Pharmacodynamics

Mechanism of Action

Eribulin mesilate (Halaven) is a non-taxane, microtubule dynamics inhibitor belonging to the halichondrin class of antineoplastic agents. It is a structurally simplified synthetic analogue of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai.

Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into non-productive aggregates. Eribulin exerts its effects via a tubulin-based antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage.

In addition, eribulin treatment of human breast cancer cells caused changes in morphology and gene expression as well as decreased migration and invasiveness in vitro. In mouse xenograft models of human breast cancer, eribulin treatment was associated with increased vascular perfusion and permeability in the tumor cores, resulting in reduced tumor hypoxia, and changes in the expression of genes in tumor specimens associated with a change in phenotype.


Clinical efficacy and safety

Breast Cancer

The efficacy of Eribulin mesilate (HALAVEN) in breast cancer is primarily supported by two randomized Phase 3 comparative studies.

The 762 patients in the pivotal Phase 3 EMBRACE study (Study 305) had locally recurrent or metastatic breast cancer, and had previously received at least two and a maximum of five chemotherapy regimens, including an anthracycline and a taxane (unless contraindicated). Patients must have progressed within 6 months of their last chemotherapeutic regimen. The HER2 status of the patients was: 16.1% positive, 74.2% negative and 9.7% unknown, whilst 18.9% of patients were triple negative. They were randomized 2:1 to receive either Eribulin mesilate (HALAVEN), or treatment of physician’s choice (TPC), which consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxane, 9% anthracycline, 10% other chemotherapy), or 3% hormonal therapy. The study met its primary endpoint with an overall survival result that was statistically significantly better in the eribulin group compared to TPC at 55% of events. This result was confirmed with an updated overall survival analysis carried out at 77% of events.

By independent review, the median progression free survival (PFS) was 3.7 months for eribulin mesilate (HALAVEN) compared to 2.2 months for the TPC arm (HR 0.865, 95% CI: 0.714, 1.048, p=0.137). In response evaluable patients, the objective response rate by the RECIST criteria was 12.2% (95% CI: 9.4%, 15.5%) by independent review for the eribulin arm compared to 4.7% (95% CI: 2.3%, 8.4%) for the TPC arm. The positive effect on OS was seen in both taxane-refractory and non-refractory groups of patients . In the OS update, the HR for eribulin mesilate versus TPC was 0.90 (95% CI: 0.71, 1.14) in favour of eribulin mesilate for taxane-refractory patients and 0.73 (95% CI: 0.56, 0.96) for patients not taxane-refractory. The positive effect on OS was seen both in capecitabine-naïve and in capecitabine pre-treated patient groups. The updated OS analysis showed a survival benefit for the eribulin mesilate group compared to TPC both in capecitabine pre-treated patients with a HR of 0.787 (95% CI: 0.645, 0.961), and for the capecitabine-naïve patients with a corresponding HR of 0.865 (95% CI: 0.606, 1.233).

The second Phase 3 study in earlier line metastatic breast cancer, Study 301, was an open-label, randomized, study in patients (n=1102) with locally advanced or metastatic breast cancer to investigate the efficacy of Eribulin mesilate (HALAVEN) monotherapy compared to capecitabine monotherapy in terms of OS and PFS as co-primary endpoint. Patients had previously received up to three prior chemotherapy regimens, including both an anthracycline and a taxane and a maximum of two for advanced disease, with the percentage who had received 0, 1 or 2 prior chemotherapy treatments for metastatic breast cancer being 20.0%, 52.0% or 27.2% respectively. The HER2 status of the patients was: 15.3% positive, 68.5% negative and 16.2% unknown, whilst 25.8% of patients were triple negative.

Progression free survival assessed by independent review was similar between eribulin mesilate and capecitabine with medians of 4.1 months vs 4.2 months (HR 1.08; [95% CI: 0.932, 1.250]) respectively. Objective response rate as assessed by independent review was also similar between eribulin mesilate and capecitabine; 11.0% (95% CI: 8.5, 13.9) in the eribulin mesilate group and 11.5% (95% CI: 8.9, 14.5) in the capecitabine group.

The overall survival in patients in HER2 negative and HER2 positive patients in the eribulin mesilate and control groups in Study 305 and Study 301 is shown below:

 

Efficacy Parameter Study 305 Updated Overall Survival ITT Population
HER2 Negative HER2 Positive
HALAVEN
(n = 373)
TPC
(n = 192)
HALAVEN
(n = 83)
TPC
(n = 40)
Number of Events 285 151 66 37
Median months 13.4 10.5 11.8 8.9
Hazard Ratio (95% CI) 0.849 (0.695, 1.036) 0.594 (0.389, 0.907)
p-value (log rank) 0.106 0.015
Efficacy Parameter Study 301 Updated Overall Survival ITT Population
HER2 Negative HER2 Positive
HALAVEN
(n = 375)
Capecitabine
(n = 380)
HALAVEN
(n = 86)
Capecitabine
(n = 83)
Number of Events 296 316 73 73
Median months 15.9 13.5 14.3 17.1
Hazard Ratio (95% CI) 0.838 (0.715, 0.983) 0.965 (0.688, 1.355)
p-value (log rank) 0.03 0.837
Note: Concomitant anti-HER2 therapy was not included in Study 305 and Study 301.

 

Soft Tissue Sarcoma

In sarcoma the efficacy of eribulin mesilate is supported by 2 single-arm Phase 2 studies (studies 207 and 217) and 1 randomized Phase 3 study.

The patients (n=452) in the pivotal Phase 3 sarcoma study (Study 309) had locally recurrent or metastatic soft tissue sarcoma of 1 of 2 subtypes – leiomyosarcoma or liposarcoma. Patients had received at least 2 prior chemotherapy regimens, 1 of which must have been an anthracycline (unless contraindicated).

Patients must have progressed within 6 months of their last chemotherapeutic regimen. They were randomized 1:1 to receive either eribulin mesilate 1.4 mg/m2 on Days 1 and 8 of a 21 day cycle or dacarbazine 850 mg/m2, 1000 mg/m2 or 1200 mg/m2 (dose determined by the investigator prior to randomization), every 21 days.

In Study 309, a statistically significant improvement in overall survival was observed in patients randomized to the eribulin mesilate arm compared to the dacarbazine arm. This translated into a 2 month improvement in median OS (13.5 months for eribulin treated patients vs. 11.5 months for dacarbazine treated patients), with a HR of 0.768 (CI 0.618, 0.954) and a statistically significant P value of 0.0169 (see Figure 3).

The secondary endpoints of PFS (2.6 months median on each arm, HR 0.877, p=0.229) and ORR (3.9 % for eribulin treated patients vs. 4.9% for dacarbazine treated subjects) did not show significant differences between the two treatment groups.

Study 207 was a Phase 2, multi-center, open-label, nonrandomized study to evaluate the efficacy and safety of eribulin in 128 subjects with advanced STS who had failed standard chemotherapy. Eligible subjects were those with histologically confirmed and measurable by RECIST criteria advanced or metastatic STS of the following variants: LMS, ADI, synovial sarcoma (SYN), or other types of sarcoma (OTH), with more than one prior combination regimen or two single agent

cytotoxic treatments for metastatic disease. PFS was assessed at the end of the study. At last follow-up, only 1 subject (in the LMS stratum) in the EES population was observed to be progression-free. The median (95% CI) PFS was similar for each of the four strata (82 [44, 175] days, 88 [69, 114] days, 81 [43, 101] days, and 72 [42, 87] days for the ADI, LMS, SYN, and OTH strata, respectively). There was little difference among the strata for the ORR (3%, 5%, 5%, and 4% for the ADI, LMS, SYN, and OTH strata, respectively).

Study 217 was an open-label, multicenter, Phase 2 study evaluating the efficacy and safety of eribulin in Japanese subjects previously treated subjects with advanced STS, one of two groups (ADI or LMS), or OTH (other than ADI or LMS). The median PFS was 4.07 months (95% CI: 2.56, 5.55) in the overall population. ORR (by IRC assessment) was 0% (0/51 subjects; 95% CI: 0.0, 7.0) in total.

Pediatric population

Soft Tissue Sarcoma

Efficacy of eribulin was assessed but not established in three open-label studies: Study 113 was a Phase 1, open-label, multicentre, dose-finding study that assessed eribulin in pediatric patients with refractory or recurrent solid tumours and lymphomas but excluding CNS tumours. A total of 22 pediatric patients (age range: 3 to 17 years) were enrolled and treated. The patients were administered eribulin intravenously on Days 1 and 8 of a 21-day cycle at three dose levels (0.97, 1.23 and 1.58 mg/m2). The maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) of eribulin was determined as 1.23 mg/m2 on Days 1 and 8 of a 21-day cycle. Study 223 was a Phase 2, open-label, multicentre study that assessed the safety and preliminary activity of eribulin in pediatric patients with refractory or recurrent rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) or Ewing sarcoma (EWS). Twenty-one pediatric patients (age range: 2 to 17 years) were enrolled and treated with eribulin at a dose of 1.23 mg/m2 intravenously on Days 1 and 8 of a 21-day cycle (the RP2D from Study 113). No patient achieved confirmed partial response (PR) or complete response (CR).

Study 213 was a Phase 1/2, open-label, multicentre study to evaluate the safety and efficacy of eribulin in combination with irinotecan hydrochloride in pediatric patients with relapsed/refractory solid tumours and lymphomas but excluding CNS tumours (Phase 1), and to assess the efficacy of the combination treatment in pediatric patients with relapsed/refractory RMS, NRSTS and EWS (Phase 2). A total of 40 pediatric patients were enrolled and treated in this study. In Phase 1, 13 pediatric patients (age range: 4 to 17 years) were enrolled and treated; the RP2D was determined as eribulin 1.23 mg/m2 on Days 1 and 8 with irinotecan hydrochloride 40 mg/m2 on Days 1 to 5 of a 21-day cycle. In Phase 2, 27 pediatric patients (age range: 4 to 17 years) were enrolled and treated at the RP2D. Three patients had confirmed PR (1 patient in each of the RMS, NRSTS, and EWS histology cohorts). The objective response rate (ORR) was 11.1%.

No new safety signals were observed in the three pediatric studies; however, due to the small patient populations no firm conclusions can be made.