A few pills twice a day keep ALK-positive non-small-cell lung cancer at bay
Editorial

A few pills twice a day keep ALK-positive non-small-cell lung cancer at bay

Lorenza Landi, Federico Cappuzzo

Onco-Hematology Department, AUSL Romagna, Ravenna, Italy

Correspondence to: Federico Cappuzzo, MD. Onco-Hematology Department, AUSL Romagna, 5, Viale Randi, 48100, Ravenna, Italy. Email: f.cappuzzo@gmail.com.

Provenance: This is an invited Editorial commissioned by the Section Editor Ming-Hui Zhang (Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China).

Comment on: 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;390:29-39.


Submitted Jul 13, 2017. Accepted for publication Jul 14, 2017.

doi: 10.21037/jtd.2017.07.76


Non-small-cell lung cancer (NSCLC) represents the paradigm of personalized treatment of human cancer. A number of oncogenic druggable alterations have been so far identified, with anaplastic lymphoma kinase (ALK) gene rearrangements being one of the most attractive (1). In the past 10 years, we have learned that the presence of such molecular event is associated with some specific pathological and clinical features, including a preferential seeding into the central nervous system (CNS) and, most importantly, anticipates response to anti-ALK agents (2-4). Front-line crizotinib, the first-in-class ALK-inhibitor, prolonged median progression-free survival (PFS) of 4 months respect to standard platinum-pemetrexed (11.9 vs. 7.0 months; HR =0.45, P<0.001), nearly doubling the probability of achieving responses [response rate (RR): 75% vs. 45%] and preserving quality of life, as demonstrated in the PROFILE 1014 trial (5). However, the drug does not definitively cure any patient and, within the first year of therapy, cancer eventually re-growths due to the occurrence of acquired resistance, with the CNS as the dominant site of progression (6). The new generation and FDA-approved ALK-inhibitors, ceritinib, alectinib and brigatinib, are more potent and brain-penetrable than crizotinib and retain activity against a wide spectrum of ALK resistance mutations (6). In single-arm studies, all these drugs resulted effective in crizotinib-failure setting, particularly in patients with brain metastases (BMs) (7-11). Furthermore, sequential use of crizotinib followed by ceritinib or alectinib produced a combined PFS exceeding 18 months (12,13). This is the reason why, the standard of care for advanced ALK positive NSCLC should include crizotinib followed by a second generation ALK inhibitor. However, it remains unclear whether upfront use of a second-generation ALK inhibitor could translate into a more durable benefit than the one observed with sequential approach.

In a recent issue of The Lancet, Hida and colleagues reported results of the J-ALEX, a phase 3 randomized Japanese trial directly comparing alectinib to crizotinib in 207 ALK rearranged NSCLCs who had never received an ALK inhibitor (14). Notably, the study also included individuals previously exposed to one line of chemotherapy and with asymptomatic BMs, regardless of prior radiation therapy (RT). Stratification was done according to ECOG performance status (0/1 vs. 2), treatment line (first vs. second) and disease stage (IIIB vs. IV). The study met its primary end-point of PFS by independent review, demonstrating an impressive reduction in the risk of progression of 66% for patients treated with alectinib (PFS: not reached, NR vs. 10.2 months; HR =0.34, P<0.0001). In addition, alectinib had greater intracranial activity (HR for PFS 0.16) also delaying the onset of BMs (HR for time to BMs onset 0.41), had a numerically higher RR (92% vs. 79%) and a more favorable safety profile than crizotinib [grade 3–4 adverse events (AEs): 26% vs. 52%]. Importantly, the PFS improvement equally emerged in all groups of subjects, irrespective of age, sex, line of therapy, or disease stage.

Collectively, these results support the upfront use of alectinib. Particularly, even if the PFS has been not yet reached, it exceeded 20 months at the lower limit, more than expected with first line crizotinib—with a median PFS of 10–11 months—followed by alectinib -with a median PFS in the range of 7–8 months (5,9,10). On this perspective, front-line alectinib could actually translate into an overall survival advantage. In addition, note that there is a not negligible fraction of patients for which disease progression after crizotinib occurs with rapid clinical deterioration, precluding the opportunity of receiving a more effective drug.

Therefore, are J-ALEX findings sufficient to change current practice in non-Japanese populations? It is not possible to exclude that the remarkable activity of alectinib could simply reflect racial differences or a more squeezing patient selection. Indeed, in the study, the dose of alectinib is half than the one used outside Japan (300 mg twice daily vs. 600 mg twice daily), suggesting some imbalance in drug metabolism. In addition, ALK positivity was confirmed in parallel by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) in 93% of cases or, by real time polymerase-chase reaction (RT-PCR) in the remaining 7%, potentially magnifying the sensitivity of a more potent ALK-inhibitor in a super-selected population. Furthermore, beyond constitutive and molecular characteristics, the number of patients having BMs at baseline is higher in the crizotinib arm (29 vs. 14 patients), and the presence of intracranial lesions was not a stratification factor. Finally, although crizotinib similarly performed with the PROFILE 1014 and 1029 (5,15) in terms of RR and PFS, the consistent proportion of subjects requiring dose interruption (74%) or reduction (20%) for AEs could have negatively affected the efficacy of the comparator arm.

Fortunately, all these points have been addressed by the global ALEX trial, a phase III, head-to-head study of alectinib 600 mg twice daily vs. standard-dose crizotinib (16). Overall, 303 ALK-IHC positive and untreated NSCLCs were included onto the study. Baseline characteristics were well balanced between the two arms. Particularly, 45% of subjects were Asians, 40% had BMs and among them, more than 80% did not receive prior brain radiation. Primary end-point was PFS by investigator assessment, whereas key secondary end point was time to CNS progression. Treatment with alectinib was associated with longer PFS (NR vs. 11.1 months, HR =0.47; P<0.001) and better safety profile (incidence of grade 3 to 5 AEs, 41% vs. 50%) and, most importantly, it prevented the occurrence of BMs (cause-specific HR =0.16, P<0.001). These findings indirectly confirmed those produced in the J-ALEX, thus placing alectinib instead of crizotinib as the new standard of care worldwide. Nevertheless, this change will have two immediate consequences. The first one is how alectinib could re-define the current management of BMs (17,18). Evidences from J-ALEX and ALEX demonstrate that the drug obtains an excellent intracranial control and prevents metastatic spread into the CNS, reinforcing the conviction that RT—especially whole brain RT—could be deferred as salvage treatment with a favorable impact in preserving neurocognitive functions. The second one concerns the molecular pattern of alectinib failure. Both target-dependent and non-target-dependent mechanisms of resistance have been described for alectinib, but they mainly refer to second line setting, for example at crizotinib progression (6). It is conceivable that a more potent and selective ALK-inhibitor such as alectinib, when used early, could shift the spectrum of resistance mechanisms in favour of non-target-dependent events, including MET amplification or histologic transformation. The knowledge of the resistance pattern will be crucial to design the optimal sequential strategy.

Beyond alectinib, two other second generation ALK-inhibitors have been tested in first-line setting (19,20). In the currently ongoing ALTA-1L trial, brigatinib is compared to crizotinib as front-line or after-chemo treatment and results are expected for 2018 (19). In the recently published ASCEND 4, whose trial design was quite similar to PROFILE 1014 and 1029, ceritinib has been compared to platinum-pemetrexed combination (20). Not surprisingly, ceritinib did better than chemotherapy, prolonging PFS in overall population (16.6 vs. 8.1 months, HR =0.55, P<0.00001), as well as in the subgroup of patients with or without CNS involvement (26.3 vs. 8.3 months; HR =0.48 and 10.7 vs. 6.7 months; HR =0.70, respectively). Unfortunately, the drug safety profile emerged as a major limitation. Dose interruption or reduction due to AEs was required in 80% of patients compared with 45% in chemo-arm, a “hard-to-justify” percentage especially for a targeted agent and in metastatic setting. Further, the efficacy of ceritinib in presence of BMs was not so convincing, as the differential PFS improvement produced by ceritinib vs. chemo for patients with BMs was less shocking than the one observed in individuals without CNS involvement (4 vs. 18 months), with no clear neuroprotective effect. For such reasons, the optimal positioning of ceritinib should probably remain the crizotinib-failure context.

In conclusion, J-ALEX and ALEX findings coupled with all the available data firmly place alectinib as the new standard of care in untreated ALK positive NSCLC, representing the second watershed in the treatment of this disease.


Acknowledgement

This work has been partially supported by Fondazione Ricerca Traslazionale (FoRT).


Footnote

Conflicts of Interest: Dr. Cappuzzo declares consultancy role for Roche, Pfizer, Novartis and Takeda. Dr. Landi declares consultancy role for Pfizer.


References

  1. 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. [Crossref] [PubMed]
  2. Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res 2008;14:4275-83. [Crossref] [PubMed]
  3. Inamura K, Takeuchi K, Togashi Y, et al. EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset. Mod Pathol 2009;22:508-15. [Crossref] [PubMed]
  4. Gainor JF, Ou SH, Logan J, et al. The central nervous system as a sanctuary site in ALK-positive non-small-cell lung cancer. J Thorac Oncol 2013;8:1570-3. [Crossref] [PubMed]
  5. Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014;371:2167-77. [Crossref] [PubMed]
  6. Gainor JF, 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;6:1118-33. [Crossref] [PubMed]
  7. Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 2014;370:1189-97. [Crossref] [PubMed]
  8. Shaw AT, Kim TM, Crinò 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;18:874-86. [Crossref] [PubMed]
  9. Ou SH, Ahn JS, De Petris L, et al. Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study. J Clin Oncol 2016;34:661-8. [Crossref] [PubMed]
  10. Shaw AT, Gandhi L, Gadgeel S, et al. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol 2016;17:234-42. [Crossref] [PubMed]
  11. Kim DW, Tiseo M, Ahn MJ, 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;35:2490-8. [Crossref] [PubMed]
  12. Gainor JF, Tan DS, De Pas T, et al. Progression-Free and Overall Survival in ALK-Positive NSCLC Patients Treated with Sequential Crizotinib and Ceritinib. Clin Cancer Res 2015;21:2745-52. [Crossref] [PubMed]
  13. Watanabe S, Hayashi H, Okamoto K, et al. Progression-Free and Overall Survival of Patients With ALK Rearrangement-Positive Non-Small Cell Lung Cancer Treated Sequentially With Crizotinib and Alectinib. Clin Lung Cancer 2016;17:528-34. [Crossref] [PubMed]
  14. 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;390:29-39. [Crossref] [PubMed]
  15. Lu S, Mok T, Lu Y, et al. Phase 3 study of first-line crizotinib vs pemetrexed−cisplatin/carboplatin (PCC) in East Asian patients (pts) with ALK+ advanced non-squamous non-small cell lung cancer (NSCLC). J Clin Oncol 2016;34:(Suppl 15; abstr 9058).
  16. Peters S, Camidge DR, Shaw AT, et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2017. [Epub ahead of print]. [Crossref] [PubMed]
  17. 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 metastases. J Clin Oncol 2016;34:123-9. [Crossref] [PubMed]
  18. Rusthoven CG, Doebele RC. Management of Brain Metastases in ALK-Positive Non-Small-Cell Lung Cancer. J Clin Oncol 2016;34:2814-9. [Crossref] [PubMed]
  19. Tiseo M, Popat S, Gettinger SN, et al. Design of ALTA-1L (ALK in lung cancer trial of brigatinib in first-line), a randomized phase 3 trial of brigatinib (BRG) versus crizotinib (CRZ) in tyrosine kinase inhibitor (TKI)-naive patients (pts) with advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). J Clin Oncol 2017;35:(suppl; abstr TPS9098).
  20. Soria JC, Tan DS, 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;389:917-29. [Crossref] [PubMed]
Cite this article as: Landi L, Cappuzzo F. A few pills twice a day keep ALK-positive non-small-cell lung cancer at bay. J Thorac Dis 2017;9(8):2311-2314. doi: 10.21037/jtd.2017.07.76