1. Nalley, Catlin

Article Content

The prognosis of patients with advanced and recurrent cervical cancer is often poor and current therapeutic approaches have relatively low response rates.

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With a need for improved therapies, researchers recently conducted a phase II study of eribulin, a Halichondrin B analog from the marine sponge H. okadai, in this patient population (J Clin Oncol 2018; doi:10.1200/JCO.2018.36.15_suppl.5526).


Previous research has shown that eribulin improves response rates and overall survival of pretreated metastatic breast cancer patients; it also has preclinical antitumor activity in squamous cell carcinoma.


"Eribulin exerts its anticancer effects via a tubulin-based antimitotic mechanism," researchers explained. "Its mechanism of microtubule (MT) inhibition is unique; only suppressing MT growth without an effect on MT shortening (Clin Can Res 2009;15:3903-3905, Pharmacol Ther 1992;55:31-51)."


Study Details

Researchers explored the clinical activity of eribulin and evaluated potential predictors of response among patients with advanced and recurrent cervical cancer.


The primary endpoint was 6-month progression-free survival (PFS6); secondary objectives, were best overall response (RECIST v1.1), toxicity (CTCAE v4.03), and overall survival. Exploratory endpoints, according to the research team, included "associations of tumor and serum GRP78 as well as apoptosis/proliferation markers, unfolded protein response markets, and tubulin sub-types with clinical activity."


Patients with advanced or recurrent cervical cancer who received <=1 prior chemotherapy regimens with measurable disease and an ECOG performance status <=2 were eligible for the study.


Thirty-two patients were enrolled from Nov. 14, 2012, to May 15, 2017, with a median age of 51 years (range 29-76). Twelve participants' disease status at entry was advanced; 20 had recurrent disease. Among the eligible patients, 26 received prior pelvic irradiation; 29 underwent prior chemotherapy with cisplatin/gemcitabine (12) and cisplatin/paclitaxel/bevacizumab (12) as the most common regimens.


Patients were treated with eribulin (1.4mg/m2 IV day 1 and 8, every 21 days) and underwent tumor assessments every 2 cycles. "Thirty evaluable patients would ensure 80 percent power when the true PFS6=26 percent with a 1-sided [alpha]<=0.1 (Ho: PFS6=10%)," researchers explained. "A prespecified futility analysis gating stage II was set if 0/15 patients showed at least stable disease at 6 months."


Investigators utilized immunohistochemistry to evaluate archival tumor samples; serial serum GRP78 levels were quantified by ELISA.


High levels of GRP78, which is a key regulator of the endoplasmic reticulum stress and unfolded protein response, has been shown to predict response to MT inhibitors in breast cancer patients (Cancer Res 2006;66(16):7849-7953, J Cancer 2011;128:726-731).


Key Findings

Six of 32 patients achieved 6-month PFS, researchers reported. Findings show a median PFS of 2.6 months (95% CI: 1.2, 4.2) and median OS of 6.6 months (95% CI: 4.4, 12.7).


Two patients were inevaluable for response having received less than 2 cycles, according to study authors. Among the evaluable patients, researchers reported that six (20%) had a partial response and 11 (37%) had stable disease (clinical benefit rate 57%). Two patients remain on study having received 21 and 29 cycles.


In terms of safety, reasons for treatment discontinuation included, disease progression (n=26; 87%), adverse event (n=1; 3%), delay in cycle initiations of >=2 weeks (n=1; 3%), and patient withdrawal of consent (n=2; 7%). Researchers reported that one patient was removed from the study due to paresthesia after 7 cycles.


Common treatment-emergent adverse events (in >=20 patients) were anemia (84%), alopecia (69%), nausea (66%), and fatigue (66%). There were a number of grade 3/4 adverse events, including anemia (38%), neutropenia (22%), leukopenia (19%), paresthesia (6%), febrile neutropenia (3%), abdominal pain (3%), diarrhea (3%), thrombocytopenia (3%), elevation in AST (3%), and headache (3%).


Dose reductions were required in four patients, one of which required two dose reductions. This was required due to grade 3 adverse events, including neutropenia, febrile neutropenia, back pain, and diarrhea.


Based on findings from this study, researchers concluded that "eribulin shows evidence of activity in recurrent/advanced cervical cancer with an acceptable toxicity profile.


"Analysis of correlative predictors of response is ongoing with attention to those patients who have a durable response," study authors concluded.


Catlin Nalley is associate editor.


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