The allure of ‘ALUR’
Authors: M. Nagasaka, V.W. Zhu, S.-H.I. Ou
Journal: Annals of Oncology (2018)

Ceritinib, alectinib, and brigatinib are second-generation (2G) anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) that have been approved based on overall response rate (ORR) and duration of response (DoR) in phase II studies demonstrating their clinical efficacy in patients with crizotinib-refractory ALK+ non-small-cell lung cancer (NSCLC) [1.Ou S.I. Further advances in the management of anaplastic lymphoma kinase-mutated non-small-cell lung cancer.J Clin Oncol. 2017; 35: 2463-2466Crossref PubMed Scopus (6) Google Scholar]. Additionally, ensartinib (another 2G ALK TKI) [2.Horn L. Infante J.R. Reckamp K.L. et al.Ensartinib (X-396) in ALK-positive non-small cell lung cancer: results from a first-in-human phase I/II, multicenter study.Clin Cancer Res. 2018; Crossref PubMed Scopus (110) Google Scholar] and lorlatinib [generally considered as a third-generation (3G) ALK TKI] [3.Shaw A.T. Felip E. Bauer T.M. et al.Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial.Lancet Oncol. 2017; 18: 1590-1599Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar] are also being investigated studies with multiple cohorts in crizotinib-refractory setting with similar encouraging clinical efficacies as the approved 2G ALK TKIs. Currently, all of these 2G ALK TKIs have been or are being investigated in advanced treatment-naïve and/or ALK TKI-naïve ALK+ NSCLC patients against platinum-based chemotherapy [ceritinib (ASCEND-4)] [4.Soria J.C. Tan D.S. Chiari R. et al.First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study.Lancet. 2017; 389: 917-929Abstract Full Text Full Text PDF PubMed Scopus (786) Google Scholar], or against crizotinib [alectinib (J-ALEX [5.Hida T. Nokihara H. Kondo M. et al.Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial.Lancet. 2017; 390: 29-39Abstract Full Text Full Text PDF PubMed Scopus (638) Google Scholar], ALEX [6.Peters S. Camidge D.R. Shaw A.T. et al.Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer.N Engl J Med. 2017; 377: 829-838Crossref PubMed Scopus (1461) Google Scholar], ALESIA), brigatinib (ALTA-1L), ensartinib (eXalt3), and lorlatinib (CROWN)]. Based on the ASCEND-4 [4] and ALEX [6.Peters S. Camidge D.R. Shaw A.T. et al.Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer.N Engl J Med. 2017; 377: 829-838Crossref PubMed Scopus (1461) Google Scholar] trial results, both ceritinib and alectinib have received front-line indication in the treatment of advanced ALK+ NSCLC patients, respectively. Among the three approved ALK TKIs (crizotinib, ceritinib, alectinib) for the front-line treatment of ALK+ NSCLC patients in the USA, alectinib has achieved the ‘preferred intervention’ status defined to be of ‘superior efficacy, safety, and evidence; and, when appropriate, affordability’ by the NCCN guidelines [7.NCCN guidelines. Non-small cell lung cancer. Version 3.2018 (21 February 2018).Google Scholar]. The phase III ALUR study in this issue of Annals of Oncology by Novello et al. demonstrated that alectinib achieved a significant improvement in median progression-free survival (PFS) when compared with single agent chemotherapy in ALK+ NSCLC patients who had progressed on one line of platinum-based chemotherapy and crizotoinib [8.S Novello, JMazières, I-JOh et al Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study. Ann Oncol 2018; 29(6): 1409–1416.Google Scholar]. Additionally, alectinib had significant CNS activity when compared with single agent chemotherapy. Cross trial comparison seems to suggest that alectinib in ALUR achieved a numerically superior median PFS (7.1 months) as assessed by the Independent Review Committee (IRC) when compared with the median PFS of 5.4 months by ceritinib as assessed by IRC in ASCEND-5 which has very similar trial design (Table 1) [9.Shaw A.T. Kim T.M. Crino L. et al.Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial.Lancet Oncol. 2017; 18: 874-886Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar]. ALUR seems to confirm the superiority of alectinib in the post-crizotinib setting over ceritinib, similarly to the superiority of alectinib (median PFS of 25.7 months by IRC in ALEX) over ceritinib (median PFS of 16.6 months by IRC in ASCEND-4) in the front-line setting. ALUR established alectinib as the de facto standard of care 2G ALK TKI for platinum-based chemotherapy- and crizotinib-refractory ALK+ NSCLC patients. While this may seem now to be an outdated standard of care using 2 G ALK TKIs post-crizotinib rather than using them as upfront treatment, there are many countries where novel cancer therapies still lack governmental approval and/or public insurance coverage [10.Haitsma G. Patel H. Gurumurthy P. Postma M.J. Access to anti-cancer drugs in India: is there a need to revise reimbursement policies?.Expert Rev Pharmacoecon Outcomes Res. 2018; : 1-8Google Scholar, 11.Global Oncology Trends 2017. Advances, complexities, and costs. https://morningconsult.com/wp-content/uploads/2017/06/QuintilesIMS-Institute-Oncology-Report.pdf (15 March 2018, date last accessed).Google Scholar]. Nevertheless, theoretically adding up the median PFS based on published phase 3 trials, sequential use of chemotherapy (median PFS of 8.1 months [ASCEND-4] [4.Soria J.C. Tan D.S. Chiari R. et al.First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study.Lancet. 2017; 389: 917-929Abstract Full Text Full Text PDF PubMed Scopus (786) Google Scholar]), crizotinib (7.7 months [PROFILE1007] [12.Shaw A.T. Kim D.W. Nakagawa K. et al.Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.N Engl J Med. 2012; 368: 2385-2394Crossref Scopus (2838) Google Scholar]), and then alectinib (7.1 months [ALUR] [8.S Novello, JMazières, I-JOh et al Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study. Ann Oncol 2018; 29(6): 1409–1416.Google Scholar]) for a total median PFS of 22.9 months still lag behind the 25.7 months achieved by upfront use of alectinib [6.Peters S. Camidge D.R. Shaw A.T. et al.Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer.N Engl J Med. 2017; 377: 829-838Crossref PubMed Scopus (1461) Google Scholar]. The ALUR results provided further evidence that upfront use of alectinib is superior to sequential use of chemotherapy, crizotinib and then alectinib.Table 1Comparison of patient characteristics and outcome between ASCEND-5 and ALURASCEND-5ALURCeritinibPemetrexed/docetaxelAlectinibPemetrexed/docetaxelRandomization1 : 12 : 1Methods of detecting ALK rearrangementAbbott molecular vysis FISHAbbott molecular vysis FISH OR IHC with D5F3 antibodyStratificationsWHO PS, CNS metastasis (yes/no)ECOG PS, CNS metastasis (yes/no), CNS metastasis (treated/untreated)N1151167235Percentage of CNS metastasis57%59%65.2%74.3%Cross-over to ALK TKIAllowedAllowedPercentage of cross-over64.7%70.6%Median dose density82%98.1% (pemetrexed)NANA98.4% (docetaxel)ORRaMasked independent review committee determined. (95%CI)39.1%6.9%36.1%11.4%(30.2–48.7)(3.0–13.1)(25–48)(3–27)Median PFSaMasked independent review committee determined.5.4 m1.6 m7.1 m1.6 m(95% CI)(4.1–6.9)(1.4–2.8)(6.3–10.8)(1.3–4.1)HR (95% CI); P-valueHR = 0.49 (0.36–0.67); P < 0.0001HR = 0.32 0.17–0.59); P < 0.001Median CNS DoR (95% CI)6.9 mNANR0 m(2.7–8.3)(3.6–NR)CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; IHC, Immunohistochemistry; NA, not available; NR, not reported; PS, performance status; WHO, World Health Organization.a Masked independent review committee determined. Open table in a new tab CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; IHC, Immunohistochemistry; NA, not available; NR, not reported; PS, performance status; WHO, World Health Organization. As all current front-line phase III trials compared/are comparing 2G or 3G ALK TKIs with crizotinib and are not comparing among themselves, it will be fair to assume all 2G/3G ALK TKIs will beat crizotinib in terms of PFS given the published data or their activity in the post-crizotinib setting. Sorting out the best 2G or 3G ALK TKI to use for advanced treatment-naïve ALK+ NSCLC patients will likely engender vigorous debate and the inevitable cross-trial comparison that everyone frowns upon but does anyway (including this editorial). The results of ALUR will allow other 2G ALK TKIs the opportunity of a much faster way to be compared head to head with alectinib without having to launch a long and expensive front-line trial as the IRC-assessed median PFS of alectinib in the ALEX trial is 25.7 months compared with IRC-assessed median PFS of 7.1 months in ALUR. From a statistical point of calculation, a 50% improvement of median PFS from ALEX which translates to a hazard ratio (HR) of 0.67 means the investigational arm will have to achieve a median PFS of 38.6 months. On the other hand, a 50% improvement of median PFS from ALUR which translates also to an HR of 0.67 means the experimental arm will have to achieve a median PFS of 10.7 months. Among all of these ALK TKIs, brigatinib from the phase II ALTA trial achieved a median PFS of 15.6 months in the post-crizotinib setting and median intracranial PFS of 18.6 months and seems to be the one ALK TKI that can challenge alectinib [13.Kim D.W. Tiseo M. Ahn M.J. et al.Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial.J Clin Oncol. 2017; 35: 2490-2498Crossref PubMed Scopus (439) Google Scholar]. Indeed, a phase III trial (Brigatinib 3001 trial) comparing brigatinib to alectinib in the post-chemotherapy and post-crizotinib setting similar to ALUR is being launched globally. Furthermore, depending on future more mature clinical activity, ensartinib [2.Horn L. Infante J.R. Reckamp K.L. et al.Ensartinib (X-396) in ALK-positive non-small cell lung cancer: results from a first-in-human phase I/II, multicenter study.Clin Cancer Res. 2018; Crossref PubMed Scopus (110) Google Scholar] and lorlatinib [3.Shaw A.T. Felip E. Bauer T.M. et al.Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial.Lancet Oncol. 2017; 18: 1590-1599Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar] could potentially adopt the same ‘ALUR’ trial design for a direct comparison to alectinib. While the natural history of ALK+ NSCLC will likely have been significantly altered in the chemo- and crizotinib-refractory setting with the multiple resistance mechanisms including multiple ALK resistance mutations and direct and indirect bypass pathways [14.Gainor J.F. Dardaei L. Yoda S. et al.Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer.Cancer Discov. 2016; 6: 1118-1133Crossref PubMed Scopus (756) Google Scholar, 15.Lin J.J. Riely G.J. Shaw A.T. Targeting ALK: precision medicine takes on drug resistance.Cancer Discov. 2017; 7: 137-155Crossref PubMed Scopus (320) Google Scholar, 16.Lin J.J. Zhu V.W. Yoda S. et al.Impact of EML4-ALK variant on resistance mechanisms and clinical outcomes in ALK-positive lung cancer.J Clin Oncol. 2018; Google Scholar, 17.Dardaei L. Wang H.Q. Singh M. et al.SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors.Nat Med. 2018; Crossref PubMed Scopus (125) Google Scholar], indirect comparison to alectinib based on the ALUR outcome will likely be used by other ALK TKIs to demonstrate their superiority to alectinib. These potential future clinical data in the post-chemo and post-crizotinib setting may be used rightly or wrongly to indirectly imply superiority in the first-line setting. Therefore, extensive prospective biomarker collections should ideally be part of any future ALK TKI head to head comparison trials adopting the ALUR trial design and survival outcome. In summary, despite the rapidly changing landscape in the treatment of ALK+ NSCLC, ALUR is not without its allure to other pharmaceutical companies that have ALK TKIs that want to challenge alectinib. None declared.