Expert Review of Anticancer Therapy ISSN: 1473-7140 (Print) 1744-8328 (Online) Journal homepage: http://www.tandfonline.com/loi/iery20 How might treatment of ALK-positive non-small cell lung cancer change in the near future? Giulio Metro, Guido Bellezza, Francesco Puma & Rita Chiari To cite this article: Giulio Metro, Guido Bellezza, Francesco Puma & Rita Chiari (2016): How might treatment of ALK-positive non-small cell lung cancer change in the near future?, Expert Review of Anticancer Therapy, DOI: 10.1080/14737140.2016.1226138 To link to this article: http://dx.doi.org/10.1080/14737140.2016.1226138 Accepted author version posted online: 18 Aug 2016. Published online: 18 Aug 2016. Submit your article to this journal View related articles View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalinformation?journalcode=iery20 Download by: [Cornell University Library] Date: 19 August 2016, At: 02:03
Publisher: Taylor & Francis Journal: Expert Review of Anticancer Therapy DOI: 10.1080/14737140.2016.1226138 Editorial How might treatment of ALK-positive non-small cell lung cancer change in the near future? Giulio Metro 1, Guido Bellezza 2, Francesco Puma 3, Rita Chiari 1 1 Medical Oncology, Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy 2 Department of Experimental Medicine, Division of Pathology and Histology, University of Perugia Medical School, Perugia, Italy 3 Department of Thoracic Surgery, Santa Maria della Misericordia Hospital, University of Perugia Medical School, Perugia, Italy Corresponding author: Giulio Metro, Medical Oncology, Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, via Dottori, 1, 06156, Perugia, Italy. Phone: +39 075-578-4185; Fax: +39 075-578-4184; E-mail: giulio.metro@yahoo.com Keywords: 1
Alectinib, ALK, ALK-TKI, ceritinib, crizotinib, lorlatinib, non-small cell lung cancer, central nervous system metastases 2
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (TK) encoded by the ALK gene on chromosome 2p23. In 2007, an oncogenic fusion protein deriving from a rearrangement between the echidonerm microtubule-associated protein-like 4 (EML-4) gene and the ALK gene was first identified in non-small cell lung cancer (NSCLC) by Soda et al. [1]. Ever since, it became evident that ALK rearrangements are present in 4-5% of patients with NSCLC, and consist of either inversions or translocations of exon 20 to 29 of ALK fused to a varying proportion of EML-4 [2]. On this basis, highly effective small molecules ALK-TK inhibitors (-TKIs) have been developed, with crizotinib being the first approved agent by both FDA and EMA for the treatment of ALKrearranged (ALK-positive), advanced NSCLC [2]. More recently, next-generation ALK-TKIs such as ceritinib and alectinib have demonstrated efficacy in ALK-positive NSCLCs pretreated with crizotinib, which has led to their approval by FDA (ceritinib and alectinib) and EMA (ceritinib) for patients who are resistant or intolerant to crizotinib [3-5]. Therefore, at the present time, crizotinib followed by either ceritinib or alectinib appears to be the optimal treatment of ALK-positive advanced NSCLC. Importantly, phase III randomized studies are ongoing in order to evaluate whether a next-generation ALK-TKI could replace crizotinib in the up-front setting. This approach might overcome some of the limitations associated with crizotinib, among which the onset of resistance, either primary or acquired, as well as the modest activity shown by crizotinib on central nervous system (CNS) metastases. Here, we will briefly discuss these topics, focusing on how ceritinib, alectinib, and other novel ALK-TKIs represent an advance in therapeutic armamentarium of ALK-positive NSCLC, also suggesting how treatment landscape may change in the near future. Primary resistance to crizotinib is an important issue in ALK-positive NSCLCs. From the PROFILE 1014 trial, in which untreated ALK-positive NSCLCs were randomized to crizotinib or platinum-pemetrexed chemotherapy, we know that the overall response rate (ORR) to up-front crizotinib is 74% [6]. Importantly, all patients enrolled into this trial had central confirmation of ALK rearrangement by fluorescence in situ hybridization (FISH) analysis. Therefore, the reason why not all of them responded to crizotinib in PROFILE 1014 could be partly due to problems of 3
false-positivity, as FISH analysis requires great expertise (ALK-negative cells can appear FISH positive owing to stochastic and isolated genomic alterations or artifact and/or because of difficulties in the correct identification of tumor cells in dark-field microscopy among a stroma of normal/inflammatory cells) [7]. Therefore, FISH test should be integrated with other techniques such as immunohistochemistry and/or reverse transcription polimerase chain reaction (RT-PCR) in order to better identify ALK-positive patients candidate to crizotinib. On the other hand, primary resistance to crizotinib can be also due to inadequate inhibition of the target by crizotinib, With regard to this, next-generation ALK-TKIs such as ceritinib and alectinib may represent a way to overcome this problem, as they have been shown preclinically to be far more potent than crizotinib against ALK kinase, with IC50 of 0.2 nm and 1.9 nm in cell-free assays, respectively [8,9]. Therefore, their up-front use instead of crizotinib could reduce the occurrence of primary resistance to ALK-targeted therapy, and clinical reports in which patients responded to ceritinib despite primary resistance to crizotinib have already been reported [10,11]. However, understanding primary resistance to crizotinib requires an extensive study of each peculiar ALK gene alteration. Recently, a study conducted on a small sample series of crizotinib-treated patients suggested that some rare ALK fusion variants (as assessed by RT-PCR) could be less prone to respond to treatment, which implies that the type of ALK variant should be more thorugrouly investigated in relation to sensitivity to ALK-TKIs [12]. As for acquired resistance, median progression free survival to first-line crizotinib has been reported to be 10.9 months in the PROFILE 1014 trial [6], which means that most patients will eventually progress within one year of treatment initiation. Biologically acquired resistance is mediated by a variety of different mechanisms, including secondary mutations within the ALK tyrosine kinase domain, copy number gains of the ALK fusion gene, and activation of alternative bypass pathways [2]. Importantly, next-generation ALK-TKIs have the potential to overcome the majority of crizotinib-resistant mutations, as well as to inhibit the ALK-TK more potently, which leads to an ORR of approximately 50% in crizotinib-resistant patients [2]. Of note, lorlatinib is a 4
next-generation ALK-TKI that retains potency against all known crizotinib-resistant mutants, and its clinical development is underway [13]. Although further studies are needed in order to address whether the type of resistance mutation will guide the decision on which ALK-TKI should be offered to crizotinib-resistant NSCLCs, it is important to pinpoint that, similarly to crizotinib, also next-generation ALK-TKIs are subject to the development of resistance under the selective pressure of treatment. With reagard to this, Shaw et al. reported a case of crizotinib-resistant tumor with an ALK C1156Y secondary mutation who did not respond to ceritinib, consistently with the fact that ceritinib is not active against the C1156Y resistance mutation, but responded to lorlatinib instead [14]. Upon the development of resistance to lorlatinib, re-biopsy of the tumor showed the gain of the additional L1198F mutation, which resensitized the tumor to crizotinib treatment. On the other hand, preclinical studies suggest that resistance to the next-generation ALK-TKI alectinib could be mediated via the activation of alternative bypass pathways, including MET amplification. This, in turn, could theoretically be overcome by subsequent treatment with crizotinib (exploiting its activity as MET-inhibitor) [15]. Taken together, these data suggest that crizotinib itself may have a role in some cases of resistance to newer generation ALK-TKIs, and that re-biopsy at the time of progression appears to be necessary in order to optimize treatment management. When compared with platinum-pemetrexed in the PROFILE 1014 trial, patients with CNS metastases had a higher intracranial response rate (IC-RR) with a non-significant trend towards higher intracranial time to tumor progression (IC-TTP) (77% versus 28%, P < 0.001 for IC-RR, and 15.7 months versus 12.5 months, P = 0.063 for IC-TTP) [16]. Nevertheless, as much as 70% and 20% patients with an without CNS metastases prior to crizotinib, respectively, will eventually relapse in the brain, suggesting that CNS is a sanctuary site where ALK-positive disease can disseminate [17]. Therefore, drugs with increased CNS activity are urgently needed. Alectinib is a very promising agent in this setting, since a preclinical study showed that it is not a substrate of P- glycoprotein (P-gp), a key efflux transporter that may impair drug penetration through the bloodbrain barrier (BBB) [18]. Consistently, a pooled analysis of crizotinib-pretreated patients with CNS 5
metastases showed that alectinib provids a CNS-ORR of 64% in individuals with measurable CNS disease (n = 50) [19]. Importantly, other next-generation ALK-TKIs have shown a remarkable activity against CNS metastases, which is crucial in view of the fact that ALK-positive NSCLCs with CNS metastases usually experience a long survival, with median survival potentially exceeding 4 years [20]. As novel and more potent ALK-TKIs are being developed, advances in the treatment of ALK-positive NSCLC will be achieved only through rational development of sequential ALK-TKI treatment based on the peculiar mechanism of resistance, which is the only way we can guarantee extended survival for these patients. For instance, crizotinib might well be beneficial in later lines of ALK-targeted therapy following either lorlatinib or alectinib, but only if resistance is due to ALK L1198F secondary mutation and MET amplification, respectively. Therefore, identifying the resistance mechanism(s) to an ALK-TKI by re-biopsy at disease progression (either in tissue or in plasma through the development of validated techniches of next generation sequencing) will be crucial for guiding sequential ALK-targeted therapy. Finally, in the era of immunotherapy, whether and how checkpoint inhibitors will fit in the future treatment of ALK-positive NSCLC is a very relevant question. The rational behind the combination of an ALK-TKI with a checkpoint inhibitor is strong, since it has been shown preclinically that forced expression of EML4-ALK markedly increases PD-L1 expression, and that treatment with alectinib attenuates PD-L1 expression in EML4/ALK-positive NSCLC cells [21]. Clinical trials are underway and many others are planned in order to assess the efficacy of these combinations. 6
Funding This article was supported by the Italian Association for Cancer Research (AIRC). Declaration of Interest R Chiari has participated in advisory boards for Pfizer and Astra Zeneca. The remaining authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. References * Paper of interest ** Paper of considerable interest 1. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007;448:561-6 This study reported for the first time the presence of an oncogenic rearrangement in the ALK gene of a NSCLC patient 2. Iacono D, Chiari R, Metro G, et al. Future options for ALK-positive non-small cell lung cancer. Lung Cancer 2015;87:211-9 3. Khozin S, Blumenthal GM, Zhang L, et al. FDA approval: ceritinib for the treatment of metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer. Clin Cancer Res 2015;21:2436-9 4. Alectinib approved for ALK+ lung cancer. Cancer Discov 2016;6:115 5. Zykadia recommended for approval in advanced non small cell lung cancer. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2015/02/news _detail_002279.jsp&mid=wc0b01ac058004d5c1 [last accessed 1 Jun 2016]. 7
6. Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALKpositive lung cancer. N Engl J Med 2014;371:2167-77 This trial established crizotinb as the most effective option in the up-front tratment of ALK-positive advanced NSCLC 7. Tsao MS, Hirsch FR, Yatabe Y. IASLC Atlas of ALK testing in lung cancer. International Association for the Study of Lung Cancer, Colorado, USA, 2013. 8. 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)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J Med Chem 2013;56:5675-90 9. 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 10. Chiari R, Metro G, Iacono D, et al. Clinical impact of sequential treatment with ALK-TKIs in patients with advanced ALK-positive non-small cell lung cancer: results of a multicenter analysis. Lung Cancer 2015;90:255-60 11. Facchinetti F, Caramella C, Auger N, et al. Crizotinib primary resistance overcome by ceritinib in a patient with ALK-rearranged non-small cell lung cancer. Tumori 2016. doi: 10.5301/tj.5000520. [Epub ahead of print] 12. Yoshida T, Oya Y, Tanaka K, et al. Differential Crizotinib Response Duration Among ALK Fusion Variants in ALK-Positive Non-Small-Cell Lung Cancer. J Clin Oncol 2016. pii: JCO658732. [Epub ahead of print]. 13. Zou HY, Friboulet L, Kodack DP, et al. PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models. Cancer Cell 2015;28:70-81 8
14. Shaw AT, Friboulet L, Leshchiner I, et al. Resensitization to crizotinib by the lorlatinib ALK resistance mutation L1198F. N Engl J Med. 2016;374:54-61 15. Isozaki H, Ichihara E, Takigawa N, et al. Non-small cell lung cancer cells acquire resistance to the ALK inhibitor alectinib by activating alternative receptor tyrosine kinases. Cancer Res 2016;76:1506-16 16. Solomon BJ, Cappuzzo F, Felip E, et al. Intracranial efficacy of crizotinib versus chemotherapy in patients with advanced ALK-positive non-small-cell lung cancer: results from PROFILE 1014. J Clin Oncol 2016 epub ahead of print 17. Costa DB, Shaw AT, Ou SH, et al. Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastases. J Clin Oncol 2015;33:1881-8 Retrospective analysis of crizotinib-treated patients within two clinical trials suggesting that crizotinib has only modest activity against CNS metastases 18. Kodama T, Hasegawa M, Takanashi K, et al. Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases. Cancer Chemother Pharmacol 2014;74:1023-8 19. Gadgeel S, Shaw T, Govindan R, et al. Pooled analysis of CNS response to alectinib in two studies of pre-treated ALK+ NSCLC. J Thorac Oncol 2015;10(9,Suppl 2):S238(abstract) Pooled analysis of alectinib treated patients within two phase II trials suggesting its high activity against CNS metastases from ALK-positive NSCLC patients 20. Johung KL, Yeh N, Desai NB, et al. Extended Survival and Prognostic Factors for Patients With ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastasis. J Clin Oncol 2016;34:123-9 21. Ota K, Azuma K, Kawahara A, et al. Induction of PD-L1 Expression by the EML4-ALK oncoprotein and downstream signaling pathways in non-small cell lung cancer. Clin Cancer Res 2015;21:4014-21 9
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