Address for correspondence:
Prof. dr hab. n. med. Piotr Rutkowski Klinika Nowotworów Tkanek Miękkich, Kości i Czerniaków, Centrum Onkologii
— Instytut im. Marii Skłodowskiej-Curie, Warszawa
e-mail: piotr.rutkowski@coi.pl
Paweł Rogala, Piotr Rutkowski
Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute — Oncology Centre, Warsaw
Olaratumab (LARTRUVO ® ) as a new therapeutic option in the treatment of patients with advanced soft tissue sarcomas
ABSTRACT
Olaratumab is a newly approved human monoclonal IgG1 antibody against platelet-derived growth factor alpha (PDGFR-a). In a relatively small, randomised phase 2 trial the drug given in combination with doxorubicin produced an overall survival improvement in patients with unresectable and/or metastatic soft tissue sarcomas. Further studies are necessary to establish the role of this agent in the treatment of advanced sarcomas. In this paper the current clinical data on olaratumab are presented.
Key words: olaratumab, doxorubicin, soft tissue sarcoma Oncol Clin Pract 2017; 13, 1: 1–7
Introduction
Olaratumab is a human-derived monoclonal IgG1 antibody against platelet-derived growth factor alpha (PDGFR-a). In a randomised phase 2 clinical trial the use of olaratumab in combination with doxo- rubicin resulted in improved overall survival of patients diagnosed with advanced/metastatic soft tissue sarcomas (STS). Based on the results of this study, in October 2016 olaratumab was registered by the Food and Drug Administration (FDA), and afterwards in 2017 by the European Medicines Agency (EMA), in combination with doxorubicin, for the treatment of patients with advanced STS. It was a fast-track registration based on the results of a phase 2 study [1]. Currently a multicentre phase 3 study (ANNOUNCE) is ongoing with the aim to ultimately establish the efficacy of this drug.
Mechanism of action
Olaratumab is a human-derived monoclonal IgG1 antibody against platelet-derived growth factor alpha (PDGFR-a) — it prevents linking of the receptor with its ligand (PDGF) and thus does not allow the activa- tion of the next signal pathway [2]. PDGFR-a is a re- ceptor with tyrosine kinase activity occurring on mes- enchymal cells [3]. This receptor was also detected on tumour cells [4], including sarcoma cells [5]. The signal transmitted to the tumour cell via this receptor causes cell proliferation and facilitates metastasis. Olara- tumab antineoplastic activity depends on binding to PDGFR-a on tumour cells and on tumour-associated fibroblasts [6].
Oncology in Clinical Practice 2017, Vol. 13, No. 1, 1–7 DOI: 10.5603/OCP.2017.0001 Translation:
dr n. med. Hanna Koseła-Paterczyk Copyright © 2017 Via Medica ISSN 2450–1654
In the murine xenograft model, the PDGFR-a block- ade with olaratumab in human prostate cancer cells PC3-ML resulted in delayed development of bone me- tastases and reduction in existing bone lesions [7]. The anti-PDGFR-a antibody also had anti-tumour activity in the lung cancer model without the PDGFR-a mutation, suggesting the important role of inhibiting this protein in the tumour stroma [8].
Selective blockade of PDGFR-a may also be associated with the avoidance of side effects associ- ated with multiple kinase inhibitors, such as PDGFR-b blockade-dependent fluid retention [9, 10] or C-KIT-de- pendent myelosuppression [11].
Pharmacokinetics
Olaratumab is administered intravenously. The volume of distribution at steady state is 7.7 litres. The steady state after intravenous administration at a dose of 15 mg/kg on days 1 and 8 of a 21-day cycle was achieved in cycle 3. Average clearance is 0.56 l/day. The estimated half-life is approximately 11 days (between 6 and 24 days). In patients with mild or moderate renal impairment (creatinine clearance calculated as Cock- croft-Gault pattern in the range of 30–89 ml/min) and mild or moderate hepatic impairment (bilirubin elevated to 3 × GGN), no clinically significant disturbances were observed in olaratumab pharmacokinetics. The pharmacokinetic parameters of this drug are not known in patients with severe renal impairment (creatinine clearance calculated using the Cockcroft-Gault pattern below 29 ml/min) and for patients with severe liver injury (bilirubin level above 3 × GGN). Age, sex, race, and weight were not observed to affect the pharmacokinet- ics of olaratumab. There is no known interaction of olaratumab with other drugs [12].
Dosage
Olaratumab is administered on days 1 and 8 of the 21-day cycle at a dose of 15 mg/kg for 60 minutes in com- bination with doxorubicin (suggested dose of 75 mg/m2) on day 1 every 21 days for up to eight cycles. In this dosing regimen doxorubicin is usually administered up to eight courses. Olaratumab is given until progression of the disease or appearance of unacceptable toxicity.
Due to infusion-related reactions observed in clinical studies, intravenous premedication with antihistamines (e.g. clemastine and diphenhydramine) and dexametha- sone during the first cycle is indicated before administra- tion of olaratumab.
In preclinical in vivo studies, olaratumab was ad- ministered in doses of up to 75 mg/kg per week with no observable adverse effects [13].
Clinical trials
Phase I study — olaratumab used in patients with advanced solid tumours. NCT00768391 [14]
In this clinical study, olaratumab was administered to humans for the first time. This multicentre and no-blinded study included patients with advanced or recurrent solid tumours and lymphomas. The study was conducted from December 2006 to March 2009. The primary objectives of the study were to assess safety profile, maximum tolerated dose, and recommended dose for phase 2 trial. Secondary endpoints of the trial included pharmacokinetics and pre-assessment of an- titumor activity.
Olaratumab was administered intravenously once a week (cohorts 1–3) or once every 2 weeks (cohorts 4–5). Patients who achieved clinical benefit (complete re- sponse, partial response, or stable disease) after 6 weeks (cohort 1–3) or 8 weeks (cohort 4–5) were able to receive additional infusions at the same dose and schedule as above until progression or toxicity. Treatment efficacy was evaluated according to RECIST 1.0 criteria.
The dosage in individual cohorts has been estab- lished on the basis of preclinical data. Significant inhibi- tion of tumour growth in the U118 glioma model was observed when olaratumab was administered at 20 and 60 mg/kg. The minimum observed drug concentration (c min) associated with tumour growth inhibition at a dose of 20 mg/kg bw was estimated at 258 μg/ml.
Significant tumour growth inhibition was observed with olaratumab at doses of 6, 20, and 60 mg/kg twice a week in studies using SKLMS-1 smooth muscle cell sarcoma.
Effective minimum concentration ranged between 155 and 210 μg/ml. Based on the results of these studies, it was found that in order to reach the level of antitumor activity, the concentration of olaratumab should be in the range of 155–258 μg/ml.
Nineteen patients were included in the study (Table 1)
— 13 were treated in cohorts 1 to 3 (given weekly), whereas 6 received the study drug in cohorts 4 and 5 (given every 2 weeks). Various doses were used: 4, 8, and 16 mg/kg weekly, and 15 and 20 mg/kg every 2 weeks.
Among all patients, the average number of drug doses was 9 (range 1–54), and the mean duration of treatment was 12.1 weeks (range 1–57.9). The main reason for discontinuation of treatment was radiological progression of the disease (13 patients); other reasons
— general status deterioration (3 patients) and side effects (2 patients). The maximum tolerated dose of olaratumab was not reached.
The most common treatment-related side ef- fects during the study were fatigue and reactions to intravenous infusion (grade 1 and 2) that occurred in 2 patients. There were only 2 grade 3 adverse events
— increase in alkaline phosphatase level (1 patient
Table 1. Characteristics of patients in phase I study with olaratumab (n = 19)
Age (years)
Average 68.7
Range 46.8–85.7
Sex (n)
Men 17
Women 2
Race (n)
White 18
Black 1
ECOG (n)
0 11
1 7
2 1
Tumour type (n)
Prostate cancer 11
Neuroendocrine tumours
Large intestine 2
Bronchus 1
Head and neck 1
Pancreas 1
Bladder cancer 1
Lung cancer 1
Endometrial cancer 1
Previous treatment [n]
Chemotherapy 16
Hormonotherapy 10
Immunotherapy 1
Other 2
with bronchial carcinoid and liver metastases). The intensity of other side effects was classified as grade 1 or 2. In general, the drug was well tolerated by pa- tients. There was no increased incidence of oedema or fluid retention; the absence of these side effects is associated with the selective blocking of PDGFR-a.
The half-life of the first dose was in the range of 3.08–7.79 days, and after several doses ranged from 3.69 to 11.3 days. Minimal observed drug concen- trations (c min) after dosing in cohorts receiving a 16 mg/kg weekly dose and 20 mg/kg biannual were above 155 μg/m, which in xenograft models was con- sidered to be effective.
Efficacy
No objective response was observed in this study.
In 12 (63.2%) patients stable disease was the best
response with an average duration of 3.9 months. In 4 patients, stabilisation lasted longer than 6 months (8.5–13.1 months).
Stable disease lasting more than 4 months was found in 2 patients with prostate cancer and 3 patients with neuroendocrine tumours. It is worth noting the dura- tion of stabilisation in patients with prostate cancer with bone metastases. The study used the RECIST criteria to measure the response to treatment — these criteria do not adequately reflect the clinical condition of patients with prostate cancer [15]. PDGFR-a may be overexpressed in prostate cancer (particularly in ad- vanced disease with bone metastases) [16]. In this study, 7 out of 11 prostate cancer patients (64%) achieved stable disease.
PDGFR-a overexpression in neuroendocrine tu- mours is associated with a shorter survival time [17]. In the study, 3 of 5 patients (60%) with neuroendocrine neoplasms achieved stable disease lasting from 8.5 to 13.1 months.
A phase I study — olaratumab used in Japanese patients with advanced solid tumours,
I5B-IE-JGDF [18]
This was single-centre study of 16 patients treated in 3 cohorts. In the first cohort, patients received olara- tumab 10 mg/kg on days 1 and 8, every 3 weeks; the sec- ond cohort was given a dose of 20 mg/kg every 2 weeks;
and the third group was given 15 mg/kg on days 1 and 8, every 3 weeks. The primary objective of the study was to determine the safety profile and pharmacokinetics of the drug.
No dose-limiting toxicity was observed, so no maximum tolerated dose was determined. The most common side effects associated with olaratumab were proteinuria (25%) and elevated AST (12.5%). One patient from the second cohort developed 2 olaratum- ab-related grade 3 adverse events: elevated levels of aspartate aminotransferase (AST) and tumour bleed- ing. In addition, side effects associated with olaratumab were reported in grade 1 and 2. The drug was well tolerated by patients.
Of 16 patients, 7 were diagnosed with colorectal cancer, 2 with gastric cancer, 4 with gastrointestinal stromal tumours (GIST), 2 with head and neck cancer, and 1 with STS (leiomyosarcoma).
Seven patients (43.8%) achieved stabilisation as the best response to treatment. The 2 longest disease stabili- sations were observed in a patient with laryngeal cancer (4.2 months) and in a patient with STS (5.6 months).
Based on the study of blood concentrations of olaratumab, recommended dosing regimens for further studies are 15 mg/kg on days 1 and 8 every 3 weeks and 20 mg/kg every 2 weeks.
Phase II study — olaratumab used in patients previously treated for metastatic gastrointestinal stromal tumours (GIST) [19]
Patients in this study were divided into 2 cohorts depending on the presence of the gene mutation for PDGFR-a. Both groups received olaratumab 20 mg/kg every 14 days for disease progression or unaccepta- ble toxicity. The aim of the study was to evaluate the 12-week response, progression-free survival (PFS), overall survival (OS), and safety.
All patients had received prior imatinib and suni- tinib, and some other tyrosine kinase inhibitors (dasat- inib, nilotinib, sorafenib). Thirty patients were included in the study, of which 21 received at least 1 dose of olaratumab. The first cohort included 7 patients with PDGFR-a gene (D842V) mutation. The second cohort included 14 patients without mutation.
Analysis of treatment effectiveness was performed in 20 patients — no objective response was observed.
Stabilisation of the disease was reported in 3 patients in cohort 1 (50%) and 2 in the second cohort (14.3%).
Progression of the disease was observed in 3 patients from the first cohort (50%) and 12 patients from the second cohort (85.7%). Stabilisation of the disease lasted more than 12 weeks in 5 patients (3 from the first cohort and 2 from the second). The median (PFS) was 32.1 (5–35.9) weeks in the first cohort and 6.1 (5.7–6.3) in the second cohort. The median OS was not achieved for the first cohort (6-month OS was 71.4%), and in the second cohort it was 24.9 weeks (14.4–49.1).
The most common side effects associated with olaratumab were: fatigue (38.1%), nausea (19%), and peripheral oedema (14.3%). Two adverse events (sun- cope and hypertension) had grade 3 intensity.
Although no objective response was noted, the re- searchers point out the relatively long PFS (as compared to historical data) in patients with PDGFR-a mutations.
Registration study Phase Ib and II — olaratumab used in combination with doxorubicin versus doxorubicin for the treatment of advanced soft tissue sarcomas [20]
In preclinical studies, olaratumab activity was ob- served when used alone or in combination with doxo- rubicin in sarcoma xenograft models. This observation and the important role of PDGF and PDGFR in tumour stromal biology were the theoretical basis for the olara- tumab study of patients with STS [6, 21].
This study consisted of 2 parts: phase 1b and phase 2.
The study was conducted in 16 centres in the United States. Phase 1b was planned to assess safety of the combination of olaratumab and doxorubicin. This part of the study was open — patients received doxorubicin
75 mg/m2 on day 1 (up to 8 cycles) and olaratumab 15 mg/kg on days 1 and 8, every 21 days.. Olaratumab was allowed to be continued until disease progression or unacceptable toxicity. In this part of the study 15 pa- tients were treated.
The primary objective of the phase 2 study was me- dian PFS; secondary goals were OS, objective response rate, safety, and pharmacokinetics.
For both phases, patients with either locally ad- vanced or metastatic STS previously untreated with anthracyclines or PDGFR or PDGFR drugs, and ECOG 0–2 performance (Eastern Cooperative Oncology Group) were allowed.
Phase 2 patients were randomised 1:1 to olaratumab and doxorubicin (regimen as in phase 1b) or doxorubicin alone (75 mg/kg on day 1 every 21 days, for 8 cycles).
The study in both parts was open label. Evaluation of response to treatment was conducted every 6 weeks according to RECIST 1.1. A total of 133 patients were included — 66 of them were randomly assigned to the combination therapy group and 67 to the monotherapy group (Table 2). Almost all patients (129) received at least 1 dose of scheduled treatment.
Median PFS in patients treated with olaratumab and doxorubicin was 6.6 months (95% CI 4.1–8.3), while PFS in patients treated with doxorubicin was 4.1 months (95% CI 2.8–5.4). The difference in favour of the com- bination reached the prerequisite level of statistical significance (this level was p = 0.1999) — HR 0.672, CI 95% 0.442–1.021, p = 0.0615. Blinded independent retrospective radiological analysis showed similar HR (0.67, 95% CI 0.4–1.12, p = 1208). Median PFS for the combination was 8.2 months (95% CI 5.5–9.8), while for monotherapy it was 4.4 months (95% CI 3.1–7.4).
The proportion of objective responses was 18.2%
(95% CI 9.8–29.6%) for olaratumab with doxorubicin and 11.9% (95% CI 5.3–22.2) for doxorubicin mono- therapy (p = 0.3421). In independent analysis, the percentage of objective responses was also 18.2% (95%
CI 9.8–29.6%) for olaratumab and doxorubicin, while for doxorubicin alone it was 7.5% (95% CI 2.5–16.6).
The median OS was 26.5 months (95% CI 20.9–31.7) for combination and 14.7 months (95% CI 9.2–17.1) for monotherapy — there was almost 12 months difference in favour of olaratumab (HR 0.46, 95% CI 0.3–0.71, p = 0.0003). In the analysis of stratification subgroups (including leiomyosarcoma vs. other histologies, no prior systemic treatment vs. previous systemic treatment, ECOG 0 vs. 1) all patients benefited from olaratumab treatment. Two post hoc analyses of OS were performed.
In one case, patients who had less than 8 cycles of treatment due to side effects and clinical progression were excluded. Median OS for combination therapy (61 patients) was 26.8 months, while for monotherapy (49 patients) it was 16.1 months (HR 0.55, p = 0.012).
Table 2. Characteristics of patients in phase I/II study Olaratumab
+ doxorubicin
Doxorubicin
Age
Median 58.5 58
Range 22–85 29–86
Sex
Men 26 (39%) 33 (49%)
Women 40 (61%) 34 (51%)
Race
White 55 (83%) 60 (90%)
Black 6 (9%) 5 (8%)
Asian 2 (3%) 2 (3%)
Other 3 (5%) 0
ECOG
0–1 62 (94%) 63 (94%)
2 4 (6%) 4 (6%)
Histological subtype
Leiomyosarcoma 24 (36%) 27 (40%)
Pleomorphic sarcoma
10 (15%) 14 (21%)
Liposarcoma 8 (12%) 15 (22%)
Angiosarcoma 4 (6%) 3 (5%)
Other 20 (32%) 8 (12%)
PDGFR status
Positive 58 (88%) 59 (88%)
Negative 8 (12%) 8 (12%)
In the second analysis, patients who completed less than 4 cycles of treatment were excluded. Median OS for olaratumab and doxorubicin (49 patients) was 31.7 months, and for doxorubicin (38 patients) alone it was 17.1 months (HR 0.47, p = 0.005).
More than 65% of patients in each of the 2 groups received subsequent line of treatment after disease pro- gression (Table 3 and 4), but the frequency of did not differ significantly. Subsequent treatment had no effect on the benefit of olaratumab. Patients in the mono- therapy group were given olaratumab after progression;
30 (46%) of 65 patients received olaratumab as the next line of treatment. Subjects in this group were given a median of 4 infusions of olaratumab (range 1–81).
The mean peak plasma concentration of olaratumab was 284 μg/mL and 293 μg/mL after the first and sec- ond dose. The half-life, assessed in the third cycle, was 14.4 days. In the olaratumab group, the mean number of doses of doxorubicin was 7, with an average cumula- tive dose of 487.6 mg/m2. In the doxorubicin group, the average drug was 4 administrations, with a cumulative
Table 3. Subsequent lines of treatment in the study of the combination of olaratumab with doxorubicin
Olaratumab + doxorubicin
(n = 66)
Doxorubicin*
(n = 67) Any further line of
treatment
44 (67%) 33 (49%)
1 18 (27%) 16 (24%)
2 12 (18%) 10 (15%)
3 9 (14%) 2 (3%)
4 1 (2%) 1 (2%)
> 4 4 (6%) 4 (6%)
*Olaratumab monotherapy after progression to doxorubicin was not counted as another line of treatment
Table 4. Treatment systems in subsequent lines
Scheme Olaratumab
+ doxorubicin (n = 66)
Doxorubicin (n = 67)
Doxorubicin 1 (1.5%) 6 (9%)
Gemcitabine/docetaxel 14 (21.2%) 8 (11.9%)
Gemcitabine 15 (22.7%) 11 (16.4%)
Pazopanib 15 (22.7%) 10 (14.9%)
Docetaxel 14 (21.2%) 8 (11.9%)
Dacarbazine 12 (18.2%) 8 (11.9%)
Trabectedin 11 (16.7%) 3 (4.5%)
Treatment in clinical trial 8 (12.1%) 2 (3%)
Ifosfamide 8 (12.1%) 8 (11.9%)
Eribulin 3 (4.5%) 2 (3%)
average of 299.6 mg/m2. The average intake of olara- tumab was 16.5 mg/m2 (range 1–83).
Thirty-one out of 64 patients in the olaratumab and doxorubicin group completed 8 cycles of treat- ment, while in the doxorubicin group 8 cycles were administered to 17 of 64 patients. In both groups the most common reason for study discontinuation was progression of the disease. The most common adverse event leading to the discontinuation of doxorubicin was the reduction in ejection fraction (3%) in 64 patients treated with combination and in 4 (6%) of 64 patients treated with monotherapy. For olaratumab, side effects was associated with infusion-related reactions, and drug administration was stopped in 2 (3%) of 64 patients.
The most common treatment-related adverse events in the olaratumab and doxorubicin group included nau- sea, fatigue, neutropaenia, and mucositis. In the doxo- rubicin group they were fatigue, nausea, hair loss, and neutropaenia. Selected side effects are listed in Table 5.
Table 5. The most common adverse events reported in patients receiving olaratumab in combination with doxorubicin compared with doxorubicin in the treatment of soft tissue sarcoma during phase 1b/2 study
Adverse events Olaratumab + doxorubicin (n = 64) Doxorubicin (n = 65) All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 Treatment-related adverse events 63 (98%) 18 (28%) 25 (39%) 63 (97%) 19 (29%) 17 (26%)
Nausea 47 (73%) 1 (2%) 0 34 (52%) 2 (3%) 0
Fatigue 44 (69%) 6 (9%) 0 45 (69%) 2 (3%) 0
Neutropaenia 37 (58%) 12 (19%) 22 (34%) 23 (35%) 5 (8%) 16 (25%)
Inflammation of mucous mem- branes
34 (53%) 2 (3%) 0 23 (35%) 3 (5%) 0
Hair loss 33 (52%) 0 0 26 (40%) 0 0
Vomiting 29 (45%) 0 0 12 (18%) 0 0
Anaemia 26 (41%) 8 (13%) 0 24 (37%) 6 (9%) 0
Neutropaenic fever 8 (13%) 7 (11%) 1 (2%) 9 (14%) 9 (14%) 0
Reactions related to infusion 8 (13%) 0 2 (3%) 0 0 0
Peripheral oedema 10 (16%) 0 0 7 (11%) 0 0
Reduction of ejection fraction 5 (8%) 1 (2%) 0 4 (6%) 0 0
Table 6. Summary of major clinical trials of new drugs in advanced soft tissue sarcomas Type of sarcoma,
study phase [reference]
Treatment line Research arms (experimental
vs. control)
Percentage of respondents
Percentage of clinical
benefit
Median PFS (months,
p value)
Median OS (months,
p value) Soft tissue other than
liposarcoma, phase 3, n = 369 [23]
Second or subse- quent (after an-
thracyclines)
Pazopanib 800 mg/m2 vs.
placebo
6% vs. 0% 73% vs. 38% 4.6 vs. 1.6 (p < 0.0001)
12.5 vs. 10.7 (p = 0.25)
Liposarcoma and leio- myosarcoma, phase 3, n = 518 [24]
Second or subse- quent (after anthracyclines)
Trabectedin 1.5 mg/m2 vs. dacar- bazine 1000 mg/m2
10% vs. 7% 61% vs. 42% 4.2 vs. 1.5 (p < 0.001)
12.4 vs. 12.9 (p = 0.37)
Liposarcoma and leio- myosarcoma, phase 3, n = 452 [25]
Third or subse- quent (after an-
thracyclines)
Methylsulfo- nyl eribulin 1.4 mg/m2 vs.
dacarbazine 850–
–1200 mg/m2
5% vs. 4% 57% vs. 52% 2.6 vs. 2.6 (p = 0.23)
13.5 vs. 11.5 (p = 0.01)
Soft tissue soft tissue, phase 2, n = 133 [20]
First line Olaratumab 15 mg/kg plus
doxorubicin 75 mg/m2 vs.
doxorubicin mono- therapy 75 mg/m2
18.2%
vs. 11.9%
77.3%
vs. 62.7%
6.6 vs. 4.1 (p = 0.06)
26.5 vs. 14.7 (p = 0,0003)
OS — overall survival; PFS — progression-free survival
Adverse events related to treatment with doxoru- bicin (neutropaenia, mucositis, nausea, vomiting) were more common in patients treated with doxorubicin and olaratumab. This did not, however, translate into an in- creased frequency of neutropaenic fever, hospitalisation, decision to stop treatment or death. Eight (13%) of the 64 patients in the combination group and 12 (18%) of
65 patients in monotherapy group discontinued treat- ment because of side effects.
Immunohistochemical analysis of PDGFR-a expres- sion showed that in both studied groups 88% of tumours were positive for PDGFR-a. However, it turned out that the test had low specificity for PDGFR-a, also detecting PDGFR-b. Re-analysis of the PDGFR-a-specific assay
showed that 33% of patients treated with olaratumab and doxorubicin had PDGFR-a positive tumours, and 34% of patients treated with doxorubicin alone had posi- tive PDGFR-a expression. Expression of PDGFR-a was irrelevant in relation to the OS (p = 0.3209) and PFS (p = 0.5924).
Summary
Adult patients with metastatic and/or unresectable STS still have poor outcomes due to very limited number of available therapies. The registration of olaratumab widens the therapeutic armamentarium in this group of patients, especially since all new drugs registered in recent years did not address the first line of treatment.
Table 6 summarises the most important studies in the systemic treatment of STS with new therapies.
Further studies are needed to confirm the results from the phase II study as well as the search for pre- dictive factors for therapy, individualisation of the histopathological data for sarcoma, and clarification of the improvement of OS without significant effect on PFS. It is also necessary to investigate the mechanism of action of olaratumab in STS (presumably the effect on the microenvironment of the tumour). Recruitment is completed for a randomised, double-blind, phase III ANNOUNCE (NCT02451943) trial comparing doxoru- bicin alone or combined with olaratumab, in which the endpoint is OS. It is also planned to investigate the com- bination of olaratumab with gemcitabine and docetaxel.
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