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

Waller, Christiane; Vynnychenko, I.; Bondarenko, Igor; Shparyk, Yaroslav; Hodge, Jeffrey; Freeman, Anne; Huber, Brian E.; Lieberman, Ronald; Shelton, Mark J.; Dave, Harish P.

doi:10.1016/j.cllc.2014.10.001

Cited by 13 publications

(13 citation statements)

References 16 publications

(31 reference statements)

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“…Although eribulin failed to show meaningful activities in clinical trials of head and neck, pancreatic and advanced non-small cell lung cancer [10,11], improvements in overall survival by eribulin were reported in a Phase 3 trial in advanced soft tissue sarcoma compared with dacarbazine [12], pointing to additional clinical uses for eribulin. Clinical trials are ongoing to evaluate eribulin effectiveness for treatment of osteosarcoma, ovarian, cervical, urothelium, brain metastasis, metastatic salivary gland and pediatric cancers with the promise that additional cancer indications will be identified.…”

Section: Introductionmentioning

confidence: 99%

Identification of Combinatorial Drugs that Synergistically Kill both Eribulin-Sensitive and Eribulin-Insensitive Tumor Cells

Toshimitsu¹

2015

Glob J Cancer Ther

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Eribulin sensitivity was examined in a panel of twenty-five human cancer cell lines representing a variety of tumor types, with a preponderance of breast and lung cancer cell lines. As expected, the cell lines vary in sensitivity to eribulin at clinically relevant concentrations. To identify combination drugs capable of increasing anticancer effects in patients already responsive to eribulin, as well as inducing de novo anticancer effects in non-responders, we performed a combinatorial high throughput screen to identify drugs that combine with eribulin to selectively kill tumor cells. Among other observations, we found that inhibitors of ErbB1/ErbB2 (lapatinib, BIBW-2992, erlotinib), MEK (E6201, trametinib), PI3K (BKM-120), mTOR (AZD 8055, everolimus), PI3K/mTOR (BEZ 235), and a BCL2 family antagonist (ABT-263) show combinatorial activity with eribulin. In addition, antagonistic pairings with other agents, such as a topoisomerase I inhibitor (topotecan hydrochloride), an HSP-90 inhibitor (17-DMAG), and gemcitabine and cytarabine, were identified. In summary, the preclinical studies described here have identified several combination drugs that have the potential to either augment or antagonize eribulin's anticancer activity. Further elucidation of the mechanisms responsible for such interactions may be important for identifying valuable therapeutic partners for eribulin.of care. Chemotherapeutic drugs are often most effective when given in combination, in particular when synergistic killing is achieved without additive toxicity. To date, potential combination therapies for eribulin have been explored with only a limited number of anticancer agents. We therefore have performed an in vitro study of eribulin combined with 34 anticancer agents in 25 different tumor cell lines of various types, through use of a combination high throughput screening (cHTS) platform. Our goals were to identify drugs that might be paired with eribulin to increase clinical efficacy in metastatic breast cancer, to identify drugs that convert eribulin non-responders to responders, and to identify new therapeutic indications for eribulin utilization. Several compelling synergy effects with approved and emerging drugs were observed. The preclinical data provides insights about future clinical development strategies.

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Section: Introductionmentioning

confidence: 99%

Identification of Combinatorial Drugs that Synergistically Kill both Eribulin-Sensitive and Eribulin-Insensitive Tumor Cells

Toshimitsu¹

2015

Glob J Cancer Ther

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“…A total of 39 studies were enrolled for the final analysis. 33 were single arm trials , the other 6 were RCTs [9][10][11][12][13][14]. A flow chart was presented in Figure 1.…”

Section: Search Resultsmentioning

confidence: 99%

“…The dose and schedule of eribulin was 1.4 mg/m 2 in 2-5 minutes intravenously on days 1 and 8 on a 21-day schedule, the currently FDA-recommended dose until unacceptable toxicity, disease progression or patient refusal. In one study [14], pharmacokinetic and pharmacodynamical analysis revealed that 0.9 mg/ m 2 is the optimal dose for NSCLC patients. The median treatment ranged from 1.5 months [34] to 7.7 months [23].…”

Section: Population Characteristicsmentioning

confidence: 99%

“…The RRs and their 95% CIs of hematologic toxicities were calculated with 6 RCTs (3 phase III studies and 3 phase II studies including 2,546 patients) [9][10][11][12][13][14]. The relative risks of all-grade neutropenia, leucopenia, anemia, febrile neutropenia and thrombocytopenia were 1.94 (95% CI, 1.37-2.74; p = 0.01), 1.81 (95% CI, 1.10-2.97; p = 0.02), 0.95 (95% CI, 0.82-1.11, p = 0.53), 2.15 (95% CI, 0.79-5.82; p = 0.12), and 0.21 (95% CI, 0.12-0.36; p < 0.001) respectively ( Figure 2).…”

Section: Relative Risk Of Hematologic Adverse Eventsmentioning

confidence: 99%

“…Due to its novel mechanism, eribulin treatment is often associated with a distinct profile of adverse events. Previous studies have showed that the common side effects of eribulin were myelosuppression, fatigue/ asthenia, alopecia, and peripheral neuropathy [9][10][11][12][13][14]. Although hematologic toxicities associated with eribulin have been reported, there has been no systematic attempt to synthesize these data and the relative risk of hematologic toxicities induced by eribulin has yet to be evaluated.…”

Section: Introductionmentioning

confidence: 99%

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Incidence and risk of eribulin mesylate related hematologic toxicity

Zhao¹,

Zhao²

2017

Oncotarget

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Eribulin mesylate, a microtubule dynamics inhibitor, has been approved for the treatment of several malignancies. Due to its novel mechanism of action, eribulin is often associated with a distinct profile of adverse events including hematologic toxicities. Here we searched PubMed and Embase database from reception to August 2017 for clinical trials with eribulin treatment. Eligible studies included trials with eribulin administered at a standard dose of 1.4 mg/m 2 intravenously on days 1 and 8 in a 21-day cycle, and adequate safety data profile reporting neutropenia, leucopenia, anemia, febrile neutropenia and thrombocytopenia. The overall incidence, relative risk (RR) and 95% confidence interval (CI) were calculated. A total of 39 studies with 6,092 subjects were included in this study. The incidences of eribulin related all-grade and high-grade hematologic toxicities were: neutropenia, 56% and 39%; leucopenia, 44% and 21%; anemia, 33% and 2%; febrile neutropenia, 5% and 5%; and thrombocytopenia, 12% and 12%. Compared with controls, eribulin was associated with a significant increased risk of all-grade (RR, 1.94; 95% CI, 1.37-2.74) and high-grade (RR, 2.58; 95% CI, 1.30-5.10) neutropenia, all-grade (RR, 1.81; 95% CI, 1.10-2.97) and high-grade (RR, 2.95; 95% CI, 1.36-6.39) leucopenia, but not with anemia and febrile neutropenia. Trial sequential analysis showed the results from neutropenia, leucopenia and anemia established sufficient and conclusive evidence. Our study suggested that eribulin therapy, compared with control, was associated with an increased risk of hematologic toxicities. Hence hematologic monitoring at regular intervals should be advised.

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A phase 1b, multicenter, open-label, dose-finding study of eribulin in combination with carboplatin in advanced solid tumors and non-small cell lung cancer

Goel

Swami

Kumar

et al. 2019

Cancer Chemother Pharmacol

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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

Cited by 13 publications

References 16 publications

Identification of Combinatorial Drugs that Synergistically Kill both Eribulin-Sensitive and Eribulin-Insensitive Tumor Cells

Identification of Combinatorial Drugs that Synergistically Kill both Eribulin-Sensitive and Eribulin-Insensitive Tumor Cells

Incidence and risk of eribulin mesylate related hematologic toxicity

A phase 1b, multicenter, open-label, dose-finding study of eribulin in combination with carboplatin in advanced solid tumors and non-small cell lung cancer

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