Drugs

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 ParameterOverall
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 ParameterIntracranial
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

  NORR95% CI
Sex
 Male8848%(37%, 59%)
 Female12749%(40%, 58%)
Race1
 White10942%(33%, 52%)
 Asian7451%(39%, 63%)
 Other933%(7%, 70%)
Age
 <6517749%(42%, 57%)
 ≥653845%(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 ReactionLORBRENA
(N=295)
All Grades (%)Grade 3 or 4 (%)
Psychiatric
Mood effectsa231.7
Nervous system
Peripheral neuropathyb472.7
Cognitive effectsc272.0
Headache180.7
Dizziness160.7
Speech effectsd120.3
Sleep effectse100
Respiratory
Dyspnea275.4
Cough180
Ocular
Vision disorderf150.3
Gastrointestinal
Diarrhea220.7
Nausea180.7
Constipation150
Vomiting121
Musculoskeletal and connective tissue
Arthralgia230.7
Myalgiag170
Back pain130.7
Pain in extremity130.3
General
Edemah573.1
Fatiguei260.3
Weight gain244.4
Pyrexia120.7
Infections
Upper respiratory tract infectionj120
Skin
Rashk140.3

*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, %99100
Grade 3-4 TEAEs6769
Grade 5 TEAEs1410
SAE, %3950
AEs leading to discontinuation, %97

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

Adverse EventsLORBRENA
N=295
Asian
N=108
White
N=145
Any TEAE, %99100
Grade 3-4 TEAEs6468
Grade 5 TEAEs1115
SAE, %2943
AEs leading to discontinuation, %55

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

Adverse EventsLORBRENA
N=295
< 65 years
(N=241)
≥ 65 years
(N=54)
Any TEAE, %100100
Grade 3-4 TEAEs6872
Grade 5 TEAEs1019
SAE, %3350
AEs leading to discontinuation, %713

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)

RaceNumber of PatientsPercentage of Patients
White14549%
Black or African American31%
Asian10837%
Other134%
Unspecified239%

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 ParametersLORBRENA (N=295)
n (%)
Sex
Men125 (42)
Women170 (58)
Race
White145 (49)
Black or African American3 (1)
Asian108 (37)
Other13 (4)
Unspecified26 (9)
Age (years)
Mean (SD)53.3 (12.1)
Median53
Min, max (years)19, 85
Age Group
< 65 years241 (82)
≥ 65 years54 (18)
Ethnicity
Not Reported295 (100)
Region
United States100 (34)
Rest of the World195 (66)
Canada7 (2)
Europe92 (31)
Asia78 (26)
Australia18 (6.1)

FDA Review

Table 10. Baseline Demographics of the Efficacy Population

Demographic ParameterLORBRENA
 (N=215)
n (%)
Sex
Male88(41)
Female127 (59)
Race
White109 (51)
Asian74 (34)
Other9 (4)
Missing23 (11)
Age (years)
Mean (SD)53.0 (11.7)
Age Group
< 65 year177 (82)
≥ 65 year38 (18)
Ethnicity
Not Reported215 (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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Page Last Updated: 11/09/2018
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