New molecular approaches to ALK inhibition are a topic of intense interest as researchers look to expand upon the positive results seen with crizotinib. Developing alternatives designed to overcome resistance mutations, stemming from changes in treatment susceptibility with agents like crizotinib, is of clinical importance. The agents discussed below exhibit activity against resistance mutations or block secondary tumor-activating pathways. A second approach is to inhibit ALK through actions on heat shock protein 90 (Hsp90). Many early clinical and preclinical results, presented in September 2012 at the 37th annual European Society for Medical Oncology (ESMO) conference in Vienna, suggest that these agents hold promise.
ALK Inhibitors in Progress
CH5424802 inhibits both wild-type and mutated ALK, including the L1196M mutation, at low nanomolar concentrations. In preclinical studies, this compound showed good potency against tumor cells with crizotinib resistance mutations.1Interim results from a phase 2 study in 34 patients with ALK-positive non-small cell lung cancer (NSCLC), reported at ESMO showed a response rate of 73.3% (one complete response and 10 partial responses); this rate occurred among the first 15 patients. In this study, patients received 300 mg of CH5424802 twice daily until disease progression or intolerable toxicity Overall, reports indicated this drug was well tolerated, with adverse that included grade 3 neutropenia (two patients) and grade 1 or 2 treatment-emergent adverse events (TEAEs) consisting of elevated transaminases, neutropenia, nausea, rash, and constipation.2
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LDK378 is a different molecule with limited preclinical data available. Researchers suspect LDK378 induces tumor regression in an ALK-positive NSCLC model and is active against tumors bearing the C1156Y mutation.1 At ESMO, early results from an open-label, dose-escalation phase 1 study in ALK-rearranged solid tumors demonstrated 24 responses among 50 enrolled patients with ALK-positive NSCLC; among this patient group, 37 were previously treated with crizotinib. A response rate of 81% was achieved in 26 patients who had progressed on crizotinib. This study evaluated a dose of 400 mg or more of LDK378 once daily. Dose-limiting toxicities included diarrhea, vomiting, nausea, dehydration, and elevated transaminases; 2% of patients discontinued because of TEAEs.3
A third agent, AP26113, is a dual inhibitor with once-daily dosing; its potency and selectivity is approximately 10-fold higher than that of crizotinib. This drug cross-reacts with other tyrosine kinases, including mutated (but not wild-type) EGFR at therapeutic levels. It has demonstrated activity in vitro against cells bearing the L1196M gatekeeper mutation. Phase 1/2 studies are progressing in different tumor types, including advanced NSCLC.1,4 Results presented at ESMO included 11 patients with NSCLC, of whom four were documented as ALK-positive and had experienced treatment failure with crizotinib; and five patients who were documented as EGFR-positive. After all patients underwent heavy pretreatment, partial responses were observed in three of the four ALK-positive patients. Adverse events were mild or moderate, the most common being fatigue and nausea. No serious TEAEs were observed.5
Similar to AP26113, preclinical results with ASP3026, shows potent activity in tumor models against certain mutations, including L1196M.. A phase 1, nonrandomized, open-label study in patients with solid tumors is underway and expected to conclude in April 2013.1
Hsp90 Inhibition
Hsp90 makes an attractive molecular target because it is overexpressed in tumor cells, plays a key role in the stability and function of several proteins, and its blockade has the advantage of simultaneously disrupting several tyrosine kinase (TK) pathways, including ALK and EGFR.6,7 Ganetespib, an inhibitor of Hsp90, is a small-molecule being evaluated clinically after preclinical studies demonstrated cytotoxic activity in tumor cell lines harboring TK inhibitor resistance mutations, among others .7 Data being published in the spring of 2013, ganetespib was 30 times more potent than crizotinib against ALK-positive NSCLC cell lines and was active against crizotinib-resistant cell lines.8
The aim of GALAXY, an ongoing phase 2/3 study, is to determine whether the addition of ganetespib to docetaxel improves outcomes in advanced NSCLC; patients who had received one prior therapy were randomly assigned to receive a standard, 21-day docetaxel regimen with or without adjuvant ganetespib (150 mg/m2 on days 1 and 15). Preliminary data were presented during the ESMO meeting, showed a trend toward reduction in mortality risk with ganetespib versus docetaxel alone (hazard ratio, 0.568; 95% CI: 0.312–1.032; P=0.056). It should be noted that these results are from a small group of patients (n=77) with a median time on treatment of 6.32 months.9
As with ganetespib and other investigational compounds being researched, current efforts and additional, larger studies to come will increase the targeted therapy options for treatment of NSCLC.
References
1. Mologni L. Inhibitors of the anaplastic lymphoma kinase. Expert Opin Investig Drugs. 2012;21(7):985-994.
2. Nishio M, Kiura K, Nakagawa K, et al. A phase I//II study of ALK inhibitor CH5424802 in patients with ALK-positive NSCLC; safety and efficacy interim results of the phase II portion. Abstract presented at the 37th ESMO Conference, Vienna, Austria. Ann Oncol. 2012;23(Supplement 9):ix153 (Abstract 4410).
3. Shaw AT, Camidge DR, Felip E, et al. Results of a first-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors. Abstract presented at the 37th ESMO Conference, Vienna, Austria. Ann Oncol. 2012;23(Supplement 9):ix153 (Abstract 4400).
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. PNAS. 2011;108(18):7535-7540.
5. Gettinger S, Weiss GJ, Salgia R, et al. A first-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies. Abstract presented at the 37th ESMO Conference, Vienna, Austria. Ann Oncol. 2012;23(Supplement 9):ix152. Abstract 4390.
6. National Cancer Institute. NCI Drug Dictionary: ganetespib. http://www.cancer.gov/drugdictionary?cdrid=598379. Accessed March 19, 2013.
7. Ying W, Du Z, Sun L, et al. Ganetespib, a unique triazolone-containing Hsp90 inhibitor, exhibits potent antitumor activity and a superior safety profile for cancer therapy. Mol Cancer Ther. 2012;11:475-484.
8. American Association for Cancer Research. Ganetespib demonstrates potency against ALK-positive lung cancer and overcomes crizotinib resistance. Press release, March 19, 2013. http://www.aacr.org.
9. Ramalingam S, Zaric B, Goss GD, et al. Preliminary results from a randomized 2b/3 study of ganetespib and docetaxel combination versus docetaxel in advanced NSCLC (the GALAXY trial). Poster presented at the 37th ESMO Conference, Vienna, Austria; September 2012.
