Articles

Trabectedin in combination with doxorubicin for first-line

treatment of advanced uterine or soft-tissue leiomyosarcoma
(LMS-02): a non-randomised, multicentre, phase 2 trial
Patricia Pautier, Anne Floquet, Christine Chevreau, Nicolas Penel, Cécile Guillemet, Corinne Delcambre, Didier Cupissol, Frédéric Selle,
Nicolas Isambert, Sophie Piperno-Neumann, Antoine Thyss, François Bertucci, Emmanuelle Bompas, Jerôme Alexandre, Olivier Collard,
Sandrine Lavau-Denes, Patrick Soulié, Maud Toulmonde, Axel Le Cesne, Benjamin Lacas, Florence Duffaud, for the French Sarcoma Group

Summary
Background Metastatic leiomyosarcomas of uterine or soft-tissue origin have poor prognosis and moderate Lancet Oncol 2015
chemosensitivity. Trabectedin has shown activity in pretreated leiomyosarcoma. We did a single-group, multicentre, Published Online
phase 2 trial (LMS-02) to assess the effect of first-line doxorubicin and trabectedin combination on disease control March 18, 2015
http://dx.doi.org/10.1016/
and survival.
S1470-2045(15)70070-7
See Online/Comment
Methods Adults (18 years to physiological age ≤70 years) with measurable metastatic or unresectable uterine http://dx.doi.org/10.1016/
leiomyosarcoma or soft-tissue leiomyosarcoma who had not received any previous chemotherapy were enrolled at S1470-2045(15)70107-5
19 centres in France. Treatment consisted of 60 mg/m² intravenous doxorubicin followed by 1·1 mg/m² trabectedin in Department of Medical
a 3 h intravenous infusion on day 1, both by the central venous route, and 6 mg subcutaneous pegfilgrastim on day 2, Oncology (P Pautier MD,
repeated every 3 weeks for up to six cycles. Surgery for residual disease was permitted. The primary endpoint was the A Le Cesne MD) and
Department of Biostatistics
proportion of patients achieving disease control, defined as complete or partial response or stable disease. Stratification (B Lacas MSc), Institut Gustave
was done by anatomical site and analyses were per protocol. This study is registered with ClinicalTrials.gov, number Roussy, Villejuif, France;
NCT02131480. Department of Medical
Oncology, Institut Bergonié,
Bordeaux, France
Findings Between July 28, 2010, and May 10, 2013, 109 patients were enrolled and treated, of whom 108 were assessable (A Floquet MD,
for response: 47 in the uterine leiomyosarcoma group and 61 in the soft-tissue leiomyosarcoma group. 32 (68%) M Toulmonde MD); Department
patients in the uterine leiomyosarcoma group and 45 (74%) in the soft-tissue leiomyosarcoma group received all of Medical Oncology, Institut
Claudius-Regaud, Toulouse,
six cycles of treatment. Of 47 patients with uterine leiomyosarcoma, 28 (59·6%, 95% CI 44·3–73·6) achieved a partial
France (C Chevreau MD);
response and 13 (27·7%, 15·6–42·6) stable disease; 41 (87·2%, 74·3–95·2) patients achieved disease control. Of Department of Medical
61 patients with soft-tissue leiomyosarcoma, two (3·3%, 95% CI 0·4–11·7) achieved a complete response, 22 (36·1%, Oncology, Centre Oscar-
25·0–50·8) had a partial response, and 32 (52·5%, 40·8–67·3) had stable disease; 56 (91·8%, 81·9–97·3) of patients Lambret, Lille, France
(N Penel MD); Department of
achieved disease control. The most common grade 3–4 treatment-associated adverse events were neutropenia (84 [78%]
Medical Oncology, Centre
of 108 patients), increased alanine aminotransferase concentration (42 [39%]), thrombocytopenia (40 [37%]), anaemia Henri-Becquerel, Rouen, France
(29 [27%]), febrile neutropenia (26 [24%]), and fatigue (21 [19%]). (C Guillemet MD); Department
of Medical Oncology, Centre
François-Baclesse, Caen, France
Interpretation Despite expected but manageable toxic effects, these results support the activity of doxorubicin plus
(C Delcambre MD); Department
trabectedin as first-line treatment for uterine leiomyosarcoma and soft-tissue leiomyosarcoma. This combination of Medical Oncology, Centre Val
should be developed further in a phase 3 trial against the present standard of care. d’Aurelle, Montpellier, France
(D Cupissol MD); Department of
Medical Oncology, Hôpital
Funding Pharmamar and Amgen.
Tenon, Paris, France
(F Selle MD); Department of
Introduction objective response and median progression-free-survival, Medical Oncology, Centre GF
Leiomyosarcomas represent almost a quarter of soft-tissue but not overall survival.5 Increasingly, new treatments in Leclerc, Dijon, France
(N Isambert MD); Department
sarcomas.1 Although gene expression patterns differ specific histological subtypes of sarcomas are being of Medical Oncology, Institut
between uterine and non-uterine leiomyosarcomas,2 both investigated, such as gemcitabine and docetaxel for Curie, Paris, France
are judged to be moderately sensitive to conventional uterine leiomyosarcomas.6,7 (S Piperno-Neumann MD);
chemotherapy. In metastatic leiomyosarcoma, treatment Additionally, phase 2 data have suggested that higher Department of Medical
Oncology Centre Antoine
with doxorubicin, gemcitabine, or dacarbazine results in proportions of patients with leiomyosarcoma might Lacassagne, Nice, France
15–17% of patients achieving objective responses (ie, achieve objective responses than those with histological (Prof A Thyss MD); Department
complete or partial responses), with a median progression- soft-tissue sarcoma subtypes when given chemotherapy, of Medical Oncology, Institut
free survival of about 5 months and an overall survival of and that uterine leiomyosarcoma might be more Paoli-Calmettes, Marseille,
France (Prof F Bertucci MD);
about 12 months.3,4 In the first-line setting, all soft-tissue chemosensitive than soft-tissue leiomyosarcoma.8 Department of Medical
sarcoma subtypes are usually treated with doxorubicin Trabectedin has shown activity in soft-tissue sarcoma, Oncology, Centre René
alone or in combination with ifosfamide.5 Increasing the with about 10% of patients achieving an objective Gauducheau, Saint Herblain,
dose intensity of doxorubicin or ifosfamide, or both, response after failure of doxorubicin and ifosfamide;9–11 France (E Bompas MD);
Department of Medical
increases both the proportion of patients achieving an some studies have suggested greater activity in pretreated

www.thelancet.com/oncology Published online March 18, 2015 http://dx.doi.org/10.1016/S1470-2045(15)70070-7 1

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Oncology, Hôpital Cochin, leiomyosarcoma than in other histological subtypes, with (G-CSF).16,17 One trial17 in patients with soft-tissue sarcoma
Paris, France a 6-month progression-free survival of 26–30%.9–11 (n=29) or breast cancer (n=9) reported a dose-limiting
(Prof J Alexandre MD);
Department of Medical
Findings from a worldwide access programme study12 of toxic effect of severe neutropenia with trabectedin
Oncology, Institut de trabectedin for relapse or disease progression after (0·8 mg/m²) followed by doxorubicin (60 mg/m²) without
Cancérologie de la Loire, Saint standard-of-care chemotherapy showed a median overall G-CSF support. Encouraging efficacy was described, with
Priest en Jarez, France survival of 16·2 months among 321 patients with partial response in five (17%) and stable disease in
(O Collard MD); Department of
Medical Oncology, Centre
pretreated leiomyosarcoma. In uterine leiomyosarcoma, 13 (45%) of patients with soft-tissue sarcoma, and five
Hospitalo-Universitaire first-line trabectedin is associated with about 10% of (56%) and three (33%) patients with breast cancer,
Dupuytren, Limoges, France patients achieving an objective response, a median respectively. A second trial16 involved first-line or second-
(S Lavau-Denes MD); progression-free survival of 5·8 months, and a median line treatment of patients with metastatic soft-tissue
Department of Medical
Oncology, Centre Paul Papin,
overall survival greater than 26 months.13 sarcoma with doxorubicin (60 mg/m²) given on day 1
Angers, France (P Soulié MD); Preclinical data also suggest that trabectedin and followed by trabectedin at 1·1 mg/m² over 3 h on day 1,
and Department of Medical doxorubicin is an effective combination in sarcoma.14,15 In with G-CSF given on day 2. Adverse events were
Oncology, La Timone vitro, trabectedin and doxorubicin resulted in synergistic predominantly haematological and hepatic, and results
University Hospital, Marseille,
France (Prof F Duffaud MD)
pro-apoptotic effects in two soft-tissue sarcoma cell lines,14 were encouraging, particularly in liposarcoma and
Correspondence to:
suggesting that combining trabectedin and doxorubicin leiomyosarcoma, with 3-month and 6-month progression-
Dr Patricia Pautier, Department might be a promising regimen.14,15 Findings from two free survival of 85% and 58%, respectively.
of Medical Oncology, Institut phase 1 studies showed that the combination was feasible These data therefore provided the rationale for us to do
Gustave-Roussy, 94805 Villejuif when given with granulocyte-colony stimulating factor this single-group, multicentre, phase 2 study (LMS-02) of
Cedex, France
patricia.pautier@
doxorubicin combined with trabectedin as first-line
gustaveroussy.fr Uterine Soft-tissue treatment in metastatic or locally advanced uterine
leiomyosarcoma leiomyosarcoma leiomyosarcoma or soft-tissue leiomyosarcoma.
(n=47) (n=61)
Age (years) 58 (35–73) 59 (32–77) Methods
Sex Patients
See Online for appendix Female 47 (100%) 40 (66%) Patients were enrolled at 19 centres in France (appendix).
Male 0 21 (34%) Eligible patients had histologically confirmed metastatic
Performance status* or unresectable uterine or soft-tissue leiomyosarcoma,
0 32 (68%) 38 (62%) with measurable disease according to Response
1 10 (21%) 22 (36%) Evaluation Criteria in Solid Tumors (RECIST; version 1.1),
2 2 (4%) 1 (2%) and had not received any previous chemotherapy in
Grade† either the adjuvant or advanced disease setting. On the
1 NA 8 (13%) basis of published findings, we estimated that the
2–3 NA 48 (79%) median overall survival for eligible patients was about
Primary site 9–16 months.5,6,18,19 Other eligibility criteria were age at
Uterus 47 (100%) 0 least 18 years and physiological age 70 years or younger,
Extremity 0 13 (21%)
with a geriatric assessment if necessary (patients aged
Retroperitoneum 0 16 (26%)
>70 years who were in good physical health and could
Pelvis 0 7 (11%)
benefit from the study were included); Eastern
Cooperative Oncology Group performance status of 2 or
Visceral 0 15 (25%)
lower; at least one target lesion in a non-irradiated area;
Other/other 0 10 (16%)
adequate organ function (absolute neutrophil count
Surgery of primitive site 41 (87%) 37 (61%)
≥1·5 × 10⁹ cells per L, platelet count ≥100×109 cells per L,
Pelvic radiotherapy 17 (36%) NA
creatinine phosphokinase <1·5 times the institutional
Metastatic disease 37 (79%)‡ 52 (85%)
upper limit of normal [ULN], normal liver function tests
Lung 33 (89%) 42 (81%)
[total bilirubin ≤1 times, aminotransferases ≤2·5 times,
Liver 13 (35%) 24 (46%)
and alkaline phosphatase ≤1·5 times the institutional
Bone 8 (22%) 6 (12%)
ULN]); and normal cardiac function as assessed by echo-
Cutaneous 2 (5%) 4 (8%)
cardiogram or normal isotopic ventriculography (left
Other 13 (35%) 13 (25%)
ventricular ejection fraction [LVEF] >50%), or both. We
Data are median (range) or number (%). Some percentages do not add up to excluded patients with a history of malignancy who were
100 because of rounding. NA=not applicable. *Data missing for three patients in in complete remission for fewer than 5 years (except for
the uterine leiomyosarcoma group. †Data missing for five patients in the soft-
those with cutaneous basal-cell carcinoma or high-grade
tissue leiomyosarcoma group. ‡37 (79%) had metastatic disease and ten (21%)
had either an unresectable locally advanced disease or uncomplete surgery, or cervical intraepithelial neoplasia), or who had CNS
local relapse after surgery. metastases.
Institutional review board and ethics committee
Table 1: Patient demographics and baseline characteristics
approval was obtained from all institutions, and all

2 www.thelancet.com/oncology Published online March 18, 2015 http://dx.doi.org/10.1016/S1470-2045(15)70070-7

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patients provided written informed consent before the central review. In patients who were progression free
start of any study-specific procedures. after six cycles, survival data and tumour imaging were
collected every 2 months for the first 6 months, every
Procedures 3 months for the next 6 months, and every 6 months
Although a 24 h perfusion of trabectedin was shown to thereafter until disease progression, after which they
be more effective than a 3 h perfusion in a randomised were collected every 3 months. Stable disease was defined
phase 2 trial in patients with sarcoma,20 we used the as an absence of response or an absence of progression.
treatment schedule and doses of trabectedin as tested in
the phase 1 study,16 because it was published before the Outcomes
results of the randomised study. Patients received The primary endpoint was the proportion of patients
60 mg/m² doxorubicin by 10–15 min central venous who achieved disease control, defined as those achieving
infusion on day 1, followed by a 3 h central venous a complete or partial response or stable disease.
infusion of 1·1 mg/m² trabectedin on day 1, followed Secondary endpoints were overall survival, defined as
by 6 mg pegfilgrastim subcutaneously on day 2. time from inclusion until death from any cause, and
Pretreatment with 20 mg dexamethasone was given progression-free survival, defined as time from inclusion
30 min before starting doxorubicin. Treatment was given until disease progression or death from any cause.
every 3 weeks for a maximum of six cycles, after which
surgery for residual disease was allowed. No treatment Statistical analysis
was permitted after surgery. The study was stratified by primary tumour location type
Treatment with aprepitant—a cytochrome CYP3A4 (uterine leiomyosarcoma vs soft-tissue leiomyosarcoma).
inhibitor—was not allowed. Other supportive measures, Each stratum of the study was classed as an independent
including transfusions and haematopoietic growth phase 2 study. We used the Simon’s optimal two-stage
factors, were permitted. Adverse events were assessed design for each of the two strata, but with two different
using the Common Terminology Criteria for Adverse hypotheses.21 We chose the p values based on the
Events version 3.0. A maximum of two dose reductions
for each drug were permitted; doses for both drugs were Uterine leiomyosarcoma Soft-tissue
reduced one level if any of the following events occurred: (n=47) leiomyosarcoma (n=61)
neutrophil count less than 0·5 × 10⁹ cells per L for more Number of treatment cycles 6 (1–6) 6 (2–6)
than 7 days despite use of G-CSF or associated with fever Number of dose reductions
(temperature ≥38·5°C); neutrophil count less than the
Number of cycles 31/231 (13%) 45/326 (14%)
ULN associated with sepsis or documented infection;
Number of patients 22 (47%) 33 (54%)
platelet count less than 25 × 10⁹ cells per L; nausea or
By drug
vomiting of grade 3 or worse; or any other
One reduction of doxorubicin 14 (30%) 22 (36%)
non-haematological toxic effects worse than grade 3. The
Two reductions of doxorubicin 8 (17%) 7 (11%)
two dose reductions permitted for doxorubicin were
One reduction of trabectedin 15 (32%) 24 (39%)
from 60 mg/m² to 50 mg/m², and then to 45 mg/m², and
Two reductions of trabectedin 7 (15%) 9 (15%)
for trabectedin from 1·1 mg/m² to 0·9 mg/m², and then
Compliance to treatment
to 0·7 mg/m². Trabectedin dose was reduced one level
Treatment completed (six cycles) 32 (68%) 45 (74%)
for total bilirubin greater than the ULN; raised aspartate
Treatment ongoing 0 0
aminotransferase or alanine aminotransferase concen-
Discontinued because of disease progression 4 (9%) 3 (5%)
trations of grade 3 or worse lasting more than 7 days, or
that had not recovered to grade 2 on day 1 of the following Stopped for toxicity 5 (11%)* 8 (13%)†

cycle; or raised alkaline phosphatase concentration of at Died during treatment 1 (2%)‡ 2 (3%)§

least grade 2. Patients who needed a delay of more than Stopped for another reason 5 (11%)¶ 3 (5%)||
3 weeks before the subsequent cycle because of adverse Surgery after chemotherapy 8 (17%) 12 (20%)
events were withdrawn from the study. Primitive site 2 (25%) 8** (67%)
Pretreatment assessments consisted of medical history, Metastatic sites 4 (50%) 4 (33%)
physical examination, laboratory tests, electrocardiogram, Both 2 (25%) 0
disease assessment, and measurement of LVEF by Death from toxic effects 0 1 (2%)††
ultrasound or isotopic ventriculography within 28 days Data are median (range), n/N (%), or number (%). *One haematological, two haematological with concurrently elevated
before study entry and after the sixth cycle. During concentrations of aminotransferases, one intestinal dilatation, and one supraventricular tachycardia. †One
treatment, weekly follow-up of haematological and liver haematological, two fatigue or asthenia, one thrombocytopenia, one fatigue and aminotransferases raised to grade 3,
two thrombocytopenia and neutropenia, and one febrile neutropenia. ‡Pulmonary embolism. §One toxic death and one
function tests was done. Tumour imaging (CT scan of
sudden and unexplained death. ¶Three medical decision, one surgery before six cycles, one chemotherapy outside the
chest, abdomen, and pelvis or MRI) was done at baseline, authorised delay for restarting chemotherapy. ||One surgery before six cycles, one patient refusal, and one serious adverse
and then after every two cycles, and 3 weeks after the last event not associated with chemotherapy. **Four patients had histological complete response. ††Pulmonary oedema.
cycle. Best overall response was assessed by the
Table 2: Treatment delivery
investigator per RECIST 1.1. There was no radiographic

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published results of doxorubicin as monotherapy or in more chemosensitive than soft-tissue leiomyosarcoma.

combination in all soft-tissue sarcoma subgroups (with The proportion of patients with uterine leiomyosarcoma
about 40–60% of patients achieving disease control),18,22 achieving disease control was 62% in a previous study.6 At
and assumed that uterine leiomyosarcoma should be the time of study design, there were no first-line trials
reporting the proportion of patients with soft-tissue
A leiomyosarcoma alone achieving disease control. In a
100 retrospective study,8 the proportion of patients with soft-
80 tissue leiomyosarcoma treated with first-line combination
therapy achieving disease control was 69% (22% achieved
60
overall responses).
40 In the uterine leiomyosarcoma stratum, to have α risk
Change from baseline (%)

and β risk of 10% (uterine leiomyosarcoma are rare, and

20
the number of patients needed is lower for higher
0 β risks), an unacceptable proportion of patients achieving
–20 disease control (p0) of 0·5 and an acceptable proportion
of patients achieving disease control (p1) of 0·7,
–40
45 patients were needed. After a planned interim
–60 assessment of the first 21 patients, if 11 or fewer patients
had not progressed (ie, stable disease, objective response,
–80
or both), the study would be stopped for absence of
–100 activity; if the number of non-progressive patients was at
B least 12, 24 patients were to be added. The study would be
100 deemed to have met its primary endpoint if at least 27 of
45 patients had not progressed.
80
In the soft-tissue leiomyosarcoma stratum, to have
60 α risk of 10%, β risk of 5%, p0=0·4, and p1=0·6, 62 patients
40 were needed. After a preplanned interim assessment of
Change from baseline (%)

the first 27 patients, if the number of non-progressive

20
patients was 11 or fewer, the study would be stopped for
0 absence of activity. If the number of non-progressive
patients was at least 12, 35 patients were to be added. The
–20
study would be deemed to have met its primary endpoint
–40 if at least 29 of 62 patients were non-progressive.
–60 Overall survival and progression-free survival were
analysed with the Kaplan-Meier method. Only patients
–80
who received any study chemotherapy were included in
–100 the response analyses. All eligible patients were included
in the survival analyses (ie, intention to treat). We used
Figure 1: Maximum change in volume of target tumour from baseline in assessable patients
Percentage change in volume of target lesions in (A) uterine and (B) soft-tissue leiomyosarcoma. Patients with
SAS version 9.3 for all statistical analyses.
100% decrease in target tumour volume are probably not in complete response according to Response Evaluation This study is registered with ClinicalTrials.gov, number
Criteria in Solid Tumors. NCT02131480.

Uterine leiomyosarcoma Soft-tissue Role of the funding source

(n=47) leiomyosarcoma (n=61) The funders of the study had no role in study design,
Proportion of patients achieving disease control 41 (87·2%, 74·3–95·2) 56 (91·8%, 81·9–97·3) data collection, data analysis, data interpretation, or
Complete response 0 2 (3·3%, 0·4–11·7) writing of the report. The corresponding author had full
Partial response 28 (59·6%, 44·3–73·6) 22 (36·1%, 25·0–50·8) access to all the data in the study and had final
Stable disease 13 (27·7%, 15·6–42·6) 32 (52·5%, 40·8–67·3)
responsibility for the decision to submit for publication.
Median duration of objective response (months) 6·6 (4·7–9·9) 12·5 (5·8–14·9)
Progression-free survival
Results
At 12 weeks (%) 87·2% (75–94) 91·8% (82–96)
Between July 28, 2010, and May 10, 2013, 109 patients
were enrolled and treated, and 108 were assessable for
At 24 weeks (%) 72·3% (58–84) 90·2% (80–95)
response and survival. 48 patients were included in the
Median (months) 8·2 (7·0–9·0) 12·9 (9·0–14·4)
uterine leiomyosarcoma stratum, but one was
Data are number (%, 95% CI), % (95% CI), or median (95% CI). subsequently defined as a soft-tissue leiomyosarcoma
and analysed in the soft-tissue leiomyosarcoma cohort.
Table 3: Proportions of patients achieving responses in the efficacy population
62 patients were included in the soft-tissue

4 www.thelancet.com/oncology Published online March 18, 2015 http://dx.doi.org/10.1016/S1470-2045(15)70070-7

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A B
100 100

80 80

Progression-free survival (%)

Overall survival (%)

60 60

40 40

20 20

0 0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Number at risk 47 47 45 44 41 32 32 30 28 22 19 19 15 14 13 12 47 46 41 40 37 27 27 24 22 11 9 8 5 4 2 2

C D
100 100

80 80
Progression-free survival (%)
Overall survival (%)

60 60

40 40

20 20

0 0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Months Months
Number at risk 61 60 59 58 56 55 55 53 51 47 42 38 38 35 32 29 61 60 56 56 55 54 52 46 42 33 27 23 23 21 17 13

Figure 2: Kaplan-Meier survival curves

Overall survival (A) and progression-free survival (B) in uterine leiomyosarcoma, and overall survival (C) and progression-free survival (D) in soft-tissue leiomyosarcoma.

leiomyosarcoma cohort, but one was diagnosed as a non-
leiomyosarcoma after pathological review. The final
analysis included 47 patients with uterine and 61 with
soft-tissue leiomyosarcoma. Tables 1 and 2 describe
characteristics of the two populations and treatment
delivery. 17 (36%) patients with uterine leiomyosarcoma
had received previous pelvic radiotherapy. 32 (68%) of
47 patients in the uterine leiomyosarcoma group and
45 (74%) of 61 in the soft-tissue leiomyosarcoma group
received six cycles of treatment. Dose modifications or
reductions were needed for 76 (14%) of 557 cycles given
and in 55 (51%) of 108 patients (table 2).
Of 47 patients with uterine leiomyosarcoma, 28 (59·6%,
95% CI 44·3–73·6) achieved a partial response and
13 (27·7%, 15·6–42·6) had stable disease; 41 (87·2%,
74·3–95·2) patients achieved disease control (figure 1;
table 3). Of 61 patients with soft-tissue leiomyosarcoma,
two (3·3%, 95% CI 0·4–11·7) achieved a complete
response, 22 (36·1%, 25·0–50·8) had a partial response,
and 32 (52·5%, 40·8–67·3) had stable disease; 56 (91·8%,
81·9–97·3) patients achieved disease control (figure 1;
table 3). Median progression-free survival was
8·2 months (95% CI 7·0–9·0) in the uterine leiomyo-
sarcoma group and 12·9 months (9·0–14·4) in the soft-
tissue leiomyosarcoma group (table 3; figure 2). With a
median follow-up of 14·5 months (IQR 8·6–21·7;
15·7 months [IQR 10·4–21·7] in the soft-tissue
leiomyosarcoma group and 9·9 months [6·1–21·5] in the
uterine leiomyosarcoma group), median overall survival
was 20·2 months (95% CI 15·1 to not reached) in the
uterine leiomyosarcoma cohort and 34·5 months
(95% CI not reached) in the soft-tissue leiomyosarcoma
cohort (figure 2).
Table 4 lists adverse events that occurred during the
study. The most common grade 3–4 treatment-associated
adverse events were neutropenia (84 [78%] of

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and fatigue. Three patients died during treatment (one

Grade 1–2 Grade 3 Grade 4 Grade 5
in the uterine leiomyosarcoma group from pulmonary
Leucocytes (≥15 × 109 cells per L) 19 (18%) 37 (34%) 45 (42%) 0 embolism, one in the soft-tissue leiomyosarcoma group
Neutropenia (≥15 × 109 cells per L) 13 (12%) 21 (19%) 63 (58%) 0 from unexplained cause, and one in the soft-tissue
Thrombocytopenia (≥100 × 109 cells per L) 54 (50%) 22 (20%) 18 (17%) 0 leiomyosarcoma group from toxic death). The toxic
Anaemia* 76 (70%) 24 (22%) 5 (5%) 0 death occurred at day 21 of cycle two and was caused by
Fatigue 66 (61%) 21 (19%) 0 0 a drug-related adverse event (acute respiratory distress
Nausea and vomiting 75 (69%) 20 (19%) 0 0 syndrome associated with pulmonary oedema after
Fever and infection 19 (18%) 0 0 0 febrile neutropenia). 13 (12%) of 108 patients stopped
Febrile neutropenia 0 16 (15%) 10 (9%) 1 (1%) treatment because of toxic effects (table 2). No
Increased alanine aminotransferase concentration* 63 (58%) 39 (36%) 3 (3%) 0 cardiotoxic effects or clinically significant decreases in
Mucositis 32 (30%) 5 (5%) 0 0 LVEF were noted after six cycles. Pelvic radiotherapy
Anorexia 0 0 0 0 had no effect on adverse events, but did result in more
Constipation 0 0 0 0 dose reductions (appendix).
Diarrhoea 0 0 0 0
Increased creatinine concentration* 0 9 (8%) 0 0 Discussion
Increased bilirubin concentration* 0 0 0 0 Our data support the notion that doxorubicin and
Increased creatinine phosphokinase concentration* 0 0 0 0 trabectedin combination is an active first-line regimen
Cardiac arrhythmia 0 0 0 0 for advanced uterine and soft-tissue leiomyosarcoma,
Pulmonary embolism 0 0 0 1 (1%) possibly resulting from synergistic activity of the
Other (unexplained) 0 0 0 1 (1%) combination. However, these results were based on
investigator assessments only. An independent radio-
Data are number of patients (%). 108 patients were included in the safety analysis. *Thresholds differ between laboratories.
logical review might have affected the proportion of
Table 4: Safety outcomes patients achieving disease-free survival and objective
responses.
Patients with metastatic leiomyosarcoma have a poor
Panel: Research in context prognosis, and in prospective clinical trials,23 a median
progression-free survival of about 6 months and an
Systematic review overall survival of about 12–15 months are usually
We searched PubMed on Sept 4, 2014, for reports of clinical trials published in English, reported for patients treated with any first-line
using the terms “metastatic leiomyosacoma”, “metastatic uterine leiomyosarcoma”, and chemotherapy, representing an unmet medical need.
“first line chemotherapy”. We identified one phase 2 study that investigated first-line Drug development in sarcoma has evolved to focus on
chemotherapy for uterine leiomyosarcoma specifically7 and no phase 3 study of histotype-specific trials in an effort to detect more robust
chemotherapy for leiomyosarcoma. Data on first-line management of metastatic effects in well-defined soft-tissue sarcoma subtypes,
leiomyosarcoma are limited; patients are mostly included in large phase 3 studies that such as trabectedin in liposarcoma and leiomyo-
include all soft-tissue sarcomas, and there have been no studies in specific anatomical or sarcoma,20 the combination of gemcitabine and
histological subgroups. In some studies, new treatments are being investigated in specific docetaxel in leiomyosarcoma,6,7 or weekly paclitaxel in
histological subtypes of sarcoma; for example, gemcitabine and docetaxel for uterine angiosarcoma.24 Since those tumours are rare, we
leiomyosarcoma,6,7 and weekly paclitaxel for angiosarcoma.24 decided to focus on one specific histological subtype
Interpretation and two subgroups (uterine and non-uterine) rather
The present study shows that studies in specific sarcoma subtypes (type, site, or both) are than undertaking a randomised phase 2 trial in the
feasible when there is some evidence of targeted activity for new compounds. Trabectedin entire leiomyosarcoma group (panel).
plus doxorubicin as a first-line chemotherapy option is an active treatment that provides Few studies have been done in defined subsets of
clinically meaningful benefits to patients with leiomyosarcoma of both uterine and non- soft-tissue sarcoma. One phase 2 study25 investigated
uterine origin, and after 6 months, the rate of progression seems to increase, which raises the efficacy of first-line gemcitabine and docetaxel in
the question of whether treatment should be continued with trabectedin alone. leiomyosarcoma. However, there was no stratification
according to leiomyosarcoma type, and the study
included only five patients with soft-tissue leiomyo-
108 patients), increased alanine aminotransferase sarcoma and 29 with uterine leiomyosarcoma; the
concentration (42 [39%]), thrombocytopenia (40 [37%]), proportion of patients achieving an objective response
anaemia (29 [27%]), febrile neutropenia (26 [24%]), and was 53%, with a median progression-free survival of
fatigue (21 [19%]). Thrombocytopenia was the most 5·6 months (95% CI 35–70). Two other phase 2
frequent adverse event that necessitated dose reduction studies6,19 focused on uterine leiomyosarcoma only:
of trabectedin and doxorubicin (data not shown). The first-line treatment with gemcitabine and docetaxel
most common drug-related adverse events of any severity resulted in 15 (36%) of 42 patients achieving an
were anaemia, increased alanine aminotransferase objective response, with a median progression-free
concentrations, neutropenia, thrombocytopenia, nausea, survival of 4·4 months (95% CI 23·5–49·6),6 and the

6 www.thelancet.com/oncology Published online March 18, 2015 http://dx.doi.org/10.1016/S1470-2045(15)70070-7


treatment with a doxorubicin and ifosfamide combin-
ation resulted in ten (30%) of 33 patients achieving an
objective response, with a median overall survival of
9·6 months.19 With 59·6% of patients in the uterine
leiomyosarcoma group and 39·3% in the soft-tissue
leiomyosarcoma group achieving an objective response,
our results compare favourably with those of other
combinations.6,19
As expected, the toxic effects reported in the LMS-02
study were mainly haematological, but with adequate
monitoring they remained manageable and were
consistent with the adverse events reported in phase 1
studies. Close monitoring of haematological and liver
function is recommended on a weekly basis. The
doxorubicin plus trabectedin combination seems to be
potentially less haematotoxic than the recently reported
first-line doxorubicin and high-dose ifosfamide
combination that was tested in all sarcoma subtypes
(46% of patients had febrile neutropenia, 35% had
grade 3–4 anaemia, and 33% had grade 3–4 thrombo-
cytopenia).5 The toxic-effect profile also compares
favourably with the gemcitabine plus docetaxel combin-
ation as first-line therapy in metastatic uterine leiomyo-
sarcoma (24% of patients had grade 3 anaemia and 15%
had grade 3–4 thrombocytopenia with gemcitabine plus
docetaxel),6 but resulted in a higher incidence of febrile
neutropenia (5% vs 0% with the gemcitabine plus
docetaxel combination). Patients in our study were not
permitted to use aprepitant, which is probably the reason
for the high proportion of patients with grade 3 nausea
and vomiting (19% of patients), resulting in dose
reductions in some. An intensified anti-emetic regimen
should be considered in future.
In the GEIS-20 randomised phase 2 study, a
doxorubicin and trabectedin combination was assessed
as first-line treatment for patients with sarcoma.26 The
combination of doxorubicin plus trabectedin was not
superior to doxorubicin alone in terms of response (13%
vs 20%, respectively, of patients achieved an overall
response) and median progression-free survival (5·7 vs
5·6 months, respectively), and the trial was terminated
early for futility. However, there are some crucial
differences between the GEIS-20 study and the LMS-02
study. First, although the doses were the same, the drug
administration schedules were different, with trabectedin
delivered first followed by doxorubicin in the GEIS-20
study; this different dose schedule could suggest a
different pharmaceutical interaction of the drugs
between the studies. However, the most likely explanation
for the absence of benefit for the combination reported
in GEIS-20 was that the trial recruited a heterogeneous
population of patients with soft-tissue sarcoma without
selection or stratification by histological subset.
Additionally, the number of patients was small (55 for
doxorubicin alone vs 52 for doxorubicin plus trabectedin)
and only 35% of patients had leiomyosarcoma (20 in the
doxorubicin group vs 15 in the combination group).
www.thelancet.com/oncology Published online March 18, 2015 http://dx.doi.org/10.1016/S1470-2045(15)70070-7
Articles
So far, outcomes have not been reported for the
uterine leiomyosarcoma or soft-tissue leiomyosarcoma
subgroups.
The results of our study suggest that responses might
vary according to anatomical subtype (objective responses
of 59·6% for patients with uterine leiomyosarcoma and
39·3% for those with soft-tissue leiomyosarcoma),
although treatment did not differentially affect survival.
In view of the rarity of these tumours, we will group both
uterine and soft-tissue leiomyosarcoma together for a
phase 3 study, but with a stratification by site.
When this study was designed, the standard of care
for patients with leiomyosarcoma receiving first-line
treatment in France was a maximum of six cycles. In
this study, after 6 months, the proportion of patients
with disease progression seemed to increase, which
raises the question of whether treatment should be
continued with trabectedin alone. Findings from a
retrospective study suggested a beneficial effect of
maintenance trabectedin in patients with sarcoma,27
confirmed by a prospective study done by the French
Sarcoma Group (TDIS study),28 which have tested the
hypothesis that continued trabectedin in patients with
disease control after six cycles is superior to restarting
treatment at progression.
The findings of the LMS-02 study show that first-line
trabectedin plus doxorubicin is an active treatment that
provides clinically meaningful benefits to patients with
leiomyosarcoma of both uterine and non-uterine origin.
To build upon these promising results, we plan to test
whether this combination confers superior outcomes
as a first-line regimen in metastatic leiomyosarcoma,
whatever their site of origin (uterine or soft tissue), by
undertaking a randomised phase 3 trial in leiomyo-
sarcoma, with the aim of comparing standard-of-care
front-line chemotherapy with this combination
regimen, and to ask the secondary question of whether
continuous trabectedin treatment improves outcomes
for patients who have shown at least stable disease after
doxorubicin plus trabectedin for six cycles.
Contributors
PP and FD were involved in study design, data analysis, data
interpretation, enrolment, recruitment, treatment, and writing of the
manuscript. AF, CC, NP, CG, CD, DC, FS, and FB were involved in
enrolment, recruitment, treatment, data collection, and manuscript
revision. NI, SP-N, AT, EB, JA, OC, SL-D, PS, MT, and ALC were
involved in enrolment, recruitment, and treatment. BL was involved in
study design, data collection, data analysis, and manuscript revision.
Declaration of interests
PP has received honoraria for advisory board participation from
GlaxoSmithKline, Roche, and Pharmamar. AF has received honoraria
for advisory board participation from Roche and has participated in
advisory boards for Pharmamar. CC has received honoraria for advisory
board participation from Pfizer, Novartis, and Merck Serono. FS has
received honoraria for advisory board participation from Roche, Merck
MSD, and Pharmamar. JA has received honoraria for advisory board
participation from Sanofi, Roche, Merck MSD, and Janssen, and has
participated in advisory boards for Pharmamar. NP, CG, CD, DC, NI,
SP-N, AT, FB, EB, OC, SL-D, PS, MT, ALC, BL, and FD declare no
competing interests.
7
 Articles
Acknowledgments
We thank Béatrice Weber (Centre Alexis Vautrin, Vandœuvre les Nancy);
Binh Bui (Institut Bergonié, Bordeaux); Youssef Tazi (Institut Gustave
Roussy, Villejuif); Rudiger Hasselberg (Institut Gustave Roussy,
Villejuif); and Annie Rey (Institut Gustave Roussy, Villejuif) for their
participation in the study.
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