Corina E. Dutcus

Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study

BACKGROUND Treatments with survival benefit are greatly needed for women with heavily pretreated metastatic breast cancer. Eribulin mesilate is a non-taxane microtubule dynamics inhibitor with a novel mode of action. We aimed to compare overall survival of heavily pretreated patients receiving eribulin versus currently available treatments. METHODS In this phase 3 open-label study, women with locally recurrent or metastatic breast cancer were randomly allocated (2:1) to eribulin mesilate (1·4 mg/m(2) administered intravenously during 2-5 min on days 1 and 8 of a 21-day cycle) or treatment of physicians choice (TPC). Patients had received between two and five previous chemotherapy regimens (two or more for advanced disease), including an anthracycline and a taxane, unless contraindicated. Randomisation was stratified by geographical region, previous capecitabine treatment, and human epidermal growth factor receptor 2 status. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT00388726. FINDINGS 762 women were randomly allocated to treatment groups (508 eribulin, 254 TPC). Overall survival was significantly improved in women assigned to eribulin (median 13·1 months, 95% CI 11·8-14·3) compared with TPC (10·6 months, 9·3-12·5; hazard ratio 0·81, 95% CI 0·66-0·99; p=0·041). The most common adverse events in both groups were asthenia or fatigue (270 [54%] of 503 patients on eribulin and 98 [40%] of 247 patients on TPC at all grades) and neutropenia (260 [52%] patients receiving eribulin and 73 [30%] of those on TPC at all grades). Peripheral neuropathy was the most common adverse event leading to discontinuation from eribulin, occurring in 24 (5%) of 503 patients. INTERPRETATION Eribulin showed a significant and clinically meaningful improvement in overall survival compared with TPC in women with heavily pretreated metastatic breast cancer. This finding challenges the notion that improved overall survival is an unrealistic expectation during evaluation of new anticancer therapies in the refractory setting. FUNDING Eisai.

Lenvatinib versus Placebo in Radioiodine-Refractory Thyroid Cancer

BACKGROUND Lenvatinib, an oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, platelet-derived growth factor receptor α, RET, and KIT, showed clinical activity in a phase 2 study involving patients with differentiated thyroid cancer that was refractory to radioiodine (iodine-131). METHODS In our phase 3, randomized, double-blind, multicenter study involving patients with progressive thyroid cancer that was refractory to iodine-131, we randomly assigned 261 patients to receive lenvatinib (at a daily dose of 24 mg per day in 28-day cycles) and 131 patients to receive placebo. At the time of disease progression, patients in the placebo group could receive open-label lenvatinib. The primary end point was progression-free survival. Secondary end points included the response rate, overall survival, and safety. RESULTS The median progression-free survival was 18.3 months in the lenvatinib group and 3.6 months in the placebo group (hazard ratio for progression or death, 0.21; 99% confidence interval, 0.14 to 0.31; P<0.001). A progression-free survival benefit associated with lenvatinib was observed in all prespecified subgroups. The response rate was 64.8% in the lenvatinib group (4 complete responses and 165 partial responses) and 1.5% in the placebo group (P<0.001). The median overall survival was not reached in either group. Treatment-related adverse effects of any grade, which occurred in more than 40% of patients in the lenvatinib group, were hypertension (in 67.8% of the patients), diarrhea (in 59.4%), fatigue or asthenia (in 59.0%), decreased appetite (in 50.2%), decreased weight (in 46.4%), and nausea (in 41.0%). Discontinuations of the study drug because of adverse effects occurred in 37 patients who received lenvatinib (14.2%) and 3 patients who received placebo (2.3%). In the lenvatinib group, 6 of 20 deaths that occurred during the treatment period were considered to be drug-related. CONCLUSIONS Lenvatinib, as compared with placebo, was associated with significant improvements in progression-free survival and the response rate among patients with iodine-131-refractory thyroid cancer. Patients who received lenvatinib had more adverse effects. (Funded by Eisai; SELECT ClinicalTrials.gov number, NCT01321554.).

Phase III Open-Label Randomized Study of Eribulin Mesylate Versus Capecitabine in Patients With Locally Advanced or Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane

Purpose This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared eribulin with capecitabine in patients with locally advanced or metastatic breast cancer (MBC). Patients and Methods Women with MBC who had received prior anthracycline- and taxane-based therapy were randomly assigned to receive eribulin or capecitabine as their first-, second-, or third-line chemotherapy for advanced/metastatic disease. Stratification factors were human epidermal growth factor receptor-2 (HER2) status and geographic region. Coprimary end points were overall survival (OS) and progression-free survival (PFS). Results Median OS times for eribulin (n = 554) and capecitabine (n = 548) were 15.9 and 14.5 months, respectively (hazard ratio [HR], 0.88; 95% CI, 0.77 to 1.00; P = .056). Median PFS times for eribulin and capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, 0.93 to 1.25; P = .30). Objective response rates were 11.0% for eribulin and 11.5% for capecitabine. Global health status and overall quality-of-life scores over time were similar in the treatment arms. Both treatments had manageable safety profiles consistent with their known adverse effects; most adverse events were grade 1 or 2. Conclusion In this phase III study, eribulin was not shown to be superior to capecitabine with regard to OS or PFS.

Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial

BACKGROUND In a phase 2 trial, lenvatinib, an inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT, showed activity in hepatocellular carcinoma. We aimed to compare overall survival in patients treated with lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma. METHODS This was an open-label, phase 3, multicentre, non-inferiority trial that recruited patients with unresectable hepatocellular carcinoma, who had not received treatment for advanced disease, at 154 sites in 20 countries throughout the Asia-Pacific, European, and North American regions. Patients were randomly assigned (1:1) via an interactive voice-web response system-with region; macroscopic portal vein invasion, extrahepatic spread, or both; Eastern Cooperative Oncology Group performance status; and bodyweight as stratification factors-to receive oral lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg) or sorafenib 400 mg twice-daily in 28-day cycles. The primary endpoint was overall survival, measured from the date of randomisation until the date of death from any cause. The efficacy analysis followed the intention-to-treat principle, and only patients who received treatment were included in the safety analysis. The non-inferiority margin was set at 1·08. The trial is registered with ClinicalTrials.gov, number NCT01761266. FINDINGS Between March 1, 2013 and July 30, 2015, 1492 patients were recruited. 954 eligible patients were randomly assigned to lenvatinib (n=478) or sorafenib (n=476). Median survival time for lenvatinib of 13·6 months (95% CI 12·1-14·9) was non-inferior to sorafenib (12·3 months, 10·4-13·9; hazard ratio 0·92, 95% CI 0·79-1·06), meeting criteria for non-inferiority. The most common any-grade adverse events were hypertension (201 [42%]), diarrhoea (184 [39%]), decreased appetite (162 [34%]), and decreased weight (147 [31%]) for lenvatinib, and palmar-plantar erythrodysaesthesia (249 [52%]), diarrhoea (220 [46%]), hypertension (144 [30%]), and decreased appetite (127 [27%]) for sorafenib. INTERPRETATION Lenvatinib was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma. The safety and tolerability profiles of lenvatinib were consistent with those previously observed. FUNDING Eisai Inc.

Abstract S6-6: A Phase III, open-label, randomized, multicenter study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes

Background: Eribulin is a non-taxane microtubule dynamics inhibitor. In a previous Phase III trial, eribulin demonstrated a statistically significant improvement in overall survival (OS) versus current treatments and a manageable toxicity profile, in heavily pre-treated patients (pts) with metastatic breast cancer (MBC). Here we report results from a Phase III trial of eribulin compared with capecitabine in earlier-line pts with MBC (NCT00337103). Patients and methods: Pts were randomized 1:1 to eribulin mesylate 1.4 mg/m 2 given on Days 1 and 8 of a 21 day cycle or capecitabine 2.5 g/m 2 /day administered orally BID on Days 1 to 14 of a 21 day cycle. Eligible pts had received prior therapy including an anthracycline and taxane, and were receiving study drug as 1 st , 2 nd , or 3 rd line therapy for advanced disease. The co-primary endpoints of this study were OS and progression free survival (PFS): pre-specified statistical significance at final analysis for eribulin versus capecitabine were p ≤ 0.0372 for OS and p Results: Of 1102 pts, 554 were randomized to eribulin and 548 capecitabine (375 and 380 pts were HER2[−], respectively). The median age was 54.0 years (range 24–80). Pts received study treatment as their 1 st (27.2%), 2 nd (57.4%) or 3 rd -line (14.7%) chemotherapeutic regimen in the setting of metastatic disease. The median number of treatment cycles was 6 for eribulin and 5 for capecitabine. Median OS was 15.9 and 14.5 months (hazard ratio [HR] 0.879; 95% confidence intervals [CI] 0.770–1.003; p = 0.056), and PFS (independent review) was 4.1 and 4.2 months (HR 1.079; 95% CI 0.932–1.250; p = 0.305) for eribulin and capecitabine, respectively. ORR (independent review) were 11.0% (95% CI 8.5–13.9) and 11.5% (95% CI 8.9–14.5; p = 0.849), respectively. OS for HER2(−) pts was 15.9 months for eribulin and 13.5 months for capecitabine (HR 0.838; 95% CI 0.715–0.983; p = 0.030). AEs were consistent with the known side-effect profiles of both drugs. The most common AEs for eribulin and capecitabine (>20% all grades) were neutropenia (54.2% vs 15.9%), hand-foot syndrome (0.2% vs 45.1%) alopecia (34.6% vs 4.0%), leukopenia (31.4% vs 10.4%), diarrhea (14.3% vs 28.8%), and nausea (22.2% vs 24.4%), respectively. Conclusion: In this Phase III trial, eribulin demonstrated a trend favoring improved OS, compared with capecitabine, although this improvement does not meet the pre-defined criteria for statistical significance. This study confirms eribulin as an active drug in pts with MBC, and exploratory analyses suggest possible benefits of eribulin in specific subsets of pts, sufficient to warrant further study. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S6-6.

Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma

We previously reported results of a randomised, open-label, phase 2 trial of lenvatinib, everolimus, and lenvatinib plus everolimus in patients with metastatic renal cell carcinoma who had progressed after one previous VEGF-targeted therapy. Our study met the primary endpoint by showing improved progressionfree survival with lenvatinib plus everolimus and lenvatinib alone versus everolimus alone, using investigator-assessed objective responses. On the basis of agreements reached with regulatory agencies, an ad hoc, retrospective, blinded, independent radiological review (IRR) was completed to assess whether the effi cacy results based on investigator assessments were supported by those of the IRR. We obtained CT and MRI scans of participants in the study, completed once every 8 weeks from random assignment until disease progression or start of another cancer treatment. IRR was done by radiologists (Parexel Inc, Billerica, MA, USA) masked to treatment using Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). The primary endpoint of this study was progression-free survival assessed by IRR, in the intention-to treat population, with two primary comparisons: lenvatinib plus everolimus versus everolimus alone, and lenvatinib alone versus everolimus alone. Progressionfree survival was analysed by the identical methodology as that reported in the primary assessment; hazard ratios (HR) were derived from stratified Cox regression models, and Mantel-Haenszel stratified log-rank tests (stratifi cation factors were haemoglobin [men, ≤130 g/L serve as a proxy for total dose and overall levels of cell death. In human patients, this is commonly achieved with conventionally fractionated radiation. These important diff erences notwithstanding, results from animal models have suggested that low dose per fraction radiation might be more effective at recruiting T-cells to a tumour microenvironment than at high doses. Ultimately, examination of existing preclinical dose comparisons do not provide a clear answer. Studies combining radiation and vaccination noted no differences between 8 Gy delivered in either a single fraction and 2 Gy delivered in more than four fractions. As mentioned by Sharabi and colleagues in their Review, Dewan and colleagues’ study using a combination of radiation and CTLA-4 blockade showed synergy with three 8 Gy fractions, but not with one 20 Gy treatment. Conversely, other models showed use of one high-dose per fraction treatment to be better than low-dose regimens. In systematic studies of patients treated with radiation and ipilimumab, systemic responses tended to improve most after low fractional doses of radiation. Additionally, in 2015, Golden and colleagues reported a promising 28% abscopal response in patients treated with fractionated radiation at a dose of 3·5 Gy per fraction (ten fractions in total) in combination with systemic granulocytemacrophage colony-stimulating factor. By contrast, a clinical trial that combined ipilimumab with one hypofractionated radiation dose of 8 Gy did not achieve its primary endpoint of overall survival. Similarly, a second study that combined ipilimumab with two or three 8 Gy fractions in 22 patients with melanoma did not result in a significantly different systemic response than might be expected from use of only ipilimumab. Sharabi and colleagues rightfully point out the uncertainty about which radiation dose per fraction might be best to use in conjunction with immunotherapy. The answer will likely depend on tumour histology, the immunotherapeutic strategy used, and many other factors. However, at least in human patients, we would caution presupposing a dose per fraction effect that is not yet established.

A phase 3, multicenter, double-blind, placebo-controlled trial of lenvatinib (E7080) in patients with 131I-refractory differentiated thyroid cancer (SELECT).

LBA6008 Background: Lenvatinib (LEN) is an oral tyrosine kinase inhibitor of the VEGFR1-3, FGFR1-4, PDGFRβ, RET, and KIT signaling networks. Based on efficacy results of the phase 2 study of patients (pts) with 131I-refractory differentiated thyroid cancer (RR-DTC), this phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) was developed. METHODS This randomized, double-blind, placebo (PBO)-controlled study enrolled pts with RR-DTC with documented disease progression within 13 months (mo). Pts were stratified by age (≤65, >65 years), region and ≤1 prior VEGFR-targeted therapies and randomized 2:1 to LEN or PBO (24mg/d, 28-d cycle). Upon progression, pts receiving PBO could crossover to open-label LEN. The primary endpoint was PFS assessed by Independent Radiologic Review; secondary endpoints included overall response rate (ORR; complete response [CR] + PR), overall survival (OS) and safety. RESULTS 392 pts (63.0 years median age; 51.0% male) were randomized. Pts on LEN had a significantly prolonged PFS vs PBO (hazard ratio 0.21, 95% confidence interval [CI] 0.14-0.31; P <.0001); median PFS was LEN: 18.3 mo (95% CI 15.1-not evaluable), PBO: 3.6 mo (95% CI 2.2-3.7). A LEN PFS benefit was observed in all predefined subgroups; median LEN PFS for pts with prior vs no prior VEGF-therapy was 15.1 mo (n=66) and 18.7 mo (n=195), respectively. Rates (n) of CRs were LEN: 1.5% (4), PBO: 0; PRs were LEN: 63.2% (165), PBO: 1.5% (2).Median exposure duration was LEN: 13.8 mo, PBO: 3.9 mo; median time to LEN response was 2.0 mo. Median OS has not been reached; deaths per arm were LEN: 71 (27.2%), PBO: 47 (35.9%). The 5 most common LEN treatment-related adverse events (TRAEs; any grade) were hypertension (68%), diarrhea (59%), appetite decreased (50%), weight loss (46%), nausea (41%). LEN grade ≥3 TRAEs (≥5%) were hypertension (42%), proteinuria (10%), weight loss (10%), diarrhea (8%), appetite decreased (5%). The dose was reduced in 78.5% of pts and discontinued due to adverse events (AEs) in 14.2% of pts. CONCLUSIONS LEN significantly improved PFS compared with PBO in pts with progressive RR-DTC. There were no unexpected toxicities and AEs were manageable. CLINICAL TRIAL INFORMATION NCT01321554.

Eribulin Monotherapy in Patients Aged 70 Years and Older With Metastatic Breast Cancer

PURPOSE Following the demonstrated efficacy and safety of eribulin mesylate in heavily pretreated patients with metastatic breast cancer, an exploratory analysis was performed to investigate the effect of age in these patients. METHODS Data were pooled from two single-arm phase II studies and one open-label randomized phase III study in which patients received eribulin mesylate at 1.4 mg/m(2) as 2- to 5-minute intravenous infusions on days 1 and 8 of a 21-day cycle. The effect of age on median overall survival (OS), progression-free survival (PFS), overall response rate (ORR), clinical benefit rate (CBR), and incidence of adverse events (AEs) was calculated for four age groups (<50 years, 50-59 years, 60-69 years, ≥ 70 years). RESULTS. Overall, 827 patients were included in the analysis (<50 years, n = 253; 50-59 years, n = 289; 60-69 years, n = 206; ≥ 70 years, n = 79). Age had no significant impact on OS (11.8 months, 12.3 months, 11.7 months, and 12.5 months, respectively; p = .82), PFS (3.5 months, 2.9 months, 3.8 months, and 4.0 months, respectively; p = .42), ORR (12.7%, 12.5%, 6.3%, and 10.1%, respectively), or CBR (20.2%, 20.8%, 20.4%, and 21.5%, respectively). Although some AEs had higher incidence in either the youngest or the oldest subgroup, there was no overall effect of age on the incidence of AEs (including neuropathy, neutropenia, and leukopenia). CONCLUSION Eribulin monotherapy in these selected older patients with good baseline performance status led to OS, PFS, ORR, CBR, and tolerability similar to those of younger patients with metastatic breast cancer. The benefits and risks of eribulin appear to be similar across age groups.

Lenvatinib for Anaplastic Thyroid Cancer

Background Lenvatinib has been approved by regulatory agencies in Japan, the United States, and the European Union for treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). Thyroid cancer, however, is a clinically diverse disease that includes anaplastic thyroid cancer (ATC), the subtype associated with the highest lethality. Effective therapy for ATC is an unmet need. Patients and methods This phase 2, single-arm, open-label study in patients with thyroid cancer, including ATC, RR-DTC, and medullary thyroid cancer was conducted from 3 September 2012 to 9 July 2015. Patients received lenvatinib 24 mg daily until disease progression or development of unacceptable toxicity. The primary endpoint was safety, and the secondary endpoint was efficacy, as assessed by progression-free survival (PFS), overall survival (OS), and objective response rate. Results At data cutoff, 17 patients with ATC were enrolled. All experienced ≥1 treatment-emergent adverse event (TEAE). The most frequent TEAEs were decreased appetite (82%), hypertension (82%), fatigue (59%), nausea (59%), and proteinuria (59%). Of note, only one patient required lenvatinib withdrawal because of a TEAE, and this TEAE was considered unrelated to lenvatinib. The median PFS was 7.4 months [95% confidence interval (CI): 1.7–12.9], the median OS was 10.6 months (95% CI: 3.8–19.8), and the objective response rate was 24%. Conclusion In this study, lenvatinib demonstrated manageable toxicities with dose adjustments and clinical activity in patients with ATC. This clinical activity of lenvatinib warrants further investigation in ATC. ClinicalTrials.gov NCT01728623.

995PDPHASE II STUDY OF LENVATINIB (LEN), A MULTI-TARGETED TYROSINE KINASE INHIBITOR, IN PATIENTS (PTS) WITH ALL HISTOLOGIC SUBTYPES OF ADVANCED THYROID CANCER (DIFFERENTIATED, MEDULLARY AND ANAPLASTIC)

palmar-plantar erythrodysesthesia syndrome (74%; 6%), fatigue (71%; 3%), decreased appetite (69%; 9%), proteinuria (51%; 0%), stomatitis (51%; 0%), diarrhea (43%; 11%), nausea (40%; 6%) and dysphonia (31%; 0%). Almost all (34/35) subjects required dose reduction, however, no subjects required study drug withdrawal due to AEs. 34 pts were evaluable for efficacy, including 21 pts with RR-DTC, 4 pts with MTC, and 9 pts with ATC. The objective response rate (ORR) based on the investigator assessment was 47.6% in RR-DTC, 25.0% in MTC, and 33.3% in ATC, respectively. Median PFS was 6.5 mo (95% CI: 5.6 - 7.3) in MTC and 5.5 mo (95% CI: 1.4 -) in ATC, respectively. Median PFS has not been determined in RR-DTC. Conclusions: AE profiles were generally similar to the data from previous clinical studies of lenvatinib with manageable toxicity with dose reduction and interruption. LEN demonstrated promising activity in all histologic subtypes of advanced thyroid cancer. Three of 9 pts with ATC have received administration of LEN for more than 6 month, which should be noteworthy. Disclosure: S. Takahashi, M. Tahara and N. Kiyota: Advisory Board: Eisai. All other authors have declared no conflicts of interest.