Second-generation ALK Tyrosine Kinase Inhibitors Research Articles

Management of Resistance to First-Line Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitor Therapy.

A decade after the discovery of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (EML4-ALK) rearrangements in non-small cell lung cancer (NSCLC), several inhibitors have gained regulatory approval, and their sequential use has deferred platinum-based chemotherapy to later lines of therapy. Nevertheless, although most ALK-driven tumors dramatically respond to ALK TKIs , all patients ultimately develop drug-resistant disease. Analysis of post-progression biopsy samples has provided invaluable insight into the mechanisms of resistance, now informing on subsequent therapeutic strategies. In particular, the identification of secondary ALK mutations, which are a common mechanism of resistance to both first-generation and to an even larger extent to second-generation ALK TKIs, may shape a personalized optimal treatment strategy beyond the current first-line choice. Alectinib has now become a preferred treatment option in the first line of therapy, and extrapolation of data obtained from post-progression samples after second-line next-generation ALK TKIs suggests that acquired resistance is likely to be mediated in more than half of patients by ALK resistance mutations. Nevertheless, clinical and preclinical evidence suggests that multiple resistance mechanisms may co-exist at different levels in the same TKI-resistant patient. Newer ALK tyrosine kinase inhibitors (TKIs) overcome some resistance mutations through higher exposure and potency, and generally present greater CNS activity, but are unlikely to overcome resistance mediated through separate oncogenic pathway activations, or epithelial to mesenchymal transition (EMT) and small cell lung cancer (SCLC) transformation. Furthermore, while resistance mutations can be detected through commonly available sequencing methods, the identification of other mechanisms of resistance is much less straightforward in the clinic. We hypothesize that the ALK resistance mutation status will likely be crucially important in the choice of second-line therapy after a second-generation TKI. Emerging clinical data also refines the optimal placing of PD-1- and PD-L1-directed immunotherapy in the treatment sequence.

Background and rationale of the eXalt3 trial investigating X-396 in the treatment of ALK+ non-small-cell lung cancer.

Despite significant advancements in the treatment of anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer (NSCLC) since the advent of crizotinib, the development of acquired resistance and poor CNS efficacy have necessitated the search for novel and more robust therapies. Ensartinib (X-396) is a novel second-generation ALK-tyrosine kinase inhibitor (TKI) that holds much clinical promise. Preclinical data have demonstrated increased potency of the drug as compared with crizotinib and other second-generation ALK-TKI therapies such as alectinib and ceritinib. This review highlights the first- and second-generation ALK inhibitors approved for the treatment of ALK-positive NSCLC and discusses the clinical trial protocol for the eXalt3 trial (NCT02767804) comparing the efficacy and safety of ensartinib to crizotinib in patients diagnosed with ALK-positive NSCLC who are naive to prior ALK-TKI treatment.

EML4-ALK fusion variant V3 is a high-risk feature conferring accelerated metastatic spread, early treatment failure and worse overall survival in ALK+ non-small cell lung cancer.

In order to identify anaplastic lymphoma kinase-driven non-small cell lung cancer (ALK+ NSCLC) patients with a worse outcome, who might require alternative therapeutic approaches, we retrospectively analyzed all stage IV cases treated at our institutions with one of the main echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion variants V1, V2 and V3 as detected by next-generation sequencing or reverse transcription-polymerase chain reaction (n = 67). Progression under tyrosine kinase inhibitor (TKI) treatment was evaluated both according to Response Evaluation Criteria in Solid Tumors (RECIST) and by the need to change systemic therapy. EML4-ALK fusion variants V1, V2 and V3 were found in 39%, 10% and 51% of cases, respectively. Patients with V3-driven tumors had more metastatic sites at diagnosis than cases with the V1 and V2 variants (mean 3.3 vs. 1.9 and 1.6, p = 0.005), which suggests increased disease aggressiveness. Furthermore, V3-positive status was associated with earlier failure after treatment with first and second-generation ALK TKI (median progression-free survival [PFS] by RECIST in the first line 7.3 vs. 39.3 months, p = 0.01), platinum-based combination chemotherapy (median PFS 5.4 vs. 15.2 months for the first line, p = 0.008) and cerebral radiotherapy (median brain PFS 6.1 months vs. not reached for cerebral radiotherapy during first-line treatment, p = 0.028), and with inferior overall survival (39.8 vs. 59.6 months in median, p = 0.017). Thus, EML4-ALK fusion variant V3 is a high-risk feature for ALK+ NSCLC. Determination of V3 status should be considered as part of the initial workup for this entity in order to select patients for more aggressive surveillance and treatment strategies.

Clinical data and role of ceritinib a second-generation ALK tyrosine kinase inhibitor for the treatment of ALK positive non-small cell lung cancer

Clinical data and role of ceritinib a second-generation ALK tyrosine kinase inhibitor for the treatment of ALK positive non-small cell lung cancer

Abstract 781: The potent ALK inhibitor AP26113 can overcome mechanisms of resistance to first- and second-generation ALK TKIs in preclinical models

Abstract Background: Disease progression in anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC) patients (pts) treated with the first-generation tyrosine kinase inhibitor (TKI) crizotinib, or the second-generation inhibitors ceritinib and alectinib, is often associated with secondary resistance mutations in ALK (such as G1202R, linked with resistance to all 3 TKIs in pts), or relapse in the brain. AP26113 is a highly potent ALK inhibitor with promising anti-tumor activity in pts with crizotinib-resistant disease. Here we broadly evaluate AP26113's ability to overcome mechanisms of resistance to first- and second-generation ALK inhibitors, in preclinical models (including brain cancer models), and describe a novel methodology to compare in vitro potency, clinical pharmacokinetic parameters, and clinical efficacy. Methods: Ba/F3 cells were engineered to express native EML4-ALK or 17 mutants resistant to crizotinib, ceritinib, and/or alectinib in clinical or preclinical studies. IC50s for all TKIs were compared to “clinically effective” plasma concentrations (Ceff) of each inhibitor, which were derived using average steady-state levels in pts, and corrected for the functional effects of protein binding in vitro. In vivo studies were performed in mice, in which Ba/F3 cells with mutant or native EML4-ALK were injected subcutaneously, or a NSCLC line with EML4-ALK (H2228) was injected into the brain. Results: The Ceff of crizotinib was only ∼2-fold above the IC50 for native ALK, suggesting that crizotinib may be susceptible to mutants that inhibit binding by only a few-fold. Indeed, 8/10 mutants previously associated with clinical resistance to crizotinib were found to have IC50s that exceed the Ceff. Similar analyses revealed mutants with IC50s that exceeded the Ceff for ceritinib (e.g. L1198F) and alectinib (e.g. I1171N), with G1202R being the most recalcitrant mutant overall. In contrast, the Ceff of AP26113 was >20-fold above the IC50 for native ALK, and exceeded the IC50 for all 17 mutants, including G2102R. In vivo, among all 4 TKIs tested (at doses effective against native ALK), only AP26113 demonstrated significant efficacy against G1202R-mutant ALK (88% tumor growth inhibition). Finally, compared to crizotinib, AP26113 markedly enhanced survival of mice bearing brain tumors. Conclusion: AP26113 inhibits all 17 clinically and preclinically observed crizotinib-, ceritinib-, and/or alectinib-resistant ALK mutants tested in vitro, has potent effects on the recalcitrant G1202R mutant in vivo and has activity in an orthotopic brain model. These results suggest AP26113 may effectively address a broad range of resistance mechanisms identified for other ALK TKIs. AP26113 is currently in a global phase 2 registration trial in patients with locally advanced or metastatic ALK+ NSCLC who were previously treated with crizotinib (NCT02094573). Citation Format: Sen Zhang, Sara Nadworny, Scott D. Wardwell, Lindsey Eichinger, Biplab Das, Emily Y. Ye, J. Graeme Hodgson, Victor M. Rivera. The potent ALK inhibitor AP26113 can overcome mechanisms of resistance to first- and second-generation ALK TKIs in preclinical models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 781. doi:10.1158/1538-7445.AM2015-781