LDK378: A Promising Next-Generation ALK Inhibitor

Wen Wee Ma, MBBS

Assistant Professor, Department of Medicine,

Roswell Park Cancer Institute,

Elm & Carlton Streets, Buffalo, NY;

wenwee.ma@roswellpark.org

Abstract

Anaplastic Lymphoma Kinase as Therapeutic Target

Gene translocations account for most oncogenicALKalterations discovered to date. Crizotinib is an efficacious treatment for patients with non-small cell lung cancer (NSCLC) harboringEML4-ALKtranslocation, 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 (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%).¹The oncogenic role ofALKwas first implicated with the discovery of nucleophosmin (NPM1)-ALK fusion protein in anaplastic large cell lymphoma (ALCL).²Thereafter, several other oncogenicALKalterations had been identified, includingTPM3/4-ALKin inflammatory myofibroblastic tumor,VCL-ALKin renal medullary carcinoma,ALKmutations/amplification in neuroblastoma, andEML4-ALKin non-small cell lung cancer (NSCLC).³The frequency ofALKrearrangements is approximately 3% to 5% of the overall NSCLC patient population.⁴ALKalterations have also been reported in other cancer types including brain, breast, colon, ovarian, prostate, and esophageal.^1,5,6

LDK378—A Next-Generation ALK Inhibitor

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 preclinicalNPM-ALK-positive ALCL model.^7,8The first-in-human crizotinib study initially focused on enrolling patients withMET-positive orALK-positive (rearranged) tumors. The study was then amended to enrich enrollment inALK-positive NSCLC in the expansion phase following observation of encouraging efficacy in twoALK-positive patients with NSCLC during dose escalation.⁹In 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.¹⁰The 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 withALK-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 oncogenicALKsignaling using a small-molecule inhibitor, which led to an interest in developing other potentALKinhibitors, particularly those that can overcome acquired resistance to crizotinib.LDK378 is a highly-selective potent ALK inhibitor optimized from Novartis&rsquo; previous lead compound TAE684.¹²In kinase assays, LDK378 potently inhibited ALK (IC₅₀of 200 pM) but not cMET (IC₅₀s of 3.17 &mu;M). Other kinases that were inhibited by LDK378 below 100 nM, were IGF-1R, InR, and STK22D with IC50&rsquo;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 carryingEML4-ALKfusion 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 theALKC1156Y mutation found in crizotinib-relapsed patients.¹³As such, LDK378 is an attractive potential treatment option in both crizotinib-na&iuml;ve and crizotinib-resistantALK-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 inALKwho previously progressed on standard therapy or for whom there was no effective therapy.¹⁴Anticancer 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.¹⁵When the results were presented at the 2013 American Society of Clinical Oncology (ASCO) annual meeting, 131 patients harboring an alteration in theALKgene, including 123 withALK-rearranged NSCLC, had been enrolled and received LDK378 at dosages of 50 mg to 750 mg once daily.^14,15Eighty-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 harborEML4-ALKtranslocation 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-na&iuml;ve and crizotinib-resistantALK-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 withALK-rearranged metastatic NSCLC who progressed on or were intolerant of crizotinib therapy.

Future Challenges

References

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 withALK-positive metastatic NSCLC who progressed during treatment with or were intolerant to crizotinib.¹⁶The 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.Despite the initial response, many patients withALK-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 theALKtyrosine kinase domain or amplification of theALKfusion gene.¹⁷TheALKmutations identified from patients with crizotinib-treated NSCLC include1151Tins,L1152R,C1156Y,F1174C,L1196M,G1202R,D1203N,S1206Y, andG1296A. 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-na&iuml;ve and -resistantALK-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).

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