Serial molecular genotyping of resistant tumors may potentially guide proper sequencing of next-generation ALK inhibitors, beginning at the initial selection of a next-generation inhibitor after crizotinib failure.
—Alice T. Shaw, MD, PhD
Since the initial discovery of ALK rearrangement in non–small cell lung cancer (NSCLC) in 2007,1 small molecule tyrosine kinase inhibitors of ALK have transformed the course of disease for those patients with ALK-rearranged (ie, ALK-positive) NSCLC. Crizotinib (Xalkori), a multitargeted tyrosine kinase inhibitor of ALK, ROS1, and CMET, was the first targeted therapy developed for patients with advanced ALK-positive NSCLC2 and has demonstrated superiority compared with first- and second-line chemotherapy in global randomized trials.3,4 However, patients invariably relapse on crizotinib, often within the first year of treatment.
To address the growing issue of crizotinib resistance, multiple next-generation ALK inhibitors have been developed. The first of these new drugs—ceritinib (Zykadia)—showed significant clinical activity in a global phase I study,5 leading to its approval in the United States, Europe, and elsewhere. Alectinib (Alecensa) now joins ceritinib as another next-generation ALK inhibitor approved in the United States for patients with advanced ALK-positive NSCLC previously treated with crizotinib.
Supporting Clinical Data
The approval of alectinib by the U.S. Food and Drug Administration (FDA) was based on two phase II studies: one conducted globally6 and one conducted in the United States and Canada.7 These studies are reviewed in this issue of The ASCO Post. Efficacy and safety results were similar between the two studies.
Overall, alectinib was highly active in ALK-positive patients who had progressed on crizotinib, inducing responses in close to 50% of patients. Responses were durable, with median durations of response of 11.2 and 13.5 months in the global and U.S./Canadian studies, respectively.6,7 Median progression-free survival was also comparable at 8.9 and 8.1 months, respectively.6,7 Alectinib was associated with primarily grade 1 or 2 side effects, with the most common being (across both studies) fatigue (41%), constipation (34%), edema (30%), and myalgias (29%).8
Focus on CNS Metastases
Both studies also highlight one of the most important aspects of alectinib’s activity: namely, its efficacy in treating central nervous system (CNS) metastases. Unlike other studies of ALK inhibitors that have examined intracranial activity retrospectively, these two studies assessed CNS activity prospectively, and the results are included in the FDA label for alectinib.
Across both studies, 60% of patients had known CNS metastases at the time of enrollment, and of these patients, 51 had baseline measurable CNS lesions. The response rate among these 51 patients was 61%, and median duration of intracranial response was 9.1 months.8 CNS responses were observed in patients regardless of prior brain radiation status, including in those who had never received brain radiation. In addition, in separate studies, alectinib has been noted to have activity not only in parenchymal CNS metastases but also in leptomeningeal disease.9,10 Taken together, these results suggest that alectinib is highly effective in patients with progressive and untreated CNS metastases, including leptomeningeal disease.
Choice of ALK Inhibitor
These two studies, along with the recent approval of alectinib, raise several important questions regarding the management of patients with advanced ALK-positive NSCLC. First, in a patient who has relapsed on crizotinib, which next-generation ALK inhibitor should be prescribed?
This question does not have a simple answer, since the pattern of relapse can differ from patient to patient, with some patients developing a single site of relapse (for example, in the CNS), and others having more extensive relapse in the CNS, the body, or both. In addition, no randomized head-to-head trials comparing next-generation ALK inhibitors have been performed, making it difficult to compare efficacy or safety.
Based on the available single-arm studies of alectinib and ceritinib in crizotinib-resistant disease, the systemic efficacy of these drugs may be roughly comparable. There may be potential advantages of alectinib over ceritinib, including alectinib’s documented intracranial activity and its favorable safety profile, but, ultimately, the choice of next-generation ALK inhibitor will need to be individualized for each patient.
A related and perhaps more important question is whether patients could benefit from both drugs, one given after the other. In the literature, there are data supporting the sequential use of alectinib after ceritinib, for example in the setting of progressive CNS disease, including in those with symptomatic disease10 or in patients who have developed the ceritinib resistance mutation F1174V.11 Similarly, ceritinib may be active after alectinib in patients who become resistant due to the alectinib resistance mutation I1171.12
Of note, both F1174 and I1171 mutations rarely emerge after crizotinib therapy. Thus, serial molecular genotyping of resistant tumors may potentially guide proper sequencing of next-generation ALK inhibitors, beginning at the initial selection of a next-generation inhibitor after crizotinib failure.
Comparing First-Line Options
The second question that needs to be addressed is whether next-generation ALK inhibitors like alectinib should be used in the first-line setting in place of crizotinib. At present, the standard approach—sequential therapy with crizotinib followed by a next-generation ALK inhibitor—is associated with a combined median progression-free survival of 18 to 20 months.13 Whether first-line use of a next-generation ALK inhibitor can lead to a comparable outcome is not yet known. However, limited data with several of the next-generation ALK inhibitors suggest that this could be the case.
In particular, in a small Japanese phase II study of 46 crizotinib-naive patients, the response rate with alectinib was 94%, and median progression-free survival was 28 months.14 In the global phase I study of ceritinib, median progression-free survival among 83 crizotinib-naive patients was also prolonged, at 18.4 months.15 Thus, single-arm studies suggest that first-line use of next-generation ALK inhibitors may be highly effective.
To directly address the question of optimal first-line therapy for advanced ALK-positive NSCLC, two first-line studies comparing alectinib with crizotinib have recently completed enrollment: one conducted in Japan (J-ALEX) and one conducted globally (ALEX). It is widely anticipated that these studies will be positive, favoring alectinib over crizotinib in terms of progression-free survival. However, what will be most important is the magnitude of progression-free survival benefit. Since sequential therapy with crizotinib followed by alectinib provides a combined median progression-free survival of 18 to 20 months, the magnitude of benefit will need to be at least 6 months to justify a switch from first-line crizotinib to first-line alectinib. Unfortunately, the ALEX study does not incorporate a crossover design (ie, patients who progress on crizotinib will not automatically cross over to alectinib), thus precluding a direct comparison of first-line alectinib vs sequential crizotinib/alectinib.
The Issue of Resistance
The third and final question concerns resistance to alectinib. As with other targeted therapies, all patients will relapse at some point on alectinib, including in the CNS. As previously mentioned, in some patients, resistance to alectinib may be due to a specific ALK resistance mutation affecting the I1171 residue.12 This is an important mutation to identify, since ceritinib has been reported to have activity against I1171 mutants.12
Another ALK resistance mutation that has been observed in alectinib-resistant tumors is G1202R. This mutation confers resistance to almost all ALK inhibitors in the clinic, except for lorlatinib (PF-06463922). In early studies, lorlatinib demonstrated potent clinical activity against resistant tumors harboring the ALK G1202R mutation.16 Thus, for some patients relapsing on alectinib, another next-generation ALK inhibitor may represent an effective therapy.
However, for likely a majority of alectinib-resistant cases, the tumors lack an ALK resistance mutation and have become ALK-independent. In these cases, patients may not benefit from another next-generation ALK inhibitor given as monotherapy. Instead, they may require combination strategies including a next-generation ALK inhibitor or standard therapies such as chemotherapy. Given its safety profile, alectinib may be a particularly attractive candidate for combination approaches.
Investigation of a few alectinib-based combinations is already underway in the clinic, including alectinib in combination with the programmed cell death ligand 1 (PD-L1) inhibitor atezolizumab and alectinib combined with bevacizumab (Avastin). Studies of these and other alectinib-based combinations should help to identify new therapeutic strategies that can overcome and even potentially prevent resistance. ■
Disclosure: Dr. Shaw reported consulting and honoraria from Genentech, Roche, Pfizer, Novartis, Ignyta, and Ariad.
1. Soda M, Choi YL, Enomoto M, et al: Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561-566, 2007.
2. Kwak EL, Bang YJ, Camidge DR, et al: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363:1693-1703, 2010.
3. Shaw AT, Kim DW, Nakagawa K, et al: Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368:2385-2394, 2013.
4. Solomon BJ, Mok T, Kim DW, et al: First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 371:2167-2177, 2014.
5. Shaw AT, Kim DW, Mehra R, et al: Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 370:1189-1197, 2014.
6. Ou SI, 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. November 23, 2015 (early release online).
7. 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. December 18, 2015 (early release online).
8. Alecensa (alectinib) prescribing information, Genentech, 2015. Available at http://www.gene.com/download/pdf/alecensa_prescribing.pdf. Accessed January 8, 2016.
9. Ou SH, Sommers KR, Azada MC, et al: Alectinib induces a durable (> 15 months) complete response in an ALK-positive non-small cell lung cancer patient who progressed on crizotinib with diffuse leptomeningeal carcinomatosis. Oncologist 20:224-226, 2015.
10. Gainor JF, Sherman CA, Willoughby K, et al: Alectinib salvages CNS relapses in ALK-positive lung cancer patients previously treated with crizotinib and ceritinib. J Thorac Oncol 10:232-236, 2015.
11. Ou SH, Milliken JC, Azada MC, et al: ALK F1174V mutation confers sensitivity while ALK I1171 mutation confers resistance to alectinib: The importance of serial biopsy post progression. Lung Cancer 91:70-72, 2016.
12. Katayama R, Friboulet L, Koike S, et al: Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib. Clin Cancer Res 20:5686-5696, 2014.
13. 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 21:2745-2752, 2015.
14. Tamura T, Seto T, Nakagawa K, et al: Updated data of a phase I/II study (AF-001JP) of alectinib, a CNS-penetrant, highly selective ALK inhibitor in ALK-rearranged advanced NSCLC. Int J Radiat Oncol Biol Phys 90:S6, 2014.
15. Felip E, Kim DW, Mehra R, et al: Efficacy and safety of ceritinib in patients with advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC): An update of ASCEND-1. 2014 European Society for Medical Oncology Meeting. Poster presented September 2014.
16. Shaw AT, Bauer TM, Felip E, et al: Clinical activity and safety of PF-06463922 from a dose escalation study in patients with advanced ALK+ or ROS1+ NSCLC. 2015 ASCO Annual Meeting. Abstract 8018. Presented May 29, 2015.