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S. Devarakonda



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    MS 16 - Novel SCLC Therapies (ID 34)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Small Cell Lung Cancer
    • Presentations: 1
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      MS16.06 - New Chemotherapies (Eribulin, Aldoxorubicin, Etirinotecan, MM398) (ID 1921)

      15:25 - 15:38  |  Author(s): S. Devarakonda

      • Abstract
      • Presentation

      Abstract:
      Small cell lung cancer (SCLC) accounts for nearly 15% of newly diagnosed lung cancers.[1] With the advent of tyrosine kinase inhibitors, the last decade has witnessed remarkable improvements in the outcomes of patients with non-small cell lung cancer (NSCLC). However, outcomes in patients with SCLC continue to remain dismal. Currently approved targeted therapies have minimal role in the management of SCLC, since unlike NSCLC, targetable tyrosine kinase alterations are rarely witnessed in SCLC.[2,3] Cytotoxic chemotherapy has therefore continued to remain the standard of care for SCLC. SCLC is usually very sensitive to first-line platinum based therapies.[4] Nevertheless, these responses are seldom durable and majority of patients relapse within weeks to months of treatment completion. Relapsed SCLC is a tough disease to treat and barely responds to conventional therapies. There is hence is an urgent need to develop novel therapeutic strategies that are capable of improving survival in patients with SCLC - particularly those with relapsed disease. Several new chemotherapeutic agents are currently being developed and actively studied in various solid tumors. The objective of this article is to highlight some of these newer chemotherapies and discuss their potential relevance in the management of SCLC. Eribulin mesylate is a non-taxane halichondrin B analogue derived from the marine sponge Halichondria okadaic.[5] Eribulin sequesters tubulin and inhibits mitotic spindle formation, leading to cell cycle arrest in G2-M and eventually cell death. Eribulin is currently FDA approved in the United States for the management of metastatic breast cancer in patients receiving prior treatment with at least two chemotherapy regimens, including an anthracycline and a taxane. In the phase III EMBRACE trial, as a part of which 762 women with breast cancer were randomized to receive eribulin or chemotherapy of the treating physician’s choice, overall survival (OS) was significantly improved with eribulin (13.1 vs. 10.6 months, HR 0.81 p=0.041).[6] Eribulin as single agent and in combination with erlotinib were shown to be active and well tolerated in patients with NSCLC treated with prior platinum based therapies.[7] In the study by Spira and colleauges, eribulin was dosed at 1.4mg/m2 on days 1 and 8 of a 21 day cycle (similar to breast cancer dosing schedule) and in a second cohort of patients at 1.4 mg/m2 on days 1, 8 and 15 of a 28 day schedule.[8] Among these, the 21 day dosing schedule was shown to be better tolerated and active with a median OS of 9.4 months in the second line setting for NSCLC. However, when used in combination with a second agent, the maximum tolerated dose (MTD) of eribulin was much lower. In a phase Ib/II study involving pretreated NSCLC patients, the MTD of eribulin was 0.9mg/m2, with 500mg/m2 of pemetrexed, administered on day 1 of a 21 day cycle.[9] Unfortunately, the combination was tolerable but showed no therapeutic benefit at this dose. Aldoxorubicin, formerly known as INNO-206, combines a molecular linker that allows doxorubicin to bind covalently to serum albumin upon intravenous administration.[10] This formulation releases doxorubicin in the acidic tumor microenvironment. Aldoxorubicin is currently being actively investigated in the management of soft-tissue sarcomas and glioblastoma. In a phase Ib/II study by Chawla and colleagues, the MTD of aldoxorubicin was 350mg/m2 administered every 21 days.[11] The drug showed a partial response rate of 20% and stable disease rate of 40% in 25 patients with advanced chemotherapy refractory cancers, among which most patients (68%) had soft tissue sarcomas. Aldoxorubicin was considered to be safe and efficacious in these patients. Currently, aldoxorubicin is being studied as part of an ongoing randomized phase IIb trial in patients with relapsed/refractory SCLC (NCT02200757). This study will compare progression free survival (PFS) between patients receiving aldoxorubicin at a dose of 230mg/m2 every 21 days, with those receiving topotecan. Irinotecan is a chemotherapeutic agent known to be active in SCLC. SN38 is the active metabolite of irinotecan, which through its inhibitory action on DNA topoisomerase I induces DNA breaks and inhibits repair. Etirinotecan pegol is a formulation designed to provide prolonged systemic exposure to SN38.[12] In a phase I dose escalation study, 66 patients received etirinotecan on three different dosing schedules and 115mg/m2 administered on days 1, 8 and 15 of 21 day cycles was established as the MTD. Diarrhea was observed in 5 patients at the 115mg/m2 dose level, with one patient experiencing grade 3 or higher diarrhea. The cholinergic diarrhea that is seen with irinotecan was not observed with etirinotecan. The drug was also shown to induce partial responses in patients with various cancers including SCLC. Etirinotecan was also recently reported to be active in heavily pretreated ovarian cancer patients.[13] In this study etirinotecan was administered at 145mg/m2 every 14 or 21 days, and the 21 day dosing schedule was found to be better tolerated and selected for further study. A phase II study that plans to study the effect of etirinotecan dosed every 21 days on PFS in patients with relapsed SCLC is currently recruiting (NCT01876446). Another formulation of irinotecan, MM-398, which is a nanoliposomal encapsulated formulation that packs nearly 80,000 irinotecan molecules in a 100nm liposome, is also being actively investigated in pancreatic, gastrointestinal, and other solid tumors.[14] Results from the NAPOLI-1 trial, a phase III study in which patients with metastatic pancreatic cancer who were previously treated with gemcitabine, were randomized to receive either single agent MM-398 at 120mg/m2 every 3 weeks or a combination of 5-fluorouracil (5FU), leucovorin (LV) and MM-398 at 80mg/m2, or 5-FU/LV alone, were recently presented.[15] The primary objective of this study was OS and in the intention to treat analysis, this was significantly improved in the MM-398/5FU/LV combination arm compared to the 5FU/LV arm (median OS 6.1 months vs. 4.2 months, HR-0.57, p=0.0009). Although there is currently no clinical data regarding the efficacy or safety of these newer drugs in patients with SCLC, considering that taxanes, anthracyclines, and DNA topoisomerase inhibitors are each individually active in SCLC, and that newer agents such as these have shown some positive preliminary results in other cancers - there is hope and optimism that over the next few years we will witness substantial progress in the management of SCLC. Overall, the need for developing and implementing well-designed biomarker driven clinical studies to investigate the role of these and other novel agents in SCLC is now greater than ever. References 1. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol 2006;24:4539-44. 2. Rudin CM, Durinck S, Stawiski EW, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 2012;44:1111-6. 3. Peifer M, Fernández-Cuesta L, Sos ML, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 2012;44:1104-10. 4. Kalemkerian GP, Akerley W, Bogner P, et al. Small cell lung cancer. J Natl Compr Canc Netw 2013;11:78-98. 5. Scarpace SL. Eribulin mesylate (E7389): review of efficacy and tolerability in breast, pancreatic, head and neck, and non-small cell lung cancer. Clin Ther 2012;34:1467-73. 6. Cortes J, O'Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet 2011;377:914-23. 7. Mok TS, Geater SL, Iannotti N, et al. Randomized phase II study of two intercalated combinations of eribulin mesylate and erlotinib in patients with previously treated advanced non-small-cell lung cancer. Ann Oncol 2014;25:1578-84. 8. Spira AI, Iannotti NO, Savin MA, et al. A phase II study of eribulin mesylate (E7389) in patients with advanced, previously treated non-small-cell lung cancer. Clin Lung Cancer 2012;13:31-8. 9. Waller CF, Vynnychenko I, Bondarenko I, et al. An open-label, multicenter, randomized phase Ib/II study of eribulin mesylate administered in combination with pemetrexed versus pemetrexed alone as second-line therapy in patients with advanced nonsquamous non-small-cell lung cancer. Clin Lung Cancer 2015;16:92-9. 10. Kratz F. A clinical update of using albumin as a drug vehicle - a commentary. J Control Release 2014;190:331-6. 11. Chawla SP, Chua VS, Hendifar AF, et al. A phase 1B/2 study of aldoxorubicin in patients with soft tissue sarcoma. Cancer 2015;121:570-9. 12. Jameson GS, Hamm JT, Weiss GJ, et al. A multicenter, phase I, dose-escalation study to assess the safety, tolerability, and pharmacokinetics of etirinotecan pegol in patients with refractory solid tumors. Clin Cancer Res 2013;19:268-78. 13. Vergote IB, Garcia A, Micha J, et al. Randomized multicenter phase II trial comparing two schedules of etirinotecan pegol (NKTR-102) in women with recurrent platinum-resistant/refractory epithelial ovarian cancer. J Clin Oncol 2013;31:4060-6. 14. Saif MW. MM-398 achieves primary endpoint of overall survival in phase III study in patients with gemcitabine refractory metastatic pancreatic cancer. JOP 2014;15:278-9. 15. Dhindsa N, Bayever E, Li C, et al. NAPOLI-1: randomized phase 3 study of MM-398 (nal-iri), with or without 5-fluorouracil and leucovorin, versus 5-fluorouracil and leucovorin, in metastatic pancreatic cancer progressed on or following gemcitabine-based therapy. Annals of Oncology (2014) 25 (suppl_2): ii105-ii117. 10.1093/annonc/mdu193.

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