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ALK inhibitors in non-small cell lung cancer: the latest evidence and developments:

ALK inhibitors in non-small cell lung cancer: the latest evidence and developments: 617355 TAM0010.1177/1758834015617355Therapeutic Advances in Medical OncologyI Sullivan and D Planchard research-article2015 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol ALK inhibitors in non-small cell lung cancer: 2016, Vol. 8(1) 32 –47 DOI: 10.1177/ the latest evidence and developments © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ Ivana Sullivan and David Planchard journalsPermissions.nav Abstract: The treatment of patients with advanced non-small cell lung cancer (NSCLC) harbouring chromosomal rearrangements of ALK (anaplastic lymphoma kinase) was revolutionized by crizotinib, a small molecule inhibitor of ALK, ROS1 and MET. Unfortunately, the disease progressed within the first 12 months in most of the patients because of the development of crizotinib resistance in the majority of patients and the emergence of acquired resistance mutations in most of them. Many of them had been reported even before its approval leading to the rapid development of second-generation ALK inhibitors for crizotinib- resistant NSCLC. In the last few years, novel potent ALK inhibitors with promising results and a good toxicity profile have become available: ceritinib (LDK378), alectinib (RG7853/ AF-802/RO5424802/CH5424802), brigatinib (AP26113), entrectinib (RXDX-101, NMS-E628), PF-06463922, ASP3026, TSR-011, X-376/X-396 and CEP-28122/CEP-37440. Moreover, HSP90 (90 kDa heat shock protein) inhibitors have demonstrated clinical activity in patients with ALK+ NSCLC. This review focuses on the molecular and clinical properties of this new generation of ALK inhibitors under development in the clinic. Keywords: alectinib, ALK rearrangement, ceritinib, crizotinib, NSCLC, resistance Correspondence to: Introduction [Ullrich and Schlessinger, 1990], is encoded by David Planchard, MD, PhD Lung cancer is the most common cause of death the ALK gene on chromosome 2p23. ALK was Gustave Roussy – Medical Oncology, 114 rue Édouard from cancer worldwide. It is estimated to be first identified as part of the NPM-ALK onco- Vaillant, Villejuif 94805, responsible for nearly one in five deaths (1.59 genic fusion protein, resulting from the transloca- France david.planchard@igr.fr million deaths, 19.4% of total cancer deaths) in tion between chromosomes 2 and 5 (t[2;5] Ivana Sullivan, MD 2012 [Ferlay et  al. 2015]. Most lung cancers [p23;q35]) associated with anaplastic large cell Gustave Roussy – Medical (~90%) are non-small cell lung cancers lymphoma [Morris et al. 1994]. The same trans- Oncology, Villejuif, France (NSCLCs), which comprise a number of sub- location has also been described in Hodgkin lym- types driven by various activated oncogenes phoma [Orscheschek et  al. 1995]. Subsequently, [Ettinger et al. 2010; Larsen et al. 2011]. Recent a small inversion within chromosome 2p results advances in molecular profiling technologies have in the formation of a fusion gene comprising por- significantly enhanced the development of per- tions of the echinoderm microtubule-associated sonalised medicine, i.e. molecularly targeted ther- protein-like 4 (EML4) gene and the ALK gene apies based on individual genetic or protein which was identified in a resected adenocarci- profiles [Arnedos et  al. 2014; Meric-Bernstam noma specimen from a 62-year-old male smoker et  al. 2013]. Consequently, molecularly targeted [Soda et al. 2007]. ALK rearrangements occur in agents for NSCLC patients have become one of 3–7% of patients with NSCLC and are more the successful personalized cancer therapies common among patients with a never/light smok- [Cardarella and Johnson, 2013; Li et  al. 2013; ing history, adenocarcinoma histology, a younger Moreira and Thornton, 2012]. age, female gender and in tumours wild type for EGFR and KRAS [Koivunen et  al. 2008; Shaw Anaplastic lymphoma kinase (ALK), a member of et  al. 2009; Wong et  al. 2009; Takahashi et  al. the insulin receptor tyrosine kinase family (RTK) 2010; Camidge et  al. 2010]. These factors may 32 http://tam.sagepub.com I Sullivan and D Planchard help clinicians to identify high-risk populations develop crizotinib resistance within the first 12 for ALK testing. However, according to the months [Camidge et al. 2012]. International Association for the Study of Lung Cancer (IASLC) and the European Society for Medical Oncology (ESMO) guidelines all patients Limitations of crizotinib in ALK+ NSCLC with advanced-stage lung adenocarcinoma or tumours with an adenocarcinoma component, Primary or intrinsic resistance irrespective of clinical characteristics should be As mentioned before, initial response rates to cri- tested for ALK (see http://www.iaslc.org and zotinib are approximately 60% which suggests http://www.esmo.org). Furthermore, at least primary resistance in a significant proportion of 27 fusion variants have been identified according cases. Some preclinical data suggest that differ- to the specific chromosomal location of the gene ences in specific ALK fusion gene products may fusion [Sasaki et al. 2010]. partially account for heterogeneous treatment responses or probably false-positive genotyping The principles and practices of personalised can- due to the various techniques used to detect ALK cer therapy significantly influenced the acceler- rearrangements [Heuckmann et  al. 2012]. Also, ated approval of the first-generation ALK some ALK translocations may not generate func- inhibitor, crizotinib (Xalkori; PF-02341066; tional rearrangements in all patients. Pfizer), by the US Food and Drug Administration (FDA) in 2011 [Gerber and Minna, 2010; Ou, 2012] (see http://www.accessdata.fda.gov/drug- Secondary or acquired resistance satfda_docs/label/2011/202570s000lbl.pdf), and To date, the principal mechanisms of acquired cri- by the European Medicines Agency (EMA) in zotinib resistance include secondary resistance 2012 (see http://www.ema.europa.eu/docs/en_ mutations in the kinase domain of ALK, for exam- GB/document_library/EPAR__Summary_for_ ple L1196M, the ‘gate-keeper’ mutation and the the_public/human/002489/WC500134762.pdf). C1156Y mutation [Choi et al. 2010]. Many other Crizotinib is an oral, small molecule inhibitor tar- resistance mutations have been described [Sasaki geting ALK, ROS1 and MET tyrosine kinases et  al. 2011; Katayama et  al. 2012; Doebele et  al. [Bergethon et al. 2012; Kwak et al. 2010; Ou et al. 2012; Ignatius Ou et  al. 2014]. Moreover, copy 2011] which showed significant (~60%) overall number gains of the ALK fusion gene [Katayama response rates (ORRs) in single-arm phase I et  al. 2011] and bypass track activation involving [Kwak et al. 2010] and phase II trials [Crinò et al. NSCLC drivers such as EGFR, c-KIT and KRAS 2011]. The results of the PROFILE 1007 phase [Sasaki et al. 2011; Doebele et al. 2012; Katayama III trial confirmed significantly higher response et al. 2012] have been reported. rates and longer progression-free survival (PFS) with crizotinib (65% and 7.7 months, respec- Central nervous system (CNS) penetration of crizo- tively) compared with chemotherapy (20% and tinib and measurements of cerebrospinal fluid (CSF) 3.0 months, respectively) as second-line treat- concentrations of the drug have not been fully inves- ment for ALK+ NSCLC [Shaw et  al. 2013a]. tigated. Most small molecule TKIs, including crizo- Moreover, crizotinib has proved superior to tinib [Costa et al. 2011; Metro et al. 2015], imatinib standard first-line platinum/pemetrexed chemo- [Motl et  al. 2006], gefitinib [Jackman et  al. 2006] therapy in untreated advanced ALK+ NSCLC and erlotinib [Clarke et al. 2010] have been shown to (PROFILE 1014). The ORR was 74% in the cri- exhibit low CSF to plasma ratios. Consequently, the zotinib arm and 45% in the chemotherapy arm. CNS is a sanctuary site where ALK+ NSCLC can The PFS was significantly longer in the crizotinib disseminate [Gainor et al. 2013]. Despite the poten- arm: median 10.9 months versus 7.0 months tial control of CNS disease with crizotinib, ~50% of [Solomon et al. 2014]. No significant differences patients develop CNS metastases during treatment in OS were seen in both trials, potentially due to with this agent [Costa et al. 2015]. Many strategies the confounding effects of crossover. had been reported for the treatment of CNS disease: high-dose crizotinib [Kim et al. 2013] and high-dose Unfortunately, as seen with other targeted thera- pemetrexed combined with high-dose crizotinib pies, such as the first-generation epidermal [Gandhi et  al. 2013]. Some experts suggested that growth factor receptor (EGFR) inhibitors in isolated CNS progression could be treated with radi- EGFR-mutated NSCLC, despite initial major otherapy while continuing crizotinib [Takeda et  al. responses to crizotinib, the majority of patients 2013]. http://tam.sagepub.com 33 Therapeutic Advances in Medical Oncology 8(1) Table 1. Molecular characteristics of second-generation ALK inhibitors. Drugs Targets other Activity against Activity against Activity against Activity against other Lack of activity than ALK L1196M C1156Y G1202R crizotinib-resistant against resistance resistance resistance mutations resistance mutation mutation mutation mutations Ceritinib IGF-R1, InsR, Yes No No G1269A, I1171T, G1202R, ROS1 S1206Y, L1152R, F1174C F1174L, V1180L Alectinib LTK, GAK Yes Yes No G1269A, S1206Y, G1202R, L1152R, F1174L, V1180L, 1151T-ins I1171T Brigatinib ROS1, EGFR Yes Yes Yes G1269A, S1206Y, NA 1151T-ins, F1174C, I1171T, D1203N, E1210K, F1245C Entrectinib TrkA, TrkB, Yes Yes NA NA NA TrkC, ROS1 PF-06463922 ROS1 Yes NA Yes G1269A NA TSR-011 TrkA, TrkB, Yes NA NA NA NA TrkC ASP3026 ROS1, ACK Yes NA NA F1174L NA X-396 MET Yes Yes NA NA NA CEP-37440 FAK NA NA NA NA NA ALK, anaplastic lymphoma kinase; NA, not available. Next-generation ALK inhibitors samples from patients with crizotinib-resistant Second-generation ALK inhibitors were developed NSCLC, revealed that ceritinib potently inhibits to enhance anti-ALK activity, to overcome crizo- resistant mutations, and especially L1196M, tinib-resistant mutations and to improve activity in G1269A, I1171T and S1206Y mutations. How- CNS disease. The molecular characteristics of ever, ceritinib was not effective against G1202R these drugs are listed in Table 1. The second-genera- and F1174C crizotinib-resistant mutations tion ALK inhibitors in clinical use and in the advanced [Friboulet et  al. 2014]. The primary source of phase of development are listed in Table 2, and the clinical data was the first-in-human, multicentre, novel ALK inhibitors in the early phase of develop- single-arm ASCEND-1 trial [ClinicalTrials.gov ment are listed in Table 3. identifier: NCT01283516] of ceritinib in patients with ALK+ advanced tumours. A total of 59 patients were enrolled in the dose escalation ALK inhibitors in the clinic phase. The maximum tolerated dose (MTD) was Ceritinib (LDK378; Zykadia; Novartis). Ceritinib is 750 mg once daily and dose-limiting toxicity an oral, ATP-competitive, small molecule tyro- (DLT) events occurred in six patients during sine kinase inhibitor of ALK, 20-fold more potent cycle 1, at doses of 400 mg or more daily. These than crizotinib in terms of ALK selectivity [Fri- events included grade 3 diarrhoea (at a daily dose boulet et  al. 2014; Marsilje et  al. 2013]. In con- of ⩾600 mg), grade 3 vomiting (at 750 mg daily), trast to crizotinib, ceritinib does not inhibit MET grade 3 dehydration (at 600 mg daily), grade 3 kinase activity but it does inhibit the insulin-like elevated transaminases, grade 2 elevated alanine growth factor 1 receptor (IGF-R1), the insulin aminotransferase (ALT) levels (at 400 mg daily) receptor (InsR) and ROS1 [Shaw et al. 2013b]. In and grade 3 hypophosphatemia (at 400 mg daily). cell-based assays, ceritinib had an IC50 of 27– These toxicities were resolved after treatment dis- 35 nM against the EML4-ALK and NPM-ALK continuation. The trial was followed by an expan- fusion kinases. The IC50s for IGF-1R, InsR and sion phase and 71 additional patients were treated ROS1 were approximately 5-11-fold higher. with the MTD. The majority of patients (122/130 ALK+ cell line models of acquired resistance to patients) had advanced NSCLC and had previ- crizotinib, including cell lines derived from biopsy ously received cytotoxic chemotherapy. A total of 34 http://tam.sagepub.com I Sullivan and D Planchard http://tam.sagepub.com 35 Table 2. Characteristics of ALK inhibitors in clinical use and in advanced phase of development. Drug name Study Phase Population Comparator ORR PFS OS Most common grade 1–2 AEs name or (number of ClinicalTrial. patients) gov ID Crizotinib PROFILE III Platinum- Pemetrexed 65% (95% 7.7 versus 20.3 (95% CI 18.1– Visual disturbance (60%), 1007 based or docetaxel CI 58–72%) 3.0 months not reached) versus diarrhoea (60%), nausea (55%), [Shaw et al. chemotherapy versus 20% (HR, 0.49; 22.8 months (95% CI vomiting (47%), constipation 2013a] pretreated (95% CI 95% CI 18.6–not reached) (42%), aminotransferase elevation (n = 347) 14–26%; 0.37–0.64; (HR, 1.02; 95% CI (38%), oedema (31%), fatigue p < 0.001) p < 0.001) 0.68–1.54; p = 0.54) (27%) PROFILE III Previously Platinum 74% (95% 10.9 versus Median OS was not Visual disturbance (71%), 1014 untreated plus CI 67–81%) 7.0 months reached in either diarrhoea (61%), oedema (49%), [Solomon (n = 343) pemetrexed versus 45% (HR, 0.45; group (HR for death vomiting (46%), constipation et al. 2014] (95% CI 95% CI with crizotinib, 0.82; (43%), aminotransferase elevation 37–53%; 0.35–0.60; 95% CI 0.54–1.26; (36%) p < 0.001) p < 0.001) p = 0.36) Ceritinib ASCEND-1 I ALK+ No 58% (95% 7.0 months NA Nausea (82%), diarrhoea (75%), [Shaw et al. advanced CI 48–67%) (95% CI vomiting (65%), fatigue (47%), 2014a] tumours 5.6–9.5 increased ALT level (35%) (n = 130)* months) ASCEND-2 II Chemotherapy No 38.6% (95% NA NA Nausea (81.4%), diarrhoea (80%), [Mok et al. and crizotinib CI 30.5– vomiting (62.9%) 2015] pretreated 47.2%) (n = 140) ASCEND-3 II Crizotinib- No 63.7% (95% NA NA Diarrhoea (82.3%), nausea [Felip et al. naive CI 54.6– (74.2%), vomiting (66.9%) 2015] (n = 124) 72.2%) ASCEND-4 III Previously Platinum Ongoing trial untreated plus [ClinicalTrials.gov identifier: NCT01828099] pemetrexed ASCEND-5 III Platinum- Pemetrexed Ongoing trial based or docetaxel [ClinicalTrials.gov identifier: NCT01828112] chemotherapy and crizotinib pretreated ASCEND-7 II Five arms study to confirm the Ongoing trial efficacy in ALK+ CNS disease [ClinicalTrials.gov identifier: NCT02336451] (Continued) Therapeutic Advances in Medical Oncology 8(1) 36 http://tam.sagepub.com Table 2. (Continued) Drug name Study Phase Population Comparator ORR PFS OS Most common grade 1–2 AEs name or (number of ClinicalTrial. patients) gov ID Alectinib AF-001JP I/II ALK inhibitor No 93.5% (95% 2-year 2-year OS: 79% Dysgeusia (30%), increased AST [Seto et al. naïve CI 82.1– PFS: 76% (95% CI 63–89%) (28%), increased blood bilirubin 2013] ( n= 46) 98.6) (95% CI (28%), increased blood creatinine [Tamura et al. 60–86%) (26%), rash (26%), constipation 2014] (24%), increased ALT (22%) AF-002JG I/II Crizotinib No 55% NA NA Fatigue (30%), myalgia (17%), [Gadgeel pretreated peripheral oedema (15%) et al. 2014] (n = 47) NP28673 II Chemotherapy No 49.2% (95% 8.9 months NA Myalgia (17%), constipation (15%), [Ignatius Ou and crizotinib CI 40.0– (immature) fatigue (14%), asthenia (11%), et al. 2015] pretreated 58.4%) increased AST (10%) (n = 138) NP28761 II Chemotherapy No 47.8% (95% 6.3 months NA Constipation (36%), fatigue (30%), [Gandhi et al. and crizotinib CI 35.6– (immature) peripheral oedema (22%), myalgia 2015] pretreated 60.2%) (22%), increased AST (21%), blood (n = 87) CPK increased (21%), nausea (20%), diarrhoea (18%), increased ALT (18%) ALEX III Previously Crizotinib Ongoing trial untreated [ClinicalTrials.gov identifier: NCT02075840] Brigatinib NCT01449461 I/II ALK+ No 71% in 13.4 NA Nausea (52%), fatigue (42%), [Camidge advanced crizotinib- months in diarrhoea (40%) et al. 2015] tumours pretreated crizotinib- (n = 137; 79 and pretreated ALK+ NSCLC) 100% in group crizotinib- naive group ALTA II Crizotinib No Ongoing trial pretreated [ClinicalTrials.gov identifier: NCT02094573] *Results from 114 NSCLC patients treated with at least 400 mg of ceritinib daily. Study conducted in Japan. ORR and PFS data from 79 ALK+ NSCLC patients. AEs, adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confident interval; CPK, creatinine phosphokinase; HR, hazard ratio; ID, identifier; ORR, overall response rate; OS, overall survival; PFS, progression-free survival. I Sullivan and D Planchard Table 3. ALK inhibitors in early phase of development. Drug name Study name or Phase Most common grade 1–2 AEs ClinicalTrials.gov identifier Entrectinib NCT02097810 I/II Paraesthesia (42%) nausea (37%), myalgia (34%), asthenia (27%), dysgeusia (27%), vomiting (21%), arthralgia (19%), diarrhoea (19%) PF-06463922 NCT01970865 I/II Hypercholesterolemia (48%), peripheral oedema (23%) and peripheral neuropathy (21%) TSR-011 NCT02048488 I/II Fatigue (17.4%), constipation (15.9%), QTc prolongation (15.9%), diarrhoea (14.5%) and headache (13%) ASP3026 NCT01401504 I Fatigue (44%), vomiting (39%), nausea (37%), and constipation (24%) X-396 NCT01625234 I/II Rash (31%), nausea (31%), vomiting (29%), fatigue (26%), oedema (17%) and pruritus (11%) CEP-37440 NCT01922752 I NA CEP-28122 Preclinical NA AEs, adverse events; ID, identifier; NA, not available. 83/122 NSCLC patients (68%) were pretreated (crizotinib or alectinib) and 83 ALK inhibitor- with crizotinib. Among the 78 NSCLC patients naive patients. The ORRs were 56.4%, 72.3% treated with 750 mg of ceritinib daily, the overall and 61.8% and the median PFS was 18.4, 9.0 response rate (ORR) was 59% (46/78 patients; and 6.9 months in the group pretreated with an 95% confidence interval [CI] 47–70%). In the ALK inhibitor, ALK inhibitor-naive patients and subgroup of 80 NSCLC crizotinib-pretreated the overall population, respectively. The most patients, the median PFS was 6.9 months common grade ⩾3 AEs were elevated ALT/AST (95% CI 5.3–8.8 months) and 10.4 months (95% levels (29.8% and 9.8%, respectively), diarrhoea CI 4.6 to could not be estimated) in the 34 (5.9%), nausea (5.9%), fatigue (5.1%), anaemia NSCLC crizotinib-naive patients. The most com- (5.1%), vomiting (4.7%) and pneumonia (4.7%) mon grade ⩾3 adverse events (AEs) were elevated [Felip et al. 2014]. Regarding its activity in CNS ALT and aspartate aminotransferase levels (21% disease, 124 patients had brain metastases at and 11%, respectively), diarrhoea (7%) and ele- baseline: 28 patients pretreated with an ALK vated lipase levels (7%), all of which were revers- inhibitor and 8 patients in the ALK inhibitor- ible after ceritinib discontinuation [Shaw et  al. naive group had measurable brain lesions 2014a]. In April 2014, the FDA granted acceler- (MBLs). The intracranial ORRs were 36% (95% ated approval to ceritinib for the treatment of CI 19–56%) in patients pretreated with an ALK patients with ALK+ metastatic NSCLC with dis- inhibitor and 63% (95% CI 25–92%) in the ALK ease progression or who are intolerant to crizo- inhibitor-naive group [Shaw et al. 2014b]. tinib (see http://www.accessdata.fda.gov/ drugsatfda_docs/label/2014/205755lbl.pdf). In The preliminary results of two phase II single- February 2015, the EMA Committee for Medici- arm studies on ceritinib in patients with ALK+ nal Products for Human Use (CHMP) adopted a NSCLC were recently presented: the ASCEND-2 positive opinion, recommending the granting of a trial [ClinicalTrials.gov identifier: conditional marketing authorisation for ceritinib NCT01685060] in patients who had received in patients with advanced ALK+ NSCLC previ- cytotoxic chemotherapy (one to three lines, ously treated with crizotinib. including one platinum doublet) and had pro- gressed on crizotinib as the last therapy, and the The updated ASCEND-1 report on the evalua- ASCEND-3 trial in crizotinib-naive patients tion of the efficacy of ceritinib at a daily dose of [ClinicalTrials.gov identifier: NCT01685138]. 750 mg was recently presented. A total of 246 The first trial enrolled 140 patients, 71.4% with patients with ALK+ NSCLC were enrolled, brain metastases, 28% of whom had no prior including 163 pretreated with an ALK inhibitor brain radiation (BRT). The ORR was 38.6% http://tam.sagepub.com 37 Therapeutic Advances in Medical Oncology 8(1) Figure 1. Ongoing phase III (ASCEND-4) study design. AUC, area under the curve; BIRC, blinded independent review committee; CR, complete response; DCR, disease-control rate; DOR, duration of response; IHC, immunohistochemistry; INV, investigator; ORR, overall response rate; OS, overall survival; PD, progressive disease; PEM, pemetrexed; PFS, progression-free survival; PR, partial response; PRO, patient- reported outcomes; PS, performance status; SD, stable disease; TTR, time to response. (95% CI 30.5–47.2%). Regarding its activity in [ClinicalTrials.gov identifier: NCT02336451]. CNS disease, 20 patients had investigator- Two randomized phase III trials are currently assessed MBL at baseline. The intracranial ORR open to evaluate ceritinib versus first-line chemo- was 45% (95% CI 23.1–68.5%). The most com- therapy (ASCEND-4, Figure 1) and second-line mon AEs (mostly grade 1–2) were nausea chemotherapy (ASCEND-5). The primary end- (81.4%), diarrhoea (80%) and vomiting (62.9%), point of both studies is PFS [ClinicalTrials.gov and 7.9% patients discontinued treatment due to identifiers: NCT01828099 and NCT01828112, AEs, none of which were predominant [Mok et al. respectively]. Given the positive results obtained 2015]. The second trial enrolled 124 patients, from PROFILE 1014 where crizotinib has been 40.3% with brain metastases, 46% of whom had compared with platinum/pemetrexed chemother- no prior BRT. The ORR was 63.7% (95% CI apy in the first-line setting, today, chemotherapy 54.6–72.2%). Regarding its activity in CNS dis- is probably not the best control arm, so further ease, 10 patients had investigator-assessed MBL trials should be made with the choice of crizotinib at baseline. The intracranial ORR was 20% (95% as control arm. CI 2.5–55.6%). The most common AEs (mostly grade 1–2) were diarrhoea (82.3%), nausea Alectinib (RG7853/AF-802/RO5424802/CH5424802, (74.2%) and vomiting (66.9%), and 7.3% Chugai-Roche). Alectinib is a highly selective, patients discontinued treatment due to AEs, none ALK inhibitor with a median inhibitory concen- of which were predominant [Felip et  al. 2015]. tration of 1.9 nM for ALK activity. In addition, it Another phase II study aimed at evaluating the exerts activity against LTK and GAK. Preclinical efficacy and safety of ceritinib in patients with studies have shown that it is also active against ALK+ NSCLC metastatic to the brain and/or to crizotinib-resistant ALK mutations (L1196M, leptomeninges (ASCEND-7) is currently recruit- C1156Y and F1174L), but not against InsR, ing participants to confirm the efficacy of ceritinib IGF-R1 and ROS1 [Kinoshita et al. 2012; Saka- in patients with ALK+ CNS disease moto et  al. 2011]. Alectinib was granted 38 http://tam.sagepub.com I Sullivan and D Planchard breakthrough therapy designation (BTD) by the assessed (122 and 69 patients, respectively), treat- FDA in June 2013 for patients with ALK+ ment with alectinib resulted in ORRs of 49.2% NSCLC who progressed on crizotinib. Japan is (95% CI 40.0–58.4%) and 47.8% (95% CI 35.6– the first country to approve alectinib in patients 60.2%), respectively. Patients whose tumours with advanced ALK-rearranged NSCLC, based shrank in response to alectinib continued to on the results of the phase I/II AF-001JP trial tar- respond for a median of 11.2 and 7.5 months, geting patients with ALK+ NSCLC who had not respectively. For patients with baseline measur- previously been treated with crizotinib or other able CNS disease (34 and 16 patients, respec- ALK inhibitors. In the phase I study, 24 patients tively), the ORR was 55.9% (95% CI 37.9–72.8%), were treated with doses of 20–300 mg twice daily and 68.8% (95% CI 41.3–89.0%), including five (BID). No DLTs or grade 4 AEs were observed and two complete responses, respectively. The up to the highest dose; thus 300 mg BID was median PFS was 8.9 and 6.3 months (immature), selected as the recommended phase II dose. In respectively [Ignatius Ou et al. 2015; Gandhi et al. the phase II trial, 46 patients were treated and 43 2015]. In summary, alectinib has demonstrated a of them (93.5%) achieved an ORR (95% CI safety profile consistent with that observed in pre- 82.1–98.6). The most frequent alectinib-related vious studies and yielded a robust treatment AEs were grade 1 or 2 dysgeusia (30%), followed response, including excellent intracranial activity by elevated AST (28%), blood bilirubin (28%) in patients who had progressed on crizotinib and and blood creatinine (26%) levels, rash (26%), had also failed on prior chemotherapy. A phase III constipation (24%) and elevated ALT (22%). trial (ALEX, Figure 2) to evaluate the efficacy Grade 3 treatment-related AEs were recorded in and safety of alectinib 600 mg BID compared 26% of the patients, and the most common were with critozinib 250 mg BID in treatment-naive neutropenia and elevated creatine phosphokinase ALK+ advanced NSCLC patients is currently levels (4%). No grade 4 AEs or deaths were recruiting patients [ClinicalTrials.gov identifier: reported [Seto et  al. 2013]. The 2-year PFS rate NCT02075840]. was 76% (95% CI 60–86%) and the 2-year OS was 79% (95% CI 63–89%) [Tamura et al. 2014]. Moreover, alectinib has demonstrated antitumour Novel ALK inhibitors under clinical activity in ALK+ NSCLC patients resistant to development crizotinib, including those with CNS metastases. Brigatinib (AP26113, Ariad). Brigantinib is a novel A phase I/II trial conducted by Gadgeel and col- potent, orally available ALK inhibitor with an leagues enrolled a total of 47 ALK+ NSCLC IC50 of 0.62 nM in a cell-free assay and a demon- patients who progressed on or were intolerant to strated ability to overcome crizotinib resistance crizotinib. The ORR was assessable in 44/47 mutations, including G1202R and activity against patients and was 55% in 24/44 patients, including ROS1 (IC50 of 16–41 nM) [Zhang et  al. 2010; one complete response (CR) and 23 partial Squillace et al. 2013]. This compound also inhib- responses (PRs). A total of 16 patients (36%) had its mutant EGFR, including T790M [Rivera et al. stable disease. The subset analysis of 21 patients 2012]. An update of a phase I/II ongoing trial in with CNS metastases at baseline showed a disease advanced malignancies, including ALK+ control rate approximating 90%. In contrast with NSCLC, has been reported by Camidge and col- the previous trial, the recommended dose for leagues [ClinicalTrials.gov identifier: phase II studies was 600 mg BID [Gadgeel et  al. NCT01449461]. All patients received brigatinib 2014]. The results were recently confirmed by at total once-daily doses of 30–300 mg. Patients two clinical trials: the global NP28673 trial [Clin- were divided into three cohorts that received icalTrials.gov identifier: NCT01801111] con- 90 mg, 90–180 mg (escalating after 7 days) or ducted by Ignatius Ou and colleagues and the 180 mg. In the dose escalation phase, two DLTs North American NP28761 trial [ClinicalTrials. were observed, grade 3 ALT elevation at 240 mg gov identifier: NCT01871805] conducted by and grade 4 dyspnoea at 300 mg. The selected Gandhi and colleagues. These studies are phase II recommended phase II dose was 180 mg. Safety single-arm, open-label, multicentre trials evaluat- was evaluated in all 137 treated patients and effi- ing the safety and efficacy of alectinib 600 mg cacy in all 79 ALK+ NSCLC patients. Of 78 BID in 138 (from 16 countries) and 87 (from US evaluable ALK+ NSCLC patients, 58 (74%) and Canada) ALK+ NSCLC patients respec- responded: 50/70 (71%) pretreated with crizo- tively, whose disease progressed on crizotinib. In tinib and 8/8 (100%) crizotinib-naive patients. the response-evaluable population that was The median PFS was 13.4 months in the http://tam.sagepub.com 39 Therapeutic Advances in Medical Oncology 8(1) Figure 2. Ongoing phase III (ALEX) study design. BID, twice a day; CNS, central nervous system; DOR, duration of response; IHC, immunohistochemistry; INV, investigator; IRC, independent review committee; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PRO, patient-reported outcomes; PS, performance status. subgroup with prior crizotinib therapy, but not kinase inhibitor of the Trk family of tyrosine reached in crizotinib-naive patients. Of the kinases TrkA (coded by the NTRK1 gene), TrkB 79 ALK+ NSCLC patients, 52 (66%) had CNS (coded by the NTRK2 gene) and TrkC (coded by metastases identified at baseline: 17 had measur- the NTRK3 gene), ROS1 and ALK. Rearrange- able disease and 35 had only unmeasurable dis- ments in NTRK1 were recently described in ease. A total of 15/17 and 33/35 had at least one approximately 3% of NSCLC that were negative follow-up scan, respectively. A total of 8/15 (53%) for other oncogenic driver mutations [Vaishnavi with measurable CNS metastases achieved an et al. 2013]. Entrectinib has demonstrated in vitro intracranial response. The toxicity profile and in vivo antitumour activity against various described in all 137 patients was nausea (52%), TRK, ROS1 or ALK-driven xenograft models of fatigue (42%) and diarrhoea (40%) which were different human cancers (NPM-ALK-driven the most common (all grades). Grade ⩾3 treat- lymphoma and EML4-ALK-driven NSCLC), ment-related AEs included elevated lipase (9%), and has demonstrated oral bioavailability and dyspnoea (7%), hypertension (5%), hypoxia been observed to efficiently cross the blood–brain (5%), pneumonia (5%), elevated amylase (4%), barrier in mice with intracranially injected NCI- fatigue (4%), pulmonary embolism (3%), ele- H2228 EML4-ALK cells [Ardini et  al. 2009, vated ALT (2%), hyponatraemia (2%) and hypo- 2011]. Entrectinib is currently being evaluated in phosphatemia (2%) [Camidge et  al. 2015]. A two phase I/II clinical trials, ALKA-372-001 and pivotal phase II ALTA (ALK in Lung cancer Trial STARTRK-1 [ClinicalTrials.gov identifier: of AP26113) trial in patients with locally advanced NCT02097810]. In the First-in-Human Study or metastatic ALK+ NSCLC pretreated with ALKA-372-001, entrectinib is administered in crizotinib is currently enrolling new patients three different administration schedules. Sched- [ClinicalTrials.gov identifier: NCT02094573]. ule A (fasted, 4 days ‘on’ and 3 days ‘off’ for 3 weeks, 1 week rest) demonstrated significant Entrectinib (RXDX-101, NMS-E628, Ignyta). Entrec- antitumour activity [De Braud et  al. 2014]. An tinib is a novel, orally available, selective tyrosine update has recently been presented. They reported 40 http://tam.sagepub.com I Sullivan and D Planchard on the completion of schedule A and the other ORR was 44% (95% CI 27–62%). In the 25 two on-going schedules B (QD) and C (4 days patients evaluable for intracranial response, 14 of ‘on’ and 3 days ‘off ’). A total of 38 patients have whom had measurable disease, the ORR was 36% been enrolled, 65% (25 patients) of whom had (95% CI 18–58%). The most common treatment- NSCLC. Entrectinib was well tolerated. The related AEs were grade 1–2 hypercholesterolemia majority of the patients reported grade 1–2 AEs, (48%), peripheral oedema (23%) and peripheral including paraesthesia (42%) nausea (37%), neuropathy (21%). The only grade ⩾3 treatment- myalgia (34%), asthenia (27%), dysgeusia (27%), related AE was hypercholesterolemia (12%). One vomiting (21%), arthralgia (19%) and diarrhoea DLT occurred in a patient who received <16 of (19%). Asthenia and muscle weakness were the 21 planned 200 mg QD doses due to grade 1–2 grade 3 AEs observed at doses of 1200 mg/m cognitive effects [Shaw et al. 2015]. (schedule A) and 400 mg/m (schedule C), respec- tively, both reversible after dose reduction. No TSR-011 (Tesaro). TSR-011 is a potent, dual ALK DLTs were observed [De Braud et al. 2015]. The and TrkA, TrkB and TrkC inhibitor. TSR-011 has phase I portion of the second study, STARTRK-1, high affinity for wild-type recombinant ALK designed to evaluate escalating doses of entrec- kinase activity, with an IC50 value of 0.7 nM, and tinib administered in a continuous daily regimen exerts sustained potent inhibition of ALK-depen- (QD) was also recently presented. A total of dent tumour growth in mouse models. Tesaro is 29 patients were enrolled at four different dose evaluating TSR-011 in an ongoing phase I/IIa trial levels (100, 200, 400 and 800 mg/m2). Two DLTs [ClinicalTrials.gov identifier: NCT02048488]. occurred at a fixed dose of 800 mg/m2 (grade The results of the phase I were presented at the 3 cognitive impairment and grade 3 asthenia), then World Conference on Lung Cancer in 2013. A resolved upon study drug discontinuation [Patel total of 19 patients were enrolled and the most fre- et al. 2015]. Antitumour activity was reported in all quent malignancies were NSCLC, ovarian and 67 patients included in both studies. Among ALK pancreatic cancer. The preliminary data demon- inhibitor- or ROS1 inhibitor-naive patients strated disease control (SD + PR) at 8 weeks (n = 17), 10/11 (91%) patients treated at or above attained in 65% of the 17 evaluable patients. TSR- 400 mg/m2 achieved objective responses as early as 011 exerted antitumour activity in at least 2/3 cycle 1 with durable responses for up to 16 cycles. NSCLC ALK+ patients with dysaesthesia who These data support further development of entrec- had previously progressed on crizotinib. The tinib and 400 mg/m2 was the selected recom- reversible DLTs included and QTc prolongation mended phase II dose for the trials [ClinicalTrials. [Weiss et  al. 2013]. An update was recently pre- gov identifier: NCT02097810]. sented. A total of 69 patients with advanced can- cer, including 46 ALK+ NSCLC patients were PF-06463922 (Pfizer). PF-06463922 has been treated at total daily doses of 30–480 mg, adminis- identified as an orally available ATP-competitive tered one, two or three times a day. Responses selective, brain penetrant inhibitor of ALK were observed at a total daily dose of 120 mg or (including mutations) and the c-Ros oncogene more in 3/5 ALK inhibitor-naive patients (60%) 1 (ROS1). In in vitro and preclinical studies, and in 3/6 patients (50%) who had progressed PF06463922 is ∼10-fold potent against wild- after crizotinib as the only ALK inhibitor. Stable type EML4-ALK and ∼40-fold potent against disease as the best response was observed in the 3 EML4-ALK L1196M compared with crizotinib patients who progressed after ceritinib or alec- [Johnson et al. 2014]. An ongoing phase I/II trial tinib. The most common grade 1–2 AEs were [ClinicalTrials.gov identifier: NCT01970865] is fatigue (17.4%), constipation (15.9%), QTc pro- currently recruiting ALK+ or ROS1+ NSCLC longation (15.9%), diarrhoea (14.5%) and head- patients with or without CNS metastases, TKI- ache (13%). Grade ⩾3 treatment-related AEs naive or exhibiting disease progression after prior included fatigue (5.8%), anaemia (5.8%) and treatment with 1–2 TKIs. At ASCO 2015, Shaw QTc prolongation (4.3%) [Arkenau et al. 2015]. and colleagues presented the preliminary results of portion I of this study. As of the cut-off date ASP3026 (Astellas Pharma). ASP3026 is a selec- (20 April 2015), 33 ALK+ and 11 ROS1+ tive, potent, ATP-competitive, small molecule patients were enrolled across 7 once-daily (QD) oral inhibitor of ALK with an IC50 of 3.5 nM in dose levels and 3 BID dose levels. All 44 patients enzymatic assays and an IC50 of 64.8 nM in were evaluated for safety, 34 for overall tumour H2228 cells. This agent also exerts activity against response and 25 for intracranial response. The ROS1 (IC50 = 8.9 nM) and ACK, and against http://tam.sagepub.com 41 Therapeutic Advances in Medical Oncology 8(1) L1196M, the crizotinib-resistant gatekeeper in enzymatic assays). In preclinical studies, CEP- mutation. The compound was evaluated in an 28122 showed high selectivity against ALK among open-label, phase I, traditional 3+3 dose escala- various types of tyrosine kinases, including InsR, tion design in patients with solid tumours and/or IGF-R1 and c-MET [Cheng et  al. 2012]. CEP- B-cell lymphoma (ALK positivity not required) 37440 is an inhibitor of ALK and of focal adhesion [ClinicalTrials.gov identifier: NCT01401504]. A kinase (FAK). CEP-37440 is undergoing clinical total of 30 patients were included. The most com- development in phase I [ClinicalTrials.gov identi- mon AEs were fatigue (44%), vomiting (39%), fier: NCT01922752] in patients with advanced or nausea (37%) and constipation (24%). Grade metastatic solid tumours but no preliminary data 3 rash and elevation of AST and ALT were also are available. observed. The MTD is 525 mg/daily but the clini- cal activity has not yet been reported [Patnaik et  al. 2013]. The dose escalation phase finally HSP90 inhibitors enrolled 33 patients, including 3 ALK+ patients, HSP90 (90 kDa heat shock protein) is a molecu- and the expansion cohort enrolled another 13 lar chaperone that plays a central role in regulat- ALK+ patients (n = 46) to evaluate the activity of ing the correct folding, stability and function of AP3026 in this sub-population. Of 15 ALK+ numerous proteins [Taipale et  al. 2010]. NSCLC patients who progressed on prior crizo- Inhibition of HSP90 activity results in aggrega- tinib, 7 (44%) achieved a PR and 8 (50%) showed tion or proteasomal degradation of these proteins, stable disease as the best response. The median which in turn promotes the simultaneous disrup- PFS in the ALK+ patients was 5.9 months (95% tion of numerous oncogenic signalling pathways CI 3.8–9.4 months) [Maitland et al. 2014]. How- critical for tumour cell proliferation and survival ever, the company reported in February 2014 [Whitesell and Lindquist, 2005]. Many of these that it had discontinued the development of proteins are kinases that have been shown to be ASP3026 for strategic reasons. oncogenic drivers in subsets of lung adenocarci- noma, including EGFR, BRAF, HER2 and, X-376 and X-396 (Xcovery). X-376 and X-396 are notably, the EML4–ALK fusion protein. more potent inhibitors of ALK but less potent Targeting the chaperone function of HSP90 is inhibitors of MET compared with crizotinib, both therefore an alternative approach to direct kinase in biochemical and cell-based assays. Moreover, inhibition for therapeutic intervention in ALK- X-396 could potently inhibit ALK kinases engi- driven cancer. In early phase clinical trials, two neered with two point mutations (L1196M and HSP90 inhibitors, retaspimycin hydrochloride C1156Y) associated with acquired resistance to (IPI-504) and ganetespib (STA-9090) demon- crizotinib. Preclinical data also suggest that X-396 strated clinical activity in ALK+ NSCLC patients has the potential to overcome acquired resistance [Sequist et al. 2010; Normant et al. 2011; Socinski to crizotinib and exhibits CNS penetration [Lovly et al. 2013]. Preliminary data from a phase II trial et  al. 2011]. Preliminary results of the phase I/II of AUY922 (a highly potent, nongeldanamycin trial of X-396 showed antitumour control in both HSP90 inhibitor) in 121 patients with advanced crizotinib-naive (n = 5) and crizotinib-resistant NSCLC, previously treated and stratified by (n = 13) ALK+ NSCLC patients. For the 11 eval- molecular status, have been reported. Clinical uable ALK+ lung cancer patients, 6 achieved a activity was seen in patients with ALK+ and PR (55%) and 2 had SD (18%) as the best EGFR-mutated disease: a PR in 6/21 (29%) response. Responses were observed in crizotinib- ALK+ NSCLC patients. Of these six responders, naive and in crizotinib-pretreated NSCLC four were crizotinib-naive and two were crizo- patients. Responses have also been observed in tinib-pretreated patients. The estimated median 2 patients with brain metastases. The most common PFS rate was 42% at 18 weeks in ALK+ patients. grade 1–2 drug-related AEs included rash (31%), The most frequent AEs were grade 1–2 eye disor- nausea (31%), vomiting (29%), fatigue (26%), ders (77%), diarrhoea (74%) and nausea (46%) oedema (17%) and pruritus (11%) but grade 3–4 [Felip et al. 2012]. AEs were rare [Horn et  al. 2014]. The expansion phase in patients with ALK+ NSCLC is ongoing Several clinical trials are on-going to evaluate [ClinicalTrials.gov identifier: NCT01625234]. HSP90 inhibitors combined with ALK inhibitors. Crizotinib is combined with ganetespib in crizo- CEP-28122 and CEP-37440 (Teva). CEP-28122 is a tinib-naive patients [ClinicalTrials.gov identifier: potent and selective ALK inhibitor (IC50 = 1.9 nM NCT01579994], and two clinical trials are open 42 http://tam.sagepub.com I Sullivan and D Planchard to patients with crizotinib-resistant disease. In simultaneously granted a breakthrough therapy one of them, onalespib (AT13387), a HSP90 designation in this setting. Ipilimumab inhibitor is administered alone or combined with (Yervoy®), which targets the CTLA-4 check- crizotinib [ClinicalTrials.gov identifier: point on activated immune cells, was the first NCT01712217], and in the other trial, AUY922 treatment ever shown to extend survival in is combined with ceritinib [ClinicalTrials.gov patients with metastatic melanoma, and was identifier: NCT01772797]. approved for that indication in 2011. Based on the promising results of a phase II trial, it is now being tested in a phase III trial for NSCLC Conclusion and future perspectives [ClinicalTrials.gov identifier: NCT01285609]. Crizotinib has become a reference treatment for Combining immune checkpoint inhibition and ALK+ NSCLC patients, and a promising treat- ALK inhibitors may represent an opportunity to ment for tumours harbouring MET amplification improve efficacy in crizotinib-resistant NSCLC and ROS1 aberrations. Unfortunately, many patients. In this context, two early phase trials are patients develop acquired resistance during the ongoing: one to assess the safety and efficacy of first year of treatment and its efficacy is limited in ceritinib combined with nivolumab in patients CNS disease. Strategies are urgently needed to with pretreated ALK+ NSCLC [ClinicalTrials. overcome inherent and acquired resistance to gov identifier: NCT02393625] and the other one ALK inhibition. Today, several second-genera- is a modified phase I trial of ipilimumab com- tion ALK inhibitors under various stages of clini- bined with mutation-specific targeted therapy cal development have shown activity in (crizotinib or erlotinib) stratified for the presence crizotinib-resistant disease with promising activ- of ALK rearrangements or EGFR mutations ity in patients with CNS involvement, but resist- [ClinicalTrials.gov identifier: NCT01998126). ance to these compounds has also been described. Acknowledgement One of the greatest uncertainties currently facing The authors thank Lorna Saint Ange for editing. the research and oncology communities is: in what sequence should ALK TKIs be prescribed? Should Funding crizotinib be prescribed in first-line targeted ther- No sources of funding were used to assist with the apy and second-generation agents be reserved for preparation of this review. Dr I. Sullivan is a subsequent lines of treatment, or, is it better to recipient of the DUERTECC/EURONCO grant start with a more potent ALK inhibitor to achieve (Diplôme Universitaire Européen de Recherche a more profound and prolonged response dura- Translationnelle Et Clinique en Cancérologie) tion? To try to answer these questions, clinical tri- als with ceritinib [ClinicalTrials.gov identifier: Conflict of interest statement NCT01828099] and alectinib [ClinicalTrials.gov The author(s) declare(s) that there is no conflict identifier: NCT02075840] in crizotinib-naive of interest. patients are on-going but additional strategic stud- ies on therapeutic sequences are needed to help us References better select the best treatment sequences in Ardini, E., Menichincheri, M., Banfi, P., Saccardo, ALK+ NSCLC in the near future. M., Rusconi, L., Avanzi, N. et al. (2011) In vitro and in vivo activity of NMS-E628 against ALK mutations resistant to Xalkori. Mol Cancer Ther 10: A232. 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ALK inhibitors in non-small cell lung cancer: the latest evidence and developments:

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617355 TAM0010.1177/1758834015617355Therapeutic Advances in Medical OncologyI Sullivan and D Planchard research-article2015 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol ALK inhibitors in non-small cell lung cancer: 2016, Vol. 8(1) 32 –47 DOI: 10.1177/ the latest evidence and developments © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ Ivana Sullivan and David Planchard journalsPermissions.nav Abstract: The treatment of patients with advanced non-small cell lung cancer (NSCLC) harbouring chromosomal rearrangements of ALK (anaplastic lymphoma kinase) was revolutionized by crizotinib, a small molecule inhibitor of ALK, ROS1 and MET. Unfortunately, the disease progressed within the first 12 months in most of the patients because of the development of crizotinib resistance in the majority of patients and the emergence of acquired resistance mutations in most of them. Many of them had been reported even before its approval leading to the rapid development of second-generation ALK inhibitors for crizotinib- resistant NSCLC. In the last few years, novel potent ALK inhibitors with promising results and a good toxicity profile have become available: ceritinib (LDK378), alectinib (RG7853/ AF-802/RO5424802/CH5424802), brigatinib (AP26113), entrectinib (RXDX-101, NMS-E628), PF-06463922, ASP3026, TSR-011, X-376/X-396 and CEP-28122/CEP-37440. Moreover, HSP90 (90 kDa heat shock protein) inhibitors have demonstrated clinical activity in patients with ALK+ NSCLC. This review focuses on the molecular and clinical properties of this new generation of ALK inhibitors under development in the clinic. Keywords: alectinib, ALK rearrangement, ceritinib, crizotinib, NSCLC, resistance Correspondence to: Introduction [Ullrich and Schlessinger, 1990], is encoded by David Planchard, MD, PhD Lung cancer is the most common cause of death the ALK gene on chromosome 2p23. ALK was Gustave Roussy – Medical Oncology, 114 rue Édouard from cancer worldwide. It is estimated to be first identified as part of the NPM-ALK onco- Vaillant, Villejuif 94805, responsible for nearly one in five deaths (1.59 genic fusion protein, resulting from the transloca- France david.planchard@igr.fr million deaths, 19.4% of total cancer deaths) in tion between chromosomes 2 and 5 (t[2;5] Ivana Sullivan, MD 2012 [Ferlay et  al. 2015]. Most lung cancers [p23;q35]) associated with anaplastic large cell Gustave Roussy – Medical (~90%) are non-small cell lung cancers lymphoma [Morris et al. 1994]. The same trans- Oncology, Villejuif, France (NSCLCs), which comprise a number of sub- location has also been described in Hodgkin lym- types driven by various activated oncogenes phoma [Orscheschek et  al. 1995]. Subsequently, [Ettinger et al. 2010; Larsen et al. 2011]. Recent a small inversion within chromosome 2p results advances in molecular profiling technologies have in the formation of a fusion gene comprising por- significantly enhanced the development of per- tions of the echinoderm microtubule-associated sonalised medicine, i.e. molecularly targeted ther- protein-like 4 (EML4) gene and the ALK gene apies based on individual genetic or protein which was identified in a resected adenocarci- profiles [Arnedos et  al. 2014; Meric-Bernstam noma specimen from a 62-year-old male smoker et  al. 2013]. Consequently, molecularly targeted [Soda et al. 2007]. ALK rearrangements occur in agents for NSCLC patients have become one of 3–7% of patients with NSCLC and are more the successful personalized cancer therapies common among patients with a never/light smok- [Cardarella and Johnson, 2013; Li et  al. 2013; ing history, adenocarcinoma histology, a younger Moreira and Thornton, 2012]. age, female gender and in tumours wild type for EGFR and KRAS [Koivunen et  al. 2008; Shaw Anaplastic lymphoma kinase (ALK), a member of et  al. 2009; Wong et  al. 2009; Takahashi et  al. the insulin receptor tyrosine kinase family (RTK) 2010; Camidge et  al. 2010]. These factors may 32 http://tam.sagepub.com I Sullivan and D Planchard help clinicians to identify high-risk populations develop crizotinib resistance within the first 12 for ALK testing. However, according to the months [Camidge et al. 2012]. International Association for the Study of Lung Cancer (IASLC) and the European Society for Medical Oncology (ESMO) guidelines all patients Limitations of crizotinib in ALK+ NSCLC with advanced-stage lung adenocarcinoma or tumours with an adenocarcinoma component, Primary or intrinsic resistance irrespective of clinical characteristics should be As mentioned before, initial response rates to cri- tested for ALK (see http://www.iaslc.org and zotinib are approximately 60% which suggests http://www.esmo.org). Furthermore, at least primary resistance in a significant proportion of 27 fusion variants have been identified according cases. Some preclinical data suggest that differ- to the specific chromosomal location of the gene ences in specific ALK fusion gene products may fusion [Sasaki et al. 2010]. partially account for heterogeneous treatment responses or probably false-positive genotyping The principles and practices of personalised can- due to the various techniques used to detect ALK cer therapy significantly influenced the acceler- rearrangements [Heuckmann et  al. 2012]. Also, ated approval of the first-generation ALK some ALK translocations may not generate func- inhibitor, crizotinib (Xalkori; PF-02341066; tional rearrangements in all patients. Pfizer), by the US Food and Drug Administration (FDA) in 2011 [Gerber and Minna, 2010; Ou, 2012] (see http://www.accessdata.fda.gov/drug- Secondary or acquired resistance satfda_docs/label/2011/202570s000lbl.pdf), and To date, the principal mechanisms of acquired cri- by the European Medicines Agency (EMA) in zotinib resistance include secondary resistance 2012 (see http://www.ema.europa.eu/docs/en_ mutations in the kinase domain of ALK, for exam- GB/document_library/EPAR__Summary_for_ ple L1196M, the ‘gate-keeper’ mutation and the the_public/human/002489/WC500134762.pdf). C1156Y mutation [Choi et al. 2010]. Many other Crizotinib is an oral, small molecule inhibitor tar- resistance mutations have been described [Sasaki geting ALK, ROS1 and MET tyrosine kinases et  al. 2011; Katayama et  al. 2012; Doebele et  al. [Bergethon et al. 2012; Kwak et al. 2010; Ou et al. 2012; Ignatius Ou et  al. 2014]. Moreover, copy 2011] which showed significant (~60%) overall number gains of the ALK fusion gene [Katayama response rates (ORRs) in single-arm phase I et  al. 2011] and bypass track activation involving [Kwak et al. 2010] and phase II trials [Crinò et al. NSCLC drivers such as EGFR, c-KIT and KRAS 2011]. The results of the PROFILE 1007 phase [Sasaki et al. 2011; Doebele et al. 2012; Katayama III trial confirmed significantly higher response et al. 2012] have been reported. rates and longer progression-free survival (PFS) with crizotinib (65% and 7.7 months, respec- Central nervous system (CNS) penetration of crizo- tively) compared with chemotherapy (20% and tinib and measurements of cerebrospinal fluid (CSF) 3.0 months, respectively) as second-line treat- concentrations of the drug have not been fully inves- ment for ALK+ NSCLC [Shaw et  al. 2013a]. tigated. Most small molecule TKIs, including crizo- Moreover, crizotinib has proved superior to tinib [Costa et al. 2011; Metro et al. 2015], imatinib standard first-line platinum/pemetrexed chemo- [Motl et  al. 2006], gefitinib [Jackman et  al. 2006] therapy in untreated advanced ALK+ NSCLC and erlotinib [Clarke et al. 2010] have been shown to (PROFILE 1014). The ORR was 74% in the cri- exhibit low CSF to plasma ratios. Consequently, the zotinib arm and 45% in the chemotherapy arm. CNS is a sanctuary site where ALK+ NSCLC can The PFS was significantly longer in the crizotinib disseminate [Gainor et al. 2013]. Despite the poten- arm: median 10.9 months versus 7.0 months tial control of CNS disease with crizotinib, ~50% of [Solomon et al. 2014]. No significant differences patients develop CNS metastases during treatment in OS were seen in both trials, potentially due to with this agent [Costa et al. 2015]. Many strategies the confounding effects of crossover. had been reported for the treatment of CNS disease: high-dose crizotinib [Kim et al. 2013] and high-dose Unfortunately, as seen with other targeted thera- pemetrexed combined with high-dose crizotinib pies, such as the first-generation epidermal [Gandhi et  al. 2013]. Some experts suggested that growth factor receptor (EGFR) inhibitors in isolated CNS progression could be treated with radi- EGFR-mutated NSCLC, despite initial major otherapy while continuing crizotinib [Takeda et  al. responses to crizotinib, the majority of patients 2013]. http://tam.sagepub.com 33 Therapeutic Advances in Medical Oncology 8(1) Table 1. Molecular characteristics of second-generation ALK inhibitors. Drugs Targets other Activity against Activity against Activity against Activity against other Lack of activity than ALK L1196M C1156Y G1202R crizotinib-resistant against resistance resistance resistance mutations resistance mutation mutation mutation mutations Ceritinib IGF-R1, InsR, Yes No No G1269A, I1171T, G1202R, ROS1 S1206Y, L1152R, F1174C F1174L, V1180L Alectinib LTK, GAK Yes Yes No G1269A, S1206Y, G1202R, L1152R, F1174L, V1180L, 1151T-ins I1171T Brigatinib ROS1, EGFR Yes Yes Yes G1269A, S1206Y, NA 1151T-ins, F1174C, I1171T, D1203N, E1210K, F1245C Entrectinib TrkA, TrkB, Yes Yes NA NA NA TrkC, ROS1 PF-06463922 ROS1 Yes NA Yes G1269A NA TSR-011 TrkA, TrkB, Yes NA NA NA NA TrkC ASP3026 ROS1, ACK Yes NA NA F1174L NA X-396 MET Yes Yes NA NA NA CEP-37440 FAK NA NA NA NA NA ALK, anaplastic lymphoma kinase; NA, not available. Next-generation ALK inhibitors samples from patients with crizotinib-resistant Second-generation ALK inhibitors were developed NSCLC, revealed that ceritinib potently inhibits to enhance anti-ALK activity, to overcome crizo- resistant mutations, and especially L1196M, tinib-resistant mutations and to improve activity in G1269A, I1171T and S1206Y mutations. How- CNS disease. The molecular characteristics of ever, ceritinib was not effective against G1202R these drugs are listed in Table 1. The second-genera- and F1174C crizotinib-resistant mutations tion ALK inhibitors in clinical use and in the advanced [Friboulet et  al. 2014]. The primary source of phase of development are listed in Table 2, and the clinical data was the first-in-human, multicentre, novel ALK inhibitors in the early phase of develop- single-arm ASCEND-1 trial [ClinicalTrials.gov ment are listed in Table 3. identifier: NCT01283516] of ceritinib in patients with ALK+ advanced tumours. A total of 59 patients were enrolled in the dose escalation ALK inhibitors in the clinic phase. The maximum tolerated dose (MTD) was Ceritinib (LDK378; Zykadia; Novartis). Ceritinib is 750 mg once daily and dose-limiting toxicity an oral, ATP-competitive, small molecule tyro- (DLT) events occurred in six patients during sine kinase inhibitor of ALK, 20-fold more potent cycle 1, at doses of 400 mg or more daily. These than crizotinib in terms of ALK selectivity [Fri- events included grade 3 diarrhoea (at a daily dose boulet et  al. 2014; Marsilje et  al. 2013]. In con- of ⩾600 mg), grade 3 vomiting (at 750 mg daily), trast to crizotinib, ceritinib does not inhibit MET grade 3 dehydration (at 600 mg daily), grade 3 kinase activity but it does inhibit the insulin-like elevated transaminases, grade 2 elevated alanine growth factor 1 receptor (IGF-R1), the insulin aminotransferase (ALT) levels (at 400 mg daily) receptor (InsR) and ROS1 [Shaw et al. 2013b]. In and grade 3 hypophosphatemia (at 400 mg daily). cell-based assays, ceritinib had an IC50 of 27– These toxicities were resolved after treatment dis- 35 nM against the EML4-ALK and NPM-ALK continuation. The trial was followed by an expan- fusion kinases. The IC50s for IGF-1R, InsR and sion phase and 71 additional patients were treated ROS1 were approximately 5-11-fold higher. with the MTD. The majority of patients (122/130 ALK+ cell line models of acquired resistance to patients) had advanced NSCLC and had previ- crizotinib, including cell lines derived from biopsy ously received cytotoxic chemotherapy. A total of 34 http://tam.sagepub.com I Sullivan and D Planchard http://tam.sagepub.com 35 Table 2. Characteristics of ALK inhibitors in clinical use and in advanced phase of development. Drug name Study Phase Population Comparator ORR PFS OS Most common grade 1–2 AEs name or (number of ClinicalTrial. patients) gov ID Crizotinib PROFILE III Platinum- Pemetrexed 65% (95% 7.7 versus 20.3 (95% CI 18.1– Visual disturbance (60%), 1007 based or docetaxel CI 58–72%) 3.0 months not reached) versus diarrhoea (60%), nausea (55%), [Shaw et al. chemotherapy versus 20% (HR, 0.49; 22.8 months (95% CI vomiting (47%), constipation 2013a] pretreated (95% CI 95% CI 18.6–not reached) (42%), aminotransferase elevation (n = 347) 14–26%; 0.37–0.64; (HR, 1.02; 95% CI (38%), oedema (31%), fatigue p < 0.001) p < 0.001) 0.68–1.54; p = 0.54) (27%) PROFILE III Previously Platinum 74% (95% 10.9 versus Median OS was not Visual disturbance (71%), 1014 untreated plus CI 67–81%) 7.0 months reached in either diarrhoea (61%), oedema (49%), [Solomon (n = 343) pemetrexed versus 45% (HR, 0.45; group (HR for death vomiting (46%), constipation et al. 2014] (95% CI 95% CI with crizotinib, 0.82; (43%), aminotransferase elevation 37–53%; 0.35–0.60; 95% CI 0.54–1.26; (36%) p < 0.001) p < 0.001) p = 0.36) Ceritinib ASCEND-1 I ALK+ No 58% (95% 7.0 months NA Nausea (82%), diarrhoea (75%), [Shaw et al. advanced CI 48–67%) (95% CI vomiting (65%), fatigue (47%), 2014a] tumours 5.6–9.5 increased ALT level (35%) (n = 130)* months) ASCEND-2 II Chemotherapy No 38.6% (95% NA NA Nausea (81.4%), diarrhoea (80%), [Mok et al. and crizotinib CI 30.5– vomiting (62.9%) 2015] pretreated 47.2%) (n = 140) ASCEND-3 II Crizotinib- No 63.7% (95% NA NA Diarrhoea (82.3%), nausea [Felip et al. naive CI 54.6– (74.2%), vomiting (66.9%) 2015] (n = 124) 72.2%) ASCEND-4 III Previously Platinum Ongoing trial untreated plus [ClinicalTrials.gov identifier: NCT01828099] pemetrexed ASCEND-5 III Platinum- Pemetrexed Ongoing trial based or docetaxel [ClinicalTrials.gov identifier: NCT01828112] chemotherapy and crizotinib pretreated ASCEND-7 II Five arms study to confirm the Ongoing trial efficacy in ALK+ CNS disease [ClinicalTrials.gov identifier: NCT02336451] (Continued) Therapeutic Advances in Medical Oncology 8(1) 36 http://tam.sagepub.com Table 2. (Continued) Drug name Study Phase Population Comparator ORR PFS OS Most common grade 1–2 AEs name or (number of ClinicalTrial. patients) gov ID Alectinib AF-001JP I/II ALK inhibitor No 93.5% (95% 2-year 2-year OS: 79% Dysgeusia (30%), increased AST [Seto et al. naïve CI 82.1– PFS: 76% (95% CI 63–89%) (28%), increased blood bilirubin 2013] ( n= 46) 98.6) (95% CI (28%), increased blood creatinine [Tamura et al. 60–86%) (26%), rash (26%), constipation 2014] (24%), increased ALT (22%) AF-002JG I/II Crizotinib No 55% NA NA Fatigue (30%), myalgia (17%), [Gadgeel pretreated peripheral oedema (15%) et al. 2014] (n = 47) NP28673 II Chemotherapy No 49.2% (95% 8.9 months NA Myalgia (17%), constipation (15%), [Ignatius Ou and crizotinib CI 40.0– (immature) fatigue (14%), asthenia (11%), et al. 2015] pretreated 58.4%) increased AST (10%) (n = 138) NP28761 II Chemotherapy No 47.8% (95% 6.3 months NA Constipation (36%), fatigue (30%), [Gandhi et al. and crizotinib CI 35.6– (immature) peripheral oedema (22%), myalgia 2015] pretreated 60.2%) (22%), increased AST (21%), blood (n = 87) CPK increased (21%), nausea (20%), diarrhoea (18%), increased ALT (18%) ALEX III Previously Crizotinib Ongoing trial untreated [ClinicalTrials.gov identifier: NCT02075840] Brigatinib NCT01449461 I/II ALK+ No 71% in 13.4 NA Nausea (52%), fatigue (42%), [Camidge advanced crizotinib- months in diarrhoea (40%) et al. 2015] tumours pretreated crizotinib- (n = 137; 79 and pretreated ALK+ NSCLC) 100% in group crizotinib- naive group ALTA II Crizotinib No Ongoing trial pretreated [ClinicalTrials.gov identifier: NCT02094573] *Results from 114 NSCLC patients treated with at least 400 mg of ceritinib daily. Study conducted in Japan. ORR and PFS data from 79 ALK+ NSCLC patients. AEs, adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confident interval; CPK, creatinine phosphokinase; HR, hazard ratio; ID, identifier; ORR, overall response rate; OS, overall survival; PFS, progression-free survival. I Sullivan and D Planchard Table 3. ALK inhibitors in early phase of development. Drug name Study name or Phase Most common grade 1–2 AEs ClinicalTrials.gov identifier Entrectinib NCT02097810 I/II Paraesthesia (42%) nausea (37%), myalgia (34%), asthenia (27%), dysgeusia (27%), vomiting (21%), arthralgia (19%), diarrhoea (19%) PF-06463922 NCT01970865 I/II Hypercholesterolemia (48%), peripheral oedema (23%) and peripheral neuropathy (21%) TSR-011 NCT02048488 I/II Fatigue (17.4%), constipation (15.9%), QTc prolongation (15.9%), diarrhoea (14.5%) and headache (13%) ASP3026 NCT01401504 I Fatigue (44%), vomiting (39%), nausea (37%), and constipation (24%) X-396 NCT01625234 I/II Rash (31%), nausea (31%), vomiting (29%), fatigue (26%), oedema (17%) and pruritus (11%) CEP-37440 NCT01922752 I NA CEP-28122 Preclinical NA AEs, adverse events; ID, identifier; NA, not available. 83/122 NSCLC patients (68%) were pretreated (crizotinib or alectinib) and 83 ALK inhibitor- with crizotinib. Among the 78 NSCLC patients naive patients. The ORRs were 56.4%, 72.3% treated with 750 mg of ceritinib daily, the overall and 61.8% and the median PFS was 18.4, 9.0 response rate (ORR) was 59% (46/78 patients; and 6.9 months in the group pretreated with an 95% confidence interval [CI] 47–70%). In the ALK inhibitor, ALK inhibitor-naive patients and subgroup of 80 NSCLC crizotinib-pretreated the overall population, respectively. The most patients, the median PFS was 6.9 months common grade ⩾3 AEs were elevated ALT/AST (95% CI 5.3–8.8 months) and 10.4 months (95% levels (29.8% and 9.8%, respectively), diarrhoea CI 4.6 to could not be estimated) in the 34 (5.9%), nausea (5.9%), fatigue (5.1%), anaemia NSCLC crizotinib-naive patients. The most com- (5.1%), vomiting (4.7%) and pneumonia (4.7%) mon grade ⩾3 adverse events (AEs) were elevated [Felip et al. 2014]. Regarding its activity in CNS ALT and aspartate aminotransferase levels (21% disease, 124 patients had brain metastases at and 11%, respectively), diarrhoea (7%) and ele- baseline: 28 patients pretreated with an ALK vated lipase levels (7%), all of which were revers- inhibitor and 8 patients in the ALK inhibitor- ible after ceritinib discontinuation [Shaw et  al. naive group had measurable brain lesions 2014a]. In April 2014, the FDA granted acceler- (MBLs). The intracranial ORRs were 36% (95% ated approval to ceritinib for the treatment of CI 19–56%) in patients pretreated with an ALK patients with ALK+ metastatic NSCLC with dis- inhibitor and 63% (95% CI 25–92%) in the ALK ease progression or who are intolerant to crizo- inhibitor-naive group [Shaw et al. 2014b]. tinib (see http://www.accessdata.fda.gov/ drugsatfda_docs/label/2014/205755lbl.pdf). In The preliminary results of two phase II single- February 2015, the EMA Committee for Medici- arm studies on ceritinib in patients with ALK+ nal Products for Human Use (CHMP) adopted a NSCLC were recently presented: the ASCEND-2 positive opinion, recommending the granting of a trial [ClinicalTrials.gov identifier: conditional marketing authorisation for ceritinib NCT01685060] in patients who had received in patients with advanced ALK+ NSCLC previ- cytotoxic chemotherapy (one to three lines, ously treated with crizotinib. including one platinum doublet) and had pro- gressed on crizotinib as the last therapy, and the The updated ASCEND-1 report on the evalua- ASCEND-3 trial in crizotinib-naive patients tion of the efficacy of ceritinib at a daily dose of [ClinicalTrials.gov identifier: NCT01685138]. 750 mg was recently presented. A total of 246 The first trial enrolled 140 patients, 71.4% with patients with ALK+ NSCLC were enrolled, brain metastases, 28% of whom had no prior including 163 pretreated with an ALK inhibitor brain radiation (BRT). The ORR was 38.6% http://tam.sagepub.com 37 Therapeutic Advances in Medical Oncology 8(1) Figure 1. Ongoing phase III (ASCEND-4) study design. AUC, area under the curve; BIRC, blinded independent review committee; CR, complete response; DCR, disease-control rate; DOR, duration of response; IHC, immunohistochemistry; INV, investigator; ORR, overall response rate; OS, overall survival; PD, progressive disease; PEM, pemetrexed; PFS, progression-free survival; PR, partial response; PRO, patient- reported outcomes; PS, performance status; SD, stable disease; TTR, time to response. (95% CI 30.5–47.2%). Regarding its activity in [ClinicalTrials.gov identifier: NCT02336451]. CNS disease, 20 patients had investigator- Two randomized phase III trials are currently assessed MBL at baseline. The intracranial ORR open to evaluate ceritinib versus first-line chemo- was 45% (95% CI 23.1–68.5%). The most com- therapy (ASCEND-4, Figure 1) and second-line mon AEs (mostly grade 1–2) were nausea chemotherapy (ASCEND-5). The primary end- (81.4%), diarrhoea (80%) and vomiting (62.9%), point of both studies is PFS [ClinicalTrials.gov and 7.9% patients discontinued treatment due to identifiers: NCT01828099 and NCT01828112, AEs, none of which were predominant [Mok et al. respectively]. Given the positive results obtained 2015]. The second trial enrolled 124 patients, from PROFILE 1014 where crizotinib has been 40.3% with brain metastases, 46% of whom had compared with platinum/pemetrexed chemother- no prior BRT. The ORR was 63.7% (95% CI apy in the first-line setting, today, chemotherapy 54.6–72.2%). Regarding its activity in CNS dis- is probably not the best control arm, so further ease, 10 patients had investigator-assessed MBL trials should be made with the choice of crizotinib at baseline. The intracranial ORR was 20% (95% as control arm. CI 2.5–55.6%). The most common AEs (mostly grade 1–2) were diarrhoea (82.3%), nausea Alectinib (RG7853/AF-802/RO5424802/CH5424802, (74.2%) and vomiting (66.9%), and 7.3% Chugai-Roche). Alectinib is a highly selective, patients discontinued treatment due to AEs, none ALK inhibitor with a median inhibitory concen- of which were predominant [Felip et  al. 2015]. tration of 1.9 nM for ALK activity. In addition, it Another phase II study aimed at evaluating the exerts activity against LTK and GAK. Preclinical efficacy and safety of ceritinib in patients with studies have shown that it is also active against ALK+ NSCLC metastatic to the brain and/or to crizotinib-resistant ALK mutations (L1196M, leptomeninges (ASCEND-7) is currently recruit- C1156Y and F1174L), but not against InsR, ing participants to confirm the efficacy of ceritinib IGF-R1 and ROS1 [Kinoshita et al. 2012; Saka- in patients with ALK+ CNS disease moto et  al. 2011]. Alectinib was granted 38 http://tam.sagepub.com I Sullivan and D Planchard breakthrough therapy designation (BTD) by the assessed (122 and 69 patients, respectively), treat- FDA in June 2013 for patients with ALK+ ment with alectinib resulted in ORRs of 49.2% NSCLC who progressed on crizotinib. Japan is (95% CI 40.0–58.4%) and 47.8% (95% CI 35.6– the first country to approve alectinib in patients 60.2%), respectively. Patients whose tumours with advanced ALK-rearranged NSCLC, based shrank in response to alectinib continued to on the results of the phase I/II AF-001JP trial tar- respond for a median of 11.2 and 7.5 months, geting patients with ALK+ NSCLC who had not respectively. For patients with baseline measur- previously been treated with crizotinib or other able CNS disease (34 and 16 patients, respec- ALK inhibitors. In the phase I study, 24 patients tively), the ORR was 55.9% (95% CI 37.9–72.8%), were treated with doses of 20–300 mg twice daily and 68.8% (95% CI 41.3–89.0%), including five (BID). No DLTs or grade 4 AEs were observed and two complete responses, respectively. The up to the highest dose; thus 300 mg BID was median PFS was 8.9 and 6.3 months (immature), selected as the recommended phase II dose. In respectively [Ignatius Ou et al. 2015; Gandhi et al. the phase II trial, 46 patients were treated and 43 2015]. In summary, alectinib has demonstrated a of them (93.5%) achieved an ORR (95% CI safety profile consistent with that observed in pre- 82.1–98.6). The most frequent alectinib-related vious studies and yielded a robust treatment AEs were grade 1 or 2 dysgeusia (30%), followed response, including excellent intracranial activity by elevated AST (28%), blood bilirubin (28%) in patients who had progressed on crizotinib and and blood creatinine (26%) levels, rash (26%), had also failed on prior chemotherapy. A phase III constipation (24%) and elevated ALT (22%). trial (ALEX, Figure 2) to evaluate the efficacy Grade 3 treatment-related AEs were recorded in and safety of alectinib 600 mg BID compared 26% of the patients, and the most common were with critozinib 250 mg BID in treatment-naive neutropenia and elevated creatine phosphokinase ALK+ advanced NSCLC patients is currently levels (4%). No grade 4 AEs or deaths were recruiting patients [ClinicalTrials.gov identifier: reported [Seto et  al. 2013]. The 2-year PFS rate NCT02075840]. was 76% (95% CI 60–86%) and the 2-year OS was 79% (95% CI 63–89%) [Tamura et al. 2014]. Moreover, alectinib has demonstrated antitumour Novel ALK inhibitors under clinical activity in ALK+ NSCLC patients resistant to development crizotinib, including those with CNS metastases. Brigatinib (AP26113, Ariad). Brigantinib is a novel A phase I/II trial conducted by Gadgeel and col- potent, orally available ALK inhibitor with an leagues enrolled a total of 47 ALK+ NSCLC IC50 of 0.62 nM in a cell-free assay and a demon- patients who progressed on or were intolerant to strated ability to overcome crizotinib resistance crizotinib. The ORR was assessable in 44/47 mutations, including G1202R and activity against patients and was 55% in 24/44 patients, including ROS1 (IC50 of 16–41 nM) [Zhang et  al. 2010; one complete response (CR) and 23 partial Squillace et al. 2013]. This compound also inhib- responses (PRs). A total of 16 patients (36%) had its mutant EGFR, including T790M [Rivera et al. stable disease. The subset analysis of 21 patients 2012]. An update of a phase I/II ongoing trial in with CNS metastases at baseline showed a disease advanced malignancies, including ALK+ control rate approximating 90%. In contrast with NSCLC, has been reported by Camidge and col- the previous trial, the recommended dose for leagues [ClinicalTrials.gov identifier: phase II studies was 600 mg BID [Gadgeel et  al. NCT01449461]. All patients received brigatinib 2014]. The results were recently confirmed by at total once-daily doses of 30–300 mg. Patients two clinical trials: the global NP28673 trial [Clin- were divided into three cohorts that received icalTrials.gov identifier: NCT01801111] con- 90 mg, 90–180 mg (escalating after 7 days) or ducted by Ignatius Ou and colleagues and the 180 mg. In the dose escalation phase, two DLTs North American NP28761 trial [ClinicalTrials. were observed, grade 3 ALT elevation at 240 mg gov identifier: NCT01871805] conducted by and grade 4 dyspnoea at 300 mg. The selected Gandhi and colleagues. These studies are phase II recommended phase II dose was 180 mg. Safety single-arm, open-label, multicentre trials evaluat- was evaluated in all 137 treated patients and effi- ing the safety and efficacy of alectinib 600 mg cacy in all 79 ALK+ NSCLC patients. Of 78 BID in 138 (from 16 countries) and 87 (from US evaluable ALK+ NSCLC patients, 58 (74%) and Canada) ALK+ NSCLC patients respec- responded: 50/70 (71%) pretreated with crizo- tively, whose disease progressed on crizotinib. In tinib and 8/8 (100%) crizotinib-naive patients. the response-evaluable population that was The median PFS was 13.4 months in the http://tam.sagepub.com 39 Therapeutic Advances in Medical Oncology 8(1) Figure 2. Ongoing phase III (ALEX) study design. BID, twice a day; CNS, central nervous system; DOR, duration of response; IHC, immunohistochemistry; INV, investigator; IRC, independent review committee; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PRO, patient-reported outcomes; PS, performance status. subgroup with prior crizotinib therapy, but not kinase inhibitor of the Trk family of tyrosine reached in crizotinib-naive patients. Of the kinases TrkA (coded by the NTRK1 gene), TrkB 79 ALK+ NSCLC patients, 52 (66%) had CNS (coded by the NTRK2 gene) and TrkC (coded by metastases identified at baseline: 17 had measur- the NTRK3 gene), ROS1 and ALK. Rearrange- able disease and 35 had only unmeasurable dis- ments in NTRK1 were recently described in ease. A total of 15/17 and 33/35 had at least one approximately 3% of NSCLC that were negative follow-up scan, respectively. A total of 8/15 (53%) for other oncogenic driver mutations [Vaishnavi with measurable CNS metastases achieved an et al. 2013]. Entrectinib has demonstrated in vitro intracranial response. The toxicity profile and in vivo antitumour activity against various described in all 137 patients was nausea (52%), TRK, ROS1 or ALK-driven xenograft models of fatigue (42%) and diarrhoea (40%) which were different human cancers (NPM-ALK-driven the most common (all grades). Grade ⩾3 treat- lymphoma and EML4-ALK-driven NSCLC), ment-related AEs included elevated lipase (9%), and has demonstrated oral bioavailability and dyspnoea (7%), hypertension (5%), hypoxia been observed to efficiently cross the blood–brain (5%), pneumonia (5%), elevated amylase (4%), barrier in mice with intracranially injected NCI- fatigue (4%), pulmonary embolism (3%), ele- H2228 EML4-ALK cells [Ardini et  al. 2009, vated ALT (2%), hyponatraemia (2%) and hypo- 2011]. Entrectinib is currently being evaluated in phosphatemia (2%) [Camidge et  al. 2015]. A two phase I/II clinical trials, ALKA-372-001 and pivotal phase II ALTA (ALK in Lung cancer Trial STARTRK-1 [ClinicalTrials.gov identifier: of AP26113) trial in patients with locally advanced NCT02097810]. In the First-in-Human Study or metastatic ALK+ NSCLC pretreated with ALKA-372-001, entrectinib is administered in crizotinib is currently enrolling new patients three different administration schedules. Sched- [ClinicalTrials.gov identifier: NCT02094573]. ule A (fasted, 4 days ‘on’ and 3 days ‘off’ for 3 weeks, 1 week rest) demonstrated significant Entrectinib (RXDX-101, NMS-E628, Ignyta). Entrec- antitumour activity [De Braud et  al. 2014]. An tinib is a novel, orally available, selective tyrosine update has recently been presented. They reported 40 http://tam.sagepub.com I Sullivan and D Planchard on the completion of schedule A and the other ORR was 44% (95% CI 27–62%). In the 25 two on-going schedules B (QD) and C (4 days patients evaluable for intracranial response, 14 of ‘on’ and 3 days ‘off ’). A total of 38 patients have whom had measurable disease, the ORR was 36% been enrolled, 65% (25 patients) of whom had (95% CI 18–58%). The most common treatment- NSCLC. Entrectinib was well tolerated. The related AEs were grade 1–2 hypercholesterolemia majority of the patients reported grade 1–2 AEs, (48%), peripheral oedema (23%) and peripheral including paraesthesia (42%) nausea (37%), neuropathy (21%). The only grade ⩾3 treatment- myalgia (34%), asthenia (27%), dysgeusia (27%), related AE was hypercholesterolemia (12%). One vomiting (21%), arthralgia (19%) and diarrhoea DLT occurred in a patient who received <16 of (19%). Asthenia and muscle weakness were the 21 planned 200 mg QD doses due to grade 1–2 grade 3 AEs observed at doses of 1200 mg/m cognitive effects [Shaw et al. 2015]. (schedule A) and 400 mg/m (schedule C), respec- tively, both reversible after dose reduction. No TSR-011 (Tesaro). TSR-011 is a potent, dual ALK DLTs were observed [De Braud et al. 2015]. The and TrkA, TrkB and TrkC inhibitor. TSR-011 has phase I portion of the second study, STARTRK-1, high affinity for wild-type recombinant ALK designed to evaluate escalating doses of entrec- kinase activity, with an IC50 value of 0.7 nM, and tinib administered in a continuous daily regimen exerts sustained potent inhibition of ALK-depen- (QD) was also recently presented. A total of dent tumour growth in mouse models. Tesaro is 29 patients were enrolled at four different dose evaluating TSR-011 in an ongoing phase I/IIa trial levels (100, 200, 400 and 800 mg/m2). Two DLTs [ClinicalTrials.gov identifier: NCT02048488]. occurred at a fixed dose of 800 mg/m2 (grade The results of the phase I were presented at the 3 cognitive impairment and grade 3 asthenia), then World Conference on Lung Cancer in 2013. A resolved upon study drug discontinuation [Patel total of 19 patients were enrolled and the most fre- et al. 2015]. Antitumour activity was reported in all quent malignancies were NSCLC, ovarian and 67 patients included in both studies. Among ALK pancreatic cancer. The preliminary data demon- inhibitor- or ROS1 inhibitor-naive patients strated disease control (SD + PR) at 8 weeks (n = 17), 10/11 (91%) patients treated at or above attained in 65% of the 17 evaluable patients. TSR- 400 mg/m2 achieved objective responses as early as 011 exerted antitumour activity in at least 2/3 cycle 1 with durable responses for up to 16 cycles. NSCLC ALK+ patients with dysaesthesia who These data support further development of entrec- had previously progressed on crizotinib. The tinib and 400 mg/m2 was the selected recom- reversible DLTs included and QTc prolongation mended phase II dose for the trials [ClinicalTrials. [Weiss et  al. 2013]. An update was recently pre- gov identifier: NCT02097810]. sented. A total of 69 patients with advanced can- cer, including 46 ALK+ NSCLC patients were PF-06463922 (Pfizer). PF-06463922 has been treated at total daily doses of 30–480 mg, adminis- identified as an orally available ATP-competitive tered one, two or three times a day. Responses selective, brain penetrant inhibitor of ALK were observed at a total daily dose of 120 mg or (including mutations) and the c-Ros oncogene more in 3/5 ALK inhibitor-naive patients (60%) 1 (ROS1). In in vitro and preclinical studies, and in 3/6 patients (50%) who had progressed PF06463922 is ∼10-fold potent against wild- after crizotinib as the only ALK inhibitor. Stable type EML4-ALK and ∼40-fold potent against disease as the best response was observed in the 3 EML4-ALK L1196M compared with crizotinib patients who progressed after ceritinib or alec- [Johnson et al. 2014]. An ongoing phase I/II trial tinib. The most common grade 1–2 AEs were [ClinicalTrials.gov identifier: NCT01970865] is fatigue (17.4%), constipation (15.9%), QTc pro- currently recruiting ALK+ or ROS1+ NSCLC longation (15.9%), diarrhoea (14.5%) and head- patients with or without CNS metastases, TKI- ache (13%). Grade ⩾3 treatment-related AEs naive or exhibiting disease progression after prior included fatigue (5.8%), anaemia (5.8%) and treatment with 1–2 TKIs. At ASCO 2015, Shaw QTc prolongation (4.3%) [Arkenau et al. 2015]. and colleagues presented the preliminary results of portion I of this study. As of the cut-off date ASP3026 (Astellas Pharma). ASP3026 is a selec- (20 April 2015), 33 ALK+ and 11 ROS1+ tive, potent, ATP-competitive, small molecule patients were enrolled across 7 once-daily (QD) oral inhibitor of ALK with an IC50 of 3.5 nM in dose levels and 3 BID dose levels. All 44 patients enzymatic assays and an IC50 of 64.8 nM in were evaluated for safety, 34 for overall tumour H2228 cells. This agent also exerts activity against response and 25 for intracranial response. The ROS1 (IC50 = 8.9 nM) and ACK, and against http://tam.sagepub.com 41 Therapeutic Advances in Medical Oncology 8(1) L1196M, the crizotinib-resistant gatekeeper in enzymatic assays). In preclinical studies, CEP- mutation. The compound was evaluated in an 28122 showed high selectivity against ALK among open-label, phase I, traditional 3+3 dose escala- various types of tyrosine kinases, including InsR, tion design in patients with solid tumours and/or IGF-R1 and c-MET [Cheng et  al. 2012]. CEP- B-cell lymphoma (ALK positivity not required) 37440 is an inhibitor of ALK and of focal adhesion [ClinicalTrials.gov identifier: NCT01401504]. A kinase (FAK). CEP-37440 is undergoing clinical total of 30 patients were included. The most com- development in phase I [ClinicalTrials.gov identi- mon AEs were fatigue (44%), vomiting (39%), fier: NCT01922752] in patients with advanced or nausea (37%) and constipation (24%). Grade metastatic solid tumours but no preliminary data 3 rash and elevation of AST and ALT were also are available. observed. The MTD is 525 mg/daily but the clini- cal activity has not yet been reported [Patnaik et  al. 2013]. The dose escalation phase finally HSP90 inhibitors enrolled 33 patients, including 3 ALK+ patients, HSP90 (90 kDa heat shock protein) is a molecu- and the expansion cohort enrolled another 13 lar chaperone that plays a central role in regulat- ALK+ patients (n = 46) to evaluate the activity of ing the correct folding, stability and function of AP3026 in this sub-population. Of 15 ALK+ numerous proteins [Taipale et  al. 2010]. NSCLC patients who progressed on prior crizo- Inhibition of HSP90 activity results in aggrega- tinib, 7 (44%) achieved a PR and 8 (50%) showed tion or proteasomal degradation of these proteins, stable disease as the best response. The median which in turn promotes the simultaneous disrup- PFS in the ALK+ patients was 5.9 months (95% tion of numerous oncogenic signalling pathways CI 3.8–9.4 months) [Maitland et al. 2014]. How- critical for tumour cell proliferation and survival ever, the company reported in February 2014 [Whitesell and Lindquist, 2005]. Many of these that it had discontinued the development of proteins are kinases that have been shown to be ASP3026 for strategic reasons. oncogenic drivers in subsets of lung adenocarci- noma, including EGFR, BRAF, HER2 and, X-376 and X-396 (Xcovery). X-376 and X-396 are notably, the EML4–ALK fusion protein. more potent inhibitors of ALK but less potent Targeting the chaperone function of HSP90 is inhibitors of MET compared with crizotinib, both therefore an alternative approach to direct kinase in biochemical and cell-based assays. Moreover, inhibition for therapeutic intervention in ALK- X-396 could potently inhibit ALK kinases engi- driven cancer. In early phase clinical trials, two neered with two point mutations (L1196M and HSP90 inhibitors, retaspimycin hydrochloride C1156Y) associated with acquired resistance to (IPI-504) and ganetespib (STA-9090) demon- crizotinib. Preclinical data also suggest that X-396 strated clinical activity in ALK+ NSCLC patients has the potential to overcome acquired resistance [Sequist et al. 2010; Normant et al. 2011; Socinski to crizotinib and exhibits CNS penetration [Lovly et al. 2013]. Preliminary data from a phase II trial et  al. 2011]. Preliminary results of the phase I/II of AUY922 (a highly potent, nongeldanamycin trial of X-396 showed antitumour control in both HSP90 inhibitor) in 121 patients with advanced crizotinib-naive (n = 5) and crizotinib-resistant NSCLC, previously treated and stratified by (n = 13) ALK+ NSCLC patients. For the 11 eval- molecular status, have been reported. Clinical uable ALK+ lung cancer patients, 6 achieved a activity was seen in patients with ALK+ and PR (55%) and 2 had SD (18%) as the best EGFR-mutated disease: a PR in 6/21 (29%) response. Responses were observed in crizotinib- ALK+ NSCLC patients. Of these six responders, naive and in crizotinib-pretreated NSCLC four were crizotinib-naive and two were crizo- patients. Responses have also been observed in tinib-pretreated patients. The estimated median 2 patients with brain metastases. The most common PFS rate was 42% at 18 weeks in ALK+ patients. grade 1–2 drug-related AEs included rash (31%), The most frequent AEs were grade 1–2 eye disor- nausea (31%), vomiting (29%), fatigue (26%), ders (77%), diarrhoea (74%) and nausea (46%) oedema (17%) and pruritus (11%) but grade 3–4 [Felip et al. 2012]. AEs were rare [Horn et  al. 2014]. The expansion phase in patients with ALK+ NSCLC is ongoing Several clinical trials are on-going to evaluate [ClinicalTrials.gov identifier: NCT01625234]. HSP90 inhibitors combined with ALK inhibitors. Crizotinib is combined with ganetespib in crizo- CEP-28122 and CEP-37440 (Teva). CEP-28122 is a tinib-naive patients [ClinicalTrials.gov identifier: potent and selective ALK inhibitor (IC50 = 1.9 nM NCT01579994], and two clinical trials are open 42 http://tam.sagepub.com I Sullivan and D Planchard to patients with crizotinib-resistant disease. In simultaneously granted a breakthrough therapy one of them, onalespib (AT13387), a HSP90 designation in this setting. Ipilimumab inhibitor is administered alone or combined with (Yervoy®), which targets the CTLA-4 check- crizotinib [ClinicalTrials.gov identifier: point on activated immune cells, was the first NCT01712217], and in the other trial, AUY922 treatment ever shown to extend survival in is combined with ceritinib [ClinicalTrials.gov patients with metastatic melanoma, and was identifier: NCT01772797]. approved for that indication in 2011. Based on the promising results of a phase II trial, it is now being tested in a phase III trial for NSCLC Conclusion and future perspectives [ClinicalTrials.gov identifier: NCT01285609]. Crizotinib has become a reference treatment for Combining immune checkpoint inhibition and ALK+ NSCLC patients, and a promising treat- ALK inhibitors may represent an opportunity to ment for tumours harbouring MET amplification improve efficacy in crizotinib-resistant NSCLC and ROS1 aberrations. Unfortunately, many patients. In this context, two early phase trials are patients develop acquired resistance during the ongoing: one to assess the safety and efficacy of first year of treatment and its efficacy is limited in ceritinib combined with nivolumab in patients CNS disease. Strategies are urgently needed to with pretreated ALK+ NSCLC [ClinicalTrials. overcome inherent and acquired resistance to gov identifier: NCT02393625] and the other one ALK inhibition. 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Journal

Therapeutic Advances in Medical OncologySAGE

Published: Dec 18, 2015

Keywords: alectinib; ALK rearrangement; ceritinib; crizotinib; NSCLC; resistance

References