Adagrasib KRAZATI MRTX849 LuciAda 200mg

Product Name: LuciAda

Chinese Name: Adagrasib

English Name: Adagrasib

Specification: 200 mg/tablet; 90 tablets/bottle.

[Summary]

Adagrasib is an irreversible inhibitor of KRAS G12C, a member of the RAS GTPase family. Its molecular formula is C32H35ClFN7O2, and its molecular weight is 604.1 g/mol.

The chemical name is {(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl}acetonitrile.

[Indications]

Adagrasib is a RAS GTPase inhibitor indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring a KRAS G12C mutation, who have received at least one prior systemic therapy.

[Storage]

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

[Dosage and Administration]

1. Patient Selection

Select patients with locally advanced or metastatic NSCLC for treatment with LuciAda based on the presence of a KRAS G12C mutation in plasma or tumor specimens. If a mutation is not detected in a plasma specimen, test tumor tissue.

Information regarding FDA-approved tests for the detection of KRAS G12C mutations is available at https://www.fda.gov/CompanionDiagnostics.

2. Recommended Dosage

The recommended dosage of LuciAda is 600 mg orally twice daily until disease progression or unacceptable toxicity occurs.

Take LuciAda at the same time every day, with or without food. Swallow the tablets whole. Do not chew, crush, or split the tablets. If vomiting occurs after taking LuciAda, do not take an additional dose. Resume dosing at the next scheduled time.

If a dose is missed, and more than 4 hours have elapsed since the scheduled dosing time, skip the missed dose. Resume dosing at the next scheduled time.

3. Dosage Adjustments for Adverse Reactions

Recommended dose reductions for adverse reactions are shown in Table 1. If an adverse reaction occurs, up to two dose reductions are permitted. Permanently discontinue LuciAda in patients who are unable to tolerate 600 mg once daily.

Table 1: Recommended LuciAda Dose Reductions for Adverse Reactions

Dose Reduction

Dose

First Dose Reduction

400 mg twice daily

Second Dose Reduction

600 mg once daily

Recommended dosage adjustments for adverse reactions are shown in Table 2.

Table 2: Recommended LuciAda Dosage Adjustments for Adverse Reactions

Adverse Reaction

Severity

Dosage Adjustment

Nausea or vomiting despite appropriate supportive care (including antiemetic therapy)

[See Warnings and Precautions]

Grade 3 or 4

1. Withhold adagrasib until resolved to Grade ≤1 or to baseline.

2. Resume adagrasib at the next lower dose level.

Diarrhea despite appropriate supportive care (including antidiarrheal therapy)

[See Warnings and Precautions]

Grade 3 or 4

1. Withhold adagrasib until resolved to Grade ≤1 or to baseline.

2. Resume adagrasib at the next lower dose level.

QTc Interval Prolongation

[See Warnings and Precautions]

Absolute QTc > 500 ms OR increase from baseline > 60 ms

1. Withhold adagrasib until QTc interval is < 481 ms or returns to baseline.

2. Resume adagrasib at the next lower dose level.

Signs or symptoms of Torsades de Pointes, polymorphic ventricular tachycardia, or severe or life-threatening arrhythmia

Permanently discontinue adagrasib. Hepatotoxicity

[See Warnings and Precautions]

Grade 2 AST or ALT

Reduce Adagrasib to the next lower dose level.

Grade 3 or 4 AST or ALT

1. Withhold Adagrasib until recovery to ≤ Grade 1 or to baseline.

2. Resume Adagrasib at the next lower dose level.

AST or ALT > 3 × ULN and Total Bilirubin > 2 × ULN, in the absence of other causes

Permanently discontinue Adagrasib.

Interstitial Lung Disease (ILD)/Non-infectious Pneumonitis

[See Warnings and Precautions]

Any Grade

1. Withhold Adagrasib if ILD/non-infectious pneumonitis is suspected.

2. Permanently discontinue Adagrasib if:

ILD/non-infectious pneumonitis is confirmed.

Other Adverse Reactions

Grade 3 or 4

1. Withhold Adagrasib until recovery to

≤ Grade 1 or to baseline.

2. Resume Adagrasib at the next lower dose level.

ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; ULN = Upper limit of normal

*Grading defined according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0

[Warnings and Precautions]

1. Gastrointestinal Adverse Reactions

LuciAda can cause severe gastrointestinal adverse reactions.

In the pooled safety population [see Adverse Reactions], severe gastrointestinal adverse reactions observed included gastrointestinal hemorrhage (3.8% incidence, including 0.8% Grade 3 or 4 events); gastrointestinal obstruction (1.6% of patients, including 1.4% Grade 3 or 4 events); colitis (0.5% of patients, including 0.3% Grade 3 events); intestinal obstruction (0.5% of patients); and stenosis (0.3% of patients). Additionally, 89% of the 366 patients experienced nausea, diarrhea, or vomiting, with 9% of these events being Grade 3. 29% of patients interrupted dosing or reduced the dose due to nausea, diarrhea, or vomiting; 0.3% of patients permanently discontinued adagrasib.

Monitor and manage patients using supportive care—including antidiarrheals, antiemetics, or fluid replacement—as clinically indicated. Suspend, reduce the dose, or permanently discontinue LuciAda based on severity [see Dosage and Administration].

2. QTc Interval Prolongation

LuciAda can cause QTc interval prolongation, which increases the risk of ventricular tachyarrhythmias (e.g., *Torsades de Pointes*) or sudden death.

In the pooled safety population [see Adverse Reactions], among 366 patients who underwent at least one post-baseline electrocardiogram (ECG) assessment, 6% had an average QTc ≥ 501 ms, and 11% had a QTc increase from baseline of > 60 ms. LuciAda can cause concentration-dependent QTc interval prolongation.

Avoid the concomitant use of LuciAda with other products known to prolong the QTc interval [see Drug Interactions]. Avoid using LuciAda in patients with congenital long QT syndrome and in patients with concurrent QTc prolongation.

Monitor ECGs and electrolytes prior to initiating LuciAda treatment, during concomitant use, and as clinically indicated in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or those for whom concomitant use of known QT-prolonging medications cannot be avoided. Suspend, reduce the dose, or permanently discontinue LuciAda based on severity [see Dosage and Administration].

3. Hepatotoxicity

LuciAda can cause hepatotoxicity, which may lead to drug-induced liver injury and hepatitis.

In the pooled safety population of 366 patients [see Adverse Reactions], drug-induced liver injury was reported in 0.3% of patients, of whom 0.3% experienced Grade 3 events. Overall, 32% of patients treated with adagrasib experienced elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST); 5% experienced Grade 3 elevations, and 0.5% experienced Grade 4 elevations. The median time to the first occurrence of ALT/AST elevation was 3 weeks (range: 0.1–48 weeks). The overall incidence of hepatotoxicity was 37%, with 7% being Grade 3 or 4. Hepatotoxicity leading to dose interruption or dose reduction occurred in 12% of patients. Adagrasib was permanently discontinued due to hepatotoxicity in 0.5% of patients.

Monitor liver laboratory tests (AST, ALT, alkaline phosphatase, and total bilirubin) prior to initiating LuciAda treatment, monthly for 3 months, or as clinically indicated; monitor more frequently in patients who develop transaminase elevations. Reduce the dose, suspend, or permanently discontinue LuciAda based on severity [see Dosage and Administration and Adverse Reactions].

4. Interstitial Lung Disease (ILD)/Non-infectious Pneumonitis

LuciAda can cause ILD/non-infectious pneumonitis, which may be fatal.

In the pooled safety population [see Adverse Reactions], ILD/non-infectious pneumonitis occurred in 4.1% of patients, with 1.4% being Grade 3 or 4; one case was fatal. The median time to the first onset of ILD/non-infectious pneumonitis was 12 weeks (range: 5–31 weeks). Adagrasib was permanently discontinued due to ILD/non-infectious pneumonitis in 0.8% of patients.

Monitor patients for new or worsening respiratory symptoms (e.g., dyspnea, cough, fever) suggestive of ILD/pneumonitis during treatment with LuciAda. Suspend LuciAda in patients with suspected ILD/non-infectious pneumonitis; permanently discontinue LuciAda if no other potential causes of ILD/non-infectious pneumonitis are identified [see Dosage and Administration].

[Adverse Reactions]

1. Gastrointestinal Adverse Reactions [see Warnings and Precautions]

2. QTc Interval Prolongation [see Warnings and Precautions]

3. Hepatotoxicity [see Warnings and Precautions]

4. Interstitial Lung Disease (ILD)/Non-infectious Pneumonitis [see Warnings and Precautions]

Specific adverse reactions are listed in the table below:

*Grouped term. 1 Hepatotoxicity includes mixed hepatocellular injury, increased blood alkaline phosphatase, increased alanine aminotransferase, increased aspartate aminotransferase, abnormal liver function tests, increased blood bilirubin, and increased conjugated bilirubin.

2 Renal impairment includes acute kidney injury and increased blood creatinine.

[Drug Interactions]

1. Effects of Other Drugs on LuciAda

a. Strong CYP3A4 Inducers

Avoid concomitant use of LuciAda with strong CYP3A inducers.

Adagrasib is a CYP3A4 substrate. Concomitant use of LuciAda with strong CYP3A inducers decreases adagrasib exposure [see Clinical Pharmacology (12.3)], which may reduce the efficacy of LuciAda.

b. Strong CYP3A4 Inhibitors

Avoid concomitant use of LuciAda with strong CYP3A inhibitors until adagrasib concentrations have reached steady state (approximately 8 days).

Adagrasib is a CYP3A4 substrate. If adagrasib concentrations have not yet reached steady state, concomitant use of strong CYP3A inhibitors will increase adagrasib concentrations [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions with LuciAda.

2. Effects of LuciAda on Other Drugs

a. Sensitive CYP3A Substrates

Avoid concomitant use of LuciAda with sensitive CYP3A substrates unless otherwise recommended in the prescribing information for those substrates.

Adagrasib is a CYP3A inhibitor. Concomitant use with LuciAda increases the exposure of CYP3A substrates, which may increase the risk of adverse reactions associated with those substrates.

b. Sensitive CYP2C9 Substrates

Avoid concomitant use of LuciAda with sensitive CYP2C9 substrates for which minimal changes in concentration may lead to serious adverse reactions, unless otherwise recommended in the prescribing information for those substrates.

Adagrasib is a CYP2C9 inhibitor. Concomitant use with LuciAda increases exposure to CYP2C9 substrates, which may increase the risk of adverse reactions associated with these substrates.

c. Sensitive CYP2D6 Substrates

Avoid concomitant use of LuciAda with sensitive CYP2D6 substrates—where minimal changes in concentration may lead to serious adverse reactions—unless otherwise recommended in the prescribing information for those substrates.

Adagrasib is a CYP2D6 inhibitor. Concomitant use with LuciAda increases exposure to CYP2D6 substrates, which may increase the risk of adverse reactions associated with these substrates.

d. P-gp Substrates

Avoid concomitant use of LuciAda with P-gp substrates—where minimal changes in concentration may lead to serious adverse reactions—unless otherwise recommended in the prescribing information for those substrates.

Adagrasib is a P-gp inhibitor. Concomitant use with LuciAda increases exposure to P-gp substrates, which may increase the risk of adverse reactions associated with these substrates.

3. Drugs Known to Prolong the QTc Interval

Avoid concomitant use of LuciAda with other products known to prolong the QTc interval. If concomitant use cannot be avoided, monitor ECGs and electrolytes prior to initiating LuciAda treatment, during concomitant use, and as clinically indicated [see Warnings and Precautions]. Discontinue LuciAda if the QTc interval is > 500 ms or the change from baseline is > 60 ms [see Dosage and Administration].

Adagrasib can cause QTc interval prolongation. Concomitant use of LuciAda with other products known to prolong the QTc interval may result in significant QTc interval prolongation and adverse reactions associated with QTc interval prolongation, including Torsades de Pointes, other serious arrhythmias, and sudden death [see Warnings and Precautions].

[Use in Specific Populations]

1. Pregnancy

Risk Summary

There are no available data on the use of LuciAda in pregnant women. In animal reproduction studies, oral administration of adagrasib to pregnant rats and rabbits during organogenesis—at exposures lower than those in humans (at the recommended dose of 600 mg twice daily)—did not result in adverse developmental effects or embryo-fetal mortality (see Data).

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.

Data

Animal Data

In an embryo-fetal development study in rats, oral administration of adagrasib once daily to pregnant rats during organogenesis at a dose level of 270 mg/kg (based on body surface area [BS