Safety of Lorlatinib in ALK-Positive Non-Small-Cell Lung Cancer and Management of Central Nervous System Adverse Events

Figures & data

Table 1. Non-central nervous system adverse events associated with lorlatinib therapy.

Adverse event	Grade and frequency, %
	Any grade	Grade 1–2	Grade 3–4
Any adverse event	97.3–100.0	23.0–54.1	44.0–72.0
Laboratory adverse events
Hypercholesterolemia	70.5–92.7	54.4–80.7	11.9–17.9
Hypertriglyceridemia	60.7–90.8	43.6–63.3	15.6–27.5
Hyperglycemia	16.5	13.8	2.8
Hyperuricemia	10.3	10.3	0.0
Increased ALT	8.7–43.1	8.0–41.3	0.0–2.7
Increased AST	10.2–40.4	9.8–37.6	0.0–2.8
Increased GGT	23.9	22.0	1.8
Increased LDL	19.3	19.3	0.0
Increased amylase/lipase	11.6–19.3	8.0–12.5	3.6–6.8
Prolonged QT interval	5.4–16.5	5.1–16.5	0.0–0.3
Clinical adverse events
Edema	26.6–55.0	25.7–51.0	0.9–7.7
Weight gain	15.4–38.3	15.4–25.7	0.0–16.8
Peripheral neuropathy	11.0–43.7	11.0–43.6	0.0–2.4
Diarrhea	10.5–21.5	10.2–20.5	0.0–1.3
Anemia	5.5–19.5	4.7–16.8	0.7–2.7
Fatigue	10.2–23.1	9.8–22.7	0.3–1.3
Hypertension	2.9–18.1	1.5–8.1	1.5–10.1
Vision disorder	9.5–18.1	9.5–18.1	0.0–0.3
Tinnitus	5.4–17.9	5.4–17.9	0.0–0.0
Constipation	9.8–17.9	9.8–17.9	0.0–0.0
Dizziness	9.1–15.4	8.1–12.8	0.7–2.6
Nausea	9.2–14.8	9.2–14.1	0.0–0.7
Vomiting	4.4–12.8	4.0–12.1	0.0–0.7
Arthralgia	10.2–19.7	10.2–19.7	0.0–0.3
Headache	7.1–10.3	7.1–10.3	0.0–0.0

The table illustrates the adverse events occurring at a rate of >10% in any of the clinical trials (the table was created based on data from [14,16,32-34]. CNS adverse events are listed in Table 3.

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: γ-glutamyl transferase; LDL: Low-density lipoprotein.

Table 2. Management of hyperlipidemia, the most common adverse event during lorlatinib therapy.

Hyperlipidemia severity	Management
Mild hypercholesterolemia (Cholesterol: ULN: 300 mg/dl) OR Moderate hypercholesterolemia (Cholesterol: 301–400 mg/dl) OR Mild hypertriglyceridemia (Triglycerides: 150–300 mg/dl) OR Moderate hypertriglyceridemia (Triglycerides: 301–500 mg/dl)	Introduce or modify lipid-lowering therapy in accordance with respective prescribing information; continue lorlatinib at same dose
Severe hypercholesterolemia (Cholesterol: 401–500 mg/dl) OR Severe hypertriglyceridemia (Triglycerides: 501–1000 mg/dl)	Introduce lipid-lowering therapy; if currently on lipid-lowering therapy, increase the dose of this therapy in accordance with respective prescribing information; or change to a new lipid-lowering therapy. Continue lorlatinib at the same dose without interruption
Life threatening hypercholesterolemia (Cholesterol: >500 mg/dl) OR Life threatening hypertriglyceridemia (Triglycerides: >1000 mg/dl)	Introduce lipid-lowering therapy or increase the dose of this therapy in accordance with respective prescribing information or change to a new lipid-lowering therapy. Withhold lorlatinib until recovery of hypercholesterolemia and/or hypertriglyceridemia to moderate or mild severity grade Rechallenge at same lorlatinib dose while maximizing lipid-lowering therapy in accordance with respective prescribing information If severe hypercholesterolemia and/or hypertriglyceridemia recur despite maximal lipid-lowering therapy in accordance with respective prescribing information, reduce lorlatinib by one dose level

ULN: Upper limit of normal.

Table created using data from [39].

Table 3. Central nervous system adverse events encountered during lorlatinib therapy.

Reference	Solomon et al. [14]^†	Bauer et al. [33]^†	Felip et al. [15]^†	Solomon et al. [46]^†	Peled et al. [41]^‡
Patient group	ALK-positive or ROS1-positive NSCLC	ALK-positive or ROS1-positive NSCLC	ALK-positive or ROS1-positive NSCLC	ALK-positive NSCLC	ALK-positive or ROS1-positive NSCLC
Lorlatinib therapy line	First or subsequent	First or subsequent	First or subsequent	First	Second or subsequent
CNS adverse events	Any grade (grade 1–2/grade 3–4)
Cognitive effects, %	17.8 (16.7/1.1)	23.1 (21.4/1.7)	23.7 (22.0/1.7)	21.5 (19.5/2.0)	17.9 (17.9/0.0)
Mood effects, %	14.9 (14.2/0.7)	21.0 (19.7/1.4)	15.6 (14.6/1.0)	16.1 (14.8/1.3)	15.4 (15.4/0.0)
Speech effects, %	7.3 (6.9/0.4)	9.5 (9.2/0.3)	8.5 (8.1/0.3)	4.7 (4.0/0.7)
Psychotic effects, %	1.8 (1.5/0.4)		6.4 (5.8–0.6)	3.4 (3.4/0.0)

† Prospective.

‡ Retrospective.

NSCLC: Non-small-cell lung cancer.

Table 4. Grading of central nervous system adverse events.

CTCAE term	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Cognitive disturbance	Mild cognitive disability; not interfering with work/school/life performance; specialized educational services/devices not indicated	Moderate cognitive disability; interfering with work/school/life performance but capable of independent living; specialized resources on part-time basis indicated	Severe cognitive disability; significant impairment of work/school/life performance	Unable to perform ADL; full-time specialized resources or institutionalization indicated	Death
Mood alteration	Mild mood alteration not interfering with function	Moderate mood alteration interfering with function, but not interfering with ADL; medication indicated	Severe mood alteration interfering with ADL	Suicidal ideation; danger to self or others	Death
Speech impairment	–	Awareness of receptive or expressive dysphasia, not impairing ability to communicate	Receptive or expressive dysphasia, impairing ability to communicate	Inability to communicate	–
Psychosis (hallucinations/delusions)	–	Transient episode	Interfering with ADL; medication, supervision or restraints indicated	Harmful to others or self; life-threatening consequences	Death

ADL: Activities of daily living; CTCAE: Common Terminology Criteria for Adverse Events (v. 3.0).

Table created using data from [48].

Table 5. Recommended dose modifications for central nervous system adverse events encountered during lorlatinib therapy.

CNS adverse events	Approach
Grade 2 (moderate) OR Grade 3 (severe)	Withhold dose until toxicity is grade ≤1, then resume lorlatinib at one reduced dose level
Grade 4 (life-threatening / urgent intervention indicated)	Permanently discontinue lorlatinib

Table created using data from [39].

CNS: Central nervous system.

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