Alectinib – a better first-line treatment than crizotinib in ALK-positive advanced non-small-cell lung cancer?
Lung cancer is by far the leading cause of cancer death worldwide.1 Patients who have non-small-cell lung cancer (NSCLC) with rearrangements of the anaplastic lymphoma kinase (ALK) gene (ALK-positive) represent a minority of cases (around 5%) but are typically younger and have never smoked, or smoked very little.2People with ALK-positive NSCLC are also more likely to develop brain metastases,3 for which, until recently, the only treatment options were radiotherapy or surgery, and which usually proved to be fatal. The treatment of these patients was transformed in 2013 when the ALK inhibitor, crizotinib (Xalkori® Pfizer Inc., New York, US), received approval from the US Food and Drug Administration (FDA) after showing response rates of over 70% in phase III studies.4However, most patients treated with first-line crizotinib relapse within a year, often due to the development of ALK resistance mutations,5prompting the development of second-line ALK inhibitors that are more potent and brain-penetrable, and include ceritinib (Zykadia®, Novartis, Basel, Switzerland)6 and alectinib (Alecensa®, Roche, Basel, Switzerland).7 These drugs are also active against the most common crizotinib-resistance mutations.
Alectinib is a potent, highly selective ALK inhibitor that is currently approved by the FDA for people with ALK-positive NSCLC who have progressed or are intolerant to crizotinib in Europe, the US, and nine other countries globally. However, recent data suggests that alectinib might also be preferable to crizotinib as a first-line treatment option. In 2016, results were presented from the J-ALEX study, an open-label, phase III clinical trial in 207 treatment-naïve, Japanese patients, with ALK-positive NSCLC. Results showed that alectinib significantly improved progression-free survival (PFS) compared with crizotinib (not reached versus 10.2 months; hazard ratio [HR] 0.34; p8This finding was consistent with previous clinical trials of crizotinib. All subgroups gained more benefit from alectinib than crizotinib, but the PFS benefit was particularly notable in patients with brain metastases (HR 0.08). Baseline characteristics were similar between the groups, apart from the fact that a higher proportion of patients taking crizotinib had brain metastases compared with those randomized to alectinib (27.9% versus 13.6%, respectively). The duration of follow-up was 12.0 months in the alectinib arm and 12.2 months in the crizotinib arm. The objective response rates (ORR) were 91.6% in the alectinib arm and 78.9% in the crizotinib arm. The disease-control rate was 100%, i.e., no patients progressed on first-line therapy. As a result, Roche received a second breakthrough therapy designation from the FDA in the first-line treatment setting.
In April 2017, the much-anticipated global ALEX study was completed. This phase III trial randomized 303 treatment-naïve people with ALK-positive NSCLC to receive either alectinib or crizotinib. The primary endpoint, median PFS, was significantly improved with alectinib compared with crizotinib, according to a media release from Roche.9 Complete results will be presented at an upcoming medical meeting.
Importantly, across all studies, alectinib has been well tolerated with minimal gastrointestinal toxicities. In the J-ALEX study, participants taking alectinib had a lower incidence of grade 3/4 adverse events (AEs) than those taking crizotinib (51.9% versus 26.2%, respectively). A higher proportion of patients in the crizotinib arm discontinued the study drug due to AEs, than in the alectinib arm (20.2% versus 8.7%, respectively). The same was true of dose interruption due to AEs (74.0% with crizotinib versus 29.1%, with alectinib). In a pooled analysis of two phase II studies of alectinib in crizotinib-resistant patients, grade 3–5 AEs occurred in 37% of patients, and AEs leading to dose interruption or dose reduction occurred in 33% of patients.10
Hot on the heels of alectinib is ceritinib, which is currently being evaluated in the ASCEND clinical studies. The ASCEND-4 phase III study compared ceritinib with platinum/pemetrexed chemotherapy in newly diagnosed patients with advanced ALK-positive NSCLC. Ceritinib was shown to be superior to chemotherapy, with a median PFS of 16.6 months in the ceritinib arm and 8.1 months in the chemotherapy arm (HR = 0.55, p11 While there have been no direct comparisons of ceritinib and crizotinib, these data are likely to result in regulatory approval of ceritinib in the first-line setting. However, there are questions around the tolerability of ceritinib; in ASCEND-4, 78% of patients in the ceritinib group experienced grade 3 or 4 adverse AEs, and 80% of ceritinib-treated patients needed dose interruption or reduction.
Based on these results, it seems likely that alectinib will become the new standard first-line therapy for ALK-positive NSCLC. The magnitude of the PFS benefit will be interesting. Sequential therapy with crizotinib followed by alectinib gives a combined median PFS of 18 to 20 months; therefore, the benefit of first-line alectinib will ideally exceed this to justify a switch from first-line crizotinib to first-line alectinib. Unfortunately, the ALEX study did not incorporate a crossover design, allowing patients who progressed on crizotinib to cross over to alectinib. In addition, we do not know yet whether these impressive PFS findings will translate to improved overall survival, the ultimate aim of cancer therapeutics.
Further data on alectinib is needed, particularly in regard to resistance. Resistance to alectinib involving secondary ALK mutations is known to occur when used as second-line therapy,12 and it remains to be seen whether how quickly resistance will develop in treatment-naïve patients. First-line use of more potent ALK inhibitors may result in different resistance mechanisms, requiring the development of new second-line therapies. Brigatinib13 and lorlatinib14 are promising next-generation ALK inhibitors and several others are in clinical development. Alectinib-based combination therapy is currently being investigated, including alectinib with the programmed cell death ligand 1 (PD-L1) inhibitor atezolizumab and alectinib with bevacizumab. Studies of these and other alectinib-based combinations may identify new treatment strategies that can overcome and perhaps prevent resistance. Nevertheless, the therapeutic landscape for ALK-positive NSCLC has been transformed over the last year, offering hope to patients who have, historically, faced a poor prognosis.
1. Siegel RL, Miller KD, Jemal A, Cancer statistics, 2016, CA Cancer J Clin, 2016;66:7-30.
2. Rodig SJ, Mino-Kenudson M, Dacic S, et al., Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population, Clin Cancer Res, 2009;15:5216-23.
3. 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;18:312-22.
4. 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.
5. Camidge DR, Pao W, Sequist LV, Acquired resistance to TKIs in solid tumours: learning from lung cancer, Nat Rev Clin Oncol, 2014;11:473-81.
6. 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.
7. Gadgeel SM, Gandhi L, Riely GJ, et al., Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study, Lancet Oncol, 2014;15:1119-28.
8. Nokihara H, Hida T, Kondo M, et al., Alectinib (ALC) versus crizotinib (CRZ) in ALK-inhibitor naive ALK-positive non-small cell lung cancer (ALK+ NSCLC): Primary results from the J-ALEX study, J Clin Oncol, 2016;34:Suppl; abstr 9008.
9. Roche Media Release, Available at: www.roche.com/media/store/releases/med-cor-2017-04-10.htm (accessed April 18, 2017).
10. Yang J, Ou SH, De Petris L, et al., Pooled efficacy and safety data from two phase II studies (NP28673 and NP28761) of alectinib in ALK+ non-small-cell lung cancer (NSCLC), J Thoracic Oncol, 2017;12 (suppl): S1170–S1171
11. 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.
12. 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.
13. Camidge DR, Bazenhova L, Salgia R, et al., Safety and efficacy of brigatinib (AP26113) in advanced malignancies, including ALK+ non–small cell lung cancer (NSCLC), J Clin Oncol, 2015;33 (suppl; abstr 8062).
14. Solomon BJ, Bauer TM, Felip E, et al., Safety and efficacy of lorlatinib (PF-06463922) from the dose-escalation component of a study in patients with advanced ALK+ or ROS1+ non-small cell lung cancer (NSCLC) J Clin Oncol, 2016;34(suppl; abstr 9009).