Table 5.

Suggested dose modifications.

AEs	AEs by grade	Guidance
GI toxicities	Grade 1/2 AEs	Interrupt/modify dose at healthcare provider and patient discretion
	Grade 3 nausea >72h Grade 3/4 vomiting >24h Grade 3 diarrhea >48h	Interrupt adagrasib until ≤ grade 1 or return to baseline, and decrease one dose level
	Symptomatic grade 3/4 amylase or lipase elevation	CT scan to rule in/out acute pancreatitis. Interrupt adagrasib until ≤ grade 1 or return to baseline, and may resume one dose level lower
	Other grade 3 AEs	Interrupt adagrasib until ≤ grade 1 or return to baseline, and may resume at same dose level or one dose level lower
	Grade 4 diarrhea Grade 3/4 pancreatitis Other grade 4 AEs	Discontinue adagrasib
Hepatic toxicities	Grade 1/2 AEs (not including grade 2 ALT/AST increase)	Interrupt/modify dose at healthcare provider and patient discretion
	Grade 2 ALT/AST increase	Decrease one dose level
	Grade 3 ALT/AST increase Grade 3 increased bilirubin ≤22 days	Interrupt adagrasib until ≤ grade 1 or return to baseline, and decrease one dose level
	Grade 4 ALT/AST increase Hy’s Law Case Grade 3 increased bilirubin >22 days	Discontinue adagrasib
	Other Grade 3/4 AEs	Interrupt adagrasib until ≤ grade 1 or return to baseline, and may resume at same dose level or one dose level lower
Cardiac toxicities	QTcF prolongation >500 ms and increase >60 ms on at least 2 ECGs ≤22 days	Interrupt adagrasib until ≤ grade 1 or return to baseline (<15 ms above baseline), check electrolytes, and decrease one or two dose levels
	QTcF prolongation >500 ms and increase >60 ms on at least 2 ECGs >22 days Decrease in LVEF ≥20% from baseline and below LLN Symptomatic left ventricular systolic dysfunction	Discontinue adagrasib
	Other grade 3/4 AEs	Interrupt adagrasib until ≤ grade 1 or return to baseline, and may resume at one dose level lower
Other toxicities	Grade 1/2 AEs	Interrupt/modify dose at healthcare provider and patient discretion
	Grade 3/4 fatigue or asthenia ≤8 days	Interrupt adagrasib until ≤ grade 1 or return to baseline, and may resume at same or lower dose level
	Grade 3/4 creatinine increased ≤22 days Other lab-based grade 3/4 AEs	Interrupt adagrasib until ≤ grade 1 or return to baseline, and may resume at same dose level or one dose level lower
	Grade 3/4 creatinine increased >22 days	Discontinue adagrasib
	Other grade 3 AEs	Interrupt adagrasib until ≤ grade 1 or return to baseline, and resume one or more dose levels lower
	Other grade 4 AEs	Interrupt adagrasib until ≤ grade 1 or return to baseline, and may resume at a lower dose level (only if not life-threatening and can be managed; otherwise permanently discontinue adagrasib)

Sequential dose reduction steps: 400 mg BID, 600 mg once daily (may be split into BID dosing for tolerability).

Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ECG, electrocardiogram; GI, gastrointestinal; LLN, lower limit of normal; LVEF, left ventricular ejection fraction; QTcF, QT corrected interval by Fredericia.