Halaven (Page 5 of 7)

14.2 Liposarcoma

The efficacy and safety of HALAVEN were evaluated in Study 2, an open-label, randomized (1:1), multicenter, active-controlled trial. Eligible patients were required to have unresectable, locally advanced or metastatic liposarcoma or leiomyosarcoma, at least two prior systemic chemotherapies (one of which must have included an anthracycline), and disease progression within 6 months of the most recent chemotherapy regimen. Patients were randomized to HALAVEN 1.4 mg/m2 administered intravenously on Days 1 and 8 of a 21-day cycle or to dacarbazine at a dose of 850 mg/m2 , 1000 mg/m2 , or 1200 mg/m2 administered intravenously every 21 days (dacarbazine dose was selected by the investigator prior to randomization). Treatment continued until disease progression or unacceptable toxicity. Randomization was stratified by histology (liposarcoma or leiomyosarcoma), number of prior therapies (2 vs. > 2), and geographic region (U.S. and Canada vs. Western Europe, Australia, and Israel vs. Eastern Europe, Latin America, and Asia). The major efficacy outcome measure was overall survival (OS). Additional efficacy outcome measures were progression-free survival (PFS) and confirmed objective response rate (ORR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Patients in the dacarbazine arm were not offered HALAVEN at the time of disease progression.

A total of 446 patients were randomized, 225 to the HALAVEN arm and 221 to the dacarbazine arm. The median age was 56 years (range: 24 to 83); 33% were male; 73% were White; 44% had ECOG performance status (PS) 0 and 53% had ECOG PS 1; 68% had leiomyosarcoma and 32% had liposarcoma; 39% were enrolled in U.S. and Canada (Region 1) and 46% were enrolled in Western Europe, Australia, and Israel (Region 2); and 47% received more than two prior systemic chemotherapies. The most common (>40%) prior systemic chemotherapies were doxorubicin (90%), ifosfamide (62%), gemcitabine (59%), trabectedin (50%), and docetaxel (48%).

Of the 143 patients with liposarcoma, the median age was 55 years (range: 32 to 83); 62% were male, 72% were White; 41% had ECOG PS of 0 and 53% had ECOG PS of 1; 35% were enrolled in Region 1 and 51% were enrolled in Region 2; and 44% received more than two prior systemic chemotherapies. The distribution of subtypes of liposarcoma, based on local histologic assessment, were 45% dedifferentiated, 37% myxoid/round cell, and 18% pleomorphic.

Study 2 demonstrated a statistically significant improvement in OS in patients randomized to HALAVEN compared with dacarbazine (see Table 6). There was no significant difference in progression-free survival in the overall population. Treatment effects of HALAVEN were limited to patients with liposarcoma based on pre-planned, exploratory subgroup analyses of OS and PFS (see Tables 6 and 7 and Figure 2). There was no evidence of efficacy of HALAVEN in patients with advanced or metastatic leiomyosarcoma in Study 2 (see Table 7).

Table 6: Efficacy Results for the Liposarcoma Stratum and All Patients* in Study 2a
Liposarcoma Stratum All Patients *
Halaven (n=71) Dacarbazine (n=72) Halaven (n=22 5 ) Dacarbazine (n=22 1 )
Overall s urvival
Deaths, n (%)52 (73)63 (88)173 (77)179 (81)
Median, months (95% CI)15.6(10.2, 18.6)8.4(5.2, 10.1)13.5(11.1, 16.5)11.3(9.5, 12.6)
Hazard ratio (HR) (95% CI)0.51 (0.35, 0.75)0.75 (0.61, 0.94)
Stratified log-rank p valueN/A 0.011
Progression-free survival
Events, n (%)57 (80)59 (82)194 (86)185 (84)
Disease progression5352180170
Median, months (95% CI)2.9 (2.6, 4.8)1.7 (1.4, 2.6)2.6 (2.0, 2.8)2.6 (1.7, 2.7)
HR (95% CI)0.52 (0.35, 0.78)0.86 (0.69, 1.06)
Objective response rate
Objective response rate (%) (95% CI)1.4 (0, 7.6)0 (0, 4.2)4.0 (1.8, 7.5)5.0 (2.5, 8.7)

a Efficacy data from one study site enrolling six patients were excluded.
*All patients = liposarcoma and leiomyosarcoma. N/A = not applicable

Kaplan-Meier Curves of Overall Survival in the Liposarcoma Stratum in Study 2
(click image for full-size original)

Figure 2: Kaplan-Meier Curves of Overall Survival in the Liposarcoma Stratum in Study 2

Table 7: Efficacy Results for the Leiomyosarcoma Stratum in Study 2a
Leiomyosarcoma Stratum
Halaven (n=15 4 ) Dacarbazine (n=1 49 )
Overall s urvival
Deaths, n (%)121 (79)116 (78)
Median, months (95% CI)12.8(10.3, 14.8)12.3(11.0, 15.1)
HR (95% CI)0.90 (0.69, 1.18)
Progression-free survival
Events, n (%)137 (89)126 (85)
Disease progression127118
Median, months (95% CI)2.2 (1.5, 2.7)2.6 (2.2, 2.9)
HR (95% CI)1.05 (0.81, 1.35)
Objective response rate (%) (95% CI)5.2 (2.3, 10)7.4(3.7, 12.8)

a Efficacy data from one study site enrolling six patients were excluded.

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