Drug Trials Snapshots: VITRAKVI

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 VITRAKVI Prescribing Information for complete information.

VITRAKVI (larotrectinib)
vi trak vee
Bayer HealthCare Pharmaceuticals Inc.
Approval date: November 26, 2018

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DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

VITRAKVI is a drug used to treat adult and pediatric patients whose cancers have a specific genetic feature (biomarker). It is to be used for patients with solid tumors that:

• are caused by certain abnormal NTRK genes and
• have spread or if surgery to remove their cancer is likely to cause severe complications, and
• there is no acceptable treatment, or the cancer grew or spread on other treatment.

How is this drug used?

VITRAKVI is a capsule or liquid usually taken by mouth 2 times a day.

What are the benefits of this drug?

Seventy-five percent of all patients who received VITRAKVI experienced complete or partial shrinkage of their tumors which lasted for more than 6 months for 73% of them.

VITRAKVI 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)?

The tables below summarize efficacy results for the clinical trials based on overall response rate and the type of tumor.

Table 2. Efficacy Results for Patients with Solid Tumors Harboring NTRK Gene Fusions

Efficacy Parameter	VITRAKVI N = 55
Overall response rate (95% CI)	75% (61%, 85%)
Complete response rate	22%
Partial response rate*	53%
Duration of response**	N = 41
Range (months)	1.6+, 33.2+
% with duration ≥ 6 months	73%
% with duration ≥ 9 months***	63%
% with duration ≥ 12 months****	39%

+ Denotes ongoing response
*Includes one pediatric patient with unresectable infantile fibrosarcoma who underwent resection following partial response and who remained disease-free at data cutoff.
**Median duration of response not reached at time of data cutoff
***3 patients with an ongoing response were followed < 9 months from onset of response.
****10 patients with an ongoing response were followed < 12 months from onset of response.

VITRAKVI Prescribing Information

Table 3. Efficacy Results by Tumor Type

Tumor Type	Patients (N=55)	ORR		DOR
		%	95% CI	Range (months)
Soft tissue sarcoma	11	91%	(59%, 100%)	3.6, 33.2+
Salivary gland	12	83%	(52%, 98%)	7.7, 27.9+
Infantile fibrosarcoma	7	100%	(59%, 100%)	1.4+, 10.2+
Thyroid	5	100%	(48%, 100%)	3.7, 27.0+
Lung	4	75%	(19%, 99%)	8.2, 20.3+
Melanoma	4	50%	NA	1.9, 17.5+*
Colon	4	25%	NA	5.6*
Gastrointestinal stromal tumor	3	100%	(29%, 100%)	9.5, 17.3
Cholangiocarcinoma	2	SD, NE	NA	NA
Appendix	1	SD	NA	NA
Breast	1	PD	NA	NA
Pancreas	1	SD	NA	NA

ORR = Overall response rate; DOR = duration of response; NA = not applicable due to small numbers or lack of response; CR = complete response; PR = partial response; NE = not evaluable; SD = stable disease; PD = progressive disease
+ Denotes ongoing response; * Observed values at data cutoff, not a range

VITRAKVI Prescribing Information

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

• Sex: VITRAKVI worked similarly in men and women.
• Race: The majority of patients in the clinical trial were White. Differences in response to VITRAKVI among races could not be determined.
• Age: The majority of patients in the clinical trial were younger than 65 years of age. Differences in response to VITRAKVI between patients below and above 65 years of age 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 below summarizes overall response rate by subgroups. Results should be interpreted with caution given the small sample size overall, and the limited number of patients in each subgroup.

Table 4. Subgroup Analyses of Overall Response Rate

Subgroup	# Patients	n (%)	95%CI
Sex
Male	29	25 (86.2%)	(68.3%, 96.1%)
Female	26	16 (61.5%)	(40.6%, 79.8%)
Race
White	37	26 (70.3%)	(53%, 84.1%)
Asian	2	2 (100%)	NA
Black	2	0 (0%)	NA
All others	14	13 (92.9%)	(66.1%, 98.8%)
Age
<65 years	43	35 (81.4%)	(66.6%, 91.6%)
Infants & Toddlers (<2 years)	6	6 (100%)	(54.1%, 100%)
Children (2 to <12 years)	6	6 (100%)	(54.1%, NA)
Adolescents (16 to <18 years)	0	0	NA
Adults (18 to <65 years)	31	23 (74.2%)	(55.4%, 88.1%)
>=65 years	12	6 (50%)	(21.1%, 78.9%)

CI = confidence interval; NA = not applicable

FDA Review

What are the possible side effects?

VITRAKVI may cause serious side effects, including nervous system problems and liver damage.

The most common side effects of VITRAKVI are tiredness, nausea, dizziness, vomiting, cough, increased liver enzymes, constipation and diarrhea.

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

The table below summarizes adverse reactions that occurred in the clinical trial in ≥10% of patients treated in VITRAKVI.

Table 5. Adverse Reactions Occurring in ≥10% of Patients Treated with VITRAKVI

Adverse Reaction	VITRAKVI N = 176
	All Grades* (%)	Grade 3-4** (%)
General
Fatigue	37	3
Pyrexia	18	1
Edema peripheral	15	0
Gastrointestinal
Nausea	29	1
Vomiting	26	1
Constipation	23	1
Diarrhea	22	2
Abdominal pain	13	2
Nervous System
Dizziness	28	1
Headache	14	0
Respiratory, Thoracic and Mediastinal
Cough	26	0
Dyspnea	18	2
Nasal congestion	10	0
Investigations
Increased weight	15	4
Musculoskeletal and Connective Tissue
Arthralgia	14	1
Myalgia	14	1
Muscular weakness	13	0
Back pain	12	1
Pain in extremity	12	1
Metabolism and Nutrition
Decreased appetite	13	2
Vascular
Hypertension	11	2
Injury, Poisoning and Procedural Complications
Fall	10	1

* National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v 4.03
** One Grade 4 adverse reaction of pyrexia

VITRAKVI Prescribing Information

The table below summarizes laboratory abnormalities in the clinical trial.

Table 6. Laboratory Abnormalities Occurring in ≥ 5% Patients Treated with VITRAKVI

Laboratory Abnormality	VITRAKVI*
	All Grades** (%)	Grade 3-4 (%)
Chemistry
Increased ALT	45	3
Increased AST	45	3
Hypoalbuminemia	35	2
Increased alkaline phosphatase	30	3
Hematology
Anemia	42	10
Neutropenia	23	7

*Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available which ranged from 170 to 174 patients.
** NCI-CTCAE v 4.03

VITRAKVI Prescribing Information

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

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

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

Tables 7-9 below summarize selected adverse events that occurred in the clinical trials by subgroups.

Table 7. Subgroup Analysis of Adverse Events by Sex

Adverse Event	VITRAKVI (N=176)
	Male (N=91) n (%)	Female (N=85) n (%)
Any TEAE	90 (99)	83 (98)
Increased ALT	28 (31)	17 (20)
Increased AST	27 (30)	18 (21)

Table 8. Subgroup Analysis of Adverse Events by Race

Adverse Event	VITRAKVI ( N=176)
	White (N=126) n (%)	Black or African American (N=14) n (%)	Asian (N=6) n (%)
Any TEAE	125 (99)	14 (100)	5 (83)
Increased ALT	21 (28)	1 (20)	3 (60)
Increased AST	19 (26)	1 (20)	3 (60)

Table 9. Subgroup Analysis of Adverse Events by Age

Adverse Event	VITRAKVI (N=176)
	<18 years (N=44) n (%)	≥18 years (N=132) n (%)
Any TEAE	42 (95)	131 (99)
Increased ALT	19 (43)	26 (20)
Increased AST	17 (39)	28 (21)

TEAE=treatment-emergent adverse event
Clinical Trial Report

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved VITRAKVI based on the evidence from three clinical trials of 176 patients with various types of solid tumors (Trial 1 / NCT02122913; Trial 2 / NCT02637687; and Trial 3 / NCT02576431). The trials were conducted at sites in the United States, Europe and Singapore.

Patients who provided data for the benefit of VITRAVI (efficacy population) are presented in Table 10 under MORE INFO.

Patients that provided data for the side effects of VIKTRAVI (safety population) are presented below.

Figure 1 below summarizes how many patients were in the clinical trials by sex.

Figure 1. Baseline Demographics by Sex (safety population)

Clinical Trial Data

Figure 2 and Table 1 below summarize the percentage of patients in the clinical trials by race.

Figure 2. Baseline Demographics by Race (safety population)

Clinical Trial Data

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

Race	Number of Patients	Percentage
White	126	72
Black or African American	14	8
Asian	6	3
Other*	23	13
Not Reported	7	4

*includes American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, Multiple and Other

Clinical Trial Data

Figure 3 below summarizes the percentage of patients in the clinical trials by age.

Figure 3. Baseline Demographics by Age (safety population)

Clinical Trial Data

Who participated in the trials?

Table 10 below summarizes patient demographics.

Table 10. Baseline Demographics of Patients in the Clinical Trials

Demographic Parameter	Efficacy Population N=55	Safety Population N=176
Sex, n (%)
Male	29 (53)	91 (52)
Female	26 (47)	85 (48)
Race, n (%)
White	37 (67)	126 (72)
Black or African American	2 (4)	14 (8)
Asian	2 (4)	6 (3)
American Indian or Alaska Native	1(2)	1 (1)
Native Hawaiian or other Pacific Islander	1 (2)	1 (1)
Multiple	1 (2)	1 (1)
Other	8 (15)	20 (11)
Not Reported	2 (4)	7 (4)
Age (years)
Range	0.3, 76.0	0.1,82.0
Median	45.0	51.0
Age Group, n (%)
<2 years	6 (11)	12 (7)
2-11 years	6 (11)	19 (11)
12-18 years	0 (0)	13 (7)
18-65 years	31 (56)	94 (53)
≥65 years	12 (22)	38 (21)
Ethnicity, n (%)
Hispanic	4 (7)	19 (11)
Non-Hispanic	38 (69)	135 (77)
Unknown/Not Reported	13 (24)	22 (12)

Clinical Trial Data

How were the trials designed?

The benefit and side effects of VITRAKVI were evaluated in three trials. Most enrolled patients had an unresectable or metastatic solid tumor with abnormal NTRK genes and no satisfactory alternative treatment options, or disease progression following treatment. The most common types of tumors were soft tissue sarcoma, salivary gland cancer, lung cancer, thyroid cancer, colon cancer, and infantile fibrosarcoma.

Patients received VITRAKVI until either tumor progression or intolerable side effects.

The benefit of VITRAKVI was evaluated by measuring the percentage of patients who achieved complete or partial shrinkage of their tumors (overall response rate) and by measuring the duration of that benefit (duration of response).

How were the trials designed?

The safety and efficacy of VITRAKVI were established in three multicenter, open-label, single-arm clinical trials that included an adult dose-finding single arm trial and a pediatric dose-finding single arm trial, and a single arm trial designed to evaluate the effectiveness of VITRAKVI by assessing overall response rate and durability of response. All patients had a metastatic solid tumor with a NTRK gene fusion and no satisfactory alternative treatment options, disease progression following treatment, or would have required surgical resection was likely to result in severe morbidity. The most common cancers were soft tissue sarcoma (16%), salivary gland tumors (11%), lung (10%), thyroid (9%), colon (8%), and infantile fibrosarcoma (8%).

Most adults (80%) received VITRAKVI 100 mg orally twice daily and 68% of pediatric patients received VITRAKVI 100 mg/m2 twice daily up to a maximum dose of 100 mg twice daily.

The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR), as determined by a blinded independent review committee (BIRC) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

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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