Ensartinib (X-396): what does it add for patients with ALK-rearranged NSCLC

Rearrangements of the anaplastic lymphoma kinase (ALK) gene were first identified in 2007 and occur in 3 to 5% of all patients with advanced non-small cell lung cancer (NSCLC) (1). Regardless of the fusion partners, these ALK rearrangements lead to oncogenic hyperactivation of cytoplasmic tyrosine kinase activity (2). Thus, small molecular tyrosine kinase inhibitors (TKIs) for the gain-of-function tyrosine kinase activity of rearranged ALK have been the focus of drug development strategy. In August of 2011, only 3 years after the clinical activity of crizotinib was first observed, it was granted accelerated U.S. Food and Drug Administration (FDA) approval as the first-in-class ALK TKI for treatment of patients with locally advanced or metastatic ALK-positive NSCLC, based on the objective response rate (ORR) of 50–61% and median response duration of 42–48 weeks (3). The most common adverse reactions (≥25%) were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. In November 2013, crizotinib received full FDA approval based on an improvement in median progression-free survival (mPFS) compared to second-line chemotherapy (7.7 vs. 3.0 months) in patients with metastatic ALK-positive NSCLC previously treated with one platinum-based chemotherapy regimen (4). Subsequently, first-line systemic therapy with crizotinib was shown to significantly improved mPFS (10.9 vs. 7.0 months) in patients with ALK-rearranged NSCLC compared to first line platinum-based, double-agent chemotherapy (5).

Patients with ALK-rearranged NSCLC commonly have several characteristic clinicopathological features: the age of onset is usually 10–15 years younger than that of the average age NSCLC patient, most are either never or light smokers, and the majority of cases are adenocarcinomas. However, these clinicopathological features are not sufficient to identify patients with ALK-rearranged NSCLC. Concurrently approved with crizotinib in August 2011, the Vysis ALK Break-Apart FISH Probe Kit (Abbott Molecular, Inc.) became the first companion diagnostic for identifying ALK-rearranged NSCLC tumors. Currently, both the National Comprehensive Cancer Network (NCCN) and the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology (CAP/IASLC/AMP) Molecular Testing Guideline unanimously recommend testing for ALK rearrangement for adenocarcinoma and mixed lung cancers with an adenocarcinoma component, regardless of histologic grade, gender, ethnicity, or smoking status (6,7). Figure 1 summarizes the current algorithm for using companion diagnostics for initial identification of patients with ALK-rearranged NSCLC, and for subsequent assessment of resistance mechanisms for treatment decision. At initial diagnosis, diagnostics for identifying ALK-rearranged tumors include fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), real-time polymerase chain reaction (RT-PCR) and next generation sequencing (NGS) (4,8,9) (Figure 1). Tumors are defined as ALK FISH-positive if at least 15% of cells show a split signal; a second confirmatory test is required if the positive signal is between 10% and 15% (4). For the Ventana ALK (D5F3) CDx Assay, ALK IHC positivity requires the presence of strong granular cytoplasmic staining (3+) (8). More recently, NGS has been proven superior to both FISH and IHC for the sensitive detection of ALK-rearranged tumors, especially for those with rare ALK fusion variants and partners (9). For NSCLC patients who acquire resistance to an ALK inhibitor, NGS assessment of the molecular mechanism of resistance should inform the individualized treatment strategy and selection of an appropriate second- or third-generation ALK inhibitor. In cases where tumor tissue is insufficient for molecular testing, plasma circulating tumor DNA (ctDNA) from liquid biopsy is increasingly used as an alternative at initial diagnosis and at treatment resistance (7).

Figure 1 Diagnostics and treatment algorithm for ALK-rearranged NSCLC. Testing for ALK rearrangements by different diagnostics is recommended for patients initially diagnosed with adenocarcinoma and mixed lung cancers with an adenocarcinoma component, regardless of histologic grade or clinical characteristics. At tumor progression, NGS and immune biomarker assays are recommended to identify resistance mechanisms and select subsequent treatment strategies. FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; dMMR, deficient mismatch repair; MSI-H, microsatellite instability high; NGS, next generation sequencing; PD-1, Programmed death-1; RT-PCR, reverse transcription polymerase chain reaction; TMB, tumor mutation burden.

Despite drugs approved for ALK-rearranged NSCLC having exceptional ORR and mPFS, patients are not cured. Almost all patients with ALK-rearranged NSCLC eventually develop acquired resistance to the ALK TKIs. Many strategies have been attempted to overcome primary and acquired resistance to ALK inhibitors (10). Two major unmet needs must be addressed to improve the treatment for ALK-rearranged NSCLC: (I) to delineate the distinct mechanisms underlying resistance to ALK TKIs so the treatment can be tailored to individual patients, and (II) to develop new ALK inhibitors or design effective combinational strategies with improved activity for both extracranial and intracranial metastases. Both ALK-dependent and independent mechanisms can contribute to the resistance mechanisms to ALK inhibitors, which include the presence of a second-site mutation in the ALK-rearranged gene (20–30% of cases), ALK amplification, MET proto-oncogene amplification, activation of bypass pathways, and histological transformation (10). Although different resistance mutations may confer variable responses to subsequent ALK inhibitor therapy, most second-generation ALK inhibitors, such as ceritinib (11), alectinib (12-14), ASP3026 (15), and brigatinib (16-18), have strong efficacy against both wild-type ALK gene amplification and secondary mutations in the ALK tyrosine kinase domain (such as the gatekeeper mutation L1196M) (15,19). Notably, third-generation ALK inhibitor lorlatinib (PF-06463922) has strong activity against the ALK G1202R mutation, which is a common cause of resistance against first- and second-generation ALK TKIs (20). However, the gain of L1198M mutation after lorlatinib treatment could resensitize ALK-rearranged NSCLC tumors to crizotinib (21). Patients with ALK-rearranged lung cancer are found to have a high incidence of brain metastasis at the initial diagnosis and after control of systemic disease with crizotinib (22). Disease progression in the central nervous system (CNS) is also common in patients receiving crizotinib, probably due to its poor brain penetration (23).

Figure 2 summarizes the clinical activity of currently available ALK inhibitors. Compared to crizotinib, all second- and third-generation ALK inhibitors can overcome specific types of treatment resistance and have better CNS penetration, partially addressing the two unmet needs (24). These new-generation ALK TKIs vary in their sensitivity against wild-type and resistant mutations, the activity in the CNS, toxicity profile, and efficacy against drug targets other than ALK rearrangements. With the growing number of new-generation ALK inhibitors and their rising first-line use, further study is needed to determine the optimal sequence and potential combinations of ALK inhibitors.

Figure 2 A summary for the current landscape for the treatment of ALK-rearranged NSCLC. The activity of ensartinib (beige color) in the phase I/II study is illustrated in the context of first-, second-, or third-line treatment after crizotinib alone or both crizotinib and at least one second generation ALK inhibitor. PD, progressive disease; Ph, phase; PFS, progression free survival; ORR, objective response rate; CNS RR, central nervous system response rate. Blue arrow, ongoing study. *US FDA accelerated approval on November 2, 2018.

Leora Horn and colleagues recently presented the results of the first-in-human phase I/II study evaluating the safety and efficacy of ensartinib (X-396) in patients with ALK-rearranged NSCLC (25). Ensartinib potently inhibited both wild-type ALK and all evaluated ALK variants (F1174, C1156Y, L1196M, S1206R, T1151, and G1202R mutants) with in vitro IC₅₀s of <4 nM. Besides ALK, ensartinib also potently inhibits TPM3-TRKA, TRKC and GOPC-ROS1 with an IC₅₀ of <1 nM, and inhibits EphA2, EphA1, EphB1 and c-MET with an IC₅₀ of 1–10 nM. In this phase I/II study, ensartinib was generally well tolerated in the 97 patients tested (i.e., 37 patients in dose escalation and 60 patients in dose expansion cohorts). The majority (92%) of patients had NSCLC. In the dose escalation cohort, there were four patients with head and neck cancer, two with colorectal cancer, and one patient each with small cell lung and breast cancer. The median age was 56 (range: 21–83) years old. Eighty (82%) patients had received at least one prior systemic therapy for advanced disease, including chemotherapy or ALK TKIs, while 58 (60%) patients had ≥2 previous lines of therapy. Thirty-five (36%) patients had brain metastases at baseline. Treatment-related adverse effects (TRAEs) occurred in 83 (86%) patients. The most common TRAEs were rash (56%), nausea (36%), pruritus (28%), vomiting (26%), and fatigue (22%). The frequency and severity of nausea and vomiting were lessened when ensartinib was taken with food. Ensartinib has a different toxicity profile from the other second-generation ALK TKIs, with 23% of patients experiencing grade 3–4 toxicity (primarily rash and pruritus). The prevalence of dermatologic adverse events is consistent with the observation that the concentration of ensartinib was 9.0 times higher in the skin than in the plasma at 12 hours after a single dose of ensartinib. Fourteen patients (14%; 14/97) required at least one dose reduction and fifteen patients (15%; 15/97) required at least one dose interruption due to an ensartinib-related toxicity. The maximum tolerated dose was not reached. The recommended phase II dose was chosen as 225 mg based on the frequency of rash observed at 250 mg without improvement in activity.

Clinical activity was observed in 60 evaluable ALK-rearranged patients: the disease control rate was 81.7%, with the overall response rate (ORR) of 60% [95% confidence interval (CI), 47.4–71.4] and 13 (21.7%) patients achieving stable disease. mPFS was 9.2 months. In the ALK-rearranged NSCLC patients who received prior crizotinib only, the ORR was 69% and mPFS was 9.0 months. In those ALK-rearranged NSCLC patients who were ALK TKI-naïve, ORR was 80% and mPFS was 26.2 months. In patients that received prior crizotinib and a second-generation ALK TKI, the mPFS was 1.9 months (95% CI, 1.7–5.7). In addition, some degree of CNS response was noted, with responses in intracranial metastases in 64% of cases. Figure 2 summarizes the clinical efficacy of ensartinib in beige color in first-, second-, and third-line settings. These data suggest that ensartinib has comparable clinical activity to other second generation ALK TKIs.

There are several limitations to the current study. First, this is a single-arm, non-comparative, ongoing phase I/II trial. Cautions should be exercised in the interpretation of the available results. A randomized phase III study, eXalt3 (NCT02767804), comparing ensartinib to crizotinib in advanced ALK-positive, TKI-naive NSCLC patients, was started in June 2016 and is currently ongoing. Second, further studies are needed to determine the resistance mechanisms to ensartinib and how to integrate its use in the current treatment landscape for patients with advanced ALK-rearranged NSCLC.

In conclusion, ensartinib is a unique, potent ALK inhibitor that has promising clinical activity and low toxicity in patients with ALK-rearranged NSCLC, most of whom had CNS metastases and had previous ALK-TKI treatment. Further study is needed to determine its role as either an initial or post-resistance therapy in ALK-rearranged NSCLC or other types of cancers.

Acknowledgments

Funding: This work was supported by “Novel Treatment Strategies for Adenocarcinomas” (UCD grant #49873) to T Li.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

References

1. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007;448:561-6. [Crossref] [PubMed]
2. Ross JS, Ali SM, Fasan O, et al. ALK Fusions in a Wide Variety of Tumor Types Respond to Anti-ALK Targeted Therapy. Oncologist 2017;22:1444-50. [Crossref] [PubMed]
3. 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]
4. Shaw AT, Solomon B, Kenudson MM. Crizotinib and testing for ALK. J Natl Compr Canc Netw 2011;9:1335-41. [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. Ettinger DS, Aisner DL, Wood DE, et al. NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 5.2018. J Natl Compr Canc Netw 2018;16:807-21. [Crossref] [PubMed]
7. Lindeman NI, Cagle PT, Aisner DL, et al. Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med 2018;142:321-46. [Crossref] [PubMed]
8. Thorne-Nuzzo T, Williams C, Catallini A, et al. A Sensitive ALK Immunohistochemistry Companion Diagnostic Test Identifies Patients Eligible for Treatment with Crizotinib. J Thorac Oncol 2017;12:804-13. [Crossref] [PubMed]
9. Guibert N, Hu Y, Feeney N, et al. Amplicon-based next-generation sequencing of plasma cell-free DNA for detection of driver and resistance mutations in advanced non-small cell lung cancer. Ann Oncol 2018;29:1049-55. [Crossref] [PubMed]
10. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med 2012;4:120ra17. [Crossref] [PubMed]
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. [Crossref] [PubMed]
12. 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;377:829-38. [Crossref] [PubMed]
13. 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]
14. 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;29:2214-22. [Crossref]
15. Li T, LoRusso P, Maitland ML, et al. First-in-human, open-label dose-escalation and dose-expansion study of the safety, pharmacokinetics, and antitumor effects of an oral ALK inhibitor ASP3026 in patients with advanced solid tumors. J Hematol Oncol 2016;9:23. [Crossref] [PubMed]
16. Gettinger SN, Bazhenova LA, Langer CJ, et al. Activity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial. Lancet Oncol 2016;17:1683-96. [Crossref] [PubMed]
17. 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]
18. Lin JJ, Zhu VW, Schoenfeld AJ, et al. Brigatinib in Patients With Alectinib-Refractory ALK-Positive NSCLC. J Thorac Oncol 2018;13:1530-8. [Crossref] [PubMed]
19. 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]
20. Shaw AT, Felip E, Bauer TM, 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;18:1590-9. [Crossref] [PubMed]
21. Shaw AT, Friboulet L, Leshchiner I, et al. Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F. N Engl J Med 2016;374:54-61. [Crossref] [PubMed]
22. Costa DB, Shaw AT, Ou SH, et al. Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastases. J Clin Oncol 2015;33:1881-8. [Crossref] [PubMed]
23. Yoshida T, Oya Y, Tanaka K, et al. Clinical impact of crizotinib on central nervous system progression in ALK-positive non-small lung cancer. Lung Cancer 2016;97:43-7. [Crossref] [PubMed]
24. Lovly CM, Pao W. Escaping ALK inhibition: mechanisms of and strategies to overcome resistance. Sci Transl Med 2012;4:120ps2. [Crossref] [PubMed]
25. Horn L, Infante JR, Reckamp KL, et al. Ensartinib (X-396) in ALK-Positive Non-Small Cell Lung Cancer: Results from a First-in-Human Phase I/II, Multicenter Study. Clin Cancer Res 2018;24:2771-9. [Crossref] [PubMed]