Nicole Meneses

PURPOSE: Eribulin mesylate (E7389), a nontaxane microtubule dynamics inhibitor, is a structurally simplified, synthetic analog of the marine natural product halichondrin B. This open-label, single-arm, phase II study evaluated efficacy and tolerability of eribulin in heavily pretreated patients with metastatic breast cancer (MBC). METHODS: MBC patients who were previously treated with an anthracycline and a taxane received eribulin mesylate (1.4 mg/m(2)) as a 2- to 5-minute intravenous (IV) infusion on days 1, 8, and 15 of a 28-day cycle. Because of neutropenia (at day 15), an alternative regimen of eribulin on days 1 and 8 of a 21-day cycle was administered. The primary end point was overall response rate. RESULTS: Of the 103 patients treated, the median number of prior chemotherapy regimens was four (range, one to 11 regimens). In the per-protocol population (n = 87), eribulin achieved an independently reviewed objective response rate (all partial responses [PRs]) of 11.5% (95% CI, 5.7 to 20.1) and a clinical benefit rate (PR plus stable disease > or = 6 months) of 17.2% (95% CI, 10.0 to 26.8). The median duration of response was 171 days (5.6 months; range, 44 to 363 days), the median progression-free survival was 79 days (2.6 months; range, 1 to 453 days), and the median overall survival was 275 days (9.0 months; range, 15 to 826 days). The most common drug-related grades 3 to 4 toxicities were as follows: neutropenia, 64%; leukopenia, 18%; fatigue, 5%; peripheral neuropathy, 5%; and febrile neutropenia, 4%. CONCLUSION: Eribulin demonstrated activity with manageable tolerability (including infrequent grade 3 and no grade 4 neuropathy) in heavily pretreated patients with MBC when dosed as a short IV infusion on days 1 and 8 of a 21-day cycle.

5520 Background: Lenvatinib is an oral receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT, and PDGFRβ. The importance of angiogenesis in endometrial cancer (EC) highlights the need to understand clinical mechanisms of escape (eg, angiopoietin-2 [Ang-2]) from antiangiogenic therapy. Methods: Patients (pts) had metastatic/unresectable EC after 1 or 2 prior platinum-based treatments (Tx), ≤2 prior chemotherapies, and ECOG PS ≤2. Pts received lenvatinib 24 mg once daily until disease progression or development of unmanageable toxicities. Primary endpoint was objective response rate (ORR: complete + partial response [CR+PR]) by RECIST 1.1. Archival tumor tissue and baseline (BL) and post-Tx plasma samples were collected for molecular analyses (reported elsewhere). Results: 133 pts were treated (median age: 62 y) and evaluated for safety, efficacy, and molecular correlative analysis. Dose reduction (31%) or Tx discontinuation (31%) occurred for toxicity. Median Tx duration was 112 days. The most common adverse events were hypertension 55% (Gr 3/4: 33%), fatigue 42% (Gr 3: 12.8%), diarrhea 35% (Gr 3: 5.3%), decreased appetite 35% (Gr 3: 2.3%), and nausea 32% (Gr 3: 3%); 1 pt had Gr 5 asthenia. Bowel obstruction, fistula formation, and perforation occurred in 3.8%, 2.3%, and 1.5%, respectively. Confirmed CR+PRs were observed in 19 pts (14.3%) by independent review (IRR) and 29 pts (21.8%) by investigator assessment (Inv). mPFS was 5.4 mos and mOS was 10.6 mos. Among 50 serum factors tested, only BL plasma Ang-2 correlated with maximal tumor shrinkage, R = 0.36 (Spearman), p < 0.001; ORR; PFS; and OS. The 24 pts with low BL Ang-2 plasma levels (cut-off value <2082 pg/mL) were compared with the 98 pts with high BL Ang-2 (>2082 pg/mL) and improved ORR (61% vs 18%), mPFS (9.5 vs 3.7 mos), and mOS (23 vs 8.9 mos) were observed. Conclusions: Lenvatinib in this population was tolerable and resulted in a 14.3% (IRR) and 21.8% (Inv) ORR and mOS of 10.6 mos.Low BL Ang-2 level appears to predict clinical benefit in a subset of pts with advanced EC who may achieve high response rates and prolonged overall survival. Further assessment is warranted. Clinical trial information: NCT01111461.

1034 Background: Eribulin is a structurally simplified analog of halichondrin B, which inhibits microtubule dynamics via a novel mechanism characterized by suppression of microtubule growth, lack of effect on microtubule depolymerization, and sequestration of tubulin into nonfunctional aggregates. This study was designed to assess the activity and tolerance of eribulin in chemotherapy refractory patients with advanced breast cancer. Methods: Eribulin was evaluated in a single-arm Phase II trial in female patients with refractory breast cancer, ECOG performance status of 0–1, measurable disease, and neuropathy ≤ Grade 2. Patients received ≥ 1 prior chemotherapy regimen, including an anthracycline and a taxane. Eribulin was administered as a 2–5 min IV bolus of 1.4 mg/m 2 on Days 1, 8, and 15 of a 28-Day cycle (Group 1). The schedule was modified to Days 1 and 8 of a 21-Day cycle (Group 2), because of dose delays. The primary efficacy endpoint was ORR according to RECIST criteria based upon independent review (IR) of tumor assessment. Results: Of 104 patients enrolled, 103 received eribulin treatment: 70 in Group 1, 33 in Group 2. Median age was 55 yrs (range 32–84). Patients had received a median of 4 prior chemotherapy regimens (range 1–11). Sixty-one percent of tumors were ER+, 14% Her2/neu 3+, and 29% were triple (ER, PR, Her-2) negative. The incidence of dose interruption, delay, or omission during Cycle 1 was 63% (Group 1) and 18% (Group 2). The most common drug related toxicities were neutropenia (75%, Grades 3: 31%, Grade 4: 30%, febrile neutropenia: 3.9%), fatigue (52%, Grade 3: 2.9%, no Grade 4), alopecia (Grade 1/2: 41%), nausea (37%, Grade 3: 1%, no Grade 4), and anemia (36%, Grade 3: 1%, no Grade 4). Peripheral neuropathy occurred in 34% of patients (Grade 3: 3.9%, no Grade 4). Best overall response rate (all PR) by IR was 14.5% and 15.2% in Groups 1 and 2, respectively; the combined ORR was 14.7% (95 % CI: 9–23%). Median PFS was 85 days, and the 6 mo PFS rate was 31%. Conclusions: Eribulin given as a 2–5 min IV infusion on Days 1, 8 of a 21-Day cycle or Days 1, 8, 15 of a 28-Day cycle exhibited a 15% PR rate by IR and a low incidence of Grade 3 neuropathy in this heavily chemotherapy pretreated population. The most common toxicity was neutropenia. The 21-Day schedule had an acceptable toxicity profile. No significant financial relationships to disclose.

9026 Background: Lenvatinib is an oral receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT, and PDGFRβ. Melanoma responses in the phase I study led to this multicenter phase II trial of lenvatinib in separate cohorts of BRAF mutant and BRAF wild-type (wt) melanoma to provide an estimate of efficacy and to identify molecular correlates of clinical benefit. Primary analyses of clinical outcomes for the BRAF wt cohort are reported here; the BRAF mutant cohort will be presented at a later date. Methods: Eligible patients (pts) had stage IV or unresectable stage III BRAF wt melanoma with ≥1 prior treatment (26/96 [27%] pts received ≥3 treatments) and no prior VEGF-targeted therapy. Lenvatinib 24 mg once daily with dose reduction for toxicity was administered until disease progression or unmanageable toxicities. Primary endpoint was response rate by independent review (IRR) using RECIST 1.1. Archival tumor tissue and baseline and posttreatment serum samples were collected for molecular analysis. Results: 93 pts were treated (median [m] age: 64 y; male: 69%; 95% AJCC stage IV). Confirmed partial responses (PRs) were observed in 8 pts (9%) with a clinical benefit rate (CR+PR+durable SD ≥23 wks) of 32% by IRR. mPFS was 3.7 mos (95% CI, 2.5-4.0) by IRR and mOS was 9.5 mos (95% CI, 8.3-12.9); 46% pts required dose reduction for management of toxicity; 12% were withdrawn from therapy due to toxicity. Treatment-related adverse events reported in ≥20% pts included hypertension 59% (34% Gr 3/4), fatigue 58% (16% Gr 3/4), nausea 44% (3% Gr 3/4), diarrhea 43% (2% Gr 3/4), decreased appetite 38%, vomiting 29% (2% Gr 3), dysphonia 27%, and proteinuria and headache 26% each (4% and 1% Gr 3/4). Serum biomarker analysis showed baseline levels of serum angiogenic factors, such as angiopoietin-2, correlated with OS. More extensive biomarker analyses are reported in an accompanying abstract. Conclusions: Lenvatinib administered to pts with advanced BRAF wt melanoma was associated with frequent but manageable toxicity. Clinical benefit was seen in some pts. Predictive biomarkers for response to lenvatinib, such as the serum level of angiogenic factors, may be useful for future clinical trials. Clinical trial information: NCT01136967.