Drugs

Drug Trials Snapshots: YONDELIS

HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the clinical trials that supported the FDA approval of this drug, and whether there were differences among sex, race and age groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your health provider about the risks and benefits of a drug. Refer to the YONDELIS Prescribing Information for complete information.

YONDELIS (trabectedin)
Yawn-del-iss
Janssen Products, LP
Approval date: October 23, 2015


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

YONDELIS is a drug used to treat patients with liposarcoma and leiomyosarcoma that cannot be removed by surgery (unresectable) or is advanced (metastatic). These are rare forms of cancer that begin in fat cells (liposarcoma) or smooth muscle cells (leiomyosarcoma) of the body.

This treatment is approved for patients who previously received chemotherapy that contained a specific class of drugs called anthracyclines.

How is this drug used?

YONDELIS is given as a continuous infusion over 24 hours into a vein.

What are the benefits of this drug?

Participants who received YONDELIS experienced a delay in the growth of their tumor (called progression-free survival), which occurred on average about 4.2 months after starting treatment, compared to participants assigned to a different drug called dacarbazine. In patients receiving dacarbazine, disease progressed at an average of 1.5 months after starting treatment.

What are the benefits of this drug (results of trials used to assess efficacy)?

The table and figure below summarize results of the primary endpoint in the trial.

Table 2. Efficacy Results for the Clinical Trial

Efficacy endpointYONDELISDacarbazine
N=345N=173
Progression‑free survival
PFS Events, n (%)217 (63%)112 (65%)
Disease progression204109
Death133
Median (95% CI) (months)4.2 (3.0, 4.8)1.5 (1.5, 2.6)
HR (95% CI)a0.55 (0.44, 0.70)
p‑valueb<0.001
Overall survivalc
Events, n (%)258 (67%)123 (64%)
Median (95% CI) (months)13.7 (12.2, 16.0)13.1 (9.1, 16.2)
HR (95% CI)a0.93 (0.75, 1.15)
p-valueb0.49
Objective Response Rate (ORR: CR+PR)
Number of patients (%)23 (7%)10 (6%)
95% CId(4.3, 9.8)(2.8, 10.4)
Duration of Response (CR+ PR)
Median (95% CI) (months)6.9 (4.5, 7.6)4.2 (2.9, NE)

a Cox proportional hazards model with treatment group as the only covariate.
b Unstratified log rank test.
c Based on 384 patients randomized to YONDELIS arm and 193 patients randomized to dacarbazine.
d Fisher′s exact CI.
CR=Complete Response; PR=Partial Response; CI=Confidence Interval, HR=hazard ratio, NE=not estimable.
YONDELIS Prescribing Information, Table 4

Figure 4. Kaplan-Meier Curves of Progression-Free Survival in the Clinical Trial

Figure summarizes results of the primary endpoint in the trial.

YONDELIS Prescribing Information, Figure 1

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

Subgroup analyses were conducted for sex, race and age.

  • Sex: YONDELIS was similarly effective in men and women.
  • Race: The majority of patients in the trial were white. Differences in response to YONDELIS could not be determined.
  • Age: The majority of patients in the trial were below 65 years of age. Differences in response to YONDELIS could not be determined.

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?

The table summarizes results for the primary efficacy endpoint by demographic subgroup.

Table 3. Progression-Free Survival Analysis by Baseline Demographic Characteristics

SubgroupYONDELIS
(Censored/Event)
Dacarbazine
(Censored/Event)
HR (95%)
Sex
Male31/7616/310.55 (0.34, 0.87)
Female97/14145/810.57 (0.43, 0.76)
Race
White96/17343/820.52 (0.39, 0.68)
Black22/228/110.54 (0.25, 1.19)
Asian4/52/81.05 (0.21, 5.29)
Age
<65 years91/17352/ 870.60 (0.46, 0.79)
≥65 years37/ 449/ 250.40 (0.23, 0.69)

Statistical Review

What are the possible side effects?

The most common side effects were nausea, fatigue, vomiting, diarrhea, constipation, decreased appetite, shortness of breath (dyspnea), headache, tissue swelling (peripheral edema), a decrease in infection-fighting white blood cells (neutropenia), low blood platelet counts (thrombocytopenia), low red blood cell count (anemia), elevated liver enzymes, and decreases in albumin, a protein found in blood.

Serious side effects included severe and fatal blood infections, muscle tissue breakdown, liver damage, leakage around the vein or catheter, breakdown of tissue, and heart failure.

What are the possible side effects (results of trials used to assess safety)?

The tables below summarize adverse events in the clinical trial.

Table 4. Selected Adverse Reactionsa occurring in ≥  10% of Patients receiving YONDELIS and at a higher incidence than in the Control Arm

System Organ Class
Adverse Reaction
YONDELIS
(N=378)
Dacarbazine
(N=172)
All Gradesb
(%)
Grades 3‑4
(%)
All Grades
(%)
Grades 3‑4
(%)
Gastrointestinal disorders
Nausea757501.7
Vomiting466221.2
Constipation370.8310.6
Diarrhea351.6230
General disorders and administration site conditions
Fatigue c698521.7
Peripheral edema280.8130.6
Metabolism and nutrition disorders
Decreased appetite371.9210.6
Respiratory, thoracic and mediastinal disorders
Dyspnea254.2201.2
Nervous system disorders
Headache250.3190
Musculoskeletal and connective tissue disorders
Arthralgia15081.2
Myalgia12060
Psychiatric disorders
Insomnia150.390

YONDELIS Prescribing Information, Table 2
a Limited to adverse reactions at a rate of ≥10% in the trabectedin arm and at a rate higher in the trabectedin arm compared with dacarbazine arm by ≥5% in overall incidence or by ≥2% for Grade 3-4 adverse reactions.
b Toxicity grade is based on NCI common toxicity criteria, version 4.0.
c Fatigue is a composite of the following adverse event terms: fatigue, asthenia, and malaise.

Table 5. Incidence of Selected Treatment-Emergent Laboratory Abnormalitiesa in the Clinical Trial

Laboratory AbnormalitiesYONDELISDacarbazine
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Chemistry
Increased ALT9031330.6
Increased AST8417321.2
Increased alkaline phosphatase701.6600.6
Hypoalbuminemia633.7513.0
Increased creatinine464.2291.2
Increased creatine phosphokinase336.490.6
Hyperbilirubinemia131.950.6
Hematology
Anemia96197912
Neutropenia66434726
Thrombocytopenia59215720

YONDELIS Prescribing Information, Table 3
ALT=Alanine Transaminase
AST=Aspartate Transaminase
a Treatment‑emergent laboratory abnormalities including those higher in the trabectedin arm compared with the dacarbazine arm by ≥5% (all Grades) or by ≥2% (Grade 3‑4). Incidence based on number of patients who had both baseline and at least one on-study laboratory measurement
YONDELIS group (range: 373 to 377 patients) and dacarbazine group (range: 166 to 168 patients).

Were there any differences in side effects among sex, race and age?

Subgroup analyses were conducted for sex, race and age.

  • Sex:  The risk of side effects was similar in men and women.
  • Race:  The majority of patients in the trial were white. Differences in side effects among races could not be determined.
  • Age: The majority of patients in the trial were below 65 years of age. Differences in side effects between patients below and above 65 years could not be determined.

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

The clinical trial did not include sufficient numbers of non-whites and subjects aged 65 and over to determine whether there were different responses among race and age groups.

According to the clinical review, the risk of side effects was similar in men and women.

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved YONDELIS based on evidence from a clinical trial of 518 patients with liposarcoma and leiomyosarcoma . The trial was conducted in 85 sites in 4
countries (Australia, Brazil, New Zealand, and the United States). Ninety-four percent of the patients were enrolled in U.S. sites.

Figure 1 summarizes how many men and women were enrolled in the clinical trial.

Figure 1. Baseline Demographics by Sex

Pie chart summarizing how many men and women were enrolled in the clinical trials used to evaluate efficacy of the drug YONDELIS.  In total, 154 men (30%) and 364 women (70%) participated in the clinical trials used to evaluate efficacy of the drug YONDELIS.

Clinical Trial Data

Figure 2 and Table 1 summarize the percentage of patients by race enrolled in the clinical trial.

Figure 2. Baseline Demographics by Race

Pie chart summarizing the percentage of patients by race enrolled in the YONDELIS clinical trial. In total, 394 Whites (76%), 63 Blacks (12%), 19 Asians (4%), 5 American Indian or Alaska Natives (1%), 14 participants that reported Unknown (3%), 18 participants that did not report (3%), and 5 Other (1%) participated in the clinical trial.

Clinical Trial Data

Table 1. Baseline Demographics by Race

RaceNumber of PatientsPercentage
White39476%
Black or African American6312%
Asian194%
American Indian or Alaska Native51%
Other51%
Unknown143%
Not Reported183%

Clinical Trial Data

Figure 3 summarizes the percentage of patients by age group enrolled in the clinical trial.

Figure 3. Baseline Demographics by Age

 Pie chart summarizing how many individuals of certain age groups were enrolled in the YONDELIS clinical trial.  In total, 403 participants were between 17 and 64 years old (78%) and 115 participants were 65 and older (22%).

Clinical Trial Data

Who participated in the trials?

The table below summarizes baseline demographics for clinical trial participants.

Table 6. Baseline Demographics for the Clinical Trial

 Dacarbazine
(N=173)
n (%)
YONDELIS
(N=345)
n (%)
Total
(N=518)
n (%)
Demographic Parameter
Sex
Male47 (27)107 (31)154 (30)
Female126 (73)238 (69)364 (70)
Age
Mean years (SD)54.5 (11.8)56.2 (10.9)55.6 (11.2)
Median (years)565756
Min, max (years)(17, 79)(18, 81)(17, 81)
Age Group
<65 years139 (80)264 (77)403 (78)
≥65 years34 (20)81 (24)115 (22)
Race
White125 (72)269 (78)394 (76)
Black or African American19 (11)44 (13)63 (12)
Asian10 (6)9 (3)19 (4)
American Indian or Alaska Native4 (2)1 (<1%)5 (1)
Other2 (1)3 (1)5 (1)
Unknown6 (4)8 (2)14 (3)
Not Reported7 (4)11 (3)18 (4)
Ethnicity
Hispanic or Latino20 (12)26 (8)46 (9)
Not Hispanic or Latino135 (78)304 (88)439 (85)
Unknown12 (7)5 (1)17 (3)
Not Reported6 (4)10 (3)16 (3)
Region
United States166 (96)323 (94)489 (94)
Australia7 (4)13 (4)20 (4)
Brazil06 (2)6 (1)
New Zealand03 (13 (1)

Clinical Trial Data

How were the trials designed?

In the clinical trial that supported the approval of YONDELIS, participants were randomly assigned to receive either YONDELIS or another chemotherapy drug called dacarbazine every 3 weeks. Treatment continued in both groups until the disease progressed or until there were unacceptable side effects. The trial measured the amount of time from the start of the trial when patients were living with the cancer up until when the cancer worsened (called progression-free survival).

How were the trials designed?

The clinical efficacy and safety of YONDELIS in patients with metastatic or recurrent leiomyosarcoma or liposarcoma were demonstrated in a randomized (2:1), open-label, active-controlled trial comparing treatment with YONDELIS 1.5 mg/m2 as a 24-hour continuous intravenous infusion once every 3 weeks to dacarbazine 1000 mg/m2 intravenous infusion (20 to 120 minutes) once every 3 weeks. Treatment continued in both arms until disease progression or unacceptable toxicity; all patients in the YONDELIS arm were required to receive dexamethasone 20 mg intravenous injection prior to each YONDELIS infusion. Patients were required to have unresectable, locally advanced or metastatic leiomyosarcoma or liposarcoma (dedifferentiated, myxoid round cell, or pleomorphic) and previous treatment with an anthracycline- and ifosfamide-containing regimen or an anthracycline-containing regimen and one additional cytotoxic chemotherapy regimen.

Randomization was stratified by subtype of soft tissue sarcoma (leiomyosarcoma vs. liposarcoma), ECOG performance status (0 vs. 1), and number of prior chemotherapy regimens (1 vs. ≥2). The efficacy outcome measures were investigator-assessed progression-free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1), overall survival (OS), objective response rate (ORR), and duration of response (DOR). Patients in the dacarbazine arm were not offered YONDELIS at the time of disease progression.

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

PRESCRIBING INFORMATION

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