Drug Trials Snapshot: EXKIVITY

HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the key clinical trials that supported the original FDA approval of this drug, and whether there were differences among sex, race, age, and ethnic 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 healthcare provider about the benefits and risks of a drug.

Some of the information in this Snapshot is for presentation purposes and does not represent the approved conditions of use of this drug. Refer to the EXKIVITY Prescribing Information for all of the approved conditions of use of this drug (e.g., indication(s), population(s), dosing regimen(s), safety information).

Snapshots are limited to the information available at the time of the original approval of the drug and do not provide information on who participated in clinical trials that supported later approvals for additional uses of the drug (if applicable).

EXKIVITY (mobocertinib)
(ex ki' vi tee)
Takeda Pharmaceuticals USA, Inc.
Original Approval date: September 15, 2021

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DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

EXKIVITY is a kinase inhibitor used to treat adult patients with a type of lung cancer (non-small cell lung cancer or NSCLC) which:

• has a specific gene mutation (EGFR exon 20 insertion mutations) and,
• is locally advanced or has spread to other parts of the body (metastatic) and,
• has progressed on or after platinum-based chemotherapy.

How is this drug used?

EXKIVITY is a capsule taken once a day by mouth. EXKIVITY may be taken with or without food.

Who participated in the clinical trials?

The FDA approved EXKIVITY based on evidence from a clinical trial of patients with EGFR exon 20 insertion mutation-positive locally advanced or metastatic NSCLC who received prior platinum-based chemotherapy. The trial was conducted at 70 sites in 9 countries (United States, Germany, Spain, Great Britain, Italy, China, Japan, South Korea and Taiwan). The same trial was used to assess the efficacy of EXKIVITY in 114 patients and the safety of EXKIVITY in 256 patients; therefore, the number of patients representing efficacy findings may differ from the number of patients representing safety findings due to different pools of study participants analyzed for efficacy and safety.

What are the benefits of this drug?

Approximately 28% of patients (32 of 114 patients) treated with EXKIVITY in the clinical study AP32788-15-101 had partial shrinkage of their cancer. Shrinkage lasted more than 6 months for 59% of patients who had a response to EXKIVITY.

EXKIVITY 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 table below summarizes the results of the major efficacy outcome measure, overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by blinded independent central review (BICR).

Table 1. Efficacy Results in Patients with EGFR Exon 20 Insertion Mutation-Positive NSCLC Whose Disease Has Progressed on or after Platinum-Based Chemotherapy in Study AP32788-15-101

Efficacy Parameter	EXKIVITY (n=114)
Overall Response Rate (ORR)a (95% CI)	28% (20, 37)b
Duration of Response (DOR)
Median (months)c, (95% CI)	17.5 (7.4, 20.3)
Patients with DOR ≥6 monthsd	59%

^a Per BICR, CI = confidence interval
^b All responses were partial responses
^c Kaplan-Meier estimate using confirmed responses only
^d Based on observed duration of response

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

• Sex: EXKIVITY worked similarly in males and females.
• Race: EXKIVITY worked similarly in White and Asian patients. There were few patients of other races.
• Age: EXKIVITY worked similarly 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?

Table 2. Overall response rates (ORR) in Study AP32788-15-101 Efficacy Population (N=114) by subgroup

Subgroup	N	ORR, % (95% CI)
Age
<65 years	72	32 (21, 44)
≥ 65 years	42	21 (10, 37)
Sex
Female	75	29 (19, 41)
Male	39	26 (13, 42)
Race
Asian	68	31 (20, 43)
White	42	21 (10, 37)
Black	3	33 (1, 91)
Region
Asia	55	29 (18, 43)
Europe	6	33 (4, 78)
North America	53	26 (15, 40)
Overall	114	28 (20, 37)

What are the possible side effects?

The most common side effects observed with EXKIVITY include diarrhea, rash, nausea, mouth sores, vomiting, decreased appetite, infection of skin around the nails, tiredness, dry skin and muscle pain.

EXKIVITY can cause life-threatening heart-rate changes (QTc prolongation), inflammation of the lung (interstitial lung disease or pneumonitis) and heart problems (cardiac toxicity including heart failure).

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

Table 3. Adverse Reactions (≥10%) in Patients with EGFR Exon 20 Insertion Mutation-Positive NSCLC Whose Disease Has Progressed on or after Platinum-Based Chemotherapy in Study AP32788-15-101

Adverse Reaction	EXKIVITY (N = 114)
	All Grades* (%)	Grade 3 or 4 (%)
Gastrointestinal Disorders
Diarrhea	92	22
Stomatitisa	46	4.4**
Vomiting	40	2.6**
Decreased appetite	39	0.9**
Nausea	37	4.4**
Decreased weight	21	0
Abdominal painb	18	1.8**
Gastroesophageal reflux disease	15	0
Dyspepsia	11	0
Skin and Subcutaneous Tissue Disorders
Rashc	78	1.8**
Paronychiad	39	0.9**
Dry skin	32	0
ruritus	24	0.9**
Alopecia	19	0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal paine	34	2.6**
General Disorders and Administration Site Conditions
Fatiguef	29	3.5**
Respiratory, Thoracic and Mediastinal Disorders
Coughg	24	0
Upper respiratory tract infectionh	16	0
Dyspneai	15	4.4
Rhinorrhea	13	0
Eye Disorders
Ocular Toxicityj	11	0
Cardiac Disorders
QTc interval prolongationk	10	3.5
Hypertensionl	10	4.4**
Nervous System Disorders
Headache	10	0

* Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 5)
** Events of Grade 3 only (no Grade 4 occurred)
^a Stomatitis includes angular cheilitis, aphthous ulcer, cheilitis, mouth ulceration, mucosal inflammation, odynophagia, and stomatitis.
^b Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain upper, abdominal tenderness, and gastrointestinal pain.
^c Rash includes acne, dermatitis, dermatitis acneiform, rash, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, and urticaria.
^d Paronychia includes nail bed tenderness, nail disorder, nail infection, onycholysis, and paronychia.
^e Musculoskeletal pain includes arthralgia, back pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain.
^f Fatigue includes asthenia, and fatigue.
^g Cough includes cough, productive cough, and upper-airway cough syndrome.
^h Upper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection, rhinitis, sinusitis, and upper respiratory tract infection.
ⁱ Dyspnea includes dyspnea, and dyspnea exertional.
^j Ocular toxicity includes dry eye, eye pruritis, abnormal sensation in eye, eye discharge, blepharitis, trichiasis, conjunctival hemorrhage, vitreous floaters, blurred vision and corneal edema.
^k QTc interval prolongation includes electrocardiogram QT prolonged, and ventricular arrhythmia.
^l Hypertension includes blood pressure increased, and hypertension.

Clinically relevant adverse reactions in <10% of patients receiving EXKIVITY included edema (9%), acute kidney injury (8%), peripheral neuropathy (7%), palmar-plantar erythrodysaesthesia (4.4%), pneumonitis (2.6%) and cardiac failure (2.6%).

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

• Sex: The occurrence of side effects was generally similar in men and women.
• Race: A higher percentage of White patients reported Grades 3 to 4 Adverse Reactions than Asian patients. There were few patients enrolled in other race categories.
• Age: The occurrence of serious and high-grade side effects was higher in patients 65 years and older as compared to those younger than 65 years of age.

Table 1. Overview of Adverse Reactions by Sex, Age, Race, Ethnicity, and Country in Patients with NSCLC Who Received EXKIVITY 160 mg Once Daily in Safety Population

Demographic Variable	EXKIVITY N=256
	All Patients n (%)	All Grades n/Ns (%)	Grades 3 to 4 n/Ns (%)
Sex, n (%)
Female	169 (66.0)	168/169 (99.4)	114/169 (67.5)
Male	87 (34.0)	87/87 (100)	50/87 (57.5)
Age group, years, n (%)
18 to <65 years	160 (62.5)	159/160 (99.4)	93/160 (58.1)
≥65 years	96 (37.5)	96/96 (100)	71/96 (74.0)
Race, n (%)
Asian	102 (39.8)	102/102 (100)	52/102 (51.0)
Black or African American	12 (4.7)	12/12 (100)	9/12 (75.0)
Unknown	3 (1.2)	3/3 (100)	2/3 (66.7)
White	139 (54.3)	138/139 (99.3)	101/139 (72.7)
Ethnicity, n (%)
Hispanic or Latino	12 (4.7)	11/12 (91.7)	9/12 (75.0)
Not Hispanic or Latino	231 (90.2)	231/231 (100)	151/231 (65.4)
Not reported	13 (5.1)	13/13 (100)	4/13 (30.8)
Country
United States	176 (68.8)	80/80 (100)	41/80 (51.2)
Non-United States	80 (31.2)	175/176 (99.4)	123/176 (69.9)

Source: FDA reviewer’s analysis
Abbreviation: N, number of patients in the safety population; n, number of patients with given characteristic; Ns, total number of patients in each category; NSCLC, non-small cell lung cancer
Safety population includes patients from studies AP32788-15-101 and TAK-788-1003 (Part 1) who received EXKIVITY at the recommended dose of 160 mg once daily.

DEMOGRAPHICS SNAPSHOT

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

Figure 1. Baseline Demographics by Sex

Source: Adapted from FDA Review

Figure 2 summarizes the percentage of patients by race enrolled in the clinical trial used to evaluate the efficacy and safety of EXKIVITY.

Figure 2. Baseline Demographics by Race

Source: Adapted from FDA Review

Figure 3 summarizes the percentage of patients by age group enrolled in the clinical trial used to evaluate the efficacy and safety of EXKIVITY.

Figure 3. Baseline Demographics by Age

Source: Adapted from FDA Review

Who participated in the trials?

Table 4. Baseline Demographics and Disease Characteristics in the Efficacy and Safety Populations of Study AP32788-15-101

	Efficacy Population N = 114	Safety Population N = 256
Sex, n (%)
Female	75 (66)	169 (66)
Male	39 (34)	87 (34)
Age at diagnosis (years), median [range]	60 [27, 84]	61 [24, 86]
< 65 Years	72 (63)	160 (63)
>= 65 Years	42 (37)	96 (38)
Race, n (%)
Asian	68 (60)	102 (40)
Black or African American	3 (3)	12 (5)
White	42 (37)	139 (54)
Not reported	1 (1)	3 (1)
Ethnicity, n (%)
Hispanic or Latino	1 (1)	12 (5)
Not Hispanic or Latino	113 (99)	231 (90)
Not Reported	0	13 (5)
Region, n (%)
Asia	55 (48)	70 (27)
Europe	6 (5)	10 (4)
North America	53 (47)	176 (69)
ECOG performance status at study entry, n (%)
0	29 (25)	82 (32)
1	85 (75)	174 (68)
Disease Stage at study entry, n (%)
Stage IIIB	1 (1)	3 (1)
Stage IV	113 (99)	244 (95)
Missing	0	9 (4)
Histopathology at study entry, n (%)
Adenocarcinoma	112 (98)	245 (96)
Adenosquamous carcinoma	0	1 (<1)
Non-Squamous	1 (1)	2 (<1)
Squamous	1 (1)	4 (2)
Other	0	4 (2)
Site involvement at study entry, n (%)
Brain	40 (35)
Bone	47 (41)	117 (46)
Liver	24 (21)
Lung	110 (97)	231 (90)
Other	93 (82)	202 (79)
Smoking History, n (%)
Current	2 (2)	3 (1)
Former	31 (27)
Never	81 (71)	167 (65)
Unknown	0	1 (<1)
Number of Prior Lines of Therapy, median [range]	2 [1, 7]
1	47 (41)
2	36 (32)
≥3	31 (27)
Prior EGFR TKI therapy, n (%)
No	85 (75)
Yes	29 (25)
Prior PD-1 or PD-L1 therapy, n (%)
No	66 (58)
Yes	48 (42)

ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; TKI = tyrosine kinase inhibitor; PD-1 = programmed cell death protein 1; PD-L1 = programmed cell death-ligand 1

How were the trials designed?

EXKIVITY was evaluated in an international, open-label, single arm, multicohort clinical trial (Study AP32788-15-101) including 114 patients with EGFR exon 20 insertion mutation-positive metastatic or locally advanced NSCLC whose disease had progressed on or after platinum-based chemotherapy. Patients had histologically or cytologically confirmed locally advanced or metastatic disease (Stage IIIB or IV) and a documented EGFR exon 20 insertion mutation based on local testing. Patients received EXKIVITY at a dose of 160 mg once daily until disease progression or intolerable toxicity. The major efficacy outcome measure was overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by blinded independent central review (BICR). Additional efficacy outcome measures included duration of response (DOR) by BICR.

How were the trials designed?

eStudy AP32788-15-101 was international, open-label, single arm, dose escalation and dose expansion study of EXKIVITY. This study included a dose-escalation phase (Part 1), which established the recommended Phase 2 dose (RP2D) of mobocertinib, followed by an expansion phase in 7 distinct disease cohorts treated at the RP2D (Part 2), and an extension cohort (Part 3). In the dose escalation phase, the doses ranged from 5 mg to 180 mg daily. The extension cohort (Part 3) included patients with locally advanced or metastatic non-small cell lung cancer, who were treated at the RP2D of 160 mg once daily, and who had been previously treated with at least one prior line of therapy. The efficacy population (N=114) included patients from all 3 parts with metastatic NSCLC with EGFR Exon 20 insertion mutations who had previously been treated with platinum-based chemotherapy and were administered the recommended dose of 160 mg daily (Part 1 [n = 6]; Expansion Cohort 1 of Part 2 [n = 22]; and Part 3 [n = 86]).

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 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.

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