Accepted Manuscript ALK inhibitors: What is the best way to treat patients with ALK-positive NSCLC? Gouji Toyokawa , MD, PhD Takashi Seto , MD, PhD PII:
S1525-7304(14)00108-9
DOI:
10.1016/j.cllc.2014.05.001
Reference:
CLLC 277
To appear in:
Clinical Lung Cancer
Received Date: 16 February 2014 Revised Date:
9 April 2014
Accepted Date: 19 May 2014
Please cite this article as: Toyokawa G, Seto T, ALK inhibitors: What is the best way to treat patients with ALK-positive NSCLC?, Clinical Lung Cancer (2014), doi: 10.1016/j.cllc.2014.05.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Clinical Lung Cancer (Review article) ALK inhibitors: What is the best way to treat patients with ALK-positive NSCLC?
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Gouji Toyokawa, MD, PhD, Takashi Seto, MD, PhD
Department of Thoracic Oncology, National Kyushu Cancer Center, 3-1-1 Notame, Minami-ku,
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Fukuoka 811-1395, Japan
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Funding sources: None
Running title: Best way to treat ALK-positive NSCLC
Correspondence to: Takashi Seto
Department of Thoracic Oncology, National Kyushu Cancer Center, 3-1-1 Notame, Minami-ku,
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Fukuoka 811-1395, Japan
Tel.: +81 92 541 3231; Fax: +81 92 551 4585. E-mail address: [email protected]
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Number of words/characters in abstract and manuscript: 250 words/1739 characters (abstract)
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and 4488 words/29780 characters (manuscript)
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Clinical Lung Cancer Editorial Office
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Dear Editors,
Dr. Seto has received honorarium from Chugai Pharmaceutical Co., Ltd., and Eli Lilly Japan K.K.
and received research funding from Chugai Pharmaceutical Co., Ltd., Pfizer Japan Inc., and Novartis
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Pharma K.K. Dr. Toyokawa declares no conflict of interest.
Takashi Seto
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Sincerely,
Department of Thoracic Oncology, National Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka 811-1395, Japan
Tel.: +81 92 541 3231; Fax: +81 92 551 4585.
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E-mail address: [email protected]
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Abstract Genetic insight into the pathogenesis of lung cancer has paved the way for a new era in the treatment of lung cancer. Recently, ALK has been identified to exert a potent transforming effect via genetic
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rearrangement in patients with lung cancer. Pre-clinical and single-arm phase I studies have shown that patients with ALK-rearranged NSCLC can be successfully treated with crizotinib. Furthermore, a phase III randomized study indicated that crizotinib is superior to standard chemotherapy in the
treatment of NSCLC patients harboring the ALK rearrangement who had received one prior
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platinum-based chemotherapy. Despite the excellent efficacy of crizotinib in patients with
ALK-positive lung cancer, resistance mechanisms, such as secondary mutations in the ALK gene, the
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activation of other oncogenes and so on, have been identified to confer resistance to crizotinib. Second-generation ALK inhibitors, such as alectinib and ceritinib, have been shown to be effective not only in crizotinib-naïve patients, but also those resistant to crizotinib. Therefore, although some agents specifically targeting ALK have been developed and their efficacy has been documented, how ALK inhibitors should be administered in the setting of ALK-rearranged NSCLC remains to be fully
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elucidated. Can second-generation ALK inhibitors replace crizotinib? Is crizotinib just a first-generation ALK inhibitor? Is the sequential use of crizotinib and second-generation ALK inhibitors the best method? In this article, we review the pre-clinical and clinical results regarding crizotinib and second-generation ALK inhibitors, as well as the resistance mechanisms, and discuss
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the best methods for treating patients with ALK-positive NSCLC.
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Key words: Non-small cell lung cancer; anaplastic lymphoma kinase; ALK inhibitors; crizotinib; resistance mechanisms
Abbreviations
ALK, anaplastic lymphoma kinase; non-small cell lung cancer, NSCLC; EGFR, epidermal growth factor receptor; EML4, echinoderm microtubule-associated protein-like 4; CI, confidence interval; PFS, progression-free survival; OS, overall survival; AEs, adverse events; TKI, tyrosine kinase inhibitor; CNG, copy number gain; CNS, central nervous system; KRAS, Kirsten rat sarcoma viral
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oncogene homolog; KIT, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog; MET, met proto-oncogene; IGF1R, insulin-like growth factor 1 receptor; HSP90, heat shock protein 90; FISH, fluorescence in-situ hybridization; IHC, immunohistochemistry; RT-PCR, reverse
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transcriptase-polymerase chain reaction; IC50, half maximal inhibitory concentration.
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Introduction The incidence of cancer-related death is on the rise in most countries, with lung cancer being the leading cause of cancer death in many developed countries, including Japan. Although the treatment
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outcomes of lung cancer remain unsatisfactory, recent basic and clinical studies have identified lung cancer patients with disorders of oncogenes, such as EGFR1, ALK2 and so on3-6, which are
exclusively limited to the adenocarcinoma histology. These oncogenes have attracted much attention as being specifically targetable by kinase inhibitors7. It is therefore crucial to precisely examine
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genetic disorders when treating lung cancer patients.
Soda et al. reported that the ALK gene fuses with EML4, resulting in a potent transforming activity
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in NSCLC, and the growth stimulating effect was shown to depend on the dimerization of EML4-ALK through the basic domain of EML4. In concrete terms, EML4-ALK oligomerizes constitutively in cells through the coiled coil domain within the EML4 region, and becomes activated to exert marked oncogenicity via the aberrant activation of downstream signaling, such as Ras/MAPK, PI3K/AKT and JAK/STAT pathways8, 9. Importantly, the mice transduced with
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NIH3T3 cells forced to express the EML4-ALK fusion gene can be successfully treated with ALK inhibitors. Clinicopathological analyses have demonstrated that the frequency of patients with NSCLC harboring the EML4-ALK fusion gene is approximately 5%, and that this fusion gene is frequently observed in relatively younger patients, non- or light smokers and those with an
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adenocarcinoma histology without other genetic disorders10-12. Regarding histological characteristics, adenocarcinoma associated with the fusion gene often exhibits a mucinous cribriform pattern or
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signet-ring cell subtype3. With respect to the variant forms of the EML4-ALK fusion gene, 11 variants have been identified to date, most of which have been shown to harbor an oncogenic activity12. Although the data of Heuchman et al. showed differential responses to ALK inhibitors according to the EML4-ALK variant, whether these variants can predict the response to treatment with inhibitors remains unclear14. The kinesin family member 5B (KIF5B) and TRK-fused gene (TFG) genes have also been shown to be fusion partners with the ALK gene in patients with lung cancer15, 16. Crizotinib is a first-in-class ALK tyrosine kinase inhibitor and has been shown to be potent and
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well tolerable in ALK-positive NSCLC patients based on a single-arm study17, 18. More importantly, the superiority of crizotinib to standard chemotherapy has been demonstrated in the setting of advanced NSCLC associated with the ALK rearrangement in patients previously treated with
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platinum-based chemotherapy2. However, resistance mechanisms to crizotinib are major concerns when administering crizotinib in ALK-positive NSCLC patients19. Second-generation ALK inhibitors, such as alectinib and ceritinib, were recently shown to be effective not only in crizotinib-naïve patients, but also in those with acquired resistance to crizotinib20-23.
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Therefore, although the biology of patients with the ALK fusion gene has been clarified and some
ALK inhibitors have been developed and shown to specifically inhibit disease progression in
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patients with the ALK fusion gene, the best method for treating patients with ALK-positive NSCLC has yet to be determined. We herein review basic and clinical results regarding crizotinib and second-generation ALK inhibitors, as well as resista
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nce mechanisms, and discuss the best method for treating patients with ALK-positive NSCLC.
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ALK inhibitors Crizotinib-phase I and II trials Crizotinib (PF-02341066), which was originally developed as an inhibitor of c-MET, is an orally
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available small-molecule inhibitor of ALK tyrosine kinase24-26. Experimental models have documented the inhibitory effects of crizotinib on cell proliferation via the induction of apoptosis and G1-S phase cell cycle arrest in ALK-positive anaplastic large-cell lymphoma cells, but not ALK-negative lymphoma cells24, and the efficacy of crizotinib against NSCLC cell lines has also
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been demonstrated25. Crizotinib has recently attracted much attention, as c-ros oncogene 1, receptor tyrosine kinase (ROS1)-rearranged lung cancer may be successfully treated with this drug27.
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Importantly, a phase I dose-escalation trial evaluating crizotinib as an oral single agent in patients with advanced cancer and the second part of a phase I study that expanded the cohort of patients with ALK-translocated NSCLC showed a dramatic activity with good tolerability of crizotinib in patients with the ALK fusion gene (PROFILE 1001)17, 18. The data for the expanded cohort showed an objective response rate of 60.8% (95% CI 52.3−68.9) with a median PFS of 9.7 months (95% CI
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7.7−12.8)18. Although the median OS data were immature, the estimated OS at six and 12 months was as high as 87.9% (95% CI 81.3−92.3) and 74.8% (66.4−81.5), respectively. Treatment-related AEs of any grades were observed in 144 of 149 patients (97%), with visual disorders (64%), gastrointestinal side effects, such as nausea (56%), diarrhea (50%), vomiting (39%) and constipation
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(28%), peripheral edema (30%), dizziness (21%), fatigue (16%), increased alanine aminotransferase (12%), rash (11%), dysgeusia (11%) and increased aspartate aminotransferase (10%) being reported
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in at least 10% of the patients. The grade 3 or 4 AEs included neutropenia (6.0%), an elevated alanine aminotransferase level (4.0%), hypophosphatemia (4.0%) and lymphopenia (4.0%). Visual disturbances are uncommon side effects not seen with other TKIs, such as gefitinib and erlotinib, and the involvement of ALK in the development of the gut and visual system in other organisms might explain this AE28. An ongoing phase II study (PROFILE 1005) also showed an objective response rate and median PFS of 59.8% and 8.1 months, respectively29. The profile of AEs was comparable to that reported in the phase I trial. Based on the results of the phase I trial, crizotinib has been approved for use in patients with ALK-rearranged NSCLC in many countries, including Japan.
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Crizotinib-phase III trial Furthermore, a randomized phase III study (PROFILE 1007) was conducted worldwide to
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compare the efficacy of crizotinib to that of chemotherapy (pemetrexed or docetaxel) in patients with advanced ALK-positive lung cancer previously treated with platinum-based chemotherapy2.
Intriguingly, crizotinib treatment achieved a significantly longer PFS, which was the primary endpoint, than chemotherapy (7.7 versus 3.0 months, respectively). The objective response rates in
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the two arms were 65% and 20%, respectively, and the overall quality of life reported by the patients
themselves was significantly better in the crizotinib arm than in the chemotherapy arm. With regard
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to the OS, no significant differences were observed between the two arms, which was assumed to be due to the small number of events noted during the follow-up period and the cross-over in patients treated with chemotherapy to crizotinib as part of a separate study. Although two patients in the crizotinib arm died of interstitial lung disease, the profile of toxicity was tolerable. Therefore, crizotinib has become a standard regimen for second-line or beyond therapy in patients with
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ALK-positive lung cancer. An ongoing phase III study (PROFILE 1014) to compare crizotinib with cisplatin or carboplatin plus pemetrexed in the first-line setting will clarify the significance of crizotinib as a first-line treatment for ALK-rearranged NSCLC.
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Resistance mechanisms to crizotinib
Despite the excellent efficacy of crizotinib in the setting of ALK-positive lung cancer, almost all
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patients experience resistance to crizotinib, and various mechanisms conferring intrinsic or acquired resistance to crizotinib have been identified, as shown in Table 219. These mechanisms can be divided into two groups: ALK-dominant or ALK non-dominant. ALK-dominant mechanisms include second mutations in the ALK gene, CNG of the fusion gene and inadequate local drug penetration to the CNS. Choi and associates first reported two secondary mutations, i.e. L1196M and C1156Y, within the kinase domain of the EML4-ALK fusion gene in the same patient who acquired resistance to crizotinib five months after the administration of the reagent30. L1196M is a gatekeeper mutation that interferes with the binding of crizotinib, and, of note, this substitution corresponds to
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T315I in the BCR-ABL fusion gene31 and T790M in the EGFR gene32. Other resistance mutations in the ALK gene have been discovered in the clinical setting or in a mutagenesis screening, including L1152R, 1151Tins, G1202R, S1206Y, F1174C, D1203N, G1269A and L1196M19, 33, 34. With regard
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to CNG of the fusion gene, two of 11 ALK-positive lung cancer patients who acquired resistance to crizotinib were reported to exhibit new onset ALK CNG, which may occur in combination with
resistance mutations35. The method for achieving the optimal control of the CNS with crizotinib remains controversial, at present36-39. The known ALK non-dominant mechanisms leading to
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crizotinib-resistance are as follows: mutations of other oncogenes, such as the EGFR and KRAS genes34, amplification of the KIT gene40, increased autophosphorylation of EGFR40 and
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transformation to sarcomatoid carcinoma41. Some of these factors conferring resistance to crizotinib have been reported to exist with or without the ALK fusion gene. Although resistance mechanisms to second-generation ALK inhibitors have yet to be clarified, we previously reported a possible mechanism conferring resistance to alectinib via amplification of the MET gene, which can be overcome with crizotinib therapy (Figure 1A)42, 43. Second-generation ALK inhibitors, such as
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alectinib20, 44, 45 and ceritinib22, 23, 46, have been shown to be effective not only in crizotinib-naïve patients, but also those resistant to crizotinib. Other treatment strategies to overcome these mechanisms have been proposed, including the use of HSP90 inhibitors47, 48, and pemetrexed2, 49. With regard to the basic background of the administration of HSP90 inhibitors, such as 17-AAG, for
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ALK-rearranged lung cancer, it was previously shown that EML4-ALK is a client protein for HSP90, and preclinical studies showed that treatment of ALK-rearranged cell lines with HSP90 inhibitors
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resulted in the reduction of the protein levels of the ALK fusion, and led to inhibition of cell proliferation47. Importantly, an in vitro analysis showed that inhibition of HSP90 was shown to be effective against ALK-rearranged cell lines with acquired resistance to crizotinib47. Clinically, objective responses to ganetespib and AUY922 were reported in patients with crizotinib-resistant ALK-rearranged NSCLC50, 51. Chemotherapy is still considered to be important in the treatment of ALK-positive NSCLC. In particular, pemetrexed appears to be one of the effective chemotherapeutic agents, as shown in the PROFILE 1007 trial, where the median PFSs in patients who received pemetrexed or docetaxel were 4.2 and 2.6 months, respectively2. In the next section, we focus on the
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data regarding second-generation ALK inhibitors.
Second-generation ALK inhibitors
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Second-generation ALK inhibitors, such as alectinib, ceritinib and AP26133, are currently under evaluation in clinical trials. These inhibitors are associated with lower IC50 values for inhibiting ALK in enzymatic and cell-based models than crizotinib, as shown in Table 3, and, importantly,
most of them harbor some degree of blocking activity against gatekeeper mutations of the ALK
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gene21.
Alectinib is a potent, selective and orally available inhibitor of ALK with ten-fold greater potency
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than crizotinib (Table 3), among various kinases, including MET and IGF1R; this high selectivity is considered to be due to its characteristic structure46. Furthermore, in vitro and in vivo analyses have shown that alectinib effectively inhibits ALK with or without the gatekeeper mutation (L1196M). A single-arm, open-label, phase I/II trial was conducted to investigate the safety and activity of alectinib for ALK inhibitor-naïve patients with ALK-rearranged NSCLC in Japan, and demonstrated
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the excellent efficacy of alectinib for treating ALK-rearranged NSCLC20. In contrast to the trials of crizotinib, positive results based on both FISH and IHC or RT-PCR analyses were required for enrollment in that study. In the phase I portion, 24 patients were treated at doses of 20-300 mg twice daily, and no dose-limiting toxicities were observed up to the highest dose. Therefore, a dose of 300
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mg twice daily was chosen as the recommended dose in the phase 2 trial, which included 46 patients treated at that dose. The objective response rate was as high as 93.5% (95% CI 82.1-98.6), and 40
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(87%) of 46 patients remained on treatment as of the data cutoff point (enrollment, between Sept 10, 2010 and April 18, 2012; the data cutoff date was July 31, 2012). Intriguingly, no progression of CNS lesions was observed in 15 patients proven to harbor brain metastases by the time of data cutoff. With regard to treatment-related AEs, the most common ones included dysgeusia (30%), increased AST (28%), increase blood bilirubin (28%), increased blood creatinine (26%), rash (26%), constipation (24%), increased ALT (22%) and so on. Twelve (26%) of 46 patients experienced AEs of grade 3, such as a decreased neutrophil count and increased blood creatine phosphokinase level, while no grade 4 AEs or deaths were reported. The study is ongoing, and the data for the one-year follow-up were reported at the
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15th World Conference on Lung Cancer21. The PFS at one-year was 83% (95% CI 68-92), although the median PFS was not reached. Ceritinib is also a potent, selective and orally available ALK inhibitor with a low IC50 of 0.00015
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µM that was developed based on the structure of TAE684, and specifically inhibits IGF1R (Table 3)48, 52. Preclinical xenograft models generated from lung cancer cell lines harboring the ALK fusion gene have shown a substantial antitumor activity48, and, clinically, phase I and II trials of ceritinib are currently under way. In a global, multi-institutional phase I study, 123 patients with
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ALK-translocated NSCLC were enrolled. Among 88 evaluable NSCLC patients, the overall response rate was 70%, while the median PFS of 123 patients was 8.6 months (95% CI 4.3-19.3)23, 53.
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Surprisingly, the efficacy of ceritinib in patients with crizotinib-resistant disease was also observed, i.e., the overall response rate was 73%, and responses were also seen in patients with untreated CNS metastases. The most common AEs were nausea (72%), diarrhea (69%), vomiting (50%) and fatigue (31%). The most common grade 3/4 AEs were ALT elevation (12%), diarrhea (7%) and AST elevation (6%). The efficacy and tolerability of the compound was also confirmed in a Japanese population54, and phase I, II and
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III studies are currently ongoing.
AP26133 is a novel tyrosine kinase inhibitor that potently inhibits mutant activated forms of the ALK and EGFR genes, as well as TKI-resistant forms including L1196M of the ALK gene and T790M of the EGFR gene22. Preliminary data for an ongoing dose-finding phase I/II study of
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AP26133 of advanced malignancy refractory to standard treatment showed the efficacy and safety of the compound in NSCLC patients previously treated with ALK inhibitors or EGFR-TKIs55. In
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addition to alectinib and ceritinib, the efficacy for CNS metastases has been reported. Therefore, second-generation ALK inhibitors appear to be well tolerated and strikingly effective in NSCLC patients harboring the ALK rearrangement, even those with or without resistance to crizotinib. In addition to alectinib, ceritinib and AP26133, the anti-tumor activity of at least two other second-generation ALK inhibitors, ASP306256, 57 and X-39658, has been shown in in vitro studies, and these are currently under clinical investigation. Although it is not clear at present whether crizotinib or second-generation ALK inhibitors will be the superior treatment, a head-to-head study comparing crizotinib with the second-generation ALK
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inhibitors would clarify this point. In fact, randomized phase III trial comparing alectinib with crizotinib is currently being performed to address this issue (NCT02075840).
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What is the best method for treating patients with ALK-positive NSCLC? As shown above, conditions surrounding patients with ALK-rearranged NSCLC have rapidly and
drastically changed. Therefore, several questions arise: what is the best way to treat this subset of patients? Should ALK inhibitors be administered as first-line treatment? Should second-generation
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ALK inhibitors replace crizotinib, or is it better to administer crizotinib followed by second-generation ALK inhibitors as sequential therapy? Or is crizotinib simply a first-generation
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ALK inhibitor?
With regard to the administration of ALK inhibitors as first-line therapy, ongoing phase III trials, including the PROFILE 1014, will help to clarify the significance of the first-line use of ALK inhibitors. Furthermore, a head-to-head trial comparing crizotinib with next-generation ALK inhibitors would help to clarify which therapy is superior in the treatment of ALK-positive NSCLC.
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This can determine whether second-generation ALK inhibitors should be used instead of crizotinib if crizotinib is shown to be inferior to those agents. From another point of view, since second-generation ALK inhibitors can be used to overcome crizotinib-resistance mediated by secondary mutations of the ALK gene, the sequential use of these drugs following crizotinib may
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prolong survival. However, careful attention must be paid since these agents are unlikely to overcome crizotinib-resistance through second or separate drivers occupying approximately 35% of
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the resistance mechanisms to crizotinib19, 35. Furthermore, with regard to mechanisms conferring resistance to alectinib, we reported a possible mechanism acting via the amplification of the MET gene that can be overcome with crizotinib, which specifically inhibits MET as well as ALK (Figure 1A)42, 43. This finding suggests that crizotinib is not simply a first-generation ALK inhibitor, but also can be used as ‘another-generation ALK inhibitor’ in some way. Therefore, it is difficult to determine which (crizotinib or second-generation ALK inhibitors) should be used first, at the moment.
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Following the acquisition of resistance to ALK inhibitors, regardless of the use of crizotinib or second-generation ALK inhibitors, specific treatment strategies should be considered according to the resistance mechanisms (Table 2, Figures 1B and 2). Figure 2 shows the proposed treatment
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strategies following the acquisition of resistance to crizotinib according to the resistance mechanism. First, patients with secondary mutations or CNG in the ALK gene (ALK-dominant) would be treated
with the sequential use of second-generation ALK inhibitors following crizotinib-resistance or the administration of HSP90 inhibitors. Second, patients with activation of EGFR via mutations or
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phosphorylation (ALK non-dominant, but partially ALK-dependent) would receive treatment
including crizotinib beyond the state of progressive disease with EGFR-TKI or AP-26113 (inhibition
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of mutant activated forms of the ALK and EGFR). Third, patients with activation of KIT via amplification (ALK non-dominant, but partially ALK-dependent) would be treated with crizotinib beyond progressive disease with KIT-TKI. Fourth, those with activation of EGFR or KRAS via their mutations (ALK non-dominant and ALK-independent) would be treated with EGFR-TKI. Chemotherapy with pemetrexed, which appears to be more effective than docetaxel in ALK-positive
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patients2, should be considered for ALK-positive patients with any possible mechanism of resistance to crizotinib. In the future, molecular-targeted inhibitors that specifically inhibit KRAS (G12C) will be used to overcome drug resistance via activation of the KRAS gene59. Figure 1B shows the proposed treatment strategy following the acquisition of resistance to second generation ALK
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inhibitors. A possible mechanism associated with MET amplification might be overcome with the use of second generation ALK inhibitors beyond progressive disease with MET-TKI, or crizotinib
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(inhibition of both MET and ALK). As a matter of course, the administration of personalized treatment according to resistance mechanisms should be followed by standard chemotherapy. Since these treatment strategies to overcome resistance are still speculative, and are not based on any concrete data thus far, future preclinical and clinical studies are warranted to clarify their therapeutic potential. In such studies, a second biopsy might help to select patients for further treatment based on the resistance mechanisms detected.
Conclusion
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We herein described the past, present and future concerning ALK-rearranged NSCLC and ALK inhibitors. Future basic and clinical studies are warranted to elucidate the biology of ALK-rearranged
Acknowledgements
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We thank Brian Quinn for providing critical comments on the manuscript.
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NSCLC in more detail and improve treatment outcomes in this subset of patients.
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References
1. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with
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non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomized phase 3 trial. Lancet Oncol 2010; 11: 121-8.
2. 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.
SC
3. Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med 2012; 18: 378-81.
M AN U
4. Lipson D, Capelletti M, Yelensky R, et al. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med 2012; 18: 382-4.
5. Mazieres J, Peters S, Lepage B, et al. Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J Clin Oncol 2013; 31: 1997-2003. 6. Vaishnavi A, Capelletti M, Le AT, et al. Oncogenic and drug-sensitive NTRK1 rearrangements
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in lung cancer. Nat Med 2013; 19: 1469-72.
7. Mok TS. Personalized medicine in lung cancer: what we need to know. Nat Rev Clin Oncol 2011; 8: 661-668.
8. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene
EP
in non-small-cell lung cancer. Nature 2007; 448: 561-6. 9. Mano H. Non-solid oncogenes in solid tumors: EML4-ALK fusion genes in lung cancer. Cancer
AC C
Sci 2008; 99: 2349-556.
10. Soda M, Isobe K, Inoue A, et al. A prospective PCR-based screening for the EML4-ALK oncogene in non-small cell lung cancer. Clin Cancer Res 2012; 18: 5682-89.
11. Gainor JF, Varghese AM, Ou SH, et al. ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res 2013; 19: 4273-81. 12. Camidge DR, Kono SA, Flacco A, et al. Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK
15
ACCEPTED MANUSCRIPT
inhibitor treatment. Clin Cancer Res 2010; 16: 5581-90. 13. Sasaki T, Rodig SJ, Chirieac LR, Janne PA. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer 2010; 46: 1773-1780.
RI PT
14. Heuckmann JM, Balke-Want H, Malchers F, et al. Differential protein stability and ALK inhibitor sensitivity of EML4-ALK fusion variants. Clin Cancer Res 2012; 18: 4682-90.
15. Takeuchi K, Choi YL, Togashi Y, et al. KIF5B-ALK, a novel fusion oncokinase identified by an
2009; 15: 3143-49.
SC
immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res
16. Rikova K, Guo A, Zeng Q, et al. Global survey of phosphotyrosine signaling identifies
M AN U
oncogenic kinases in lung cancer. Cell 2007; 131: 1190-203.
17. 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.
18. 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
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2012; 13: 1011-19.
19. Camidge DR, Doebele RC. Treating ALK-positive lung cancer—early success and future challenges. Nat Rev Clin Oncol 2012; 9: 268-77. 20. Seto T, Kiura K, Nishio M, et al. CH5424802 (RO5424802) for patients with ALK-rearranged
EP
advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study. Lancet Oncol 2013; 14: 590-8.
AC C
21. Inoue A, Nishio M, Kiura K, et al. One-year follow-up of a Phase I/II study of a highly selective ALK inhibitor CH5424802/RO5424802 in ALK-rearranged advanced non-small cell lung cancer (NSCLC). WCLC 2013; P3.11-034.
22. Solomon B, Wilner KD, Shaw AT. Current status of targeted therapy for anaplastic lymphoma kinase-rearranged non-small cell lung cancer. Clin Phamacol Ther 2013; 95: 15-23. 23. Shaw AT, Mehra R, Kim DW, et al. Clinical activity of the ALK inhibitor LDK378 in advanced, ALK-positive NSCLC. J Clin Oncol 31, 2013 (suppl; abstr 8010). 24. Christensen JG, Zou HY, Arango ME, et al. Cytoreductive antitumor activity of PF-2341066, a
16
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novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther 2007; 6: 3314-22. 25. McDermott U, lafrate AJ, Gray NS, et al. Genomic alterations of anaplastic lymphoma kinase
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may sensitize tumors to anaplastic lymphoma kinase inhibitors. Cancer Res 2008; 68: 3389-95. 26. Cui JJ, Tran-Dubé 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.
non-small-cell lung cancer. J Clin Oncol 2012; 30: 3425-6.
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27. Komiya T, Thomas A, Khozin S, et al. Response to crizotinib in ROS1-rearranged
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28. Palmer RH, Vernersson E, Grabbe C, et al. Anaplastic lymphoma kinase: signaling in development and disease. Biochem J 2009; 420: 345-61.
29. Kim DW, Ahn M-J, Shi Y, et al. Updated results of a global phase II study with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC). ESMO 2012; abstract 2252. 30. Choi YL, Soda M, Yamashita Y, et al. EML4-ALK mutations in lung cancer that confer
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resistance to ALK inhibitors. N Engl J Med 2010; 363: 1734-39.
31. Gorre ME, Mohammed M, Ellwood K, Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001; 293: 876-80. 32. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or
e73.
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erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005; 2:
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33. Zhang S, Wang F, Keats J, et al. Crizotinib-resistant mutants of EML4-ALK identified through an accelerated mutagenesis screen. Chem Biol Drug Des 2011; 78: 999-1005.
34. Gridelli C, Peters S, Sgambato A, et al. ALK inhibitors in the treatment of advanced NSCLC. Cancer Treat Rev 2014; 40: 300-6.
35. Doebele RC, Pilling AB, Aisner DL, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 2012; 18: 1472-82. 36. Maillet D, Martel-Lafay I, Arpin D, et al. Ineffectiveness of crizotinib on brain metastases in two cases of lung adenocarcinoma with EML4-ALK rearrangement. J Thorac Oncol 2013; 8: e30-1.
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37. Kaneda H, Okamoto I, Nakagawa K. Rapid response of brain metastasis to crizotinib in a patient with ALK rearrangement-positive non-small-cell lung cancer. J Thorac Oncol 2013; 8: e32-3. 38. Gainor JF, Ou SH, Logan J, et al. The Central Nervous System as a Sanctuary Site in
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ALK-Positive Non-Small Cell Lung Cancer. J Thorac Oncol 2013; 8: 1570-73. 39. Peled N, Zach L, Liran O, et al. Effective Crizotinib Schedule for Brain Metastases in ALK Rearrangement Metastatic Non-Small-Cell Lung Cancer. J Thorac Oncol 2013; 8: e112-3.
40. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in
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ALK-rearranged lung cancers. Sci Transl Med 2012; 4: 120ra17.
41. Kobayashi Y, Sakao Y, Ito S, et al. Transformation to sarcomatoid carcinoma in ALK-rearranged
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adenocarcinoma, which developed acquired resistance to crizotinib and received subsequent chemotherapies. J Thorac Oncol 2013; 8: e75-8.
42. Toyokawa G, Takenoyama M, Watanabe S, et al. Dramatic response to crizotinib in an ALK-positive adenocarcinoma with disseminated intravascular coagulation. J Thorac Oncol 2013; 8: e96-8.
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43. Toyokawa G, Seto T, Takenoyama M, et al. Crizotinib can overcome acquired resistance to CH5424802: Is amplification of the MET gene a key factor? J Thorac Oncol 2014, in press. 44. Sakamoto H, Tsukaguchi T, Hiroshima S, et al. CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell 2011; 19: 679-90.
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45. Kinoshita K, Asoh K, Furuichi N, et al. Design and synthesis of a highly selective, orally active and potent anaplastic kinase inhibitor. Bioorg Med Chem 2012; 20: 1271-80.
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46. Marsilje TH, Pei W, Chen B, et al. Synthesis, Structure-Activity Relationships, and in Vivo Efficacy of the Novel Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor 5-Chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)pheny l)pyrimidine-2,4-diamine (LDK378) Currently in Phase 1 and Phase 2 Clinical Trials. J Med Chem 2013; 56: 5675-90. 47. Katayama R, Khan TM, Benes C, et al. Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harbouring the fusion oncogene EML4-ALK. Proc Natl Acad Sci U. S. A. 2011; 108: 7535-40.
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48. Chen Z, Akbay EA, Mikse OR, et al. Co-clinical trials demonstrate superiority of crizotinib to chemotherapy in ALK-rearranged non-small cell lung cancer and predict strategies to overcome resistance. Clin Cancer Res 2013, in press.
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49. Camidge DR, Kono SA, Lu X, et al. Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed. J Thorac Oncol 2011; 6: 774-80.
50. Sang J, Acquaviva J, Friedland JC, et al. Targeted inhibition of the molecular chaperone Hsp90
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overcomes ALK inhibitor resistance in non-small cell lung cancer. Cancer Discov 2013; 3: 430-43.
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51. Felip E, Carcereny E, Barlesi F, et al. Phase II activity of the HSP90 inhibitor AUY922 in patients with ALK-Rearranged (ALK+) or EGFR mutated advanced non-small cell lung cancer. Ann Oncol 2012; 23, ix152: abstr 4380.
52. Galkin AV, Melnick JS, Kim S, et al. Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. Proc Natl Aced Sci U S A 2007; 104: 270-5.
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53. Mehra R, Camidge DR, and Sharma S, et al. First-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors. J Clin Oncol 30, 2012 (suppl; abstr 3007). 54. Seto T, Murakami H, Hirai F, et al. Phase I study of the ALK inhibitor LDK378 in Japanes patients with advanced, ALK-rearranged NSCLC and other tumors harboring genetic ALK
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alterations. WCLC 2013; P1.11-007.
55. Camidge DR, Bazhenova L, Salgia R, et al. First-in-human dose-finding study of the
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ALK/EGFR inhibitor AP26113 in patients with advanced malignancies: Updated results. J Clin Oncol 31, 2013 (suppl; abstr 8031).
56. Kuromitsu S, Mori M, Shimada I, et al. Antitumor activities of ASP3026 against EML4-ALK-dependent tumor models. Mol Cancer Ther 10, 2011 (suppl; abstr A227).
57. Mori M, Kuromitsu S, Ueno Y, et al. ASP3026, a selective ALK inhibitor, induces tumor regression in a crizotinib-refractory model and prolongs survival in an intrapleurally xenograft model. Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research. 2012 (abstr 866).
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58. Lovly CM, Heuckmann JM, de Stanchina E, et al. Insights into ALK-driven cnacers revealed through development of novel ALK tyrosine kinase inhibitors. Cancer Res 2011; 71: 4920-31. 59. Ostrem JM, Peters U, Sos ML, et al. K-Ras(G12C) inhibitors allosterically control GTP affinity
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and effector interactions. Nature 2013; 503: 548-51.
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Figure Legends
Figure 1. (A) FISH assay showing amplification of the MET gene. Blue: DAPI; red: MET gene;
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green: 7q11.21. (B) The proposed treatment strategy following the acquisition of resistance to the second-generation ALK inhibitors: amplification of the MET gene, second-generation ALK
inhibitors beyond progressive disease with MET-TKI, or crizotinib (inhibition of both MET and
ALK) or Pem-based CTx. ALKi, ALK inhibitor; PD, progressive disease; Crz, crizotinib; Pem,
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pemetrexed; CTx, chemotherapy. Other abbreviations, see Abbreviations.
Figure 2. The proposed treatment strategies following the acquisition of resistance to crizotinib, based on mechanism of resistance. Upper row: secondary mutations or CNG in the ALK gene (ALK dominant), the sequential use of second-generation ALK inhibitors following crizotinib-resistance or the administration of HSP90 inhibitors or Pem-based CTx. Second row: activation of EGFR via
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mutations or phosphorylation (ALK non-dominant, but partially ALK-dependent), crizotinib beyond progressive disease with EGFR-TKI or AP-26113 (inhibition of mutant activated forms of the ALK and EGFR) or Pem-based CTx. Third row: activation of KIT via the amplification (ALK non-dominant, but partially ALK-dependent), crizotinib beyond progressive disease with KIT-TKI
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or Pem-based CTx. Lower row: activation of EGFR or KRAS via their mutations (ALK non-dominant and ALK-independent), EGFR-TKI or Pem-based CTx. The personalized treatment
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according to the mechanism of resistance should be followed by standard chemotherapy. Star-like marks denote mutations in the ALK, EGFR and KRAS genes. Crz, crizotinib: ALKi, ALK inhibitor; HSP90i, HSP90 inhibitor; Pem, pemetrexed; CTx, chemotherapy; PD, progressive disease. Other abbreviations, see Abbreviations.
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Table 1. Phase III studies comparing crizotinib with standard chemotherapy PFS
PROFILE1007
2013
Treatment regimen
No. of pts
Response rate (%)
Crizotinib
173
65
PEM or DOC
174
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P-value
5.000
0.008
ALK
0.11
-
MET
0.028
-
Enzymatic
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0.005-0.011
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0.015-0.045 (L1196M)
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Cell-based
AP-26113 IC50 (µM)
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Crizotinib IC50 (µM)
-
0.027
-
1.3
-
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S1525-7304(14)00108-9
DOI:
10.1016/j.cllc.2014.05.001
Reference:
CLLC 277
To appear in:
Clinical Lung Cancer
Received Date: 16 February 2014 Revised Date:
9 April 2014
Accepted Date: 19 May 2014
Please cite this article as: Toyokawa G, Seto T, ALK inhibitors: What is the best way to treat patients with ALK-positive NSCLC?, Clinical Lung Cancer (2014), doi: 10.1016/j.cllc.2014.05.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Clinical Lung Cancer (Review article) ALK inhibitors: What is the best way to treat patients with ALK-positive NSCLC?
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Gouji Toyokawa, MD, PhD, Takashi Seto, MD, PhD
Department of Thoracic Oncology, National Kyushu Cancer Center, 3-1-1 Notame, Minami-ku,
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Fukuoka 811-1395, Japan
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Funding sources: None
Running title: Best way to treat ALK-positive NSCLC
Correspondence to: Takashi Seto
Department of Thoracic Oncology, National Kyushu Cancer Center, 3-1-1 Notame, Minami-ku,
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Fukuoka 811-1395, Japan
Tel.: +81 92 541 3231; Fax: +81 92 551 4585. E-mail address: [email protected]
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Number of words/characters in abstract and manuscript: 250 words/1739 characters (abstract)
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and 4488 words/29780 characters (manuscript)
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Clinical Lung Cancer Editorial Office
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Dear Editors,
Dr. Seto has received honorarium from Chugai Pharmaceutical Co., Ltd., and Eli Lilly Japan K.K.
and received research funding from Chugai Pharmaceutical Co., Ltd., Pfizer Japan Inc., and Novartis
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Pharma K.K. Dr. Toyokawa declares no conflict of interest.
Takashi Seto
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Sincerely,
Department of Thoracic Oncology, National Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka 811-1395, Japan
Tel.: +81 92 541 3231; Fax: +81 92 551 4585.
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E-mail address: [email protected]
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Abstract Genetic insight into the pathogenesis of lung cancer has paved the way for a new era in the treatment of lung cancer. Recently, ALK has been identified to exert a potent transforming effect via genetic
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rearrangement in patients with lung cancer. Pre-clinical and single-arm phase I studies have shown that patients with ALK-rearranged NSCLC can be successfully treated with crizotinib. Furthermore, a phase III randomized study indicated that crizotinib is superior to standard chemotherapy in the
treatment of NSCLC patients harboring the ALK rearrangement who had received one prior
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platinum-based chemotherapy. Despite the excellent efficacy of crizotinib in patients with
ALK-positive lung cancer, resistance mechanisms, such as secondary mutations in the ALK gene, the
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activation of other oncogenes and so on, have been identified to confer resistance to crizotinib. Second-generation ALK inhibitors, such as alectinib and ceritinib, have been shown to be effective not only in crizotinib-naïve patients, but also those resistant to crizotinib. Therefore, although some agents specifically targeting ALK have been developed and their efficacy has been documented, how ALK inhibitors should be administered in the setting of ALK-rearranged NSCLC remains to be fully
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elucidated. Can second-generation ALK inhibitors replace crizotinib? Is crizotinib just a first-generation ALK inhibitor? Is the sequential use of crizotinib and second-generation ALK inhibitors the best method? In this article, we review the pre-clinical and clinical results regarding crizotinib and second-generation ALK inhibitors, as well as the resistance mechanisms, and discuss
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the best methods for treating patients with ALK-positive NSCLC.
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Key words: Non-small cell lung cancer; anaplastic lymphoma kinase; ALK inhibitors; crizotinib; resistance mechanisms
Abbreviations
ALK, anaplastic lymphoma kinase; non-small cell lung cancer, NSCLC; EGFR, epidermal growth factor receptor; EML4, echinoderm microtubule-associated protein-like 4; CI, confidence interval; PFS, progression-free survival; OS, overall survival; AEs, adverse events; TKI, tyrosine kinase inhibitor; CNG, copy number gain; CNS, central nervous system; KRAS, Kirsten rat sarcoma viral
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oncogene homolog; KIT, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog; MET, met proto-oncogene; IGF1R, insulin-like growth factor 1 receptor; HSP90, heat shock protein 90; FISH, fluorescence in-situ hybridization; IHC, immunohistochemistry; RT-PCR, reverse
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transcriptase-polymerase chain reaction; IC50, half maximal inhibitory concentration.
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Introduction The incidence of cancer-related death is on the rise in most countries, with lung cancer being the leading cause of cancer death in many developed countries, including Japan. Although the treatment
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outcomes of lung cancer remain unsatisfactory, recent basic and clinical studies have identified lung cancer patients with disorders of oncogenes, such as EGFR1, ALK2 and so on3-6, which are
exclusively limited to the adenocarcinoma histology. These oncogenes have attracted much attention as being specifically targetable by kinase inhibitors7. It is therefore crucial to precisely examine
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genetic disorders when treating lung cancer patients.
Soda et al. reported that the ALK gene fuses with EML4, resulting in a potent transforming activity
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in NSCLC, and the growth stimulating effect was shown to depend on the dimerization of EML4-ALK through the basic domain of EML4. In concrete terms, EML4-ALK oligomerizes constitutively in cells through the coiled coil domain within the EML4 region, and becomes activated to exert marked oncogenicity via the aberrant activation of downstream signaling, such as Ras/MAPK, PI3K/AKT and JAK/STAT pathways8, 9. Importantly, the mice transduced with
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NIH3T3 cells forced to express the EML4-ALK fusion gene can be successfully treated with ALK inhibitors. Clinicopathological analyses have demonstrated that the frequency of patients with NSCLC harboring the EML4-ALK fusion gene is approximately 5%, and that this fusion gene is frequently observed in relatively younger patients, non- or light smokers and those with an
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adenocarcinoma histology without other genetic disorders10-12. Regarding histological characteristics, adenocarcinoma associated with the fusion gene often exhibits a mucinous cribriform pattern or
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signet-ring cell subtype3. With respect to the variant forms of the EML4-ALK fusion gene, 11 variants have been identified to date, most of which have been shown to harbor an oncogenic activity12. Although the data of Heuchman et al. showed differential responses to ALK inhibitors according to the EML4-ALK variant, whether these variants can predict the response to treatment with inhibitors remains unclear14. The kinesin family member 5B (KIF5B) and TRK-fused gene (TFG) genes have also been shown to be fusion partners with the ALK gene in patients with lung cancer15, 16. Crizotinib is a first-in-class ALK tyrosine kinase inhibitor and has been shown to be potent and
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well tolerable in ALK-positive NSCLC patients based on a single-arm study17, 18. More importantly, the superiority of crizotinib to standard chemotherapy has been demonstrated in the setting of advanced NSCLC associated with the ALK rearrangement in patients previously treated with
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platinum-based chemotherapy2. However, resistance mechanisms to crizotinib are major concerns when administering crizotinib in ALK-positive NSCLC patients19. Second-generation ALK inhibitors, such as alectinib and ceritinib, were recently shown to be effective not only in crizotinib-naïve patients, but also in those with acquired resistance to crizotinib20-23.
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Therefore, although the biology of patients with the ALK fusion gene has been clarified and some
ALK inhibitors have been developed and shown to specifically inhibit disease progression in
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patients with the ALK fusion gene, the best method for treating patients with ALK-positive NSCLC has yet to be determined. We herein review basic and clinical results regarding crizotinib and second-generation ALK inhibitors, as well as resista
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nce mechanisms, and discuss the best method for treating patients with ALK-positive NSCLC.
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ALK inhibitors Crizotinib-phase I and II trials Crizotinib (PF-02341066), which was originally developed as an inhibitor of c-MET, is an orally
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available small-molecule inhibitor of ALK tyrosine kinase24-26. Experimental models have documented the inhibitory effects of crizotinib on cell proliferation via the induction of apoptosis and G1-S phase cell cycle arrest in ALK-positive anaplastic large-cell lymphoma cells, but not ALK-negative lymphoma cells24, and the efficacy of crizotinib against NSCLC cell lines has also
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been demonstrated25. Crizotinib has recently attracted much attention, as c-ros oncogene 1, receptor tyrosine kinase (ROS1)-rearranged lung cancer may be successfully treated with this drug27.
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Importantly, a phase I dose-escalation trial evaluating crizotinib as an oral single agent in patients with advanced cancer and the second part of a phase I study that expanded the cohort of patients with ALK-translocated NSCLC showed a dramatic activity with good tolerability of crizotinib in patients with the ALK fusion gene (PROFILE 1001)17, 18. The data for the expanded cohort showed an objective response rate of 60.8% (95% CI 52.3−68.9) with a median PFS of 9.7 months (95% CI
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7.7−12.8)18. Although the median OS data were immature, the estimated OS at six and 12 months was as high as 87.9% (95% CI 81.3−92.3) and 74.8% (66.4−81.5), respectively. Treatment-related AEs of any grades were observed in 144 of 149 patients (97%), with visual disorders (64%), gastrointestinal side effects, such as nausea (56%), diarrhea (50%), vomiting (39%) and constipation
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(28%), peripheral edema (30%), dizziness (21%), fatigue (16%), increased alanine aminotransferase (12%), rash (11%), dysgeusia (11%) and increased aspartate aminotransferase (10%) being reported
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in at least 10% of the patients. The grade 3 or 4 AEs included neutropenia (6.0%), an elevated alanine aminotransferase level (4.0%), hypophosphatemia (4.0%) and lymphopenia (4.0%). Visual disturbances are uncommon side effects not seen with other TKIs, such as gefitinib and erlotinib, and the involvement of ALK in the development of the gut and visual system in other organisms might explain this AE28. An ongoing phase II study (PROFILE 1005) also showed an objective response rate and median PFS of 59.8% and 8.1 months, respectively29. The profile of AEs was comparable to that reported in the phase I trial. Based on the results of the phase I trial, crizotinib has been approved for use in patients with ALK-rearranged NSCLC in many countries, including Japan.
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Crizotinib-phase III trial Furthermore, a randomized phase III study (PROFILE 1007) was conducted worldwide to
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compare the efficacy of crizotinib to that of chemotherapy (pemetrexed or docetaxel) in patients with advanced ALK-positive lung cancer previously treated with platinum-based chemotherapy2.
Intriguingly, crizotinib treatment achieved a significantly longer PFS, which was the primary endpoint, than chemotherapy (7.7 versus 3.0 months, respectively). The objective response rates in
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the two arms were 65% and 20%, respectively, and the overall quality of life reported by the patients
themselves was significantly better in the crizotinib arm than in the chemotherapy arm. With regard
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to the OS, no significant differences were observed between the two arms, which was assumed to be due to the small number of events noted during the follow-up period and the cross-over in patients treated with chemotherapy to crizotinib as part of a separate study. Although two patients in the crizotinib arm died of interstitial lung disease, the profile of toxicity was tolerable. Therefore, crizotinib has become a standard regimen for second-line or beyond therapy in patients with
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ALK-positive lung cancer. An ongoing phase III study (PROFILE 1014) to compare crizotinib with cisplatin or carboplatin plus pemetrexed in the first-line setting will clarify the significance of crizotinib as a first-line treatment for ALK-rearranged NSCLC.
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Resistance mechanisms to crizotinib
Despite the excellent efficacy of crizotinib in the setting of ALK-positive lung cancer, almost all
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patients experience resistance to crizotinib, and various mechanisms conferring intrinsic or acquired resistance to crizotinib have been identified, as shown in Table 219. These mechanisms can be divided into two groups: ALK-dominant or ALK non-dominant. ALK-dominant mechanisms include second mutations in the ALK gene, CNG of the fusion gene and inadequate local drug penetration to the CNS. Choi and associates first reported two secondary mutations, i.e. L1196M and C1156Y, within the kinase domain of the EML4-ALK fusion gene in the same patient who acquired resistance to crizotinib five months after the administration of the reagent30. L1196M is a gatekeeper mutation that interferes with the binding of crizotinib, and, of note, this substitution corresponds to
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T315I in the BCR-ABL fusion gene31 and T790M in the EGFR gene32. Other resistance mutations in the ALK gene have been discovered in the clinical setting or in a mutagenesis screening, including L1152R, 1151Tins, G1202R, S1206Y, F1174C, D1203N, G1269A and L1196M19, 33, 34. With regard
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to CNG of the fusion gene, two of 11 ALK-positive lung cancer patients who acquired resistance to crizotinib were reported to exhibit new onset ALK CNG, which may occur in combination with
resistance mutations35. The method for achieving the optimal control of the CNS with crizotinib remains controversial, at present36-39. The known ALK non-dominant mechanisms leading to
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crizotinib-resistance are as follows: mutations of other oncogenes, such as the EGFR and KRAS genes34, amplification of the KIT gene40, increased autophosphorylation of EGFR40 and
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transformation to sarcomatoid carcinoma41. Some of these factors conferring resistance to crizotinib have been reported to exist with or without the ALK fusion gene. Although resistance mechanisms to second-generation ALK inhibitors have yet to be clarified, we previously reported a possible mechanism conferring resistance to alectinib via amplification of the MET gene, which can be overcome with crizotinib therapy (Figure 1A)42, 43. Second-generation ALK inhibitors, such as
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alectinib20, 44, 45 and ceritinib22, 23, 46, have been shown to be effective not only in crizotinib-naïve patients, but also those resistant to crizotinib. Other treatment strategies to overcome these mechanisms have been proposed, including the use of HSP90 inhibitors47, 48, and pemetrexed2, 49. With regard to the basic background of the administration of HSP90 inhibitors, such as 17-AAG, for
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ALK-rearranged lung cancer, it was previously shown that EML4-ALK is a client protein for HSP90, and preclinical studies showed that treatment of ALK-rearranged cell lines with HSP90 inhibitors
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resulted in the reduction of the protein levels of the ALK fusion, and led to inhibition of cell proliferation47. Importantly, an in vitro analysis showed that inhibition of HSP90 was shown to be effective against ALK-rearranged cell lines with acquired resistance to crizotinib47. Clinically, objective responses to ganetespib and AUY922 were reported in patients with crizotinib-resistant ALK-rearranged NSCLC50, 51. Chemotherapy is still considered to be important in the treatment of ALK-positive NSCLC. In particular, pemetrexed appears to be one of the effective chemotherapeutic agents, as shown in the PROFILE 1007 trial, where the median PFSs in patients who received pemetrexed or docetaxel were 4.2 and 2.6 months, respectively2. In the next section, we focus on the
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data regarding second-generation ALK inhibitors.
Second-generation ALK inhibitors
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Second-generation ALK inhibitors, such as alectinib, ceritinib and AP26133, are currently under evaluation in clinical trials. These inhibitors are associated with lower IC50 values for inhibiting ALK in enzymatic and cell-based models than crizotinib, as shown in Table 3, and, importantly,
most of them harbor some degree of blocking activity against gatekeeper mutations of the ALK
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gene21.
Alectinib is a potent, selective and orally available inhibitor of ALK with ten-fold greater potency
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than crizotinib (Table 3), among various kinases, including MET and IGF1R; this high selectivity is considered to be due to its characteristic structure46. Furthermore, in vitro and in vivo analyses have shown that alectinib effectively inhibits ALK with or without the gatekeeper mutation (L1196M). A single-arm, open-label, phase I/II trial was conducted to investigate the safety and activity of alectinib for ALK inhibitor-naïve patients with ALK-rearranged NSCLC in Japan, and demonstrated
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the excellent efficacy of alectinib for treating ALK-rearranged NSCLC20. In contrast to the trials of crizotinib, positive results based on both FISH and IHC or RT-PCR analyses were required for enrollment in that study. In the phase I portion, 24 patients were treated at doses of 20-300 mg twice daily, and no dose-limiting toxicities were observed up to the highest dose. Therefore, a dose of 300
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mg twice daily was chosen as the recommended dose in the phase 2 trial, which included 46 patients treated at that dose. The objective response rate was as high as 93.5% (95% CI 82.1-98.6), and 40
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(87%) of 46 patients remained on treatment as of the data cutoff point (enrollment, between Sept 10, 2010 and April 18, 2012; the data cutoff date was July 31, 2012). Intriguingly, no progression of CNS lesions was observed in 15 patients proven to harbor brain metastases by the time of data cutoff. With regard to treatment-related AEs, the most common ones included dysgeusia (30%), increased AST (28%), increase blood bilirubin (28%), increased blood creatinine (26%), rash (26%), constipation (24%), increased ALT (22%) and so on. Twelve (26%) of 46 patients experienced AEs of grade 3, such as a decreased neutrophil count and increased blood creatine phosphokinase level, while no grade 4 AEs or deaths were reported. The study is ongoing, and the data for the one-year follow-up were reported at the
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15th World Conference on Lung Cancer21. The PFS at one-year was 83% (95% CI 68-92), although the median PFS was not reached. Ceritinib is also a potent, selective and orally available ALK inhibitor with a low IC50 of 0.00015
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µM that was developed based on the structure of TAE684, and specifically inhibits IGF1R (Table 3)48, 52. Preclinical xenograft models generated from lung cancer cell lines harboring the ALK fusion gene have shown a substantial antitumor activity48, and, clinically, phase I and II trials of ceritinib are currently under way. In a global, multi-institutional phase I study, 123 patients with
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ALK-translocated NSCLC were enrolled. Among 88 evaluable NSCLC patients, the overall response rate was 70%, while the median PFS of 123 patients was 8.6 months (95% CI 4.3-19.3)23, 53.
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Surprisingly, the efficacy of ceritinib in patients with crizotinib-resistant disease was also observed, i.e., the overall response rate was 73%, and responses were also seen in patients with untreated CNS metastases. The most common AEs were nausea (72%), diarrhea (69%), vomiting (50%) and fatigue (31%). The most common grade 3/4 AEs were ALT elevation (12%), diarrhea (7%) and AST elevation (6%). The efficacy and tolerability of the compound was also confirmed in a Japanese population54, and phase I, II and
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III studies are currently ongoing.
AP26133 is a novel tyrosine kinase inhibitor that potently inhibits mutant activated forms of the ALK and EGFR genes, as well as TKI-resistant forms including L1196M of the ALK gene and T790M of the EGFR gene22. Preliminary data for an ongoing dose-finding phase I/II study of
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AP26133 of advanced malignancy refractory to standard treatment showed the efficacy and safety of the compound in NSCLC patients previously treated with ALK inhibitors or EGFR-TKIs55. In
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addition to alectinib and ceritinib, the efficacy for CNS metastases has been reported. Therefore, second-generation ALK inhibitors appear to be well tolerated and strikingly effective in NSCLC patients harboring the ALK rearrangement, even those with or without resistance to crizotinib. In addition to alectinib, ceritinib and AP26133, the anti-tumor activity of at least two other second-generation ALK inhibitors, ASP306256, 57 and X-39658, has been shown in in vitro studies, and these are currently under clinical investigation. Although it is not clear at present whether crizotinib or second-generation ALK inhibitors will be the superior treatment, a head-to-head study comparing crizotinib with the second-generation ALK
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inhibitors would clarify this point. In fact, randomized phase III trial comparing alectinib with crizotinib is currently being performed to address this issue (NCT02075840).
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What is the best method for treating patients with ALK-positive NSCLC? As shown above, conditions surrounding patients with ALK-rearranged NSCLC have rapidly and
drastically changed. Therefore, several questions arise: what is the best way to treat this subset of patients? Should ALK inhibitors be administered as first-line treatment? Should second-generation
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ALK inhibitors replace crizotinib, or is it better to administer crizotinib followed by second-generation ALK inhibitors as sequential therapy? Or is crizotinib simply a first-generation
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ALK inhibitor?
With regard to the administration of ALK inhibitors as first-line therapy, ongoing phase III trials, including the PROFILE 1014, will help to clarify the significance of the first-line use of ALK inhibitors. Furthermore, a head-to-head trial comparing crizotinib with next-generation ALK inhibitors would help to clarify which therapy is superior in the treatment of ALK-positive NSCLC.
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This can determine whether second-generation ALK inhibitors should be used instead of crizotinib if crizotinib is shown to be inferior to those agents. From another point of view, since second-generation ALK inhibitors can be used to overcome crizotinib-resistance mediated by secondary mutations of the ALK gene, the sequential use of these drugs following crizotinib may
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prolong survival. However, careful attention must be paid since these agents are unlikely to overcome crizotinib-resistance through second or separate drivers occupying approximately 35% of
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the resistance mechanisms to crizotinib19, 35. Furthermore, with regard to mechanisms conferring resistance to alectinib, we reported a possible mechanism acting via the amplification of the MET gene that can be overcome with crizotinib, which specifically inhibits MET as well as ALK (Figure 1A)42, 43. This finding suggests that crizotinib is not simply a first-generation ALK inhibitor, but also can be used as ‘another-generation ALK inhibitor’ in some way. Therefore, it is difficult to determine which (crizotinib or second-generation ALK inhibitors) should be used first, at the moment.
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Following the acquisition of resistance to ALK inhibitors, regardless of the use of crizotinib or second-generation ALK inhibitors, specific treatment strategies should be considered according to the resistance mechanisms (Table 2, Figures 1B and 2). Figure 2 shows the proposed treatment
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strategies following the acquisition of resistance to crizotinib according to the resistance mechanism. First, patients with secondary mutations or CNG in the ALK gene (ALK-dominant) would be treated
with the sequential use of second-generation ALK inhibitors following crizotinib-resistance or the administration of HSP90 inhibitors. Second, patients with activation of EGFR via mutations or
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phosphorylation (ALK non-dominant, but partially ALK-dependent) would receive treatment
including crizotinib beyond the state of progressive disease with EGFR-TKI or AP-26113 (inhibition
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of mutant activated forms of the ALK and EGFR). Third, patients with activation of KIT via amplification (ALK non-dominant, but partially ALK-dependent) would be treated with crizotinib beyond progressive disease with KIT-TKI. Fourth, those with activation of EGFR or KRAS via their mutations (ALK non-dominant and ALK-independent) would be treated with EGFR-TKI. Chemotherapy with pemetrexed, which appears to be more effective than docetaxel in ALK-positive
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patients2, should be considered for ALK-positive patients with any possible mechanism of resistance to crizotinib. In the future, molecular-targeted inhibitors that specifically inhibit KRAS (G12C) will be used to overcome drug resistance via activation of the KRAS gene59. Figure 1B shows the proposed treatment strategy following the acquisition of resistance to second generation ALK
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inhibitors. A possible mechanism associated with MET amplification might be overcome with the use of second generation ALK inhibitors beyond progressive disease with MET-TKI, or crizotinib
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(inhibition of both MET and ALK). As a matter of course, the administration of personalized treatment according to resistance mechanisms should be followed by standard chemotherapy. Since these treatment strategies to overcome resistance are still speculative, and are not based on any concrete data thus far, future preclinical and clinical studies are warranted to clarify their therapeutic potential. In such studies, a second biopsy might help to select patients for further treatment based on the resistance mechanisms detected.
Conclusion
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We herein described the past, present and future concerning ALK-rearranged NSCLC and ALK inhibitors. Future basic and clinical studies are warranted to elucidate the biology of ALK-rearranged
Acknowledgements
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We thank Brian Quinn for providing critical comments on the manuscript.
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NSCLC in more detail and improve treatment outcomes in this subset of patients.
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References
1. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with
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non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomized phase 3 trial. Lancet Oncol 2010; 11: 121-8.
2. 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.
SC
3. Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med 2012; 18: 378-81.
M AN U
4. Lipson D, Capelletti M, Yelensky R, et al. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med 2012; 18: 382-4.
5. Mazieres J, Peters S, Lepage B, et al. Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J Clin Oncol 2013; 31: 1997-2003. 6. Vaishnavi A, Capelletti M, Le AT, et al. Oncogenic and drug-sensitive NTRK1 rearrangements
TE D
in lung cancer. Nat Med 2013; 19: 1469-72.
7. Mok TS. Personalized medicine in lung cancer: what we need to know. Nat Rev Clin Oncol 2011; 8: 661-668.
8. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene
EP
in non-small-cell lung cancer. Nature 2007; 448: 561-6. 9. Mano H. Non-solid oncogenes in solid tumors: EML4-ALK fusion genes in lung cancer. Cancer
AC C
Sci 2008; 99: 2349-556.
10. Soda M, Isobe K, Inoue A, et al. A prospective PCR-based screening for the EML4-ALK oncogene in non-small cell lung cancer. Clin Cancer Res 2012; 18: 5682-89.
11. Gainor JF, Varghese AM, Ou SH, et al. ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res 2013; 19: 4273-81. 12. Camidge DR, Kono SA, Flacco A, et al. Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK
15
ACCEPTED MANUSCRIPT
inhibitor treatment. Clin Cancer Res 2010; 16: 5581-90. 13. Sasaki T, Rodig SJ, Chirieac LR, Janne PA. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer 2010; 46: 1773-1780.
RI PT
14. Heuckmann JM, Balke-Want H, Malchers F, et al. Differential protein stability and ALK inhibitor sensitivity of EML4-ALK fusion variants. Clin Cancer Res 2012; 18: 4682-90.
15. Takeuchi K, Choi YL, Togashi Y, et al. KIF5B-ALK, a novel fusion oncokinase identified by an
2009; 15: 3143-49.
SC
immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res
16. Rikova K, Guo A, Zeng Q, et al. Global survey of phosphotyrosine signaling identifies
M AN U
oncogenic kinases in lung cancer. Cell 2007; 131: 1190-203.
17. 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.
18. 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
TE D
2012; 13: 1011-19.
19. Camidge DR, Doebele RC. Treating ALK-positive lung cancer—early success and future challenges. Nat Rev Clin Oncol 2012; 9: 268-77. 20. Seto T, Kiura K, Nishio M, et al. CH5424802 (RO5424802) for patients with ALK-rearranged
EP
advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study. Lancet Oncol 2013; 14: 590-8.
AC C
21. Inoue A, Nishio M, Kiura K, et al. One-year follow-up of a Phase I/II study of a highly selective ALK inhibitor CH5424802/RO5424802 in ALK-rearranged advanced non-small cell lung cancer (NSCLC). WCLC 2013; P3.11-034.
22. Solomon B, Wilner KD, Shaw AT. Current status of targeted therapy for anaplastic lymphoma kinase-rearranged non-small cell lung cancer. Clin Phamacol Ther 2013; 95: 15-23. 23. Shaw AT, Mehra R, Kim DW, et al. Clinical activity of the ALK inhibitor LDK378 in advanced, ALK-positive NSCLC. J Clin Oncol 31, 2013 (suppl; abstr 8010). 24. Christensen JG, Zou HY, Arango ME, et al. Cytoreductive antitumor activity of PF-2341066, a
16
ACCEPTED MANUSCRIPT
novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther 2007; 6: 3314-22. 25. McDermott U, lafrate AJ, Gray NS, et al. Genomic alterations of anaplastic lymphoma kinase
RI PT
may sensitize tumors to anaplastic lymphoma kinase inhibitors. Cancer Res 2008; 68: 3389-95. 26. Cui JJ, Tran-Dubé 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.
non-small-cell lung cancer. J Clin Oncol 2012; 30: 3425-6.
SC
27. Komiya T, Thomas A, Khozin S, et al. Response to crizotinib in ROS1-rearranged
M AN U
28. Palmer RH, Vernersson E, Grabbe C, et al. Anaplastic lymphoma kinase: signaling in development and disease. Biochem J 2009; 420: 345-61.
29. Kim DW, Ahn M-J, Shi Y, et al. Updated results of a global phase II study with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC). ESMO 2012; abstract 2252. 30. Choi YL, Soda M, Yamashita Y, et al. EML4-ALK mutations in lung cancer that confer
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resistance to ALK inhibitors. N Engl J Med 2010; 363: 1734-39.
31. Gorre ME, Mohammed M, Ellwood K, Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001; 293: 876-80. 32. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or
e73.
EP
erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005; 2:
AC C
33. Zhang S, Wang F, Keats J, et al. Crizotinib-resistant mutants of EML4-ALK identified through an accelerated mutagenesis screen. Chem Biol Drug Des 2011; 78: 999-1005.
34. Gridelli C, Peters S, Sgambato A, et al. ALK inhibitors in the treatment of advanced NSCLC. Cancer Treat Rev 2014; 40: 300-6.
35. Doebele RC, Pilling AB, Aisner DL, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 2012; 18: 1472-82. 36. Maillet D, Martel-Lafay I, Arpin D, et al. Ineffectiveness of crizotinib on brain metastases in two cases of lung adenocarcinoma with EML4-ALK rearrangement. J Thorac Oncol 2013; 8: e30-1.
17
ACCEPTED MANUSCRIPT
37. Kaneda H, Okamoto I, Nakagawa K. Rapid response of brain metastasis to crizotinib in a patient with ALK rearrangement-positive non-small-cell lung cancer. J Thorac Oncol 2013; 8: e32-3. 38. Gainor JF, Ou SH, Logan J, et al. The Central Nervous System as a Sanctuary Site in
RI PT
ALK-Positive Non-Small Cell Lung Cancer. J Thorac Oncol 2013; 8: 1570-73. 39. Peled N, Zach L, Liran O, et al. Effective Crizotinib Schedule for Brain Metastases in ALK Rearrangement Metastatic Non-Small-Cell Lung Cancer. J Thorac Oncol 2013; 8: e112-3.
40. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in
SC
ALK-rearranged lung cancers. Sci Transl Med 2012; 4: 120ra17.
41. Kobayashi Y, Sakao Y, Ito S, et al. Transformation to sarcomatoid carcinoma in ALK-rearranged
M AN U
adenocarcinoma, which developed acquired resistance to crizotinib and received subsequent chemotherapies. J Thorac Oncol 2013; 8: e75-8.
42. Toyokawa G, Takenoyama M, Watanabe S, et al. Dramatic response to crizotinib in an ALK-positive adenocarcinoma with disseminated intravascular coagulation. J Thorac Oncol 2013; 8: e96-8.
TE D
43. Toyokawa G, Seto T, Takenoyama M, et al. Crizotinib can overcome acquired resistance to CH5424802: Is amplification of the MET gene a key factor? J Thorac Oncol 2014, in press. 44. Sakamoto H, Tsukaguchi T, Hiroshima S, et al. CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell 2011; 19: 679-90.
EP
45. Kinoshita K, Asoh K, Furuichi N, et al. Design and synthesis of a highly selective, orally active and potent anaplastic kinase inhibitor. Bioorg Med Chem 2012; 20: 1271-80.
AC C
46. Marsilje TH, Pei W, Chen B, et al. Synthesis, Structure-Activity Relationships, and in Vivo Efficacy of the Novel Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor 5-Chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)pheny l)pyrimidine-2,4-diamine (LDK378) Currently in Phase 1 and Phase 2 Clinical Trials. J Med Chem 2013; 56: 5675-90. 47. Katayama R, Khan TM, Benes C, et al. Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harbouring the fusion oncogene EML4-ALK. Proc Natl Acad Sci U. S. A. 2011; 108: 7535-40.
18
ACCEPTED MANUSCRIPT
48. Chen Z, Akbay EA, Mikse OR, et al. Co-clinical trials demonstrate superiority of crizotinib to chemotherapy in ALK-rearranged non-small cell lung cancer and predict strategies to overcome resistance. Clin Cancer Res 2013, in press.
RI PT
49. Camidge DR, Kono SA, Lu X, et al. Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed. J Thorac Oncol 2011; 6: 774-80.
50. Sang J, Acquaviva J, Friedland JC, et al. Targeted inhibition of the molecular chaperone Hsp90
SC
overcomes ALK inhibitor resistance in non-small cell lung cancer. Cancer Discov 2013; 3: 430-43.
M AN U
51. Felip E, Carcereny E, Barlesi F, et al. Phase II activity of the HSP90 inhibitor AUY922 in patients with ALK-Rearranged (ALK+) or EGFR mutated advanced non-small cell lung cancer. Ann Oncol 2012; 23, ix152: abstr 4380.
52. Galkin AV, Melnick JS, Kim S, et al. Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. Proc Natl Aced Sci U S A 2007; 104: 270-5.
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53. Mehra R, Camidge DR, and Sharma S, et al. First-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors. J Clin Oncol 30, 2012 (suppl; abstr 3007). 54. Seto T, Murakami H, Hirai F, et al. Phase I study of the ALK inhibitor LDK378 in Japanes patients with advanced, ALK-rearranged NSCLC and other tumors harboring genetic ALK
EP
alterations. WCLC 2013; P1.11-007.
55. Camidge DR, Bazhenova L, Salgia R, et al. First-in-human dose-finding study of the
AC C
ALK/EGFR inhibitor AP26113 in patients with advanced malignancies: Updated results. J Clin Oncol 31, 2013 (suppl; abstr 8031).
56. Kuromitsu S, Mori M, Shimada I, et al. Antitumor activities of ASP3026 against EML4-ALK-dependent tumor models. Mol Cancer Ther 10, 2011 (suppl; abstr A227).
57. Mori M, Kuromitsu S, Ueno Y, et al. ASP3026, a selective ALK inhibitor, induces tumor regression in a crizotinib-refractory model and prolongs survival in an intrapleurally xenograft model. Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research. 2012 (abstr 866).
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ACCEPTED MANUSCRIPT
58. Lovly CM, Heuckmann JM, de Stanchina E, et al. Insights into ALK-driven cnacers revealed through development of novel ALK tyrosine kinase inhibitors. Cancer Res 2011; 71: 4920-31. 59. Ostrem JM, Peters U, Sos ML, et al. K-Ras(G12C) inhibitors allosterically control GTP affinity
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M AN U
SC
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and effector interactions. Nature 2013; 503: 548-51.
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Figure Legends
Figure 1. (A) FISH assay showing amplification of the MET gene. Blue: DAPI; red: MET gene;
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green: 7q11.21. (B) The proposed treatment strategy following the acquisition of resistance to the second-generation ALK inhibitors: amplification of the MET gene, second-generation ALK
inhibitors beyond progressive disease with MET-TKI, or crizotinib (inhibition of both MET and
ALK) or Pem-based CTx. ALKi, ALK inhibitor; PD, progressive disease; Crz, crizotinib; Pem,
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pemetrexed; CTx, chemotherapy. Other abbreviations, see Abbreviations.
Figure 2. The proposed treatment strategies following the acquisition of resistance to crizotinib, based on mechanism of resistance. Upper row: secondary mutations or CNG in the ALK gene (ALK dominant), the sequential use of second-generation ALK inhibitors following crizotinib-resistance or the administration of HSP90 inhibitors or Pem-based CTx. Second row: activation of EGFR via
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mutations or phosphorylation (ALK non-dominant, but partially ALK-dependent), crizotinib beyond progressive disease with EGFR-TKI or AP-26113 (inhibition of mutant activated forms of the ALK and EGFR) or Pem-based CTx. Third row: activation of KIT via the amplification (ALK non-dominant, but partially ALK-dependent), crizotinib beyond progressive disease with KIT-TKI
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or Pem-based CTx. Lower row: activation of EGFR or KRAS via their mutations (ALK non-dominant and ALK-independent), EGFR-TKI or Pem-based CTx. The personalized treatment
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according to the mechanism of resistance should be followed by standard chemotherapy. Star-like marks denote mutations in the ALK, EGFR and KRAS genes. Crz, crizotinib: ALKi, ALK inhibitor; HSP90i, HSP90 inhibitor; Pem, pemetrexed; CTx, chemotherapy; PD, progressive disease. Other abbreviations, see Abbreviations.
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Table 1. Phase III studies comparing crizotinib with standard chemotherapy PFS
PROFILE1007
2013
Treatment regimen
No. of pts
Response rate (%)
Crizotinib
173
65
PEM or DOC
174
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P-value
5.000
0.008
ALK
0.11
-
MET
0.028
-
Enzymatic
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0.005-0.011
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0.015-0.045 (L1196M)
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Cell-based
AP-26113 IC50 (µM)
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Crizotinib IC50 (µM)
-
0.027
-
1.3
-
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