Drug Trials Snapshots: NINLARO
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 NINLARO Prescribing Information for complete information.
NINLARO (ixazomib)
(nin-LAR-oh)
Takeda Pharmaceuticals
Approval date: November 20, 2015
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
NINLARO is a drug used to treat a form of blood cancer called multiple myeloma. It is to be used in combination with two other drugs in patients whose cancer came back after or did not respond to, at least one previous treatment.
How is this drug used?
NINLARO is a capsule taken by mouth according to a specific schedule.
What are the benefits of this drug?
Patients taking NINLARO lived longer without their disease worsening (average of 20.6 months) compared to patients taking another drug (average of 14.7 months).
What are the benefits of this drug (results of trials used to assess efficacy)?
The efficacy of NINLARO was evaluated by progression-free survival (PFS) according to the 2011 International Myeloma Working Group (IMWG) Consensus Uniform Response Criteria as assessed by a blinded independent review committee (IRC) based on central lab results. Response was assessed every four weeks until disease progression.
The approval of NINLARO was based upon a statistically significant improvement in PFS of the NINLARO regimen compared to the placebo regimen. PFS results are summarized in the table and figure below.
Table 2. Progression-Free Survival and Response Rate
| NINLARO + Lenalidomide and Dexamethasone (N = 360) | Placebo + Lenalidomide and Dexamethasone (N = 362) | |
|---|---|---|
| Progression-free Survival | ||
| PFS Events, n (%) | 129 (36) | 157 (43) |
| Median (months) (95% CI) | 20.6 (17.0, NE) | 14.7 (12.9, 17.6) |
| Hazard Ratio* (95% CI) | 0.74 (0.59, 0.94) | |
| p-value† | 0.012 | |
| Response Rate | ||
| Overall Response Rate, n (%) | 282 (78) | 259 (72) |
| Complete Response | 42 (12) | 24 (7) |
| Very Good Partial Response | 131 (36) | 117 (32) |
| Partial Response | 109 (30) | 118 (33) |
NE: Not evaluable.
*Hazard ratio is based on a stratified Cox’s proportional hazard regression model. A hazard ratio less than 1 indicates an advantage for the NINLARO regimen.
†P-value is based on the stratified log-rank test.
NINLARO Prescribing Information, Table 7
The median time to response was 1.1 months in the NINLARO regimen and 1.9 months in the placebo regimen. The median duration of response was 20.5 months in the NINLARO regimen and 15 months in the placebo regimen for responders in the response evaluable population.
Figure 4. Kaplan-Meier Plot of Progression-Free Survival
NINLARO 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: NINLARO was similarly effective in men and women.
- Race: The majority of patients were white. Differences in response to NINLARO could not be determined.
- Age: NINLARO was similarly effective in patients below and above 65 years of age.
Were there any differences in how well the drug worked in clinical trials among sex, race and age groups?
The table below summarizes progression-free survival (PFS) based on sex, race, and age.
Table 3. Hazard Ratio for PFS for Sex, Race, and Age
| Hazard Ratio | Lower 95% CI, Upper 95% CI |
|---|---|---|
| Sex | ||
| Male | 0.75 | 0.55, 1.02 |
| Female | 0.73 | 0.51, 1.04 |
| Race | ||
| White | 0.74 | 0.58, 0.95 |
| Asian | 0.74 | 0.25, 2.04 |
| Age | ||
| > | 0.74 | 0.51, 1.06 |
| ≥65 | 0.73 | 0.53, 01.0 |
FDA Review
What are the possible side effects?
The most common side effects of NINLARO are diarrhea, constipation, low blood platelet count (thrombocytopenia), peripheral neuropathy (numbness and pain from nerve damage, usually in the hands and feet), nausea, peripheral edema (fluid under the skin causing swelling), vomiting and back pain.
What are the possible side effects (results of trials used to assess safety)?
The table below summarizes the adverse reactions occurring in at least 5% of patients with at least a 5% difference between the NINLARO regimen and the placebo regimen.
Table 4. Non-Hematologic Adverse Reactions Occurring in ≥ 5% of Patients with a ≥ 5% Difference Between the NINLARO Regimen and the Placebo Regimen (All Grades, Grade 3 and Grade 4)
| NINLARO + Lenalidomide and Dexamethasone N=360 | Placebo + Lenalidomide and Dexamethasone N=360 | |||||
|---|---|---|---|---|---|---|
| System Organ Class / Preferred Term | N (%) | N (%) | ||||
| All | Grade 3 | Grade 4 | All | Grade 3 | Grade 4 | |
| Infections and infestations | ||||||
| Upper respiratory tract infection | 69 (19) | 1 (> | 0 | 52 (14) | 2 (> | 0 |
| Nervous system disorders | ||||||
| Peripheral neuropathies* | 100 (28) | 7 (2) | 0 | 77 (21) | 7 (2) | 0 |
| Gastrointestinal disorders | ||||||
| Diarrhea | 151 (42) | 22 (6) | 0 | 130 (36) | 8 (2) | 0 |
| Constipation | 122 (34) | 1 (> | 0 | 90 (25) | 1 (> | 0 |
| Nausea | 92 (26) | 6 (2) | 0 | 74 (21) | 0 | 0 |
| Vomiting | 79 (22) | 4 (1) | 0 | 38 (11) | 2 (> | 0 |
| Skin and subcutaneous tissue disorders | ||||||
| Rash* | 68 (19) | 9 (3) | 0 | 38 (11) | 5 (1) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||
| Back pain | 74 (21) | 2 (> | 0 | 57 (16) | 9 (3) | 0 |
| General disorders and administration site conditions | ||||||
| Edema peripheral | 91 (25) | 8 (2) | 0 | 66 (18) | 4 (1) | 0 |
Note: Adverse reactions included as preferred terms are based on MedDRA version 16.0.
*Represents a pooling of preferred terms
NINLARO Prescribing Information, Table 4
Table 5 represents pooled information from adverse event and laboratory data.
Table 5. Thrombocytopenia and Neutropenia
| NINLARO + Lenalidomide and Dexamethasone N=360 | Placebo + Lenalidomide and Dexamethasone N=360 | |||
|---|---|---|---|---|
| N (%) | N (%) | |||
| Any Grade | Grade 3-4 | Any Grade | Grade 3-4 | |
| Thrombocytopenia | 281 (78) | 93 (26) | 196 (54) | 39 (11) |
| Neutropenia | 240 (67) | 93 (26) | 239 (66) | 107 (30) |
NINLARO Prescribing Information, Table 5
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 were white. Differences in side effects among races could not be determined.
- Age: The risk of side effects was similar in patients below and above 65 years of age.
Were there any differences in side effects of the clinical trials among sex, race and age groups?
According to NINLARO Prescribing information, there were no differences in safety for subjects below and above 65 years of age.
The table below summarizes overall adverse events by sex and age.
Table 6. Summary of Adverse Events by Sex in the Clinical Trial
| NINLARO + Lenalidomide and Dexamethasone N=360 | Placebo + Lenalidomide and Dexamethasone N=360 | |||
|---|---|---|---|---|
| Male N=208 | Female N=152 | Male N=200 | Female N=160 | |
| Any TEAE | 200 (96) | 151 (99) | 196 (98) | 159 (99) |
| Serious Adverse Event | 82 (39) | 61 (40) | 93 (47) | 65 (41) |
TEAE=treatment-emergent adverse event
Clinical Trial Data
WHO WAS IN THE CLINICAL TRIALS?
Who participated in the clinical trials?
The FDA approved NINLARO based on evidence from a clinical trial of 722 patients with multiple myeloma whose disease came back after, or did not respond to, previous treatment. The trial was conducted at 147 centers in 26 countries in North America (including Unites States), Europe, and Asia.
Figure 1 summarizes how many men and women were enrolled in the clinical trial.
Figure 1. Baseline Demographics by Sex
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
Table 1. Baseline Demographics by Race
| Race | Number of Patients | Percentage |
|---|---|---|
| White | 611 | 84.6% |
| Black or African American | 13 | 1.8% |
| Asian | 64 | 8.9% |
| Other | 12 | 1.7% |
| Missing | 22 | 3.0% |
Source: From Clinical Reviewer
The figure below summarizes the ages of patients in the clinical trial.
Figure 3. Baseline Demographics by Age
Clinical Trial Data
Who participated in the trials?
The table below summarizes demographics of patients in the clinical trial.
Table 7. Demographics of Patients in the Clinical Trial
| Demographic Subgroup | NINLARO+Lenalidomide and Dexamethasone N=360 | Placebo+Lenalidomide and Dexamethasone N=362 | Total N=722 |
|---|---|---|---|
| Sex, n (%) | |||
| Male | 207 (57.5) | 202 (56.1) | 409 (56.6) |
| Female | 153 (42.5) | 160 (44.2) | 313 (43.4) |
| Age Group, n (%) | |||
| 65> | 148 (41) | 157 (43) | 304 (42) |
| >=65 years | 212 (59) | 205 (57) | 418 (58) |
| Race, n (%) | |||
| White | 310 (86.1) | 301 (83.1) | 611 (84.6) |
| Black or African American | 7 (1.9) | 6 (1.7) | 13 (1.8) |
| Asian | 30 (8.3) | 34 (9.4) | 64 (8.9) |
| Other | 6 (1.7) | 6 (1.7) | 12 (1.7) |
| Not reported | 7 (1.9) | 15 (4.1) | 22 (3.0) |
Clinical Trial Data
How were the trials designed?
The trial randomly assigned half the patients to take NINLARO in combination with lenalidomide and dexamethasone or placebo plus lenalidomide and dexamethasone. Neither the patients nor the healthcare providers knew which patients were receiving which treatment. The treatment continued until the disease progressed or the side effects became too toxic.
How were the trials designed?
The efficacy and safety of NINLARO in combination with lenalidomide and dexamethasone was evaluated in a randomized, double-blind, placebo-controlled, multicenter study in patients with relapsed and/or refractory multiple myeloma who had received at least one prior line of therapy. Patients who were refractory to lenalidomide or proteasome inhibitors were excluded from the study. Treatment continued until disease progression or unacceptable toxicity. Randomization was stratified according to number of prior lines of therapy (1 versus 2 or 3), myeloma International Staging System (ISS) (stage I or II versus III), and previous therapy with a proteasome inhibitor (exposed or naïve).
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