion of NSCLC patients, the results of EGFR testing is available once frontline chemotherapy was already started or sometimes at the time of front-line therapy failure. In pretreated patients, Phase III trials [38] showed that erlotinib and gefitinib are active in patients harboring activating EGFR mutations, with a modest but statistically significant efficacy over placebo in EGFR wild-type individuals, demonstrated only for erlotinib [39,40]. In second-line setting, several trials and two meta-analyses [38,41] showed that both gefitinib and erlotinib produced a similar survival than standard second-line chemotherapy irrespective of any clinical or biological characteristics. Five Phase III studies (TITAN, HORGE, TAILOR, DELTA and PROSE trials) compared erlotinib with standard second-line chemotherapy [42-46]. In all trials, no difference in survival was detected between erlotinib and chemotherapy (Table 2), including studies specifically conducted in the EGFR wild-type population and without any confounding effect of the crossover, such as the TAILOR trial [44]. A meta-analysis of four randomized studies comparing gefitinib to docetaxel as second-line therapy demonstrated that both agents had similar efficacy in terms of OS with a more favorable toxicity profile for gefitinib [47]. More recently, a large meta-analysis showed no difference in survival between standard second-line chemotherapy and EGFR TKIs in EGFR wild-type population [38]. Overall, available data indicated that in pretreated NSCLC selection based on EGFR mutation status is less relevant than in front-line setting and that an EGFR TKI represents a reasonable option for second-line therapy even in the EGFR wild-type population. An important option for patients not progressing after standard first-line chemotherapy is represented by maintenance therapy and several studies investigated the role of erlotinib or gefitinib in this specific setting. The SATURN [48] trial was a Phase III study comparing erlotinib to placebo in patients with no evidence of progression following four cycles of first-line platinum-based chemotherapy. The co-primary end points were PFS in all patients and PFS in patients overexpressing EGFR by immunohistochemistry (IHC). PFS was significantly prolonged with erlotinib in all patients (HR = 0.71, p < 0.0001) and in EGFR IHCpositive (HR = 0.69, p < 0.0001). Importantly, PFS subgroup analysis showed a benefit produced by erlotinib in all patients, irrespective of any clinical or biological characteristic, including in EGFR wild-type patients (HR = 0.78, p = 0.0185). As expected, presence of EGFR mutations was associated with a marked improvement in PFS with erlotinib (HR = 0.10,
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Table 2. Second-line Phase III trials comparing standard chemotherapy with erlotinib. Study
Patients (n)
TITAN [42]
424
HORG [43]
297
TAILOR [44]
229
DELTA [45]
301
PROSE* [46]
285
Treatment arms
Erlotinib versus chemotherapy (docetaxel or pemetrexed) Erlotinib versus pemetrexed Erlotinib versus docetaxel Erlotinib versus docetaxel Erlotinib versus chemotherapy (docetaxel or pemetrexed)
PFS (months)
HR p value
OS (months)
HR p value
1.6 versus 2.2
1.19
5.3 versus 5.5
0.96
3.6 versus 2.9 2.4 versus 2.9 2.0 versus 3.2
NR
8.2 versus 10.1 5.4 versus 8.2 14.8 versus 12.2
NR
0.08
0.13 0.72 0.01 1.22 0.09 1.28
NR
0.73
0.98 0.78 0.10 0.91 0.52 1.05
NR 0.12
0.75
*Shown data are restricted to EGFR wild-type NSCLC population. HR: Hazard ratio; NR: Not reported; OS: Overall survival; PFS: Progression-free survival.
p < 0.0001). The PFS improvement produced by erlotinib translated in a significant survival benefit in the whole population (HR = 0.81, p = 0.0088), in EGFR wild-type (HR = 0.77, p = 0.0243), but not in EGFR-mutated patients, probably because of the confounding effect of crossover. Although the primary end point was PFS, OS was assessed as a secondary regulatory end point and contributed to the drug’s approval by the FDA and the European Medicines Agency. Considering the toxicity profile, maintenance therapy with erlotinib was generally well tolerated with a safety profile generally comparable to that observed in other studies with the same agent. Interestingly, patients benefiting more from maintenance erlotinib were individuals with stable disease as best response from first-line platinum-doublet chemotherapy, with no survival benefit in patients responding to chemotherapy [48]. The ATLAS trial was a Phase III study comparing maintenance erlotinib plus bevacizumab versus bevacizumab alone in NSCLC patients not progressing after four cycles of platinum-based chemotherapy plus bevacizumab [49]. Although the study met the primary end point of PFS, the difference in survival was not statistically significant, reducing the potential impact of this strategy on clinical practice. Two additional studies investigated the role of gefitinib as maintenance therapy. The INFORM trial [50] was a Phase III study comparing gefitinib with placebo in NSCLC patients not progressing after four cycles of platinum-based chemotherapy. Although PFS significantly favored the gefitinib arm, the difference in survival was not statistically significant probably because of the confounding effect of the crossover in a study population entirely represented by Asiatic people. The Phase III WJTOG0203 trial [51] compared platinumdoublet chemotherapy up to six cycles to platinum-based chemotherapy for three cycles followed by gefitinib 1208
maintenance, with the aim to demonstrate a survival improvement for the sequential strategy. The study failed to meet the primary end point of OS (HR = 0.86; p = 0.11), despite a possible survival improvement in patients with adenocarcinoma histology. 3.
Crizotinib in ALK-positive NSCLC
Initially reported in 2007 as a result of an inversion in chromosome 2p, which results in the fusion of the N-terminal portion of the echinoderm microtubule-associated proteinlike 4 (EML4) gene with the kinase domain of ALK, ALK translocation represents one of the newest and appealing biomarker in NSCLC [52]. Similar to other oncogenic drivers, this event has been described in adenocarcinoma especially but not exclusively in never-smoker population. Despite its low incidence, ranging 7% of cases, current guidelines consider ALK rearrangements as a standard biomarker to test at diagnosis in order to identify those patients suitable for anti-ALK strategies [53]. Crizotinib (PF 02341066, XalkoriÒ, Pfizer) a multi-target receptor TKI, was initially synthesized as a MET inhibitor [54,55]. In the Phase I trial, A8081001, an enriched cohort of 25 patients harboring a wide range of MET alterations received crizotinib but only in MET-amplified tumors -- such as NSCLC, gastroesophageal carcinoma and glioblastoma -an impressive tumor shrinkage was observed [56-59]. However, the occurrence of similar dramatic responses in those NSCLC cases that carried an ALK rearrangement moved the enthusiasm of researchers toward clinical development of the drug on this molecularly defined setting. Updated results of this Phase I trial confirmed an impressive activity in terms of RR of > 60% with an interesting PFS exceeding 9 months [60].
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TKIs to treat NSCLC
Similar findings were observed in a second single-arm Phase II study, in which 261 pretreated NSCLC ALK-positive patients receiving crizotinib had a probability of response of 60%; notably, responses were long-lasting and PFS ranged 8 months [61]. Based on these results, in August 2011, crizotinib received the FDA approval for the treatment of ALK-positive NSCLC. The superiority of crizotinib versus standard chemotherapy as second-line treatment has been demonstrated in the recently completed PROFILE 1007 Phase III trial [17]. The study, enrolling 347 patients with advanced ALK-rearranged NSCLC who failed one prior platinum-based regimen to receive crizotinib or chemotherapy with either pemetrexed or docetaxel, met its primary end point of PFS. Patients treated with crizotinib had a 51% relative reduction in risk of progression compared with those receiving standard chemotherapy (7.7 vs 3.0 months, HR = 0.49, p < 0.001). Treatment with crizotinib was also associated with higher RR (65 vs 20%, ITT population, p < 0.001) and better toxicity profile. Notably, the subset analyses confirmed a significant PFS benefit in favor of crizotinib arm independently of age (> 65 vs < 65 years), gender, performance status (EGOG PS 0 -- 1 vs 2), histology (adenocarcinoma vs non-adenocarcinoma) and presence of brain metastases. Consistent with what was observed in all Phase III trials with front-line EGFR TKIs [9-16], the improvement in PFS did not translate in a significant advantage in OS in favor of crizotinib therapy. Also in this case, the vast majority of patients assigned to the chemotherapy arm received crizotinib at progression, with an inevitable confounding effect on survival. Despite this, the unusual silhouette of survival curves seems to suggest an inversion in the natural course of ALK-positive disease. Finally, a large randomized Phase III trial (NCT01154140, www.clinicaltrials.gov) comparing crizotinib with the association of platinum and pemetrexed as front line in ALK-positive NSCLC just completed accrual and its results will be available in 2014. Although ALK-positive NSCLCs dramatically respond to crizotinib, no patient can be cured, and after a median of 10 months, the vast majority of patients inevitably relapses and dies because of disease progression. Several mechanisms have been identified as responsible for acquired resistance, including ALK point mutations in the gatekeeper site, ALK amplification or the emergence of a second driver, such as EGFR or KRAS mutations [62]. Moreover, there are a growing number of patients for whom disease progression occurs only in CNS, supporting the hypothesis of an inadequate CNS crizotinib penetration [63]. Different compounds are currently under investigation in crizotinib-refractory patients. LDK378 (Novartis Pharmaceuticals) is an oral potent second-generation ALK inhibitor that demonstrated efficacy in crizotinib-naı¨ve and crizotinib-pretreated patients [64]. Data from a dose-escalating Phase I study (NCT01283516) showed that LDK378 is highly active and well tolerated, with RR of 70 and 73% in the whole population and in crizotinib-resistant patients, respectively, including individuals harboring an ALK
secondary mutation [64]. Due to these impressive results and its favorable toxicity profile, LDK378 received the FDA breakthrough therapy designation for ALK-positive NSCLC in March 2013, in order to accelerate the development of this new compound. Two confirmatory Phase II studies in crizotinib-resistant patients (NCT01685060) and in crizotinib-naı¨ve patients (NCT01685138) with metastatic NSCLC are currently ongoing. In addition, two large Phase III trials of LDK378 versus chemotherapy are now enrolling patients. The first trial (NCT01828112) compares LDK378 with pemetrexed or docetaxel in ALK-positive NSCLC previously exposed to platinum-doublet chemotherapy and crizotinib, whereas the second trial (NCT01828099) compares LDK378 versus standard cisplatin- or carboplatin-pemetrexed as front-line treatment in ALK-positive NSCLC. Further, the first clinical results from the Phase I/II study with CH5424802, a novel and selective ALK inhibitor, have been recently published. This new target agent produced an exciting RR of 94%. More interestingly, patients with brain metastases also experienced durable disease control rate (DCR > 6 months) [65]. Finally, AP26113, a dual ALK/EGFR inhibitor, and the heat shock protein 90 inhibitor ganetespib [66,67] showed interesting activity and a favorable toxicity in early phases of development. Crizotinib in ROS1-positive NSCLC In addition to ALK-rearranged lung cancers, an encouraging antitumor effect emerged for a small fraction of NSCLC patients with ROS1 translocations treated with crizotinib. From a molecular point of view, ALK and ROS1 share a high degree of homology in their TK domains, thus suggesting that ALK TKIs, such as crizotinib, may also inhibit ROS1 and preclinical models confirmed this hypothesis [68,69]. Studies investigating incidence and clinical features of ROS1translocated patients showed that such molecular event is present in approximately 1% of NSCLC, mainly in never- or light smoker, with a prevalent adenocarcinoma histology [70]. Recently, Ou et al. reported the preliminary results of a Phase I study enrolling 20 ROS1-positive NSCLC patients exposed to crizotinib. RR was 50%, including one complete response and nine partial responses with a DCR of 70% after only 2 months of therapy [71]. 3.1
4.
Discussion
In the past few years, new insights in molecular biology rapidly changed the therapeutic landscape of NSCLC with the opportunity to develop specific therapies for a subset of molecularly defined patients. Currently, we have the possibility to identify a ‘driver genetic alteration’ in up to 60% of lung adenocarcinoma (Figure 2) [72,73]. Although many of these gene alterations are relatively rare, their identification with specific and approved tests is crucial and strongly recommended, considering that a tailored approach with target
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agents can deeply impact on patient outcome and change the natural history of the disease, as demonstrated with TKIs for EGFR-mutated patients and, more recently, for ALK-positive patients.
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5.
Expert opinion
Cancer treatment is currently based on individualized therapy, and biomarker analysis represents the most relevant factors for treatment decision. The era of targeted therapy for NSCLC became a reality since the discovery of EGFR mutations. Available data from randomized Phase III trials clearly demonstrated that EGFR TKIs, such as erlotinib, gefitinib or afatinib, are the best option that we can offer today as front-line therapy only in EGFR-mutant patients; therefore, it should be mandatory to obtain EGFR assessment before starting systemic treatment. Other genomic alterations, such as gene amplification and rearrangements, can be detected and characterized as ‘oncogenic driver’ in NSCLC, underlying a potential sensibility to specific compounds. ALK translocation represents one of the newest and most attractive genomic alterations in NSCLC, and despite its quite low incidence, current guidelines consider ALK rearrangements as a standard biomarker to test at diagnosis, considering the deep impact of crizotinib therapy in ALK-positive population. A dramatic tumor shrinkage and a significant gain in outcome is obtained with TKI treatment in these molecularly selected NSCLC patients, but, unfortunately, none with a metastatic disease is definitively cured and a consistent proportion of EGFR-mutant and ALK-positive patients are no longer sensitive to those compounds. Virtually all individuals, after an initial response, finally relapse and die from their disease. Understanding molecular events responsible for development of TKIs acquired or inner resistance is crucial Bibliography
for improving outcome, and several approaches are under clinical evaluation, including the use of novel and more selective TKIs or combined strategies with inhibitors of multiple pathways. Moreover, testing for different biomarkers represents a cost and often is not feasible to all patients, mainly for the limited amount of available tumor tissue. Today, in the era of targeted therapies, all the efforts should be made in all patients with the aim of characterizing the biological portrait of their tumor, offering the best therapy for each patient. That is the reason why many investigators are exploring the possibility of assessing tumor biomarkers in plasma, and new techniques today allow characterizing circulating DNA and circulating tumor cells. These approaches are currently under investigation and are not available in all centers. Finally, the possibility to obtain additional tumor tissue at progression or to explore biomarkers in plasma should be always considered in order to decipher the complex phenomenon of resistance. In the next future, this information will represent the backbone of clinical trials with novel and targeted agents, aiming to offer newer and tailored treatment options for the cure of our patients.
Declaration of interest This manuscript is supported by the Italian Association for Cancer Research IG 2012 -- 13157, Fondazione Ricerca Traslazionale and Istituto Tumori Toscano Project F13/16. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.
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Affiliation Gabriele Minuti MD, Armida D’Incecco MD, Lorenza Landi MD & Federico Cappuzzo† MD † Author for correspondence Istituto Toscano Tumori, Ospedale Civile, Oncologia Medica, Viale Alfieri 36, 57100-Livorno, Italy Tel: +39 0586223189; Fax: +39 0586223457; E-mail: [email protected]
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Protein kinase inhibitors to treat non-small-cell lung cancer Gabriele Minuti, Armida D’Incecco, Lorenza Landi & Federico Cappuzzo† 1.
Introduction
Istituto Toscano Tumori, Ospedale Civile, Oncologia Medica, Livorno, Italy
2.
EGFR protein kinase inhibitors
3.
Crizotinib in ALK-positive
Introduction: Activating mutations of the EGFR and rearrangement of anaplastic lymphoma kinase (ALK) best illustrate the therapeutic relevance of molecular characterization in NSCLC patients. Areas covered: For this review article, all published data on the most relevant Phase III trials with tyrosine kinase inhibitors (TKIs) for the treatment of NSCLC were collected and analyzed. Expert opinion: Eight Phase III trials clearly established EGFR TKIs as the best therapeutic option for front-line therapy in EGFR-mutated patients. In pretreated NSCLC, EGFR TKIs are considered more effective than standard monotherapy with cytotoxics in presence of classical EGFR mutations, whereas in the EGFR wild-type population, a similar efficacy to docetaxel or pemetrexed in term of survival has been demonstrated. In ALK-translocated NSCLC, a Phase III trial demonstrated the superiority of a multi-target TKI, including ALK, in terms of progression-free survival, response rate and toxicity profile when compared to standard second-line chemotherapy. New agents targeting EGFR or ALK are under evaluation particularly in individuals with acquired resistance to EGFR TKIs or crizotinib.
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NSCLC 4.
Discussion
5.
Expert opinion
Keywords: afatinib, crizotinib, erlotinib, gefitinib, NSCLC Expert Opin. Pharmacother. (2014) 15(9):1203-1213
1.
Introduction
Lung cancer is the leading cause of cancer-related mortality worldwide in men and is secondary only to breast cancer in women [1]. NSCLC accounts for 75% of all lung cancers and includes different subtypes, underlying relevant biological differences. The most part of patients with NSCLC are diagnosed in advanced stage, with a 5-year survival rate of < 5% [2]. In the past years progresses conducted in the field of cancer biology have significantly impacted on NSCLC treatment, mainly in adenocarcinoma histology, and, today, the old ‘one size fit all’ chemotherapeutic approach has been substitute by a novel approach, where treatment selection is based on biological characteristics (Figure 1). Alterations in gene sequence or expression can occur in the cell-signaling and regulatory pathways involved in cell cycle control, apoptosis, proteasome regulation and angiogenesis. As a consequence of genetic alterations, tumor can become highly dependent for proliferation and survival on the function of a single oncogene, defined as ‘driver oncogene’ (Figure 2) [3]. The demonstration of cells with genetic abnormalities that become addicted to oncogenes [4] is a rational basis for the development of targeted therapies. Specifically, the treatment of NSCLC has dramatically changed since the discovery of the biological and therapeutic importance of acquired genetic alterations in two genes that encode pharmacologically targetable tyrosine kinases (TK), EGFR [5-7] and Anaplastic lymphoma kinase (ALK) [8]. Drugs targeting the TK domain of EGFR, such as gefitinib, erlotinib or afatinib, demonstrated superiority over standard chemotherapy in patients harboring activating EGFR mutations (Table 1) [9-16] and crizotinib is now approved by the FDA for patients with ALK translocation [17]. 10.1517/14656566.2014.909412 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
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Article highlights. .
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In the past years, progresses conducted in the field of cancer biology have significantly impacted on NSCLC treatment, mainly in adenocarcinoma histology, with the opportunity to identify molecularly defined subgroup of patients. Tailored approach with targeted agents, such as gefitinib, erlotinib or afatinib, demonstrated superiority versus standard chemotherapy in patients harboring activating EGFR mutations, and crizotinib is now approved for patients with anaplastic lymphoma kinase (ALK) translocation. An important option for patients not progressing after standard first-line chemotherapy is represented by maintenance therapy. Several studies investigated the role of erlotinib or gefitinib in this setting. Unfortunately, after an initial response, a consistent proportion of EGFR-mutant and ALK-positive patients inevitably progress. Several approaches are under clinical evaluation to overcome acquired resistance, including the use of novel and more selective tyrosine kinase inhibitors or combined strategies with inhibitors of multiple pathways. The possibility to obtain additional tumor tissue at progression or to explore biomarkers in plasma will represent the backbone of clinical trials evaluating novel targeted agents, aiming to offer newer tailored treatments for the cure of NSCLC patients.
This box summarizes key points contained in the article.
Aim of the present paper is to review the available data from Phase III trials with protein kinase inhibitors in advanced NSCLC. 2.
EGFR protein kinase inhibitors
The first successful example of targeted therapy based on driver mutations in lung cancer involved EGFR that encodes for one of the four receptor of the ErbB family, including EGFR (ErbB-1; HER1), HER2 (c-ErbB-2), HER3 (c-ErbB- 3) and HER4 (c-ErbB-4). EGFR gene mutations were first identified in 2004 and classical activating EGFR mutations are localized in exon 19, mainly consisting of an in-frame deletion (45 -50%), and in exon 21, with a L858R point mutation (40 -45%). Preclinical models demonstrated that EGFR mutations increase sensitivity to TK inhibitors (TKIs), most likely through induction of critical structural modifications of the ATPbinding site in the TK domain [6,7]. Additional mutations have been characterized, including mutations in exon 20, classically associated with EGFR TKIs resistance, and other uncommon mutations with an undefined predictive role [18]. Since their identification, it was clear that EGFR mutations, predominantly discovered in adenocarcinoma histology, in Asian race, in never-smokers and in female [5], outlined a distinct subgroup of NSCLC patients. In the past years, eight Phase III trials [9-16] had clearly established that EGFR-mutated 1204
patients benefit more from first-line treatment with EGFR TKIs than from standard chemotherapy with platinum doublet, at least in terms of response rate (RR), progression-free survival (PFS), toxicity profile and quality of life (QoL), with no differences in overall survival (OS), most likely because of crossover effect (Table 1). Gefitinib (ZD 1839, IressaÒ, AstraZeneca) and erlotinib (OSI 774, TarcevaÒ, Genentech) are orally bioavailable synthetic anilinoquinazoline compounds that selectively bind to the ATP-binding site of EGFR TK intracellular domain, blocking EGFR autophosphorylation. Afatinib (GilotrifÒ, Boehringer Ingelheim) is a highly selective anilinoquinazoline that irreversibly binds directly to the ATP site in the kinase domain of both EGFR and human epidermal growth factor receptor 2 (HER2). In European countries, gefitinib and afatinib are approved for patients with EGFR mutations only, whereas erlotinib is also approved in second or third line for EGFR wild-type patients. Several and large Phase III trials evaluated the efficacy of reversible EGFR TKIs both in unselected and selected NSCLC population as front-line therapy.
EGFR TKIs front line in unselected NSCLC The two large randomized Phase III trials (INTACT 1 and INTACT 2), evaluating the role of gefitinib in combination with standard chemotherapy in first-line setting, failed to demonstrate any benefit in terms of survival for patients receiving gefitinib, even when the analysis was restricted to patients harboring EGFR mutation [19,20]. As observed for gefitinib, the combination of erlotinib with platinum-based chemotherapy (carboplatin and paclitaxel in TRIBUTE, cisplatin and gemcitabine in TALENT) did not demonstrate any gain in term of OS over chemotherapy alone [21,22]. Gridelli et al. explored the possibility of giving erlotinib as front-line treatment in unselected NSCLC in a randomized Phase III trial. The TORCH study [23] was conducted in a cohort of 760 NSCLC patients to evaluate whether first-line erlotinib followed at progression by cisplatin plus gemcitabine was not inferior in term of OS to the reverse standard sequence. As expected, median PFS was significantly in favor of standard arm, and, most importantly for clinical practice, survival was statistically longer for patients treated with chemotherapy first. Therefore, the TORCH trial confirmed that upfront chemotherapy is the gold standard for unselected population and that EGFR TKIs can be offered as front-line only in patients harboring activating EGFR mutations. An important clinical question is whether erlotinib could be indicated as front-line treatment in EGFR-unselected NSCLC unfit for chemotherapy. In the TOPICAL study, erlotinib was compared to placebo in patients with a poor performance status or unsuitable for chemotherapy [24]. No difference in OS was observed, confirming that front-line erlotinib is not beneficial in EGFR undefined patients. 2.1
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TKIs to treat NSCLC
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Stratification for EGFR, ALK and histolory
EGFR Mut+
ALK+
EGFR TKI
Crizotinib
EGFR WT/ALKnon-squamous
EGFR WT/ALKsquamous
Platinum doublet + bevacizumab OR platinum + pemetrexed +/- bevacizumab
Platinum-based doublet
Figure 1. This figure illustrates an algorithm for first-line treatment in metastatic NSCLC based on biological information. ALK: Anaplastic lymphoma kinase; Mut: Mutated; TKI: Tyrosine kinase inhibitor; WT: Wild-type.
UNKNOWN ≈ 50% KRAS 26.9% EGFR 9.4% ALK 4% MET 4% RET 1.9% ROS 11.7% BRAF 1.6% HER 20.9% PIK3CA 2.6%
Figure 2. This figure illustrates targetable oncogenic drivers in lung adenocarcinoma. Data taken from [3,72,73]. ALK: Anaplastic lymphoma kinase; HER2: Human epidermal growth factor receptor 2; MET: Mesenchymal-epithelial transition; PIK3CA: Phosphatidylinositol 3 kinase.
EGFR TKIs front line in selected NSCLC The IPASS trial was the first Phase III trial conducted in a NSCLC population selected for clinical characteristics predictive for presence of EGFR mutations. In this study, untreated Asiatic patients with advanced lung adenocarcinoma, non- or former/light smokers were randomized to receive gefitinib or carboplatin-paclitaxel [9]. The primary objective was to assess the noninferiority of gefitinib versus carboplatin-paclitaxel in terms of PFS. The study exceeded the primary objective and demonstrated superiority of gefitinib relative to chemotherapy in terms of PFS in the intent-to-treat (ITT) population. Patients assigned to the gefitinib arm had a significant reduction in the risk of progression (hazard ratio [HR] = 0.78, p < 0.001), with no difference in OS probably because of the confounding effect of post-study treatments. Importantly, the PFS 2.2
benefit observed in this trial was confined to patients harboring EGFR mutations, with a clear detrimental effect of gefitinib in individuals with EGFR wild-type. In the First-SIGNAL trial [10], another Asian study conducted in a clinically selected population, gefitinib significantly improved PFS (HR = 0.81, p = 0.044) and offered better QoL when compared to chemotherapy, with a similar OS for the two arms of treatment. Similar to the IPASS study, the benefit in PFS favored the gefitinib arm only in patients with EGFR mutations. Therefore, both the IPASS and the First-SIGNAL trials demonstrated that EGFR TKI can be offered as front-line therapy only in EGFR-mutated patients and clinical characteristics are not sufficient for a proper patient selection. Two randomized Phase III studies have been performed in Japanese patients to compare the efficacy of gefitinib versus chemotherapy in the first-line setting. Both trials, the WJTOG3405 [11] and the NEJ002 [12], confirmed that in NSCLC patients with EGFR mutations, gefitinib produces higher RR and longer PFS than platinum-doublet chemotherapy. In 2011, Zhou et al. published the results of the OPTIMAL trial, a Phase III study comparing erlotinib with carboplatin and gemcitabine in Chinese patients harboring EGFR mutations [13]. A striking HR of 0.16 for PFS (13.1 vs 4.6 months, p < 0.0001) was reported for subjects receiving the experimental treatment with erlotinib. The possibility of translating these findings to Western populations was a major theme of discussion. Rosell et al. duplicated the results of erlotinib over standard first-line chemotherapy in European EGFR-mutated population in a large Phase III trial (EURTAC) [14]. In this study, patients receiving erlotinib had a 63% relative reduction in risk of progression compared to chemotherapy (9.7 vs 5.2 months; HR = 0.37, p < 0.0001), leading to the approval of the drug in firstline setting only in EGFR-mutated patients.
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Table 1. First-line Phase III trials comparing standard chemotherapy with platinum doublet versus EGFR TKIs in EGFR-mutated population. Study
EGFR-TKI versus Chemotherapy
Patients (n)
RR (%)
PFS (months)
HR p value
OS (months)
HR p value
IPASS* [9]
Gefitinib versus CBDCA + TXL Gefitinib versus CDDP + GEM Gefitinib versus CDDP + TXT Gefitinib versus CBDCA + TXL Erlotinib versus CBDCA + GEM Erlotinib versus Platinum-doublet Afatinib versus CDDP + PEM Afatinib versus CDDP + GEM
97 versus 111 159 versus 150 88 versus 89 114 versus 114 82 versus 72 77 versus 76 230 versus 115 242 versus 122
71.2 versus 47.3 84.6 versus 37.5 62.1 versus 32.2 73.7 versus 30.7 83.0 versus 36.0 54.5 versus 10.5 56.0 versus 23.0 66.9 versus 23.0
9.5 versus NR 8.0 versus 6.3 9.2 versus 6.3 10.4 versus 5.5 13.1 versus 4.6 NR
0.48
21.6 versus 21.9 27.2 versus 25.6 36.0 versus 39.0 27.7 versus 26.6 NR
1.00
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FIRST SIGNAL* [10] WJTOG 3405 [11] NEJ 002 [12]
OPTIMAL [13]
EURTAC [14]
LUX LUNG 3 [15] LUX LUNG 6 [16]
11.1 versus 6.9 11.0 versus 5.6
< 0.0001 0.54 0.008 0.48 < 0.001 0.36 < 0.001 0.16 < 0.0001 0.34 < 0.0001 0.58 0.0004 0.28 < 0.0001
0.99 1.04 NR 1.18 NR 0.89 0.48 1.06 0.06
22.9 versus 20.8
NR
NR
NR
NR
0.95 0.75
*Shown data are restricted to EGFR-mutant population. CBDCA: Carboplatin; CDDP: Cisplatin; GEM: Gemcitabine; HR: Hazard ratio; NR: Not reported; OS: Overall survival; PEM: Pemetrexed; PFS: Progression-free survival; RR: Response rate; TKI: Tyrosine kinase inhibitor; TXL: Paclitaxel; TXT: Docetaxel.
The role of afatinib in first-line setting has been investigated in two Phase III studies. The LUX-LUNG 3 trial [15] compared afatinib with cisplatin plus pemetrexed in patients with advanced lung adenocarcinoma harboring EGFR mutations. The primary end point, PFS, assessed by independent review has been significantly prolonged (11.1 vs 6.9 months) in the afatinib arm compared to chemotherapy arm (HR = 0.58; p = 0.001) and particularly in patients with classical EGFR mutations (HR = 0.47; p = 0.001). Recently, Wu et al. published the results of the LUX-LUNG 6 trial [16], conducted in Asian patients harboring EGFR mutations and randomized to afatinib or cisplatin plus gemcitabine. The study showed that patients treated with afatinib had a significantly longer PFS than individuals receiving chemotherapy (median PFS = 11.0 vs 5.6 months, HR = 0.28, p < 0.0001), as well as higher RR (66.9 vs 23.0%, p < 0.0001). Therefore, in clinical practice, we have three EGFR TKIs available for EGFR-mutated patients, two reversible (gefitinib and erlotinib) and one irreversible (afatinib). At the present time, no study directly compared these three agents in patients with EGFR mutations. Nevertheless, indirect comparisons suggested that the three agents are equally effective with higher toxicity, particularly skin rash and diarrhea, reported in the afatinib studies. Recently, Pfizer announced that the 1206
ARCHER 1009 study [25], a Phase III, multicenter, double-blinded trial comparing dacomitinib (PF00299804, Pfizer, USA), an irreversible EGFR, HER2 and HER4 inhibitor, with erlotinib in pretreated NSCLC, did not met its primary end point, reinforcing the hypothesis that efficacy differences among currently available EGFR TKIs are minimal, if any. Resistance to EGFR TKIs and new generation EGFR TKIs
2.3
In the vast majority of patients with EGFR-activating mutations, an EGFR TKI treatment induces a dramatic tumor shrinkage with a median PFS ranging from 8 to 13 months. Unfortunately, after an initial response, all patients inevitably progress. Several mechanisms responsible for acquired resistance have been described, including the T790M missense mutation in exon 20 of EGFR [26], additional secondary EGFR mutations [27], MET amplification [28], HER2 amplification [26], small cell transformation [26], BRAF mutations [29] or combined events (Figure 3) [26]. One of the possible strategies to overcome resistance is to intensify EGFR inhibition through the use of compounds with additional activity against other ERBB family receptors. Second-generation EGFR TKIs, such as neratinib, dacomitinib and afatinib, showed promising activity in preclinical models [30-32]. Nevertheless,
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TKIs to treat NSCLC
EGFR TKIs in maintenance or as second-line therapy
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2.4
T790M 60% MET amplification ≈ 4% HER2 amplification 8% Small cell transformation 1% Concomitant mecanisms of resistance 10% UNKNOWN ≈ 18%
Figure 3. This figure illustrates the principal events responsible for acquired resistance in EGFR-mutant patient treated with EGFR TKIs. Data taken from [26,28]. HER2: Human epidermal growth factor receptor 2; MET: Mesenchymal-epithelial transition; TKIs: Tyrosine kinase inhibitors.
afatinib and neratinib demonstrated only a modest efficacy in clinical trials [33-35]. This lack of clinical activity in EGFR TKIs refractory patients is probably due to the high concentrations required to inhibit the T790M-mutated form of EGFR and the dose-related toxicity limitations derived from the concurrent inhibition of the wild-type form. Finally, as previously reported, an intensified strategy with irreversible EGFR TKIs, such as dacomitinib, failed to demonstrate a better outcome in pretreated NSCLC when compared to erlotinib [25]. Alternative strategies to overcome EGFR TKIs resistance, currently under clinical evaluation in Phase III trial, include the continuation of EGFR inhibition along with chemotherapy at the time of progression (the IMPRESS trial, NCT01544179) or the ‘re-challenge’ with EGFR TKIs after chemotherapy (the ICARUS trial, NCT01530334). Therefore, the ideal inhibitor should be more active and less toxic than older compounds. Covalent pyrimidine EGFR inhibitors seem to be good candidate to test in clinical, considering their ability to simultaneously inhibit EGFR mutant clone, including T790M, and spare EGFR wild-type. Preliminary results of a Phase I/II study with CO-1686, an oral covalent TKI, suggested a relevant activity in T790M-mutated NSCLC patients previously exposed to first-generation EGFR TKIs with a good tolerability, lacking the typical class adverse events [36]. Similarly, the ongoing Phase I trial with AZD9291, an oral and irreversible third-generation selective inhibitor of both EGFR-activating mutation and T790M, showed tumor shrinkage in a promising percentage of EGFR TKIs refractory patients, especially in those with T790M-positive NSCLC [37].
In clinical practice, not all EGFR-mutated NSCLC patients receive EGFR TKIs as front-line therapy, which is related to several factors, including the small amount of tumor tissue, facilities available or simply the time necessary for obtaining the results of the test. In a consistent proportion of NSCLC patients, the results of EGFR testing is available once frontline chemotherapy was already started or sometimes at the time of front-line therapy failure. In pretreated patients, Phase III trials [38] showed that erlotinib and gefitinib are active in patients harboring activating EGFR mutations, with a modest but statistically significant efficacy over placebo in EGFR wild-type individuals, demonstrated only for erlotinib [39,40]. In second-line setting, several trials and two meta-analyses [38,41] showed that both gefitinib and erlotinib produced a similar survival than standard second-line chemotherapy irrespective of any clinical or biological characteristics. Five Phase III studies (TITAN, HORGE, TAILOR, DELTA and PROSE trials) compared erlotinib with standard second-line chemotherapy [42-46]. In all trials, no difference in survival was detected between erlotinib and chemotherapy (Table 2), including studies specifically conducted in the EGFR wild-type population and without any confounding effect of the crossover, such as the TAILOR trial [44]. A meta-analysis of four randomized studies comparing gefitinib to docetaxel as second-line therapy demonstrated that both agents had similar efficacy in terms of OS with a more favorable toxicity profile for gefitinib [47]. More recently, a large meta-analysis showed no difference in survival between standard second-line chemotherapy and EGFR TKIs in EGFR wild-type population [38]. Overall, available data indicated that in pretreated NSCLC selection based on EGFR mutation status is less relevant than in front-line setting and that an EGFR TKI represents a reasonable option for second-line therapy even in the EGFR wild-type population. An important option for patients not progressing after standard first-line chemotherapy is represented by maintenance therapy and several studies investigated the role of erlotinib or gefitinib in this specific setting. The SATURN [48] trial was a Phase III study comparing erlotinib to placebo in patients with no evidence of progression following four cycles of first-line platinum-based chemotherapy. The co-primary end points were PFS in all patients and PFS in patients overexpressing EGFR by immunohistochemistry (IHC). PFS was significantly prolonged with erlotinib in all patients (HR = 0.71, p < 0.0001) and in EGFR IHCpositive (HR = 0.69, p < 0.0001). Importantly, PFS subgroup analysis showed a benefit produced by erlotinib in all patients, irrespective of any clinical or biological characteristic, including in EGFR wild-type patients (HR = 0.78, p = 0.0185). As expected, presence of EGFR mutations was associated with a marked improvement in PFS with erlotinib (HR = 0.10,
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Table 2. Second-line Phase III trials comparing standard chemotherapy with erlotinib. Study
Patients (n)
TITAN [42]
424
HORG [43]
297
TAILOR [44]
229
DELTA [45]
301
PROSE* [46]
285
Treatment arms
Erlotinib versus chemotherapy (docetaxel or pemetrexed) Erlotinib versus pemetrexed Erlotinib versus docetaxel Erlotinib versus docetaxel Erlotinib versus chemotherapy (docetaxel or pemetrexed)
PFS (months)
HR p value
OS (months)
HR p value
1.6 versus 2.2
1.19
5.3 versus 5.5
0.96
3.6 versus 2.9 2.4 versus 2.9 2.0 versus 3.2
NR
8.2 versus 10.1 5.4 versus 8.2 14.8 versus 12.2
NR
0.08
0.13 0.72 0.01 1.22 0.09 1.28
NR
0.73
0.98 0.78 0.10 0.91 0.52 1.05
NR 0.12
0.75
*Shown data are restricted to EGFR wild-type NSCLC population. HR: Hazard ratio; NR: Not reported; OS: Overall survival; PFS: Progression-free survival.
p < 0.0001). The PFS improvement produced by erlotinib translated in a significant survival benefit in the whole population (HR = 0.81, p = 0.0088), in EGFR wild-type (HR = 0.77, p = 0.0243), but not in EGFR-mutated patients, probably because of the confounding effect of crossover. Although the primary end point was PFS, OS was assessed as a secondary regulatory end point and contributed to the drug’s approval by the FDA and the European Medicines Agency. Considering the toxicity profile, maintenance therapy with erlotinib was generally well tolerated with a safety profile generally comparable to that observed in other studies with the same agent. Interestingly, patients benefiting more from maintenance erlotinib were individuals with stable disease as best response from first-line platinum-doublet chemotherapy, with no survival benefit in patients responding to chemotherapy [48]. The ATLAS trial was a Phase III study comparing maintenance erlotinib plus bevacizumab versus bevacizumab alone in NSCLC patients not progressing after four cycles of platinum-based chemotherapy plus bevacizumab [49]. Although the study met the primary end point of PFS, the difference in survival was not statistically significant, reducing the potential impact of this strategy on clinical practice. Two additional studies investigated the role of gefitinib as maintenance therapy. The INFORM trial [50] was a Phase III study comparing gefitinib with placebo in NSCLC patients not progressing after four cycles of platinum-based chemotherapy. Although PFS significantly favored the gefitinib arm, the difference in survival was not statistically significant probably because of the confounding effect of the crossover in a study population entirely represented by Asiatic people. The Phase III WJTOG0203 trial [51] compared platinumdoublet chemotherapy up to six cycles to platinum-based chemotherapy for three cycles followed by gefitinib 1208
maintenance, with the aim to demonstrate a survival improvement for the sequential strategy. The study failed to meet the primary end point of OS (HR = 0.86; p = 0.11), despite a possible survival improvement in patients with adenocarcinoma histology. 3.
Crizotinib in ALK-positive NSCLC
Initially reported in 2007 as a result of an inversion in chromosome 2p, which results in the fusion of the N-terminal portion of the echinoderm microtubule-associated proteinlike 4 (EML4) gene with the kinase domain of ALK, ALK translocation represents one of the newest and appealing biomarker in NSCLC [52]. Similar to other oncogenic drivers, this event has been described in adenocarcinoma especially but not exclusively in never-smoker population. Despite its low incidence, ranging 7% of cases, current guidelines consider ALK rearrangements as a standard biomarker to test at diagnosis in order to identify those patients suitable for anti-ALK strategies [53]. Crizotinib (PF 02341066, XalkoriÒ, Pfizer) a multi-target receptor TKI, was initially synthesized as a MET inhibitor [54,55]. In the Phase I trial, A8081001, an enriched cohort of 25 patients harboring a wide range of MET alterations received crizotinib but only in MET-amplified tumors -- such as NSCLC, gastroesophageal carcinoma and glioblastoma -an impressive tumor shrinkage was observed [56-59]. However, the occurrence of similar dramatic responses in those NSCLC cases that carried an ALK rearrangement moved the enthusiasm of researchers toward clinical development of the drug on this molecularly defined setting. Updated results of this Phase I trial confirmed an impressive activity in terms of RR of > 60% with an interesting PFS exceeding 9 months [60].
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TKIs to treat NSCLC
Similar findings were observed in a second single-arm Phase II study, in which 261 pretreated NSCLC ALK-positive patients receiving crizotinib had a probability of response of 60%; notably, responses were long-lasting and PFS ranged 8 months [61]. Based on these results, in August 2011, crizotinib received the FDA approval for the treatment of ALK-positive NSCLC. The superiority of crizotinib versus standard chemotherapy as second-line treatment has been demonstrated in the recently completed PROFILE 1007 Phase III trial [17]. The study, enrolling 347 patients with advanced ALK-rearranged NSCLC who failed one prior platinum-based regimen to receive crizotinib or chemotherapy with either pemetrexed or docetaxel, met its primary end point of PFS. Patients treated with crizotinib had a 51% relative reduction in risk of progression compared with those receiving standard chemotherapy (7.7 vs 3.0 months, HR = 0.49, p < 0.001). Treatment with crizotinib was also associated with higher RR (65 vs 20%, ITT population, p < 0.001) and better toxicity profile. Notably, the subset analyses confirmed a significant PFS benefit in favor of crizotinib arm independently of age (> 65 vs < 65 years), gender, performance status (EGOG PS 0 -- 1 vs 2), histology (adenocarcinoma vs non-adenocarcinoma) and presence of brain metastases. Consistent with what was observed in all Phase III trials with front-line EGFR TKIs [9-16], the improvement in PFS did not translate in a significant advantage in OS in favor of crizotinib therapy. Also in this case, the vast majority of patients assigned to the chemotherapy arm received crizotinib at progression, with an inevitable confounding effect on survival. Despite this, the unusual silhouette of survival curves seems to suggest an inversion in the natural course of ALK-positive disease. Finally, a large randomized Phase III trial (NCT01154140, www.clinicaltrials.gov) comparing crizotinib with the association of platinum and pemetrexed as front line in ALK-positive NSCLC just completed accrual and its results will be available in 2014. Although ALK-positive NSCLCs dramatically respond to crizotinib, no patient can be cured, and after a median of 10 months, the vast majority of patients inevitably relapses and dies because of disease progression. Several mechanisms have been identified as responsible for acquired resistance, including ALK point mutations in the gatekeeper site, ALK amplification or the emergence of a second driver, such as EGFR or KRAS mutations [62]. Moreover, there are a growing number of patients for whom disease progression occurs only in CNS, supporting the hypothesis of an inadequate CNS crizotinib penetration [63]. Different compounds are currently under investigation in crizotinib-refractory patients. LDK378 (Novartis Pharmaceuticals) is an oral potent second-generation ALK inhibitor that demonstrated efficacy in crizotinib-naı¨ve and crizotinib-pretreated patients [64]. Data from a dose-escalating Phase I study (NCT01283516) showed that LDK378 is highly active and well tolerated, with RR of 70 and 73% in the whole population and in crizotinib-resistant patients, respectively, including individuals harboring an ALK
secondary mutation [64]. Due to these impressive results and its favorable toxicity profile, LDK378 received the FDA breakthrough therapy designation for ALK-positive NSCLC in March 2013, in order to accelerate the development of this new compound. Two confirmatory Phase II studies in crizotinib-resistant patients (NCT01685060) and in crizotinib-naı¨ve patients (NCT01685138) with metastatic NSCLC are currently ongoing. In addition, two large Phase III trials of LDK378 versus chemotherapy are now enrolling patients. The first trial (NCT01828112) compares LDK378 with pemetrexed or docetaxel in ALK-positive NSCLC previously exposed to platinum-doublet chemotherapy and crizotinib, whereas the second trial (NCT01828099) compares LDK378 versus standard cisplatin- or carboplatin-pemetrexed as front-line treatment in ALK-positive NSCLC. Further, the first clinical results from the Phase I/II study with CH5424802, a novel and selective ALK inhibitor, have been recently published. This new target agent produced an exciting RR of 94%. More interestingly, patients with brain metastases also experienced durable disease control rate (DCR > 6 months) [65]. Finally, AP26113, a dual ALK/EGFR inhibitor, and the heat shock protein 90 inhibitor ganetespib [66,67] showed interesting activity and a favorable toxicity in early phases of development. Crizotinib in ROS1-positive NSCLC In addition to ALK-rearranged lung cancers, an encouraging antitumor effect emerged for a small fraction of NSCLC patients with ROS1 translocations treated with crizotinib. From a molecular point of view, ALK and ROS1 share a high degree of homology in their TK domains, thus suggesting that ALK TKIs, such as crizotinib, may also inhibit ROS1 and preclinical models confirmed this hypothesis [68,69]. Studies investigating incidence and clinical features of ROS1translocated patients showed that such molecular event is present in approximately 1% of NSCLC, mainly in never- or light smoker, with a prevalent adenocarcinoma histology [70]. Recently, Ou et al. reported the preliminary results of a Phase I study enrolling 20 ROS1-positive NSCLC patients exposed to crizotinib. RR was 50%, including one complete response and nine partial responses with a DCR of 70% after only 2 months of therapy [71]. 3.1
4.
Discussion
In the past few years, new insights in molecular biology rapidly changed the therapeutic landscape of NSCLC with the opportunity to develop specific therapies for a subset of molecularly defined patients. Currently, we have the possibility to identify a ‘driver genetic alteration’ in up to 60% of lung adenocarcinoma (Figure 2) [72,73]. Although many of these gene alterations are relatively rare, their identification with specific and approved tests is crucial and strongly recommended, considering that a tailored approach with target
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agents can deeply impact on patient outcome and change the natural history of the disease, as demonstrated with TKIs for EGFR-mutated patients and, more recently, for ALK-positive patients.
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5.
Expert opinion
Cancer treatment is currently based on individualized therapy, and biomarker analysis represents the most relevant factors for treatment decision. The era of targeted therapy for NSCLC became a reality since the discovery of EGFR mutations. Available data from randomized Phase III trials clearly demonstrated that EGFR TKIs, such as erlotinib, gefitinib or afatinib, are the best option that we can offer today as front-line therapy only in EGFR-mutant patients; therefore, it should be mandatory to obtain EGFR assessment before starting systemic treatment. Other genomic alterations, such as gene amplification and rearrangements, can be detected and characterized as ‘oncogenic driver’ in NSCLC, underlying a potential sensibility to specific compounds. ALK translocation represents one of the newest and most attractive genomic alterations in NSCLC, and despite its quite low incidence, current guidelines consider ALK rearrangements as a standard biomarker to test at diagnosis, considering the deep impact of crizotinib therapy in ALK-positive population. A dramatic tumor shrinkage and a significant gain in outcome is obtained with TKI treatment in these molecularly selected NSCLC patients, but, unfortunately, none with a metastatic disease is definitively cured and a consistent proportion of EGFR-mutant and ALK-positive patients are no longer sensitive to those compounds. Virtually all individuals, after an initial response, finally relapse and die from their disease. Understanding molecular events responsible for development of TKIs acquired or inner resistance is crucial Bibliography
for improving outcome, and several approaches are under clinical evaluation, including the use of novel and more selective TKIs or combined strategies with inhibitors of multiple pathways. Moreover, testing for different biomarkers represents a cost and often is not feasible to all patients, mainly for the limited amount of available tumor tissue. Today, in the era of targeted therapies, all the efforts should be made in all patients with the aim of characterizing the biological portrait of their tumor, offering the best therapy for each patient. That is the reason why many investigators are exploring the possibility of assessing tumor biomarkers in plasma, and new techniques today allow characterizing circulating DNA and circulating tumor cells. These approaches are currently under investigation and are not available in all centers. Finally, the possibility to obtain additional tumor tissue at progression or to explore biomarkers in plasma should be always considered in order to decipher the complex phenomenon of resistance. In the next future, this information will represent the backbone of clinical trials with novel and targeted agents, aiming to offer newer and tailored treatment options for the cure of our patients.
Declaration of interest This manuscript is supported by the Italian Association for Cancer Research IG 2012 -- 13157, Fondazione Ricerca Traslazionale and Istituto Tumori Toscano Project F13/16. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.
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Affiliation Gabriele Minuti MD, Armida D’Incecco MD, Lorenza Landi MD & Federico Cappuzzo† MD † Author for correspondence Istituto Toscano Tumori, Ospedale Civile, Oncologia Medica, Viale Alfieri 36, 57100-Livorno, Italy Tel: +39 0586223189; Fax: +39 0586223457; E-mail: [email protected]
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