Clinical Trial Information for GAVRETO

Study design in the RET+ advanced thyroid cancer population1,29

Efficacy and safety with GAVRETO (400 mg orally once daily) were evaluated in patients with advanced or metastatic RET fusion+ thyroid cancer in the ARROW study, a phase 1/2, nonrandomized, open-label, single-arm, multicohort, multicenter clinical trial. All patients with RET fusion-positive thyroid cancer were required to have disease progression following standard therapy and measurable disease by RECIST. All patients must also have had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1.

The major efficacy outcome measures were overall response rate (ORR) and duration of response (DoR), as assessed by a blinded independent central review (BICR) according to RECIST v1.1.

RECIST=Response Evaluation Criteria in Solid Tumors; RET+=rearranged during transfection positive.

GAVRETO was studied in patients with RET+ advanced thyroid cancers1

RET fusion-positive thyroid cancer (n=9)*
Median age
(range), years		GenderRace/
ethnicity		ECOG
status		History of CNS
metastases at
baseline		Patient
identification
61 years
(46-74)		33% female
67% male		78% White
22% Asian
11% Hispanic/
Latino		0-1: 100%56%89% NGS
11% FISH

*All patients had papillary thyroid cancer. All patients had metastatic disease. Patients had received a median of 2 prior therapies (range 1-8). Prior systemic treatments included prior radioactive iodine (100%) and prior sorafenib and/or lenvatinib (56%).
CNS=central nervous system; FISH=fluorescence in situ hybridization; NGS=next-generation sequencing.

Clinical Results for GAVRETO

Efficacy results with GAVRETO in advanced or metastatic RET fusion+ thyroid cancer1,31

Overall Response Rate (n=9)

89% ORR

89% ORR

(95% CI: 52%-100%)

Duration of and Time to Response (n=8)1,31

Median DOR Not Reached
  • 100% of patients continued to respond to treatment at 6 months*
  • Median time to first response was 1.9 months
    (range: 1.8 months-5.5 months)31,34

Patients enrolled by July 11, 2019. Data cutoff: May 22, 2020.
*Based on observed duration of response.
NE=not estimable; NR=not reached.

Disease control rates in RET fusion+ thyroid cancer34

Disease control rate (DCR), a prespecified secondary endpoint, was assessed in the subsets of patients in the efficacy populations with sufficient evidence of a RET rearrangement and baseline measurable disease confirmed on blinded independent central review. DCR is defined as ORR (CR + PR) + SD.34

  • Stable disease (SD) is defined as neither sufficient shrinkage to qualify for PR or CR nor sufficient increase to qualify for progressive disease (PD), per RECIST v1.133,34
  • Importantly, SD can reflect the natural history of the disease and may not be due to a direct therapeutic effect. Therefore, please interpret these results with caution

All (n=9)

100% DCR bar chart

Patients enrolled by July 11, 2019. Data cutoff: May 22, 2020.

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References:

 

1. GAVRETO® [Package insert], South San Francisco, CA: Rigel Pharmaceuticals, Inc.

 

29. Phase 1/2 study of the highly-selective RET inhibitor, pralsetinib (BLU-667), in participants with thyroid cancer, non-small cell lung cancer, and other advanced solid tumors (ARROW). https://clinicaltrials.gov/ct2/show/NCT03037385. Accessed May 7, 2024.

 

31. GAVRETO: Data on file, Rigel Pharmaceuticals, Inc. June 2024.

 

33. Schwartz LH, Litière S, de Vries E, et al. RECIST 1.1–update and clarification: from the RECIST committee. Eur J Cancer. 2016;62:132-137.

 

34. Subbiah V, Hu M, Wirth LJ, et al. Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study. Lancet Diabetes Endocrinol. 2021:S2213-8587(21)00120-0. doi:10.1016/S2213-8587(21)00120-0.

Indications & Important Safety Information

INDICATIONS

GAVRETO (pralsetinib) is indicated for the treatment of:

  • Adult patients with metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA-approved test
  • 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

IMPORTANT SAFETY INFORMATION

Interstitial Lung Disease (ILD)/Pneumonitis: Severe, life-threatening, and fatal ILD/pneumonitis can occur in patients treated with GAVRETO. Pneumonitis occurred in 12% of patients who received GAVRETO, including 3.3% with Grade 3-4, and 0.2% with fatal reactions. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Withhold GAVRETO and promptly investigate for ILD in any patient who presents with acute or worsening of respiratory symptoms (e.g., dyspnea, cough, and fever). Withhold, reduce dose or permanently discontinue GAVRETO based on severity of confirmed ILD.

Hypertension: Occurred in 35% of patients, including Grade 3 hypertension in 18% of patients. Overall, 8% had their dose interrupted and 4.8% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications. Do not initiate GAVRETO in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating GAVRETO. Monitor blood pressure after 1 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue GAVRETO based on the severity.

Hepatotoxicity: Serious hepatic adverse reactions occurred in 1.5% of patients treated with GAVRETO. Increased aspartate aminotransferase (AST) occurred in 49% of patients, including Grade 3 or 4 in 7% and increased alanine aminotransferase (ALT) occurred in 37% of patients, including Grade 3 or 4 in 4.8%. The median time to first onset for increased AST was 15 days (range: 5 days to 2.5 years) and increased ALT was 24 days (range: 7 days to 3.7 years). Monitor AST and ALT prior to initiating GAVRETO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose or permanently discontinue GAVRETO based on severity.

Hemorrhagic Events: Serious, including fatal, hemorrhagic events can occur with GAVRETO. Grade ≥3 events occurred in 4.1% of patients treated with GAVRETO including one patient with a fatal hemorrhagic event. Permanently discontinue GAVRETO in patients with severe or life-threatening hemorrhage.

Tumor Lysis Syndrome (TLS): Cases of TLS have been reported in patients with medullary thyroid carcinoma receiving GAVRETO. Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as clinically indicated.

Risk of Impaired Wound Healing: Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, GAVRETO has the potential to adversely affect wound healing. Withhold GAVRETO for at least 5 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of GAVRETO after resolution of wound healing complications has not been established.

Embryo-Fetal Toxicity: Based on findings from animal studies and its mechanism of action, GAVRETO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with GAVRETO and for 2 weeks after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with GAVRETO and for 1 week after the last dose.

Common adverse reactions (≥25%) were musculoskeletal pain, constipation, hypertension, diarrhea, fatigue, edema, pyrexia, and cough. Common Grade 3/4 laboratory abnormalities (≥2%) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased leukocytes, decreased sodium, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased calcium (corrected), decreased platelets, increased alkaline phosphatase, increased potassium, decreased potassium, and increased bilirubin.

Avoid coadministration of GAVRETO with strong or moderate CYP3A inhibitors, P-gp inhibitors, or combined P-gp and strong or moderate CYP3A inhibitors. If coadministration cannot be avoided, reduce the GAVRETO dose. Avoid coadministration of GAVRETO with strong or moderate CYP3A inducers. If coadministration cannot be avoided, increase the GAVRETO dose.

Lactation: Advise women not to breastfeed during treatment with GAVRETO and for 1 week after the last dose.

Pediatric Use: Monitor open growth plates in adolescent patients. Consider interrupting or discontinuing GAVRETO if abnormalities occur.

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please click here to see the full Prescribing Information and Patient Information for GAVRETO.