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Drug Trials Snapshots: LORBRENA

Drug Trials Snapshots: LORBRENA

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 LORBRENA Package Insert for complete information.

LORBRENA (lorlatinib)
lor-BREN-ah
Pfizer Labs
Approval date: November 2, 2018


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

LORBRENA is a drug used to treat patients with a type of non-small cell lung cancer (NSCLC) that

  • is caused by an abnormal anaplastic lymphoma kinase (ALK) gene and,
  • has spread to other parts of your body (metastatic) and,
  • has progressed while on one or more anti-cancer drugs approved for treatment of ALK-positive lung cancer.

How is this drug used?

LORBRENA is a tablet taken by mouth once a day.

What are the benefits of this drug?

Overall, 48% of patients who had measurable cancer lesions prior to taking LORBRENA had a complete or partial shrinkage of the lesions which lasted an average of 12.5 months. Approximately 60% of patients who had measurable cancer lesions in the brain prior to taking LORBRENA had a complete or partial shrinkage of the lesions in the brain which lasted an average of 19 months.

LORBRENA was approved under FDA’s accelerated approval program, which provides earlier patient access to a promising new drug while the company continues to conduct clinical trials to confirm that the drug works well.

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

Efficacy results from the trial are summarized below. The major efficacy outcome measure was overall response rate (ORR) and intracranial ORR according to RECIST v 1.1 assessed by Independent Central Review (ICR) Committee. Efficacy population was limited to all patients who had metastatic ALK positive NSCLC that progressed on prior ALK inhibitors and who received 100 mg LORBRENA once daily.

Table 2. Efficacy Results in Trial 1

Efficacy Parameter Overall
N=215
Overall response ratea (95% CI)b
Complete response
Partial response
48% (42, 55)
4%
44%
Duration of response
Median, monthsc (95% CI)

12.5 (8.4, 23.7)

Abbreviations: CI=confidence interval; N=number of patients; NR=not reached.

a Per Independent Central Review.
b Using exact method based on binomial distribution.
c Estimated using the Kaplan‑Meier method.

Table 3. Intracranial Response Rate in Patients with Measurable Intracranial Lesions in Trial 1

Efficacy Parameter Intracranial
N=89
Intracranial response ratea (95% CI)b
Complete response
Partial response
60% (49, 70)
21%
38%
Duration of response
Median, monthsc (95% CI)

19.5 (12.4, NR)

Abbreviations: CI=confidence interval; N=number of patients; NR=not reached.

a Per Independent Central Review.
b Using exact method based on binomial distribution.
c Estimated using the Kaplan‑Meier method.

LORBRENA Prescribing Information

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

  • Sex: LORBRENA worked similarly among men and women.
  • Race: LORBRENA worked similarly in White and Asian patients. The number of patients in other races was limited; therefore, differences among races could not be determined.
  • Age: There was a limited number of patients older than 65 years of age, however, no difference in how well LORBRENA worked in patients below and above 65 years of age was observed.

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

Efficacy subgroup analyses are summarized below.

Table 4. Confirmed ORR per IRC by Sex, Race, and Age

    N ORR 95% CI
Sex
  Male 88 48% (37%, 59%)
  Female 127 49% (40%, 58%)
Race1
  White 109 42% (33%, 52%)
  Asian 74 51% (39%, 63%)
  Other 9 33% (7%, 70%)
Age
  <65 177 49% (42%, 57%)
  ≥65 38 45% (29%, 62%)

1Race was missing for 23 patients

FDA Review

What are the possible side effects?

LORBRENA may cause serious side effects including high levels of fat in the blood, complete or partial block of the signal that controls the heartbeat, life-threatening inflammation of the lungs, and side effects affecting the brain, including seizures, hallucinations, changes in mood (including suicidal ideation), speech, mental status, and sleep.

The most common side effects of LORBRENA are swelling of the feet and legs (edema), weakness, numbness and pain from nerve damage, changes in memory, judgement or reasoning, difficulty breathing, tiredness, weight gain due to retaining water, joint pain, mood changes, and diarrhea.

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

The table below summarizes adverse reactions that occurred during the trial. Safety population was defined as all patients who received at least one dose of LORBRENA. It includes all patients from efficacy population (215) and an additional 80 patients with metastatic NSCLC with other mutations, different prior treatments, and different doses of LORBRENA.

Table 5. Adverse Reactions Occurring in ≥10% of Patients in Trial 1*

Adverse Reaction LORBRENA
(N=295)
All Grades (%) Grade 3 or 4 (%)
Psychiatric
Mood effectsa 23 1.7
Nervous system
Peripheral neuropathyb 47 2.7
Cognitive effectsc 27 2.0
Headache 18 0.7
Dizziness 16 0.7
Speech effectsd 12 0.3
Sleep effectse 10 0
Respiratory
Dyspnea 27 5.4
Cough 18 0
Ocular
Vision disorderf 15 0.3
Gastrointestinal
Diarrhea 22 0.7
Nausea 18 0.7
Constipation 15 0
Vomiting 12 1
Musculoskeletal and connective tissue
Arthralgia 23 0.7
Myalgiag 17 0
Back pain 13 0.7
Pain in extremity 13 0.3
General
Edemah 57 3.1
Fatiguei 26 0.3
Weight gain 24 4.4
Pyrexia 12 0.7
Infections
Upper respiratory tract infectionj 12 0
Skin
Rashk 14 0.3

*Adverse reactions were graded using NCI CTCAE version 4.0.

Abbreviations: NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; SOC=System organ class.
a Mood effects (including affective disorder, affect lability, aggression, agitation, anxiety, depressed mood, depression, euphoric mood, irritability, mania, mood altered, mood swings, personality change, stress, suicidal ideation).
b Peripheral neuropathy (including burning sensation, carpal tunnel syndrome, dysesthesia, formication, gait disturbance, hypoesthesia, muscular weakness, neuralgia, neuropathy peripheral, neurotoxicity, paresthesia, peripheral sensory neuropathy, sensory disturbance).
c Cognitive effects (including events from SOC Nervous system disorders: amnesia, cognitive disorder, dementia, disturbance in attention, memory impairment, mental impairment; and also including events from SOC Psychiatric disorders: attention deficit/hyperactivity disorder, confusional state, delirium, disorientation, reading disorder).
d Speech effects (including aphasia, dysarthria, slow speech, speech disorder)
e Sleep effects (including abnormal dreams, insomnia, nightmare, sleep disorder, sleep talking, somnambulism)
f Vision disorder (including blindness, diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters).
g Myalgia (including musculoskeletal pain, myalgia).
h Edema (including edema, edema peripheral, eyelid edema, face edema, generalized edema, localized edema, periorbital edema, peripheral swelling, swelling).
I Fatigue (including asthenia, fatigue).
j Upper respiratory infection (including fungal upper respiratory infection, upper respiratory infection, viral upper respiratory infection).
k Rash (including dermatitis acneiform, maculopapular rash, pruritic rash, rash).

LORBRENA Prescribing Information

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

  • Sex: The occurrence of side effect was similar among men and women.
  • Race: The occurrence of side effects was similar among White and Asian patients. The number of patients in other races was limited; therefore, differences among other races could not be determined.
  • Age: There was a limited number of patients above 65 years of age, however, no difference in occurrence of side effects between those below and above 65 years of age was observed.

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

The tables below summarize occurrence of adverse events in LORBRENA treated patients by subgroups.

Table 6. Subgroup Analysis of AEs by Sex (safety population)

Adverse Events
Male
N=125
Female
N=170
Any TEAE, % 99 100
Grade 3-4 TEAEs 67 69
Grade 5 TEAEs 14 10
SAE, % 39 50
AEs leading to discontinuation, % 9 7

Table 7. Subgroup Analysis of AEs by Race (safety population)

Adverse Events LORBRENA
N=295
Asian
N=108
White
N=145
Any TEAE, % 99 100
Grade 3-4 TEAEs 64 68
Grade 5 TEAEs 11 15
SAE, % 29 43
AEs leading to discontinuation, % 5 5

Table 8. Subgroup Analysis of AEs by Age (safety population)

Adverse Events LORBRENA
N=295
< 65 years
(N=241)
≥ 65 years
(N=54)
Any TEAE, % 100 100
Grade 3-4 TEAEs 68 72
Grade 5 TEAEs 10 19
SAE, % 33 50
AEs leading to discontinuation, % 7 13

TEAE=treatment emergent adverse events; SAE=serious adverse events

Adapted from FDA Review

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved LORBRENA based on evidence from one clinical trial (Trial 1/NCT01970865) of 295 patients with metastatic NSCLC. Patients were previously treated with anti-cancer drugs, but their disease has progressed despite that treatment. The trial was conducted at 47 sites in Asia, Australia, Canada, Europe, and the United States.

Demographics of the 215 patients who provided data for evaluation of benefits of LORBRENA (efficacy population) are presented in Table 10, under the MORE INFO section.

Demographics of the 295 patients who provided data for side effects of LORBRENA (safety population) is presented below.

Figure 1 summarizes how many men and women were in the clinical trial used to evaluate safety.

Figure 1. Baseline Demographics by Sex (safety population)

Pie chart summarizing how many men and women were in the clinical trial.  In total, 125 men (42%) and 170 women (58%) participated in the clinical trial

FDA Review

Figure 2 and Table 1 summarize the percentage of patients by race in the clinical trial used to evaluate safety.

Figure 2. Baseline Demographics by Race (safety population)

Pie chart summarizing the percentage of patients by race. In total, 145 Whites (49%), 3 Blacks (1%), 108 Asians (37%), and 39 Others (13%), participated in the clinical trial.

*Other includes unspecified

FDA Review

Table 1. Demographics of Trial by Race (safety population)

Race Number of Patients Percentage of Patients
White 145 49%
Black or African American 3 1%
Asian 108 37%
Other 13 4%
Unspecified 23 9%

FDA Review

The figure below summarizes the percentage of patients by age group in the clinical trial used to evaluate safety.

Figure 3. Baseline Demographics by Age

Pie chart summarizing how many individuals of certain age groups were in the clinical trial.  In total, 241 patients were below 65 years old (82%) and 54 patients were 65 and older (18%).

FDA Review

Who participated in the trials?

The tables below summarize the demographics of the safety and efficacy populations.

Table 9. Baseline Demographics of the Safety Population

Demographic Parameters LORBRENA (N=295)
n (%)
Sex
Men 125 (42)
Women 170 (58)
Race
White 145 (49)
Black or African American 3 (1)
Asian 108 (37)
Other 13 (4)
Unspecified 26 (9)
Age (years)
Mean (SD) 53.3 (12.1)
Median 53
Min, max (years) 19, 85
Age Group
< 65 years 241 (82)
≥ 65 years 54 (18)
Ethnicity
Not Reported 295 (100)
Region
United States 100 (34)
Rest of the World 195 (66)
Canada 7 (2)
Europe 92 (31)
Asia 78 (26)
Australia 18 (6.1)

FDA Review

Table 10. Baseline Demographics of the Efficacy Population

Demographic Parameter LORBRENA
 (N=215)
n (%)
Sex
Male 88(41)
Female 127 (59)
Race
White 109 (51)
Asian 74 (34)
Other 9 (4)
Missing 23 (11)
Age (years)
Mean (SD) 53.0 (11.7)
Age Group
< 65 year 177 (82)
≥ 65 year 38 (18)
Ethnicity
Not Reported 215 (100)

FDA Review

How were the trials designed?

The benefits and side effects of LORBRENA were evaluated in one clinical trial.

Patients had metastatic, non-small cell lung cancer (NSCLC) and at least one measurable cancer lesion. The cancer had progressed while on anti-cancer drugs that treat ALK-positive lung cancers. The benefit of LORBRENA was assessed by measuring if and how much the cancer lesions decreased in size during treatment and how long that tumor shrinkage lasted.

How were the trials designed?

The efficacy and safety of LORBRENA were evaluated in a single, non-randomized, multi-center, dose-ranging trial. A subgroup of enrolled patients had metastatic ALK positive NSCLC that progressed on prior ALK inhibitors, and at least one measurable target lesion according to Response Evaluation Criteria in solid Tumors (RECIST) version 1.1 (v 1.1). Patients received LORBRENA daily at a range of doses from 10 mg daily to 200 mg daily (in single or divided oral doses); however, the evaluation of tumor responses was conducted in patients who received LORBRENA 100 mg once daily.

The major efficacy outcome measures were overall response rate (ORR) according to RECIST v 1.1 and intracranial ORR as assessed by Independent Central Review (ICR) Committee.

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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