Gavreto

GAVRETO- pralsetinib capsule
Genentech, Inc.

1 INDICATIONS AND USAGE

1.1 Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer

GAVRETO is indicated for the treatment of adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA approved test.

This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.1)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

1.2 RET -Mutant Medullary Thyroid Cancer

GAVRETO is indicated for the treatment of adult and pediatric patients 12 years of age and older with advanced or metastatic RET -mutant medullary thyroid cancer (MTC) who require systemic therapy.

This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.2)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

1.3 RET Fusion-Positive Thyroid Cancer

GAVRETO is indicated for the treatment of adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).

This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.3)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection

Select patients for treatment with GAVRETO based on the presence of a RET gene fusion (NSCLC or thyroid cancer) or RET gene mutation (MTC) [see Clinical Studies (14)].

Information on FDA-approved tests for RET gene fusion (NSCLC) is available at http://www.fda.gov/CompanionDiagnostics.

An FDA-approved test for the detection of RET gene fusion (thyroid cancer) and RET gene mutations is not currently available.

2.2 Recommended Dosage

The recommended dosage of GAVRETO is 400 mg orally once daily on an empty stomach (no food intake for at least 2 hours before and at least 1 hour after taking GAVRETO) [see Clinical Pharmacology (12.3)]. Continue treatment until disease progression or until unacceptable toxicity.

If a dose of GAVRETO is missed, it can be taken as soon as possible on the same day. Resume the regular daily dose schedule for GAVRETO the next day.

Do not take an additional dose if vomiting occurs after GAVRETO but continue with the next dose as scheduled.

2.3 Dosage Modifications for Adverse Reactions

The recommended dose reductions and dosage modifications for adverse reactions are provided in Table 1 and Table 2.

Table 1: Recommended Dose Reductions for GAVRETO for Adverse Reactions

Dose Reduction	Recommended Dosage
First	300 mg once daily
Second	200 mg once daily
Third	100 mg once daily

Permanently discontinue GAVRETO in patients who are unable to tolerate 100 mg taken orally once daily.

The recommended dosage modifications for adverse reactions are provided in Table 2.

Table 2: Recommended Dosage Modifications for GAVRETO for Adverse Reactions

Adverse Reaction	Severity *	Dosage Modification
* Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03
ILD/Pneumonitis [see Warnings and Precautions (5.1)]	Grade 1 or 2	Withhold GAVRETO until resolution. Resume by reducing the dose as shown in Table 1.
		Permanently discontinue GAVRETO for recurrent ILD/pneumonitis.
	Grade 3 or 4	Permanently discontinue for confirmed ILD/pneumonitis.
Hypertension [see Warnings and Precautions (5.2)]	Grade 3	Withhold GAVRETO for Grade 3 hypertension that persists despite optimal antihypertensive therapy. Resume at a reduced dose when hypertension is controlled.
	Grade 4	Discontinue GAVRETO.
Hepatotoxicity [see Warnings and Precautions (5.3)]	Grade 3 or 4	Withhold GAVRETO and monitor AST/ALT once weekly until resolution to Grade 1 or baseline.
		Resume at reduced dose (Table 1).
		If hepatotoxicity recurs at Grade 3 or higher, discontinue GAVRETO.
Hemorrhagic Events [see Warnings and Precautions (5.4)]	Grade 3 or 4	Withhold GAVRETO until recovery to baseline or Grade 0 or 1.
		Discontinue GAVRETO for severe or life-threatening hemorrhagic events.
Other Adverse Reactions [see Adverse Reactions (6.1)]	Grade 3 or 4	Withhold GAVRETO until improvement to ≤ Grade 2. Resume at reduced dose (Table 1).
		Permanently discontinue for recurrent Grade 4 adverse reactions.

2.4 Dose Modification for Use with Combined P-glycoprotein (P-gp) and Strong CYP3A Inhibitors

Avoid coadministration of GAVRETO with known combined P-gp and strong CYP3A inhibitors. If coadministration with a combined P-gp and strong CYP3A inhibitor cannot be avoided, reduce the current dose of GAVRETO as recommended in Table 3. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume GAVRETO at the dose taken prior to initiating the combined P-gp and strong CYP3A inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Table 3: Recommended Dosage Modifications for GAVRETO for Coadministration with Combined P-gp and Strong CYP3A Inhibitors

Current GAVRETO Dosage	Recommended GAVRETO Dosage
400 mg orally once daily	200 mg orally once daily
300 mg orally once daily	200 mg orally once daily
200 mg orally once daily	100 mg orally once daily