ONCAlert | 2018 SGO Annual Meeting on Women’s Cancer

LDK378: A Promising Next-Generation ALK Inhibitor

Wen Wee Ma, MBBS
Published Online: Jan 07,2014
 Wen Wee Ma, MBBS

Wen Wee Ma, MBBS

Assistant Professor, Department of Medicine,
Roswell Park Cancer Institute,
Elm & Carlton Streets, Buffalo, NY;
wenwee.ma@roswellpark.org

Abstract

Gene translocations account for most oncogenic ALK alterations discovered to date. Crizotinib is an efficacious treatment for patients with non-small cell lung cancer (NSCLC) harboring EML4-ALK translocation, but resistance eventually develops during therapy. LDK378 is a highly selective and potent inhibitor of ALK, and has demonstrated preclinical antitumor activity against tumors with acquired crizotinib resistance. In a phase I trial, LDK378 induced tumor response in 70% of patients with crizotinib-resistant NSCLC and gained Breakthrough Therapy designation from the FDA. Phase III studies evaluating LDK378 in crizotinib-naïve and crizotinib-resistant NSCLC are currently under way.

Anaplastic Lymphoma Kinase as Therapeutic Target

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor superfamily. Structurally, the intracellular kinase domain shares close homology to that of insulin receptor (InR; 46%), insulin-like growth factor receptor- 1 (IGF-1R; 47%), and leukocyte receptor tyrosine kinase (LTK; 79%).1 The oncogenic role of ALK was first implicated with the discovery of nucleophosmin (NPM1)-ALK fusion protein in anaplastic large cell lymphoma (ALCL).2 Thereafter, several other oncogenic ALK alterations had been identified, including TPM3/4-ALK in inflammatory myofibroblastic tumor, VCL-ALK in renal medullary carcinoma, ALK mutations/amplification in neuroblastoma, and EML4-ALK in non-small cell lung cancer (NSCLC).3 The frequency of ALK rearrangements is approximately 3% to 5% of the overall NSCLC patient population.4 ALK alterations have also been reported in other cancer types including brain, breast, colon, ovarian, prostate, and esophageal.1,5,6

Crizotinib (PF-02341066) is an oral ATP-competitive small-molecule inhibitor against MET kinase and also potently inhibits ALK signaling, and the agent induced apoptosis and tumor regression in a preclinical NPM-ALK-positive ALCL model.7,8 The first-in-human crizotinib study initially focused on enrolling patients with MET-positive or ALK-positive (rearranged) tumors. The study was then amended to enrich enrollment in ALK-positive NSCLC in the expansion phase following observation of encouraging efficacy in two ALK-positive patients with NSCLC during dose escalation.9 In the expansion phase, 143 evaluable patients with ALK-positive NSCLC were enrolled to receive crizotinib 250 mg twice daily on an every-28-day cycle, which induced tumor response in 87 patients (60.8%), including 3 complete responses and 84 partial responses.10 The median duration of response was 49.1 weeks. The most common grade 3 or 4 adverse events (AEs) were neutropenia, elevated alanine aminotransferase, hypophosphatemia, and lymphopenia. Crizotinib was compared with cytotoxic chemotherapy (pemetrexed or docetaxel) in the phase III PROFILE 1007 trial in patients with ALK-positive, locallyadvanced or metastatic NSCLC with one prior platinum- based treatment, and the agent demonstrated superior progression-free survival (PFS; 7.7 months vs 3.0 months;hazard ratio [HR]=0.49; P<.001) and response rate ([RR], 65% vs 20%; P<.001).11 The success of crizotinib demonstrated the feasibility in targeting oncogenic ALK signaling using a small-molecule inhibitor, which led to an interest in developing other potent ALK inhibitors, particularly those that can overcome acquired resistance to crizotinib.

LDK378—A Next-Generation ALK Inhibitor

LDK378 is a highly-selective potent ALK inhibitor optimized from Novartis’ previous lead compound TAE684.12 In kinase assays, LDK378 potently inhibited ALK (IC50 of 200 pM) but not cMET (IC50s of 3.17 μM). Other kinases that were inhibited by LDK378 below 100 nM, were IGF-1R, InR, and STK22D with IC50’s 8, 7, and 23 nM respectively. However, the potent biochemical inhibition of IGF-1R and InR were not reproducible in cellular kinase assay. LDK378 also did not affect insulin levels or glycemic control in a mouse model, with multiple dosing at pharmacologically active dosages tested, which was consistent with results from the cellular kinase assay. In a preclinical cancer model, tumor regression in xenografts derived from NCI-H2228 carrying EML4-ALK fusion gene and correlates with inhibition of STAT3 phosphorylation. LDK378 was also efficacious in NCI-H2228 that was induced to become resistant to crizotinib that carried the ALK C1156Y mutation found in crizotinib-relapsed patients.13 As such, LDK378 is an attractive potential treatment option in both crizotinib-naïve and crizotinib-resistant ALK-translocated NSCLC.

In the phase I trial, LDK378 administered orally once daily continuously every 21 days was evaluated in patients with advanced cancers harboring a gene alteration in ALK who previously progressed on standard therapy or for whom there was no effective therapy.14 Anticancer effect was observed at 400 mg daily and above, and the maximum tolerated dosage was determined to be 750 mg daily. LDK378 was rapidly absorbed upon ingestion with Tmax of 5 to 6 hours and a half-life of about 36 hours.15 When the results were presented at the 2013 American Society of Clinical Oncology (ASCO) annual meeting, 131 patients harboring an alteration in the ALK gene, including 123 with ALK-rearranged NSCLC, had been enrolled and received LDK378 at dosages of 50 mg to 750 mg once daily.14,15 Eighty-eight evaluable patients with NSCLC were treated with LDK378 at 400 mg to 750 mg daily. The overall response rate (ORR) was 70%, and the ALK inhibitor was efficacious in the 64 patients who were crizotinib-resistant, achieving an ORR of 73%. The median PFS among the 123 evaluable patients with NSCLC was 8.6 months (95% CI, 4.3-19.3 months). The most common AEs were nausea (72%), diarrhea (69%), vomiting (50%), and fatigue (31%). The most common Grade 3 or 4 AEs were diarrhea (7%), and elevated alanine aminotransferase and aspartate aminotransferase (12% and 6% respectively). Interestingly, responses were also observed in patients with untreated metastases in the central nervous system, suggesting that the drug penetrates the blood–brain barrier.

Clinical Pearls

  • Approximately 3% to 5% of patients with NSCLC harbor EML4-ALK translocation and eventually develop resistance to crizotinib treatment.
  • LDK378 is a highly selective and potent inhibitor of ALK but not MET, and demonstrated efficacy in both crizotinib-naïve and crizotinib-resistant ALK-rearranged NSCLC in a phase I study.
  • LDK378 received Breakthrough Therapy designation by the FDA in March 2013, which speeds the development for the treatment of patients with ALK-rearranged metastatic NSCLC who progressed on or were intolerant of crizotinib therapy.
The impressive clinical efficacy of LDK378 during this early-phase study led to the designation of Breakthrough Therapy by the FDA in March 2013 for the treatment of patients with ALK-positive metastatic NSCLC who progressed during treatment with or were intolerant to crizotinib.16 The designation was intended to expedite the development and review of drugs that treat serious and life-threatening conditions and that have demonstrated substantial improvement over existing therapies on at least one clinically significant endpoint.

Future Challenges

Despite the initial response, many patients with ALK-rearranged NSCLC eventually become refractory to crizotinib treatment, and several mechanisms of acquired crizotinib-resistance have been discovered. A third of the acquired resistance may be due to secondary mutations in the ALK tyrosine kinase domain or amplification of the ALK fusion gene.17 The ALK mutations identified from patients with crizotinib-treated NSCLC include 1151Tins, L1152R, C1156Y, F1174C, L1196M, G1202R, D1203N, S1206Y, and G1296A. The other third bypass the ALK inhibition by activating compensatory signaling pathways such as EGFR, KIT, or KRAS, whereas the mechanisms for the last third have not yet been determined. In addition to developing LDK378 as monotherapy in crizotinib-naïve and -resistant ALK-rearranged NSCLC (ClinicalTrials.gov Identifier NCT01828099, NCT01828112), efforts are also under way to develop rational LDK378-based combination therapies, including combination therapy with the heat-shock protein 90 inhibitor AUY922 (NCY01772797).

References

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  6. Schoppmann SF, Streubel B, Birner P: Amplification but not translocation of anaplastic lymphoma kinase is a frequent event in oesophageal cancer. Eur J Cancer. 2013; 49:1876-1881.
  7. Zou HY, Li Q, Lee JH, et al. An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res. 2007; 67:4408-4417.
  8. Christensen JG, Zou HY, Arango ME, et al. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther. 2007;6:3314-3322.
  9. Kwak EL, Bang Y-J, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2011;363:1693- 1703.
  10. Camidge DR, Bang Y-J, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012;13:1011-1019.
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  13. Li N, Michellys P-Y, Kim S, et al. Activity of a potent and selective phase I ALK inhibitor LDK378 in naive and crizotinib-resistant preclinical tumor models. Available at: http://mct.aacrjournals.org/cgi/content/meeting_ abstract/10/11_MeetingAbstracts/B232. Accessed December 3, 2013.
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  16. Two drugs deemed breakthrough therapies. Cancer Disc. 2013;3:478.
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LDK378: A Promising Next-Generation ALK Inhibitor
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