6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

QTc Prolongation and Torsades de Pointes [see Warnings and Precautions (5.1)]
Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.2)]
Cardiac Toxicity [see Warnings and Precautions (5.3)]
Diarrhea [see Warnings and Precautions (5.4)]
Embryo-Fetal Toxicity [see Warnings and Precautions (5.5)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population described in WARNINGS AND PRECAUTIONS reflects exposure to EXKIVITY as a single agent at a dose of 160 mg orally once daily in 256 patients, including 114 patients with EGFR exon 20 insertion mutation-positive locally advanced or metastatic NSCLC from Study AP32788-15-101, and patients with other solid tumors. Forty-eight percent (48%) were exposed for 6 months or longer and 12% were exposed for greater than one year. The most common (>20%) adverse reactions were diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain. The most common (≥2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes, increased amylase, increased lipase, decreased potassium, decreased hemoglobin, increased creatinine, and decreased magnesium.

EGFR Exon 20 Insertion Mutation-Positive Locally Advanced or Metastatic NSCLC Previously Treated with Platinum-Based Chemotherapy

The safety of EXKIVITY was evaluated in a subset of patients in Study AP32788-15-101 with EGFR exon 20 insertion mutation-positive locally advanced or metastatic NSCLC who received prior platinum-based chemotherapy [see Clinical Studies (14)]. Patients with a history of interstitial lung disease, drug-related pneumonitis, radiation pneumonitis that required steroid treatment; significant, uncontrolled, active cardiovascular disease; or prolonged QTc interval were excluded from enrollment in this trial. A total of 114 patients received EXKIVITY 160 mg once daily until disease progression or unacceptable toxicity; 60% were exposed for 6 months or longer and 14% were exposed for greater than 1 year.

Serious adverse reactions occurred in 46% of patients who received EXKIVITY. Serious adverse reactions in ≥2% of patients included diarrhea, dyspnea, vomiting, pyrexia, acute kidney injury, nausea, pleural effusion, and cardiac failure. Fatal adverse reactions occurred in 1.8% of patients who received EXKIVITY, including cardiac failure (0.9%), and pneumonitis (0.9%).

Permanent discontinuation occurred in 17% of patients who received EXKIVITY. Adverse reactions requiring permanent discontinuation of EXKIVITY in at least ≥2% of patients were diarrhea and nausea.

Dosage interruptions of EXKIVITY due to an adverse reaction occurred in 51% of patients. Adverse reactions which required dosage interruption in >5% of patients included diarrhea, nausea and vomiting.

Dose reductions of EXKIVITY due to an adverse reaction occurred in 25% of patients. The adverse reaction requiring dose reduction in >5% of patients was diarrhea.

Table 3 summarizes the adverse reactions in Study AP32788-15-101.

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)
Adverse Reaction	All Grades * (%)	Grade 3 or 4 (%)
* Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 5) † Stomatitis includes angular cheilitis, aphthous ulcer, cheilitis, mouth ulceration, mucosal inflammation, odynophagia, and stomatitis. ‡ Events of Grade 3 only (no Grade 4 occurred) § Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain upper, abdominal tenderness, and gastrointestinal pain. ¶ Rash includes acne, dermatitis, dermatitis acneiform, rash, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, and urticaria. # Paronychia includes nail bed tenderness, nail disorder, nail infection, onycholysis, and paronychia. Þ 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. ß Fatigue includes asthenia, and fatigue. à Cough includes cough, productive cough, and upper-airway cough syndrome. è Upper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection, rhinitis, sinusitis, and upper respiratory tract infection. ð Dyspnea includes dyspnea, and dyspnea exertional. ø Ocular toxicity includes dry eye, eye pruritus, abnormal sensation in eye, eye discharge, blepharitis, trichiasis, conjunctival hemorrhage, vitreous floaters, blurred vision and corneal edema. ý QTc interval prolongation includes electrocardiogram QT prolonged, and ventricular arrhythmia. £ Hypertension includes blood pressure increased, and hypertension.
Gastrointestinal Disorders
Diarrhea	92	22
Stomatitis†	46	4.4‡
Vomiting	40	2.6‡
Decreased appetite	39	0.9‡
Nausea	37	4.4‡
Decreased weight	21	0
Abdominal pain§	18	1.8‡
Gastroesophageal reflux disease	15	0
Dyspepsia	11	0
Skin and Subcutaneous Tissue Disorders
Rash¶	78	1.8‡
Paronychia#	39	0.9‡
Dry skin	32	0
Pruritus	24	0.9‡
Alopecia	19	0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal painÞ	34	2.6‡
General Disorders and Administration Site Conditions
Fatigueß	29	3.5‡
Respiratory, Thoracic and Mediastinal Disorders
Coughà	24	0
Upper respiratory tract infectionè	16	0
Dyspneað	15	4.4
Rhinorrhea	13	0
Eye Disorders
Ocular Toxicityø	11	0
Cardiac Disorders
QTc interval prolongationý	10	3.5
Hypertension £	10	4.4‡
Nervous System Disorders
Headache	10	0

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

Table 4 summarizes the laboratory abnormalities in Study AP32788-15-101.

Table 4: Select Laboratory Abnormalities (≥20%) Worsening from Baseline 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
Laboratory Abnormality	EXKIVITY* (N = 114)
Laboratory Abnormality	All Grades† (%)	Grade 3 or 4 (%)
* The denominator used to calculate the rate varied from 93 to 113 based on the number of patients with a baseline and at least one post-treatment value. The laboratory abnormalities are values that reflect worsening from baseline. † Grades per NCI CTCAE v5.0
Hematology
Decreased red blood cells	59	3.5
Decreased lymphocytes	52	15
Decreased platelets	26	0.9
Decreased leukocytes	25	0
Chemistry
Increased creatinine	52	2.7
Increased amylase	40	13
Increased lipase	35	10
Decreased potassium	29	5
Increased alkaline phosphatase	25	1.8
Decreased albumin	23	1.8
Decreased magnesium	23	2.7
Increased alanine aminotransferase	22	2.7
Increased aspartate aminotransferase	21	1.8
Decreased sodium	20	0.9