Alectinib as first-line therapy for ALK-rearranged NSCLC: a no-brainer?
Authors: A.A. Thai, B.J. Solomon
Journal: Annals of Oncology (2018)

Despite substantial recent advances in systemic treatment of non-small-cell lung cancer patients harbouring anaplastic lymphoma kinase gene rearrangements (ALK+ NSCLC), prevention and control of CNS metastases remains an ongoing challenge. Brain metastases, which are present in 23%–31% of patients with ALK+ NSCLC at diagnosis, or that subsequently develop over the course of treatment, are associated with significant functional, psychological and economic morbidity as well as increased risk of mortality [1.Peters S. Bexelius C. Munk V. Leighl N. The impact of brain metastasis on quality of life, resource utilization and survival in patients with non-small-cell lung cancer.Cancer Treat Rev. 2016; 45: 139-162Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 2.Guerin A. Sasane M. Zhang J. et al.Brain metastases in patients with ALK+ non-small cell lung cancer: clinical symptoms, treatment patterns and economic burden.J Med Econ. 2015; 18: 312-322Crossref PubMed Scopus (69) Google Scholar, 3.Costa D.B. Shaw A.T. Ou S.H. 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: 1881-1888Crossref PubMed Scopus (515) Google Scholar, 4.Doebele R.C. Lu X. Sumey C. et al.Oncogene status predicts patterns of metastatic spread in treatment-naive nonsmall cell lung cancer.Cancer. 2012; 118: 4502-4511Crossref PubMed Scopus (218) Google Scholar, 5.Berger L.A. Riesenberg H. Bokemeyer C. Atanackovic D. CNS metastases in non-small-cell lung cancer: current role of EGFR-TKI therapy and future perspectives.Lung Cancer. 2013; 80: 242-248Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 6.Burudpakdee C. Wong W. Seetasith A. et al.Economic impact of preventing brain metastases with alectinib in ALK-positive non-small cell lung cancer.Lung Cancer. 2018; 119: 103-111Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar]. Moreover, the cumulative risk of developing new brain metastases or having progression of established intracranial metastases are particularly problematic in patients with ALK+ NSCLC where effective systemic treatments have resulted in high rates of extracranial control and long-term survival [3.Costa D.B. Shaw A.T. Ou S.H. 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: 1881-1888Crossref PubMed Scopus (515) Google Scholar,7.Solomon B.J. Kim D.-W. Wu Y.-L. et al.Final overall survival analysis from a study comparing first-line crizotinib versus chemotherapy in ALK-mutation-positive non-small-cell lung cancer.J Clin Oncol. 2018; 36: 2251-2258Crossref PubMed Scopus (254) Google Scholar,8.Rangachari D. Yamaguchi N. VanderLaan P.A. et al.Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers.Lung Cancer. 2015; 88: 108-111Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar]. Multiple drugs have been approved, and more still in development, since crizotinib was established as the first standard of care treatment of patients with ALK+ NSCLC [9.Shaw A.T. Kim D.-W. Nakagawa K. et al.Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.N Engl J Med. 2013; 368: 2385-2394Crossref PubMed Scopus (2847) Google Scholar,10.Solomon B.J. Mok T. Kim D.W. et al.First-line crizotinib versus chemotherapy in ALK-positive lung cancer.N Engl J Med. 2014; 371: 2167-2177Crossref PubMed Scopus (2463) Google Scholar]. Crizotinib, however, has poor CNS penetration, in part due to efflux mediated byp-glycoprotein located on the blood–brain barrier [11.Chuan Tang S. Nguyen L.N. Sparidans R.W. et al.Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar.Int J Cancer. 2014; 134: 1484-1494Crossref PubMed Scopus (120) Google Scholar,12.Costa D.B. Kobayashi S. Pandya S.S. et al.CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib.J Clin Oncol. 2011; 29: e443-e445Crossref PubMed Scopus (508) Google Scholar]. And despite the modest intracranial activity of crizotinib [10.Solomon B.J. Mok T. Kim D.W. et al.First-line crizotinib versus chemotherapy in ALK-positive lung cancer.N Engl J Med. 2014; 371: 2167-2177Crossref PubMed Scopus (2463) Google Scholar,12.Costa D.B. Kobayashi S. Pandya S.S. et al.CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib.J Clin Oncol. 2011; 29: e443-e445Crossref PubMed Scopus (508) Google Scholar, 13.Hamilton G. Rath B. Burghuber O. Pharmacokinetics of crizotinib in NSCLC patients.Expert Opin Drug Metab Toxicol. 2015; 11: 835-842Crossref PubMed Scopus (39) Google Scholar, 14.Solomon B.J. 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; 34: 2858-2865Crossref PubMed Scopus (194) Google Scholar], the CNS remains the most common site of disease progression in patients treated with crizotinib [14.Solomon B.J. 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; 34: 2858-2865Crossref PubMed Scopus (194) Google Scholar]. While newer generation ALK tyrosine kinase inhibitors (TKIs) alectinib and ceritinib have been approved by the US Food and Drug Administration for the first-line treatment of ALK+ NSCLC [15.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 (1486) Google Scholar,16.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 (800) Google Scholar], robust, prospective analysis of intracranial efficacy has been lacking. In this issue ofAnnals of Oncology, Gadgeel et al. [17.Gadgeel S. Peters S. Mok T. et al.Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study.Ann Oncol. 2018; 29: 2214-2222Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar] report on the intracranial efficacy of alectinib in the ALEX study, a phase III trial that compared alectinib with crizotinib in the first-line treatment of ALK+ NSCLC [15.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 (1486) Google Scholar]. This study, which has recently been updated, was strongly positive in favour of alectinib with a median investigator-assessed progression-free survival of 34.8 months for alectinib compared with 10.5 months for crizotinib [18.Camidge D. Peters S. Mok T. et al.Updated efficacy and safety data from the global phase III ALEX study of alectinib (ALC) vs crizotinib (CZ) in untreated advanced ALK+ NSCLC [abstract] In ASCO Chicago. 2018; Google Scholar]. Importantly, the trial included 122 patients with treated or untreated baseline brain metastases (representing 40% of the study population), reflecting the prevalence of brain metastases in this population and allowing for formal, protocol-specified, prospective assessment of intracranial efficacy of alectinib. Intracranial overall response rates (ORR) to alectinib were exceptionally high regardless of prior brain radiotherapy (prior brain radiotherapy: 85.7% alectinib versus 71.4% in crizotinib; without prior brain radiotherapy: 78.6% versus 40%). Moreover, intracranial complete responses (CR) were achieved in 61.5% of previously irradiated patients receiving alectinib compared with 10.5% with crizotinib. The high intracranial ORR described by Gadgeel et al. in this phase III study are consistent with those seen in the pooled analysis of two phase II studies of alectinib in crizotinib-resistant patients [19.Gadgeel S.M. Shaw A.T. Govindan R. et al.Pooled analysis of CNS response to alectinib in two studies of pretreated patients with ALK-positive non-small-cell lung cancer.J Clin Oncol. 2016; 34: 4079-4085Crossref PubMed Scopus (143) Google Scholar] . They contrast with the modest intracranial efficacy of crizotinib reported in pooled analyses in the PROFILE 1005 and 1007 trials by Costa et al. [3.Costa D.B. Shaw A.T. Ou S.H. 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: 1881-1888Crossref PubMed Scopus (515) Google Scholar] and subsequent prospective analysis of intracranial efficacy of first line crizotinib in the PROFILE 1014 trial [14.Solomon B.J. 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; 34: 2858-2865Crossref PubMed Scopus (194) Google Scholar]. These results serve to clarify management in the commonly encountered clinical scenario of patients with ALK+ NSCLC who have brain metastases at diagnosis. The high intracranial ORR and rates of complete radiologic response in the alectinib arm are at least comparable to responses seen with brain radiotherapy [20.Weickhardt A.J. Scheier B. Burke J.M. et al.Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer.J Thoracic Oncol. 2012; 7: 1807-1814Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar]. Furthermore, intracranial responses seen with alectinib appear durable. In patients with measurable CNS disease, the median intracranial duration of response (DOR) in patients on the alectinib arm with prior brain radiotherapy was not reached and was 17.3 months in those without prior brain radiotherapy. In patients with non-measurable and/or measurable CNS disease, the median intracranial DOR was not reached in patients regardless of prior brain radiotherapy. These results suggest that upfront whole brain radiotherapy or stereotactic ablative radiotherapy may reasonably be avoided in many patients with CNS disease given the high and durable intracranial responses to alectinib. The investigators are to be credited for performing additional analyses in this study using the Response Assessment in Neuro-Oncology (RANO) – Brain Metastases (BM) criteria, a standardized uniform method of intracranial assessment [21.Lin N.U. Lee E.Q. Aoyama H. et al.Response assessment criteria for brain metastases: proposal from the RANO group.Lancet Oncol. 2015; 16: e270-e278Abstract Full Text Full Text PDF PubMed Scopus (510) Google Scholar]. Reassuringly, results by RANO-BM were consistent with those using RECIST criteria confirming the robustness of the findings. For example, the 12 month cumulative incidence rate (CIR) of CNS progression, without prior non-CNS progression was 19% (95% CI 9.7–30.7) in the alectinib arm compared with 59.4% (95% CI 43.6–72.1) in the crizotinib arm. In addition to responses in existing brain metastases, the analysis of the cumulative incidence of brain metastases demonstrates the effect of alectinib in preventing the emergence of new brain metastases in patients without brain metastases at baseline. The CIR of CNS progression at 12 months, without prior non-CNS progression, was lower with alectinib compared with crizotinib in patients with brain metastases (12 month CIR: 16% versus 58.3%, HR 0.18) and in patients without baseline CNS metastases (12 month CIR: 4.6% versus 31.5%, HR 0.14). The effect was independent of prior radiotherapy. This analysis indicates that alectinib is able to modify the natural history of CNS disease in ALK+ NSCLC by preventing or delaying the emergence of CNS disease. These results likely translate into significant improvements in quality of life, function and survival for patients, and reduce the well-documented health economic burden associated with the development of CNS metastases [2.Guerin A. Sasane M. Zhang J. et al.Brain metastases in patients with ALK+ non-small cell lung cancer: clinical symptoms, treatment patterns and economic burden.J Med Econ. 2015; 18: 312-322Crossref PubMed Scopus (69) Google Scholar,6.Burudpakdee C. Wong W. Seetasith A. et al.Economic impact of preventing brain metastases with alectinib in ALK-positive non-small cell lung cancer.Lung Cancer. 2018; 119: 103-111Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar]. The CNS analyses of ALEX presented here by Gadgeel et al. provide strong rationale for the use of alectinib in patients with ALK+ NSCLC both with and without brain metastases, given the robust evidence of intracranial and extracranial efficacy. There are additional promising CNS active ALK inhibitors, including brigatinib and lorlatinib [22.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 (457) Google Scholar, 23.Shaw A.T. Ou S.-H.I. Felip E. et al.Efficacy and safety of lorlatinib in patients (pts) with ALK+ non-small cell lung cancer (NSCLC) with one or more prior ALK tyrosine kinase inhibitor (TKI): a phase I/II study.J Clin Oncol. 2017; 35 (9006): 9006Crossref Google Scholar, 24.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 (442) Google Scholar], currently under evaluation in phase III trials. Analysis of CNS efficacy in these studies, including understanding the impact on established brain metastases and prevention of new brain metastases, will be important to how these newer generation ALK TKIs will ultimately contribute to the management of patients with ALK+ NSCLC. None declared.