Management of NSCLC: focus on crizotinib.

Drug Evaluation

Management of NSCLC: focus on crizotinib Lorenza Landi & Federico Cappuzzo† 1.

Introduction

Istituto Toscano Tumori, Medical Oncology Department, Livorno, Italy

2.

Crizotinib background

3.

Clinical trials with crizotinib in

Introduction: Presence of Anaplastic lymphoma kinase (ALK) translocations identifies a distinct subgroup of NSCLC with different prognosis and therapeutic opportunities. In cancer cells, ALK gene fusion acts as oncogenic driver, representing an attractive therapeutic target in NSCLC. Areas covered: For the purpose of this review article, data from preclinical and clinical trials with crizotinib were collected and analyzed. Expert opinion: Available data demonstrated that crizotinib is the best option we can offer today to ALK-positive NSCLC not previously exposed to ALK inhibitors, irrespective of line of therapy. In two large Phase III trials, crizotinib demonstrated to improve response rate and progression-free survival when compared to standard chemotherapy, both in first- and second-line treatment. Furthermore, results from pivotal Phase I and II studies indicated that crizotinib was active even in heavily pretreated populations. In addition, crizotinib displayed a favorable toxicity profile with a broad spectrum of adverse events, most of which is easily to manage and rarely require dose reduction or interruption. Unfortunately, almost all patients became refractory to crizotinib due to emergence of acquired resistance. The optimal management of these patients has not yet been defined. Novel ALK inhibitors are under investigation.

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Toronto on 03/06/15 For personal use only.

ALK-positive NSCLC 4.

Crizotinib safety profile

5.

Mechanisms of acquired resistance to crizotinib

6.

Clinical trials with crizotinib in NSCLC with MET amplification or ROS1 translocation

7.

Conclusion

8.

Expert opinion

Keywords: acquired resistance, anaplastic lymphoma kinase-positive NSCLC, anaplastic lymphoma kinase inhibitor, crizotinib, oncogene-addicted NSCLC Expert Opin. Pharmacother. (2014) 15(17):2587-2597

1.

Introduction

NSCLC remains the leading cause of cancer-related death worldwide [1], with two thirds of patients presenting in advanced stage at diagnosis. For decades, oncologists have invariably treated patients with metastatic NSCLC and acceptable performance status (PS) with platinum-based chemotherapy, obtaining only a modest improvement in survival and considerable toxicities [2]. In the last few years, improvements in the knowledge of the mechanisms underlying this lethal disease have radically impacted on management of NSCLC, mainly in patients with adenocarcinoma histology [3]. The identification of key genetic events driving lung tumor growth and metastatic spread led to postulate the concept of oncogene addiction [4]. According to this model, cancer cells are highly dependent on the function of a single driver oncogene and its inhibition by selective targeted agent translates into a marked antitumor activity. As a consequence, treatment selection is now based on biological rather than clinical characteristics. In NSCLC, the first validated biomarker is represented by the EGFR activating mutations, mainly represented by deletion in exon 19 or the L858R substitution in exon 21 [5-7]. Indeed, eight large randomized trials conducted in > 1900 EGFR mutant patients clearly demonstrated the superiority of EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib or afatinib, when compared to conventional platinum-based chemotherapy [8-15]. More importantly, from patient

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L. Landi & F. Cappuzzo

Box 1. Drug summary. Drug name Phase Indication

Crizotinib (PF 02341066) Approved Xalkori is indicated for the treatment of anaplastic lymphoma kinase (ALK)-positive advanced NSCLC Crizotinib is a first-in-class, oral, potent, ATPcompetitive small-molecule inhibitor of MET and ALK tyrosine kinases and their oncogenic variants Crizotinib dose-dependently inhibits kinase activity of ALK and c-mesenchymal-to-epithelial transition and their downstream signaling pathways, thus arresting tumor cell proliferation both in in vitro and in vivo models Crizotinib is administered orally (R)-3-[1-(2,6-Dichloro-3-fluorophenyl)-ethoxy]5-[(1-piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine


Pharmacology description/mechanism of action

Route of administration Chemical structure

NH CI N

F CI

H2N

Pivotal trial(s)

N

PROFILE 1001 [23,24], PROFILE 1007 [26] and PROFILE 1014 [27]

perspective, the presence of an actionable EGFR mutation allows to replace chemotherapy with better-tolerated targeted agents. The other successful example of targeted-oriented therapy in lung cancer involves the anaplastic lymphoma kinase (ALK) gene fusions [16]. 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 microtubuleassociated protein-like 4 (EML4) gene with the kinase domain of ALK, ALK translocation represents one of the newest and appealing biomarker in NSCLC [16,17]. Generally, all so far identified ALK gene rearrangements are constituted by two portions. The first is the highly conserved break point within ALK, located in the intron immediately upstream of the exons encoding the kinase domain; the second is the 5¢-end partners containing a coiled-coil or leucine zipper domain responsible for oligomerization of fusion protein and ligand-independent activation of the ALK TK activity. Constitutive activation of downstream signaling pathways, such as the Ras/MAPK, PI3K/AKT, and JAK/STAT, result in uncontrolled cancer cell proliferation and survival (Figure 1) [17]. As for EGFR and human epidermal receptor 2 deregulations [18-20], preclinical experiences demonstrated that ALK gene fusions represent a true oncogenic driver and, as showed in in vivo studies, ALK inhibition determines tumor regression in mouse models [21]. The possibility to obtain cancer arrest in patients carrying this specific molecular alteration led to the development of ALK inhibitors. Crizotinib (PF 02341066, Xalkori; Pfizer Inc., New York, NY) (Box 1), an oral selective TKI of both ALK and mesenchymal-to-epithelial transition (MET) receptors, is the first 2588

N

O

inhibitor licensed in clinical practice for treatment of NSCLC carrying ALK gene rearrangements detected by break-apart fluorescent in situ hybridization (FISH) [22]. A number of trials demonstrated the efficacy of the drug in ALK-positive NSCLC irrespective of line of therapy, thus establishing a new standard of care in ALK-positive NSCLCs [23-27]. Furthermore, the toxicity profile of crizotinib appeared not to negatively affect patients’ quality of life [26,27]. Beyond ALK translocation, there are at least two additional molecular aberrations candidate as predictors for crizotinib sensitivity. Indeed, preliminary results from Phase I trials suggested the potential efficacy of crizotinib in lung cancer patients with ROS1 translocations or MET amplification [28-31]. The aim of the present review article is to discuss available data on crizotinib in the treatment of advanced NSCLC with different driver alterations. 2.

Crizotinib background

Chemistry and pharmacology Crizotinib is a selective ATP-competitive small-molecule inhibitor of ALK and c-MET TKs and their oncogenic variants, including ALK fusion proteins or c-MET mutant variants. It has been synthesized based on its parental compound PHA-665752 [32,33]. PHA-665752 was a potent MET inhibitor binding the ATP site of the TK domain of MET that demonstrated antitumor activity in preclinical models. However, the high metabolic clearance, low solubility at pH 7.4 and scarce permeability made PHA-665752 unsuitable for its use in clinical trial. Crizotinib was specifically 2.1

Expert Opin. Pharmacother. (2014) 15(17)

Crizotinib

Cell membrane

ALK fusion protein Crizotinib P


PLC

PKC

PI3K

AKT

P STAT

RAS

mTOR RAF

MAPK/ERK

Gene transcription, cell proliferation, survival

Figure 1. ALK downstream signaling activation and ALK-pathway inhibition. ALK: Anaplastic lymphoma kinase.

designed to be less lipophilic and to have a better interaction in the TK pocket [32]. In enzymatic inhibition assays, as well as in a panel of > 120 kinases, crizotinib selectively inhibited ALK and MET kinases, resulting ~20-fold more potent than against other kinases. Consistent with its mechanism of action crizotinib dose-dependently inhibits kinase activity of ALK and c-MET and their downstream signaling pathways, thus arresting tumor cell proliferation both in in vitro and in vivo models. In different cell lines harboring the NPM-ALK (Karpas299 or SU-DHL-1 anaplastic large cell lymphoma cells) and the EML4-ALK (in H3122 human NSCLC cells) fusion oncogenes or amplification of the c-MET gene locus, crizotinib suppressed kinase activity, leading to growth tumor inhibition and apoptosis [17,34]. Crizotinib also potently inhibited cancer cell proliferation in an NPM-ALK-dependent Karpas299 xenograft models, determining complete tumor regression of all tumors at the dose of 100 mg/kg daily for 14 days. In addition, downstream signaling mediators, such as phospholipase C, Akt and STAT3, were also inhibited by crizotinb [17]. Taken into account, all these preclinical data provided the rationale for testing crizotinib in clinical trials in molecularly selected population. Pharmacokinetics Pharmacokinetic (PK) data of crizotinib derived from the first part of the Phase I A8081001 or PROFILE 1001 trial, a 2.2

typical escalating dose phase aiming to determine the maximal tolerated dose (MTD) in which crizotinib was initially tested at 50 mg daily and then escalated up to 300 mg twice in a day in a cohort of 36 patients with different types of advanced cancers [23]. Furthermore, a single-day dose of crizotinib was administered at -7 in order to define single-dose PK characteristics; additionally, two other sub-studies investigating the effect of food on crizotinib and the effect of midazolam on CYP 3A, respectively, were simultaneously conducted [35,36]. After oral administration of a single daily dose in fasting condition, peak plasma concentrations were reached after 4 h. PKs were linear from a 100 mg daily dose to a dose of 300 mg twice daily. For repeated 250 mg twice-daily dose, steady-state concentrations were reached after 15 days and the average terminal half-life ranged between 43 and 51 h. The mean steady-state trough plasma level at the recommended dose (250 mg BID) was 250 ng/ml or 75 nM of free drug, which exceeded the predicted ALK and MET inhibition activity observed in preclinical models (~26 and 13 nM, respectively) [35]. Furthermore, a recent published work conducted in healthy population evaluating bioavailability and bioequivalence of three oral crizotinib formulations and the effect of food confirmed that crizotinib can be administered without regard to meals [37]. In the midazolam-cohort population, PK profile was evaluated after administration of a single 2-mg dose of midazolam before and at day 28 of cycle 1 of crizotinib at recommended dose. As midazolam is metabolized by CYP3A, a 3.6-fold


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Table 1. Efficacy of crizotinib in PROFILE trials. Trial

PROFILE 1001 [23], (Ph.I) PROFILE 1005 [25], (Ph.II)* PROFILE 1007 [26], (Ph. III)


PROFILE 1014 [27], (Ph.III)

No

143 255 173 174 172 171

Treatment

RR %

CRZ CRZ CRZ PEM/TXT CRZ Platinum/PEM

61 53 65 20 74 45

Median duration of response (months) 12.2 10.7 8.0 6.1 12.2 5.7

PFS

OS

mPFS (months)

HR p -value

mOS (months)

HR p -value

9.7 8.5 7.7 6.3 10.9 7.0

0.49 < 0.001 0.45 < 0.001

NR NR 20.3 22.8 nr nr

0.54 0.54 0.82 0.18

*Mature population. CRZ: Crizotinib; HR: Hazard ratio; NR: Not reported; nr: Not reached; PEM: Pemetrexed; PFS: Progression-free survival; RR: Response rate; TXT: Docetaxel.

increase in its plasma level was detected after 28 days of crizotinib, thus indicating that crizotinib acts as a moderate CYP3A inhibitor. CYP3A isoforms are mainly responsible for crizotinib metabolism. The drug inhibits CYP3A in a time-dependent fashion, thus having the potential for autoinhibition. Indeed, total clearance of crizotinib from plasma was higher for a single dose of 250 mg than after 250 mg twice-in-a-day dose [36]. 3. Clinical trials with crizotinib in ALKpositive NSCLC

To date, the role of crizotinib in ALK-positive NSCLC has been evaluated in four trials and their results are reported in Table 1 [23-27]. The first open-label, multicenter, Phase I trial of crizotinib, the A8081001 study, started accrual in 2006 and consisted of two parts. In the above-mentioned escalating phase conducted in 36 patients with different types of advanced cancers, two patients experienced grade 3 fatigue at the higher dose level of 300 mg twice in a day and a dose reduction to 250 mg twice daily was determined as the MTD and as recommended dose to test in subsequent Phase II studies [35]. As initially synthesized as a MET inhibitor, the second part of this trial aimed to test the activity of crizotinib with a specific focus on tumors harboring MET deregulation, including MET amplification or MET mutation. Overall, a total 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 -- impressive tumor shrinkage was observed [38-40]. However, during the escalating phase, the occurrence of similar dramatic responses in two NSCLC cases that carried an ALK rearrangement shifted investigators toward clinical development of the drug on this molecularly defined setting and protocol was amended to screen simultaneously patients for both ALK translocation and MET amplification. Preliminary results of the first 82 ALK-positive NSCLC patients enrolled in the expansion cohort of the Phase I trial PROFILE 1001 have been 2590

published 4 years ago. Treatment with crizotinib determined a response rate (RR) of 57%, with an estimated 6-month progression-free survival (PFS) of 72%, with no median reached [23]. Two years later, updated results after an enrollment of ~150 patients confirmed an exciting activity in terms of RR of > 60% with an interesting PFS exceeding 9 months [24]. Similar findings have been observed in a large, multicenter, single-arm Phase II study, known as PROFILE 1005 [25]. This trial was initially conceived as a compendium to the randomized Phase III trial PROFILE 1007, in which crizotinib was compared to chemotherapy as second-line therapy in ALK-positive NSCLC. Indeed, according to trial design, patients in standard arm were not permitted to directly crossover to crizotinib at the time of progression; as a consequence, these patients had to be enrolled in PROFILE 1005. Nevertheless, after the completion of US accrual in PROFILE 1007, some major changes in eligibility criteria allowed to include in the PROFILE 1005 all NSCLC patients with ALK translocations irrespective of the line of treatment and presence of measurable disease. At data cutoff on January 2012, a total of 901 patients were included onto the study. Two-hundred and sixty-one patients, constituting the mature population, were analyzed for efficacy and not surprisingly RR was 60%. Notably, responses were long lasting (median duration of response 46 weeks) and PFS ranged 8 months [25]. Based on these results, on August 2011, crizotinib received the FDA accelerated approval for the treatment of ALKpositive NSCLC. The superiority of crizotinib versus standard chemotherapy has been recently demonstrated in two large Phase III studies [26,27]. The first trial, the PROFILE 1007, compared second-line crizotinib to standard chemotherapy with either pemetrexed or docetaxel in patients with advanced ALKrearranged NSCLC who failed one prior platinum-based regimen [26]. The study, enrolling 347 patients, met its primary endpoint 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, hazard ratio (HR) 0.49, p < 0.001). Treatment with crizotinib



Crizotinib

was also associated with higher RR (65% vs 20%, intention to treat population, p < 0.001) and better toxicity profile. By splitting results according to type of chemotherapy, the worst outcome in terms of RR and PFS was observed in docetaxel arm than in pemetrexed arm (RR 7% vs 29%; PFS 4.2 months vs 2.6 months). Notably, the subset analyses confirmed a significant PFS benefit in favor of crizotinib arm independent of age (> 65 years vs < 65 years), gender, PS (EGOG PS 0 -- 1 vs 2), histology (adenocarcinoma vs non-adenocarcinoma) and presence of brain metastases. Consistent with those observed in all Phase III trials with front-line EGFR-TKIs [8-15], the improvement in PFS did not translate in a significant advantage in overall survival 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 [26]. The second trial, the PROFILE 1014, aimed to demonstrate the improvement in PFS of crizotinib over standard platinum-base chemotherapy in previously untreated advanced non-squamous ALK-positive NSCLC [27]. Overall, a total of 343 patients were stratified according to ethnicity (Caucasian vs Asian), ECOG PS (0 vs 1) and presence of brain metastases (yes vs no) and then randomized 1:1 to receive crizotinib or the combination of pemetrexed with either cisplatin or carboplatin, every 3 weeks for a maximum of six cycles. According to the trial design, at the time of progression, patients randomized in standard arm crossed over to crizotinib, whereas patients in experimental arm were allowed to continue crizotinib beyond progression at investigator’s discretion. The study met its primary endpoint demonstrating the superiority of crizotinib over chemotherapy in prolonging PFS (median 10.9 vs 7.0 months; HR 0.454; 95% CI 0.346 - 0.596; p < 0.0001). Moreover, patients receiving crizotinib had a higher probability of response than those receiving chemotherapy (74 vs 45%; p < 0.0001). Considering that > 60% of patients in standard arm received crizotinib at the time of progression, no difference in OS was observed between the two groups (HR 0.821; 95% CI 0.536 - 1.255; p = 0.1804) [27]. These results clearly established crizotinib as the standard of care in untreated advanced ALK-positive non-squamous NSCLC. Finally, another twin Phase III study comparing crizotinib versus the same chemotherapy regimen as frontline treatment in advanced ALK-positive NCSLC is currently ongoing in Asian population (PROFILE 1029) and results will be available in 2015. 4.

Crizotinib safety profile

Data about tolerability of crizotinib derived from the aforementioned trials PROFILE 1001, PROFILE 1005,

PROFILE 1007 and PROFILE 1014 [23-27]. Generally, treatment with crizotinib was overall well tolerated, although > 90% of enrolled patients experienced any drug-related adverse events (AEs), the majority of which was generally of grade 1 or 2 in severity and percentages of patients discontinuing treatment due to unresolved toxicity were 2, 4, 6 and 5% in the PROFILE 1001, PROFILE 1005, PROFILE 1007 and PROFILE 1014, respectively [23-27]. The most common AEs were gastrointestinal disorders, such as nausea, vomiting and diarrhea, and visual disorders, each occurring in > 40% of cases, followed by increased transaminases level, peripheral edema and fatigue [23-27]. Other less-common AEs included neutropenia, constipation, abdominal pain, anorexia, dysgeusia and asymptomatic bradycardia [23-27]. Main AEs observed in PROFILE trials are reported in Table 2. Severe and potential life-threatening (grade 3 -- 4) AEs, including pneumonitis or interstitial lung disease, QTc prolongation and hepatotoxicity, were reported in < 2% of cases [23,41]. The occurrence of all of the common AEs occurred within the first days of therapy and appeared to improve over time. For example, visual disorders, including visual impairment, photopsia, blurred vision, photophobia and diplopia, usually started early in the course of treatment and were enhanced by changes in lighting. Moreover, they were transient, lasting seconds and their frequency seemed to be inversely correlated with the duration of treatment. The only late and cumulative effect seemed to be peripheral edema. Importantly, the majority of AEs are safely managed with symptomatic drugs, including anti-emetics or antidiarrheal. Nevertheless, temporary drug discontinuation or dose reduction should be recommended for specific toxicities: in the case of grade 3/4 transaminases elevation with concurrent grade £ 1 total bilirubin elevation or grade 4 neutropenia, treatment with crizotinib should be interrupted until recovery and then resumed at 200 mg twice daily, whereas permanent discontinuation should be considered for patients with grade ‡ 2 ALT or AST elevation with concurrent grade ‡ 2 total bilirubin elevation. Beyond clinical trials, new insights concerning the spectrum of AEs derived from clinical practice. Transient hypogonadism is one of the unique and rapidly occurring effect of crizotinib and it has been observed in > 80% of male patients [42]. Decrease in testosterone levels, together with declining in luteinizing hormone and follicle-stimulating hormone levels, can be observed after a median time of 14 -- 21 days of drug assumption. Nevertheless, management of hypogonadism requires hormone replacement in only few cases, whereas crizotinib dose reduction is not necessary. It is important to remember that symptoms related to androgen deficiency, such as fatigue and sexual dysfunctions, can be often confused with psychological or functional cancer-related conditions; as a consequence, serum testosterone levels should be routinely checked in order to promptly detect a hypogonadism.


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Table 2. Most common (occurring in > 10% of patients) adverse events in PROFILE trials.


PROFILE 1001 [23] n = 82

Nausea Vomiting Diarrhea Visual disorders Elevated transaminase levels Edema Fatigue Neutropenia

PROFILE 1005 [25] n = 901*

PROFILE 1007 [26] n = 172

PROFILE 1014 [27] n = 171

Any grade n (%)

Grade 3 -- 4 n (%)

Any grade n (%)

Grade 3 -- 4 n (%)

Any grade n (%)

Grade 3 -- 4 n (%)

Any grade n (%)

Grade 3 -- 4 n (%)

43(52) 35 (43) 38 (46) 34 (41) 9 (11)

1 1 1 0 1

423 352 369 468 252

7 (0.8) 7 (0.8) 9(1.0) 1(0.1) 48(5.3)

94 (55) 80 (47) 103 (60) 103 (60) 66 (38)

2 (1) 2 (1) 0 0 27 (16)

95 (56) 78 (46) 105 (61) 122 (71) 61 (36)

2 (1) 3 (2) 4 (2) 1 (1) 24 (14)

13 (16) 8 (10) 1 (1)

0 0 0

3(0.3) 18 (1.9) 50 (5.5)

54 (31) 46 (27) NR

0 0 23 (13)

83 (49) 48 (29) 12 (7)

1 (1) 5 (3) 3 (2)

(1) (1) (1) (1)

(46.9) (39.1) (41.0) (51.9) (27.9)

211 (23.4) 163 (18.1) 84 (9.3)

*Overall population. NR: Not reported.

Mechanisms of acquired resistance to crizotinib 5.

Despite an initial dramatic response, after a median time of 10 months, virtually all patients become refractory to crizotinib due to the emergence of acquired resistance. So far, several mechanisms underlying acquired resistance have been elucidated and they conventionally belong to two categories (Figure 2) [43-48]. The first group involves mechanisms defined as target dependent because they preserve ALK dominance, including mutations in the kinase domain of ALK or ALK fusion gene amplification, with the latter alone or in combination with mutations [44,45]. ALK mutations account for up to 30% of acquired resistances, occur at comparable frequencies and seem to be associated with different sensitivities to crizotinib and other ALK inhibitors [45]. A broad spectrum of ALK mutations has been identified in preclinical and clinical models. The first and most well characterized is the L1196M mutation, also called ‘gatekeeper’ for its ability of interfering with ligand site of crizotinib [47]. Other mutations are G1202R, S1206Y, G1269A, 1151ins and recently F1174C and D1203N [46,48]. Notably, as reported in the seminal Phase I trial of crizotinib, different resistant mutant clones may exist in the same patient [47]. The second category, also named as non-target--dependent, involves activation of other pathways, such as EGFR or c-KIT gene amplification or EGFR or KRAS mutations [44,45]. Interestingly, the emergence of EGFR or KRAS mutant clones might be observed even without the preservation of the original ALK translocation. Finally, in a consistent proportion of patients (15%), the mechanism of resistance remains unknown. On the clinical point of view, we evaluate a disease progression according to RECIST criteria [49] and consider as resistant those tumors that increase in size or in number of lesions while on crizotinib therapy. Furthermore, not all 2592

RECIST progressions have the same clinical meaning, and also, not all RECIST progressions necessarily require an immediate therapeutic change. Some patients often progress slowly, in limited pre-existing sites (oligoprogression) or in a single new site and without worsening of their symptoms. In addition, to complicate this scenario, data from clinical trials indicate that there is an increasing number of patients for which disease progression occurs only in CNS, supporting the hypothesis of an inadequate CNS drug penetration [24,44,45]. In such conditions, probably sustained by an ALK-dominant mechanism of resistance, premature discontinuation of ALK inhibition could not be the preferred choice due to the risk of disease flare, as recently described [50,51]. Although no randomized prospective trials have been designed to specifically address this question, continuation of crizotinib beyond progression in association with local therapies, including radiotherapy, local ablation and surgery, could represent a suitable option for optimizing duration of crizotinib therapy [24,52,53]. A retrospective study reported that the addition of local treatments direct against the only sites of disease progression might increase the total duration of systemic therapy of several months [52]. Furthermore, continuation of crizotinib beyond progression at the investigator’s discretion was permitted in all PROFILE trials [53]. In particular, in 120 patients enrolled in the PROFILE 1001 and 1005, median duration of crizotinib beyond RECIST progression was ~20 months, whereas median survival from the time of first progression was significantly longer than the one reported in the group of patients who did not continue the drug (16.4 vs 3.9 months, HR 0.27, p < 0.0001) [53]. It is important to remember that benefiting patients were more likely to have good PS at progression, had responded to prior crizotinib therapy and site of progression was amenable for local therapy, such as brain, thus highlighting the importance of a proper patient selection.


Crizotinib

Unknown = 20% Target dependent = 50% ALK mutations • L1196M • G1202R • S1206Y • G1269A • 1151T ins • Others


ALK amplification Non target dependent = 30% • c-KIT amplification • New driver mutations • Increased EGFR signalling

Figure 2. Mechanisms of acquired resistance to crizotinib. ALK: Anaplastic lymphoma kinase.

On the other side, there are those patients who experience a rapid radiological and clinical progression. In these cases, progressing clones have become completely independent from the original target or addicted to a second driver and treatment with crizotinib should be replaced by conventional chemotherapy with pemetrexed or with platinum compound, if not previously received, or by novel specific targeted agent, if available [45]. Several novel second-generation ALK inhibitors are currently under investigations in clinical trials, in both crizotinib-refractory and crizotinib-naı¨ve settings [54,55]. Ceritinib (Zykadia, Novartis Pharmaceuticals) is a novel, more potent second-generation ALK inhibitor demonstrating efficacy in NSCLC with acquired resistance to crizotinib [54]. Shaw et al. recently published the results of a Phase I trial enrolling 130 patients with ALK-positive solid tumors, the vast majority of which (94%) was NSCLC and pretreated with crizotinib (68%). Particularly, in crizotinib-resistant population, RR was 56% and responses were also durable (median duration of response, DOR, 8.2 months, 95% CI 6.9 -- 11.4) with a PFS of 6.9 months (95% CI 5.6 -- 9.5). Based on these findings, on April 2014, ceritinib granted FDA accelerated approval for treatment of patients with ALK-positive crizotinib-refractory NSCLC. Another promising second-generation ALK inhibitor is alectinib (CH424802, Roche), which gained the FDA breakthrough therapy designation for ALK-positive NSCLC due to the encouraging results that emerged from a Phase I ongoing trial [55].

Clinical trials with crizotinib in NSCLC with MET amplification or ROS1 translocation

6.

In NSCLC, MET amplification is a rare event with an expected frequency of < 4%; unlike other oncogenic drivers such as EGFR mutations, ALK translocation or ROS1

translocation, presence of MET amplification has been described also in patients with smoking history [31]. As anticipated, the activity of crizotinib at the standard dose of 250 mg twice in a day in MET-amplified NSCLC is under evaluation as a part of the ongoing Phase I PROFILE 1001 trial [30]. In this study, c-MET status was assessed by FISH and positivity was defined as an increase in ratio of MET gene copy number gain relative to centromere 7 (MET/CEP7) ‡ 1.8. Patients were then stratified according to the levels of amplification within three categories as low (MET/CEP7 ratio ‡ 1.8 -- £ 2.2), intermediate (MET/ CEP7 ratio > 2.2 -- < 5) and high (MET/CEP7 ratio ‡ 5). Among the 16 individuals enrolled, 3 did not meet criteria for amplification, whereas 13 patients resulted MET positive (low, n = 1; intermediate, n = 6; high, n = 6) and were dosed with crizotinib. Treatment-related AEs were consistent with the well-known safety profile of the drug and mainly represented by grade 1 -- 2 diarrhea (47%), nausea (41%), vomiting (47%), peripheral edema (24%) and visual impairment (24%). Interestingly, antitumor activity was restricted to both intermediate/high MET amplification groups (RR = 50%) [31]. In addition to ALK-rearranged and MET-amplified 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 [28-30]. 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 disease control rate of 70% after only 2 months of therapy [29]. Furthermore, European clinicians collected data from a large


2593



Table 3. Principal ongoing or planned trials with crizotinib. Trial

Phase

No

Treatment

End point

NCT01639001

III

200

PFS

NCT02075840

III

286

CRZ versus CDDP/PEM or CBDCA/PEM CRZ versus alectinib

NCT01712217

I/II

228

AT13387 versus AT13387 + CRZ (Phase II)

DLT (Phase I) PFS (Phase II)

NCT02183870

II

30

CRZ

RR

Eudract 2014-001263-12

II

40

CRZ

RR, safety and tolerability

PFS

Key eligibility criteria

Status

ALK-positive* advanced NSCLC East Asian population No prior therapy ALK-positivez NSCLC No prior therapy Asymptomatic or pretreated brain MET permitted ALK-positive NSCLC At least 8 weeks of CRZ therapy in absence of toxicities or progression ROS1-positive§ NSCLCs Any line of therapy ROS1-positive{ or METamplified# NSCLC At least one prior chemotherapy line

Active, recruiting Not yet recruiting

Active, recruiting

Active, recruiting Not yet recruiting

ALK positive: Presence of ALK rearrangement, using the Vysis ALK Break Apart FISH Probe Kit (*) or by immunohistochemistry (z) test (Ventana Medical Systems, Inc) using rabbit monoclonal primary antibody assay (D5F3); (§) ROS1 positive: Presence of ROS1 rearrangements assessed by central FISH testing; ({) ROS1 translocation assessed by using 6q22 ROS1 BreakApart FISH probe RUO Kit Vysis LSI/WCP Hybridization Buffer (Abbott, USA); (#)MET amplification: Assessed by using Vysis MET SpectrumRed FISH probe kit (Abbott, USA). CBDCA/PEM: Carboplatin/pemetrexed; CDDP/PEM: Cisplatin/pemetrexed; CRZ: Crizotinib; DLT: Dose-limiting toxicities; PFS: Progression-free survival; RR: Response rate.

case series of 28 advanced ROS 1-positive NSCLC treated with crizotinib, reporting an RR of 77% [56]. Notably none of these subjects had received prior ALK-TKIs and the vast majority of patients (64%) were heavily pretreated with two or more lines of chemotherapy. Finally, assessing efficacy, safety and tolerability of crizotinib in pretreated metastatic NSCLC with MET amplification or ROS1 translocation is the object of a Phase II Italian trial, the accrual of which will start within the next few months (METROS trial, Eudract number2014-001263-12). A list of the principal planned or ongoing trials with crizotinib is reported in Table 3. 7.

Conclusion

Presence of ALK translocation defines a distinct group of NSCLC, mainly represented by younger subjects, never smokers and with adenocarcinoma histology, and 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. At present, available data from well-conducted clinical trials demonstrated that crizotinib is the best option we can offer today in NSCLC patients with ALK translocations. Furthermore, crizotinib has a unique profile of AEs, most of which is easily to manage and rarely require dose reduction or interruption. Unfortunately, as for other NSCLCs, no patients can be cured and after a median time of 9 -- 10 months virtually all patients progress due to the onset of acquired resistance. Management of crizotinib-resistant 2594

patients represents one of the major challenges for thoracic oncologists. In the next few years, results of ongoing trials with novel ALK inhibitors and dedicated translational research studies might help to define the optimal sequence of treatment for ALK-positive NSCLC patients. 8.

Expert opinion

The treatment of NSCLC has dramatically changed with the identification of key genetic driver alterations [57]. This translational revolution radically impacted the way to approach this disease. Today we know that the knowledge of genetic makeup of a metastatic lung tumor at baseline assures to assign patients to target treatment according to the specific profile of their tumor [57]. In addition, the use of sophisticated genomic techniques allows the identification of some driving events, for which the proper agent is already available and much efforts should be made in order to avoid that even one of our patients can loose the opportunity of receiving its effective drug. In this context, crizotinib represents one of the successful examples of drug optimization with a rapid timeline from identification of target and drug availability for clinical use, and results of clinical trials clearly indicated crizotinib as the standard of care for ALK-positive NSCLC, irrespective of the line of therapy [23-27]. Moreover, one of the consequences of its accelerated approval is the limited clinical experience concerning toxicity profile and optimal therapy management. Although there is a general agreement in considering crizotinib as a well-tolerated drug, some aspects have to be clarified.



Crizotinib

In humans, the normal function of ALK protein is partially unknown; however, the predominance of gastrointestinal and visual disorders observed in crizotinib-treated patients seems to be related to its involvement in the gut and visual systems, as reported for other organisms [58,59]. On the other side, little is known about anti-MET properties or off-target effects of crizotinib. Last but not least, irrespective of pathogenetic mechanism, the clinical significance of some potential severe AEs, such as cardiac and hepatic toxicity, remains largely undetermined. In the coming years, a comprehensive analysis of the growing amount of data deriving from Phase III trials together with clinical experience will help us to better define which patients have to be ‘handled with care’ due to a high risk of developing significant toxicity. The other critical issue concerns the optimal management of crizotinib-resistant cases. As demonstrated in other oncogene-addicted NSCLCs, such as those with EGFR activating mutations, the molecular portrait of a tumor is something evolving over time and tumor clones invariably were able to grow irrespective of target inhibition [45]. Ideally, repeating biopsy at the time of progression should be considered as an essential procedure in order to define molecular mechanisms underlying resistance and to select which patients are more likely to respond to novel drugs. At this proposal, second-generation ALK inhibitors, particularly ceritinib, showed an interesting activity in crizotinib-resistant setting [54,55]. Nevertheless, scarce data on correlation between sensitivity to novel ALK inhibitors and mechanisms of resistance are available. Indeed, in the Phase I trial of ceritinib, a small percentage (15%) of patients repeated tumor biopsy at the time of progression and tumor samples were analyzed only for ALK status [54]. Consequently, it is not possible to conclude if ceritinib is equally effective against both targetdependent and non--target-dependent resistant clones. Moreover, the availability of more potent ALK inhibitors, such as ceritinib or alectinib, raises the question if their use to prevent Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

2.

3.

DeSantis C, Naishadham D, Jemal A, et al. Cancer statistics for African Americans, 2013. CA Cancer J Clin 2013;63:151-66 Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. N Engl J Med 2002;346:92-8 Govindan R, Ding L, Griffith M, et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 2012;150:1121-34

the onset of acquired resistance in frontline setting makes sense. To address this question, the design of future trials might directly compare not only crizotinib versus one of the second-generation inhibitors, but also the sequence of treatments. Waiting for a new standard of care after crizotinib failure, continuation of drug beyond progression as long as the patient-derived benefit coupled with local ablative therapies could represent a suitable option mainly in patients with indolent or oligoprogressive disease [24,52,53]. Even if there is a general consensus in adopting this approach in ‘real life’ population, formal guidelines aiming to standardize the definition of clinical benefit and to ensure the exact interpretation of clinical trials are urgently needed. Finally, beyond ALK translocations, recent findings suggested that also MET amplification and ROS1 translocations could be predictive for crizotinib sensitivity [28-31]. Although these molecular events are rare when separately considered, taken together, they account for up to 5% of all NSCLCs. As a consequence, considering the annual incidence of NSCLC [1], it is reasonable to suppose that in the next few years, crizotinib could be beneficial for thousands of patients each year in the Western countries and elsewhere. Results from ongoing trials specifically conducted in these molecularly defined populations will clarify this point.

Declaration of interest This manuscript is supported by Associazione Italiana per la Ricerca sul Cancro (AIRC), IG 2012-13157, Fondazione Ricerca Traslazionale (FoRT) and Istituto Toscano Tumori (ITT) 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.

4.

Sharma SV, Settleman J. Oncogene addiction: setting the stage for molecularly targeted cancer therapy. Genes Dev 2007;21:3214-31

5.

Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-39

6.

Paez JG, Ja¨nne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-500

7.

Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from “never


smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 2004;101:13306-11 8.

Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-57

9.

Han JY, Park K, Kim SW, et al. Firstsignal: first-line single-agent Iressa versus gemcitabine and cisplatin trial in neversmokers with adenocarcinoma of the lung. J Clin Oncol 2012;30:1122-8

10.

Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small cell lung cancer harbouring mutations of the

2595


epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010;11:121-8 11.


12.

13.

14.

15.

16.

..

17.

18.

2596

Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380-8 Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as firstline treatment for patients with advanced EGFR mutation-positive non-small- cell lung cancer (OPTIMAL, CTONG0802): a multicentre,open-label, randomised, phase 3 study. Lancet Oncol 2011;12:735-42 Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutationpositive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239-46 Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2012;31:3327-34 Wu YL, Zhou C, Hu CP, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUXLung 6): an open-label, randomised phase 3 trial. Lancet Oncol 2014;15:213-22 Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007;448:561-6 The first evidence in literature of anaplastic lymphoma kinase (ALK)translocation in NSCLC. Yamazaki S, Vicini P, Shen Z, et al. Pharmacokinetic/pharmacodynamic modeling of crizotinib for anaplastic lymphoma kinase inhibition and antitumor efficacy in human tumor xenograft mouse models. J Pharmacol Exp Ther 2012;340:549-57 Cappuzzo F, Varella-Garcia ML, Shigematsu H, et al. Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive

non-small-cell lung cancer patients. J Clin Oncol 2005;23:5007-18 19.

20.

21.

22.

23.

24.

Cappuzzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 2005;97:643-55 Cappuzzo F, Bemis L, Varella-Garcia ML, et al. HER2 mutation and response to trastuzumab therapy in non-small-cell lung cancer. N Engl J Med 2006;354:2619-21 Soda M, Takada S, Takeuchi K, et al. A mouse model for EML4-ALK-positive lung cancer. Proc Natl Acad Sci USA 2008;105:19893-7 Ou SH. Crizotinib a novel and first in class multitargeted tyrosine kinase inhibitor for the treatment of anaplastic lymphoma kinase rearranged non-small cell lung cancer and beyond. Drug Des Devel Ther 2011;5:471-85 Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363:1693-703 Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol 2012;13:1011-19

25.

Kim D-W, Ahn MJ, Shi Y, et al. Results of a global phase II study with crizotinib in advanced ALK positive non-small cell lung cancer. J Clin Oncol 2012;30(Suppl):abstract 7533

26.

Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368:2385-94 First demonstration of superiority of crizotinib over chemotherapy in pretreated ALK positive NSCLC.

..

27.

..

Mok T, Kim D-W, Wu Y-L, et al. First-line crizotinib versus pemetrexed--cisplatin or pemetrexed--carboplatin in patients (pts) with advanced ALK-positive nonsquamous non-small cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014). J Clin Oncol 2014;32(Suppl):abstract 8002 First demonstration of superiority of crizotinib over standard platinumbased chemotherapy in untreated ALK positive NSCLC. Expert Opin. Pharmacother. (2014) 15(17)

28.

Chin LP, Soo RA, Soong R, et al. Targeting ROS1 with anaplastic lymphoma kinase inhibitors: a promising therapeutic strategy for a newly defined molecular subset of non-small-cell lung cancer. J Thorac Oncol 2012;7:1625-30

29.

Ou S, Camidge R, Engelman J, et al. Clinical activity of crizotinib in patients with advanced non- small cell lung cancer (NSCLC) harboring ROS1 gene rearrangement. Ann Oncol 2012;23(Suppl):2091a First demonstration of activity of crizotinib in ROS1 translocated NSCLC.

.

30.

Awad MM, Katayama R, McTigue M, et al. Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med 2013;368:2395-401

31.

Camidge DR, Ou S-H I, Shapiro G, et al. Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer (NSCLC). J Clin Oncol 2014;32(Suppl):abstract 8001

32.

Cui JJ, Tran-Dube M, Shen H, et al. Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem 2011;54:6342-63

33.

Tanizaki J, Okamoto I, Okamoto K, et al. MET tyrosine kinase inhibitor crizotinib (PF-02341066) shows differential antitumor effects in non-small cell lung cancer according to MET alterations. J Thorac Oncol 2011;6:1624-31

34.

Christensen JG, Zou HY, Arango ME, et al. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther 2007;6:3314-22

35.

Kwak EL, Camidge DR, Clark J, et al. Clinical activity observed in a phase I dose escalation trial of an oral anti c-met and ALK inhibitor, PF-02341066. J Clin Oncol 2009;27(15 Suppl):abstract 3509

36.

Tan W, Wilner KD, Bang Y, et al. Pharmacokinetics (PK) of PF-02341066, a dual ALK/MET inhibitor after multiple oral doses to advanced cancer patients. J Clin Oncol 2010;28(Suppl 15):abstract 2596

Crizotinib

37.


38.

39.

40.

41.

42.

43.

44.

Xu H, O’Gorman M, Boutros T, et al. Evaluation of crizotinib absolute bioavailability, the bioequivalence of three oral formulations, and the effect of food on crizotinib pharmacokinetics in healthy subjects. J Clin Pharmacol 2014. [Epub ahead of print] Ou SH, Kwak EL, Siwak-Tapp C, et al. Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification. J Thorac Oncol 2011;6:942-6 Lennerz JK, Kwak EL, Ackerman A, et al. MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib. J Clin Oncol 2011;29:4803-10 Chi AS, Batchelor TT, Kwak EL, et al. Radiographic and clinical improvement after treatment of a MET-amplified recurrent glioblastoma with a mesenchymal-epithelial transition inhibitor. J Clin Oncol 2012;30:e30-3 Pfizer, Inc. EU Xalkori (crizotinib) Summary of product characteristics. 2014. Available from: http://www.ema. europa.eu/docs/enGB/documentlibrary/ EPAR-product information/human/ 002489/WC500134759.pdf [Accessed 13 April 2014] Weickhardt AJ, Doebele RC, Purcell WT, et al. Symptomatic reduction in free testosterone levels secondary to criotinib use in male cancer patients. Cancer 2013;119:2383-90 Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. J Clin Oncol 2013;31:1105-11 Camidge DR, Doebele RC. Targeting ALK-positive lung cancer -- early succes and future challenges. Nat Rev Clin Oncol 2012;9:268-77

45.

Camidge DR, Pao W, Sequist L. Acquired resistance to TKIs in solid tumors: learning from lung cancer. Nat Rev Clin Oncol 2014;11(8):473-81

46.

Katayama R, Shaw AT, Khna TM, et al. Mechanisms of acquired crizotinib resistance in ALK rearranged lung cancers. Sci Transl Med 2012;4:120ra17

47.

..

48.

49.

50.

51.

52.

Choi YL, Soda M, Yamashita Y, et al. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med 2010;363:1734-9 First evidence in literature of secondary ALK mutations as mechanism of acquired resistance to crizotinib. Sasaki T, Okuda K, Zheng W, et al. The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers. Cancer Res 2010;70:10038-43 Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205-16 Pop O, Pirvu A, Toffart AC, et al. Disease flare after treatment discontinuation in a patient with EML4ALK lung cancer and acquired resistance to crizotinib. J Thorac Oncol 2012;8:e1-8 Kuriyama Y, Kim YH, Nagai H, et al. Disease flare after discontinuation of crizotinib in anaplastic lymphoma Kinase positive lung cancer. Case Rep Oncol 2013;6:430-3 Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol 2012;7:1807-14


53.

Ou SH, Janne PA, Bartlett CH, et al. Clinical benefit of continuing ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK-positive NSCLC. Ann Oncol 2014;25:415-22

54.

Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 2014;370:1189-97

55.

Ou S, Gadgeel S, Chiappori A, et al. Safety and efficacy analysis of RO5424802/CH5424802 in anaplastic lymphoma kinase (ALK)-positive nonsmall cell lung cancer (NSCLC) patients who have failed crizotinib in a dosefinding phase I study (AF-002JG, NCT01588028). Eur J Cancer 2013;49(Suppl 3):s19

56.

Mazieres J, Zalcman G, Crino L, et al. Efficacy of crizotinib in ROS1-rearranged lung cancer: the European experience. J Clin Oncol 32(Suppl):abstract 11035

57.

Johnson DH, Schiller JH. Recent clinical advances in lung cancer management. J Clin Oncol 2014;32:973-82

58.

Palmer RH, Vernesson E, Grabbe C, et al. Anaplastic lymphoma kinase protein: signalling in development and disease. Biochem J 2009;420:345-61

59.

Pulford K, Morris SW, Turturro F, et al. Anaplastic lymphoma kinase proteins in growth control and cancer. J Cell Physiol 2004;199:330-58

Affiliation

Lorenza Landi & Federico Cappuzzo† MD † Author for correspondence Istituto Toscano Tumori, Medical Oncology Department, Ospedale Civile, viale Alfieri 36, 57100 Livorno, Italy Tel: +39 0586223189; Fax: +39 0586223457; E-mail: [email protected]

2597

ALK-driven tumors and targeted therapy: focus on crizotinib.

New modalities of cancer treatment for NSCLC: focus on immunotherapy.

First-line crizotinib shows promise in patients with NSCLC.

MET-Mutated NSCLC with Major Response to Crizotinib.

Focus on Nintedanib in NSCLC and Other Tumors.

Residents focus on fatigue management.

Management of vestibular schwannoma: focus on vertigo.

Efficacy of crizotinib and pemetrexed-based chemotherapy in Chinese NSCLC patients with ROS1 rearrangement.

A safety assessment of crizotinib in the treatment of ALK-positive NSCLC patients.

Patient Dose Management: Focus on Practical Actions.

Epilepsy during pregnancy: focus on management strategies.

Ceritinib in patients with advanced, crizotinib-treated, anaplastic lymphoma kinase-rearranged NSCLC: Japanese subset.

Management of atrial fibrillation: focus on the role of dronedarone.

Management of autoimmune hepatitis: Focus on pharmacologic treatments beyond corticosteroids.

Management of acute hyperglycemic emergencies: focus on diabetic ketoacidosis.

Treatment of psoriasis: focus on clinic-based management with infliximab.

PCSK9 inhibition in the management of hyperlipidemia: focus on evolocumab.

Contemporary management of uterine fibroids: focus on emerging medical treatments.

Retargeting the management of hypercholesterolemia - focus on evolocumab.

Management of Patients with Atrial Fibrillation: Focus on Treatment Options.

Management Strategies in Advanced Uterine Leiomyosarcoma: Focus on Trabectedin.

Focus on treatment complications and optimal management surgery.

Focus on treatment complications and optimal management: radiation oncology.

Activity of crizotinib over choroidal metastases in non-small-cell lung cancer (NSCLC)-ALK rearranged: a case report.