The prolonged front-line progression-free survival seen with second-generation inhibitors, coupled with rationally developed second-line options, should ultimately translate to longer overall survival [in ALK-positive NSCLC].— Alice T. Shaw, MD, PhD
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Anaplastic lymphoma kinase (ALK) rearrangements define a subset of non–small cell lung cancer (NSCLC) patients for whom ALK inhibitors are highly effective. In PROFILE 1014, the multitargeted ALK inhibitor crizotinib (Xalkori) was shown to be superior to platinum/pemetrexed (Alimta) chemotherapy in newly diagnosed patients with advanced ALK-positive NSCLC.1 In that study, median progression-free survival was 10.9 months with crizotinib compared to 7 months with chemotherapy (hazard ratio [HR] = 0.45, P < .001). Other efficacy endpoints as well as safety and patient-reported outcomes also favored crizotinib, firmly establishing crizotinib as the standard first-line therapy for advanced ALK-positive NSCLC.
Second-generation ALK inhibitors, including ceritinib (Zykadia), alectinib (Alecensa), and the investigational agent brigatinib, have followed closely on the heels of crizotinib. More potent and brain-penetrable than crizotinib, these drugs also retain activity against the most common crizotinib-resistance mutations, such as the gatekeeper ALK L1196M mutation.2-4 In single-arm studies, second-generation ALK inhibitors have been shown to be effective in the majority of crizotinib-resistant patients, leading to regulatory approval of ceritinib and alectinib in the post-crizotinib setting.5,6 At the present time, standard therapy of advanced ALK-positive NSCLC consists of sequential crizotinib followed by a second-generation ALK inhibitor.
Changing Paradigm
However, based on several recent studies testing second-generation inhibitors in the front-line setting, this treatment paradigm is about to change. One of the studies fueling this change is the ASCEND-4 trial recently reported by Soria and colleagues in The Lancet and reviewed in this issue of The ASCO Post.7 In this global randomized phase III trial, ceritinib was compared head-to-head with platinum/pemetrexed chemotherapy in newly diagnosed patients with advanced ALK-positive NSCLC. As expected, ceritinib easily beat chemotherapy, with a median progression-free survival of 16.6 months in the ceritinib arm and 8.1 months in the chemotherapy arm (HR = 0.55, P < .00001).
Consistent with these data, in two previous single-arm studies of ceritinib in crizotinib-naive patients (ASCEND-1 and ASCEND-3), median progression-free survival was similarly prolonged at 18.4 months in each study.5,8 Of note, in a retrospective analysis, sequential treatment with crizotinib followed by ceritinib was associated with a comparable median “combined” progression-free survival of 17.4 months.9 Although the ideal comparator arm in ASCEND-4 would have received crizotinib (or better yet, crizotinib followed by ceritinib), the prolonged progression-free survival seen with ceritinib across three separate trials suggests that patients almost certainly derive greater benefit from front-line ceritinib compared to front-line crizotinib. Thus, more potent target inhibition, particularly in the brain, coupled with suppression of common on-target mechanisms of resistance does appear to translate into more durable clinical responses.
ASCEND-4 Limitations
While the positive results of this study are likely to lead to regulatory approval of ceritinib as first-line therapy in advanced ALK-positive NSCLC, two major issues may dampen the impact of this study. First, the standard dose of ceritinib—750 mg daily under fasting conditions (ie, not administered within 2 hours of a meal)—is difficult for patients to tolerate due to gastrointestinal side effects and liver function test abnormalities. In ASCEND-4, 78% of patients in the ceritinib group experienced grade 3 or 4 adverse events, and 80% of ceritinib-treated patients required dose interruption or dose reduction. By comparison, among patients treated with crizotinib in PROFILE 1014, 54% experienced grade 3 or 4 adverse events, 41% required dose interruption, and only 6% required dose reduction.1 Thus, from a toxicity standpoint, patients may fare better starting with a less toxic drug (crizotinib), before transitioning to a more toxic drug (ceritinib) at disease progression.
Second, a more tolerable and more brain-penetrable ALK inhibitor—alectinib—has recently been tested in the upfront setting and is widely anticipated to become the new standard of care. In the J-ALEX study, alectinib was compared head-to-head with crizotinib in Japanese patients with crizotinib-naive, ALK-positive NSCLC.10 At the second preplanned interim analysis, alectinib was found to significantly improve progression-free survival compared with crizotinib (median = not reached vs 10.2 months, HR = 0.34, P < .0001). All subgroups of patients derived greater benefit from alectinib, but this benefit was particularly notable in patients with brain metastases, in whom median progression-free survival was not reached vs 10.2 months (HR = 0.09, P = .0002).11 Of note, in ASCEND-4, median progression-free survival with ceritinib in the subgroup of patients with brain metastases was only 10.7 months, highlighting the relatively weaker central nervous system (CNS) activity of ceritinib.
Importantly, across all studies, alectinib has been shown to be well tolerated with minimal gastrointestinal toxicities. In a pooled analysis of two phase II studies of alectinib in crizotinib-resistant patients, grade 3–5 adverse events occurred in 37% of patients, and adverse events leading to dose interruption or dose reduction occurred in 33% of patients.6 Results from the global ALEX study comparing alectinib with crizotinib as first-line therapy in ALK-positive NSCLC are expected this spring. If the global ALEX results replicate the findings of J-ALEX, alectinib will become the preferred first-line treatment (over crizotinib or ceritinib) for ALK-positive NSCLC.
Nevertheless, the results of ASCEND-4 signal the beginning of a new chapter in the treatment of advanced ALK-positive NSCLC. In just 5 years, standard front-line therapy has moved from cytotoxic chemotherapy to crizotinib and now to second-generation inhibitors. The median progression-free survival of 16.6 months with first-line ceritinib is particularly remarkable in light of the historically poor overall survival seen with metastatic NSCLC, including ALK-positive NSCLC.12
Unanswered Questions
In addition to ceritinib and alectinib, other second- and third-generation ALK inhibitors are also being tested in randomized first-line trials. Several of these drugs have broader activity than ceritinib or alectinib against ALK resistance mutations,13-15 as well as potent CNS activity, raising the possibility of even more durable responses in the first-line setting. Since these trials use crizotinib as the comparator, establishing which next-generation inhibitor is best in the front-line setting will have to be inferred from cross-trial comparisons of efficacy and safety.
In conclusion, emerging data on first-line use of second-generation ALK inhibitors will likely lead to a fundamental change in the treatment landscape of ALK-positive NSCLC. The prolonged front-line progression-free survival seen with ceritinib and alectinib reflects improved systemic as well as CNS control of disease and will likely lead to regulatory approval of these two drugs for newly diagnosed ALK-positive NSCLC.
However, many questions remain to be answered. For example, what are the resistance mechanisms underlying relapses on first-line ceritinib or alectinib? Both on-target and off-target mechanisms of resistance have been described for these two drugs, but they have been primarily in the setting of second-line treatment (post-crizotinib).13 Will the spectrum of resistance mechanisms shift with first-line use of more potent and selective ALK inhibitors, favoring off-target mechanisms like MET amplification or histologic transformation? Compared with on-target secondary ALK mutations, off-target mechanisms have been more difficult to surmount in the clinic. Elucidating these resistance mechanisms will be crucial to developing effective second-line treatments.
Finally, will first-line use of second-generation inhibitors improve the most important endpoint: overall survival? While analysis of overall survival will inevitably be confounded by post-study treatments, the prolonged front-line progression-free survival seen with second-generation inhibitors, coupled with rationally developed second-line options, should ultimately translate to longer overall survival. ■
Dr. Shaw is Director, Center for Thoracic Cancers, Massachusetts General Hospital and Associate Professor of Medicine, Harvard Medical School, Boston.
Disclosure: Dr. Shaw has received honoraria from or is a consultant for Novartis, Pfizer, Genentech/Roche, Ariad, Ignyta, Blueprint Medicines, Loxo Oncology, Daiichi Sankyo, Taiho, EMD Serono, and Foundation Medicine and is on the scientific advisory boards of Blueprint Medicines and KSQ Therapeutics.
References
1. 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.
2. Friboulet L, Li N, Katayama R, et al: The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov 4:662-673, 2014.
3. Sakamoto H, Tsukaguchi T, Hiroshima S, et al: CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell 19:679-690, 2011.
4. Katayama R, Khan TM, Benes C, et al: Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci U S A 108:7535-7540, 2011.
5. Kim DW, Mehra R, Tan DS, et al: Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): Updated results from the multicentre, open-label, phase 1 trial. Lancet Oncol 17:452-463, 2016.
6. 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). 2016 World Conference on Lung Cancer. Abstract P3.02a-016. Presented December 7, 2016.
7. 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 389:917-929, 2017.
8. Felip E, Orlov S, Park K, et al: Phase II study of ceritinib in previously treated ALKi-naive patients with ALK+ NSCLC: Whole-body efficacy in all patients and in patients with baseline brain metastases. 2016 ESMO Congress. Abstract 1208O. Presented October 9, 2016.
9. 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.
10. Nokihara H, Hida T, Kondo M, et al: Alectinib versus crizotinib in ALK inhibitor naive ALK-positive non-small cell lung cancer: Primary results from the J-ALEX study. 2016 ASCO Annual Meeting. Abstract 9008. Presented June 3, 2016.
11. Kim YH, Hida T, Nokihara H, et al: Alectinib versus crizotinib in ALK-positive non-small cell lung cancer: Primary results from phase III study (J-ALEX). 2016 World Conference on Lung Cancer. Abstract MA07.03. Presented December 6, 2016.
12. Shaw AT, Yeap BY, Solomon BJ, et al: Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: A retrospective analysis. Lancet Oncol 12:1004-1012, 2011.
13. 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 6:1118-1133, 2016.
14. Zou HY, Friboulet L, Kodack DP, et al: PF-06463922, an ALK/ROS1 inhibitor, overcomes resistance to first and second generation ALK inhibitors in preclinical models. Cancer Cell 28:70-81, 2015.
15. Zhang S, Anjum R, Squillace R, et al: The potent ALK inhibitor brigatinib (AP26113) overcomes mechanisms of resistance to first- and second-generation ALK inhibitors in preclinical models. Clin Cancer Res 22:5527-5538, 2016.
