Mechanism of Action (MOA)

In preclinical studies, pralsetinib was designed for potent and selective inhibition of RET1,27

In cellular assays, pralsetinib inhibited RET at approximately 14-, 40-, and 12-fold lower concentrations than VEGFR2, FGFR2, and JAK2, respectively.

Kinome

Pralsetinib exhibited anti-tumor activity in cultured cells and animal tumor implantation models harboring oncogenic RET fusions or mutations, including KIF5B-RET, CCDC6-RET, RET M918T, RET C634W, RET V804E, RET V804L, and RET V804M.

tumor growth

Pralsetinib prolonged survival in mice implanted intracranially with tumor models expressing KIF5B-RET or CCDC6-RET.

ATP=adenosine triphosphate; FGFR2=fibroblast growth factor receptor 2; JAK2=Janus kinase 2; RET=rearranged during transfection; VEGFR2=vascular endothelial growth factor receptor 2.

EXPLORE RET+
mNSCLC DATA
EXPLORE RET+ ADVANCED
THYROID CANCER DATA

Important Safety Information & Indications

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-mutant medullary thyroid cancer (MTC) who require systemic therapy
  • 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)

These indications are approved under accelerated approval based on overall response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMPORTANT SAFETY INFORMATION

Interstitial Lung Disease (ILD)/Pneumonitis occurred in 10% of patients who received GAVRETO, including 2.7% with Grade 3/4, and 0.5% 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 29% of patients, including Grade 3 hypertension in 14% of patients. Overall, 7% had their dose interrupted and 3.2% 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 2.1% of patients treated with GAVRETO. Increased aspartate aminotransferase (AST) occurred in 69% of patients, including Grade 3/4 in 5% and increased alanine aminotransferase (ALT) occurred in 46% of patients, including Grade 3/4 in 6%. The median time to first onset for increased AST was 15 days (range: 5 days to 1.5 years) and increased ALT was 22 days (range: 7 days to 1.7 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.

Grade ≥ 3 hemorrhagic events occurred in 2.5% 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.

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.

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 final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with GAVRETO and for 1 week after the final dose. Advise women not to breastfeed during treatment with GAVRETO and for 1 week after the final dose.

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

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

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555.

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

    • GAVRETO Prescribing Information. Genentech, Inc. February 2022.

      GAVRETO Prescribing Information. Genentech, Inc. February 2022.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.3.2022. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 18, 2022. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.3.2022. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 18, 2022. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Thyroid Carcinoma V.3.2021. © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed October 18, 2021. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Thyroid Carcinoma V.3.2021. © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed October 18, 2021. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • VanderLaan PA, Rangachari D, Costa DB. The rapidly evolving landscape of biomarker testing in non-small cell lung cancer. Cancer Cytopathol. 2021;129(3):179-181.

      VanderLaan PA, Rangachari D, Costa DB. The rapidly evolving landscape of biomarker testing in non-small cell lung cancer. Cancer Cytopathol. 2021;129(3):179-181.

    • Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med. 2018;142(3):321-346.

      Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med. 2018;142(3):321-346.

    • Rolfo C, Mack P, Scagliotti GV, et al. Liquid biopsy for advanced NSCLC: a consensus statement from the International Association for the Study of Lung Cancer. J Thorac Oncol. 2021:S1556-0864(21)02284-X. doi:10.1016/j.jtho.2021.06.017.

      Rolfo C, Mack P, Scagliotti GV, et al. Liquid biopsy for advanced NSCLC: a consensus statement from the International Association for the Study of Lung Cancer. J Thorac Oncol. 2021:S1556-0864(21)02284-X. doi:10.1016/j.jtho.2021.06.017.

    • Drusbosky LM, Rodriguez E, Dawar R, Ikpeazu CV. Therapeutic strategies in RET gene rearranged non-small cell lung cancer. J Hematol Oncol. 2021;14(50):1-8.

      Drusbosky LM, Rodriguez E, Dawar R, Ikpeazu CV. Therapeutic strategies in RET gene rearranged non-small cell lung cancer. J Hematol Oncol. 2021;14(50):1-8.

    • Barlesi F, Mazieres J, Merlio JP, et al. Routine molecular profiling of cancer: results of a one-year nationwide program of the French Cooperative Thoracic Intergroup (IFCT) for advanced non-small cell lung cancer (NSCLC) patients. Lancet. 2016;387(10026):1415-1426. doi:10.1016/S0140-6736(16)00004-0.

      Barlesi F, Mazieres J, Merlio JP, et al. Routine molecular profiling of cancer: results of a one-year nationwide program of the French Cooperative Thoracic Intergroup (IFCT) for advanced non-small cell lung cancer (NSCLC) patients. Lancet. 2016;387(10026):1415-1426. doi:10.1016/S0140-6736(16)00004-0.

    • Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014;311(19):1998-2006.

      Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014;311(19):1998-2006.

    • Solomon BJ, Kim DW, Wu YL, et al. J Clin Oncol. 2018;36(22):2251-2258.

      Solomon BJ, Kim DW, Wu YL, et al. J Clin Oncol. 2018;36(22):2251-2258.

    • Gutierrez ME, Choi K, Lanman RB, et al. Genomic profiling of advanced non–small cell lung cancer in community settings: gaps and opportunities. Clin Lung Cancer. 2017;18(6):651-659.

      Gutierrez ME, Choi K, Lanman RB, et al. Genomic profiling of advanced non–small cell lung cancer in community settings: gaps and opportunities. Clin Lung Cancer. 2017;18(6):651-659.

    • Mazières J, Drilon A, Lusque A. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol. 2019;30(8):1321-1328.

      Mazières J, Drilon A, Lusque A. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol. 2019;30(8):1321-1328.

    • Addeo A, Malapelle U, Luigi Banna G, Subbiah V, Friedlaender A. Immunotherapy in non-small cell lung cancer harbouring driver mutations. Cancer Treat Rev. 2021;96:102179. doi:10.1016/j.ctrv.2021.102179.

      Addeo A, Malapelle U, Luigi Banna G, Subbiah V, Friedlaender A. Immunotherapy in non-small cell lung cancer harbouring driver mutations. Cancer Treat Rev. 2021;96:102179. doi:10.1016/j.ctrv.2021.102179.

    • Chen R, Tao Y, Xu X, et al. Discover Med. 2018;26(143):155-166.

      Chen R, Tao Y, Xu X, et al. Discover Med. 2018;26(143):155-166.

    • Lisberg A, Cummings A, Goldman JW, et al. J Thorac Oncol. 2018;13(8):1138-1145.

      Lisberg A, Cummings A, Goldman JW, et al. J Thorac Oncol. 2018;13(8):1138-1145.

    • Offin M, Guo R, Wu SL, et al. Immunophenotype and response to immunotherapy of RET-rearranged lung cancers. JCO Precis Oncol. 2019;3:PO.18.00386. doi:10.1200/PO.18.00386.

      Offin M, Guo R, Wu SL, et al. Immunophenotype and response to immunotherapy of RET-rearranged lung cancers. JCO Precis Oncol. 2019;3:PO.18.00386. doi:10.1200/PO.18.00386.

    • American Cancer Society. Thyroid Cancer. https://www.cancer.org/cancer/thyroid-cancer/about/what-is-thyroid-cancer.html. Accessed September 15, 2021.

      American Cancer Society. Thyroid Cancer. https://www.cancer.org/cancer/thyroid-cancer/about/what-is-thyroid-cancer.html. Accessed September 15, 2021.

    • National Cancer Institute. Thyroid cancer treatment (adult) (PDQ®)–health professional version. https://www.cancer.gov/types/thyroid/hp/thyroid-treatment-pdq. Accessed September 15, 2021.

      National Cancer Institute. Thyroid cancer treatment (adult) (PDQ®)–health professional version. https://www.cancer.gov/types/thyroid/hp/thyroid-treatment-pdq. Accessed September 15, 2021.

    • Drilon A, Hu ZI, Lai GGY, Tan DSW. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol. 2018;15(3):151-167.

      Drilon A, Hu ZI, Lai GGY, Tan DSW. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol. 2018;15(3):151-167.

    • Kato S, Subbiah V, Marchlik E, Elkin SK, Carter JL, Kurzrock R. RET aberrations in diverse cancers: next generation sequencing of 4,871 patients. Clin Cancer Res. 2017;23(8):1988-1997.

      Kato S, Subbiah V, Marchlik E, Elkin SK, Carter JL, Kurzrock R. RET aberrations in diverse cancers: next generation sequencing of 4,871 patients. Clin Cancer Res. 2017;23(8):1988-1997.

    • Santoro M, Porta GP, Berger N, et al. Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype. J Clin Invest. 1992;89(5):1517-1522.

      Santoro M, Porta GP, Berger N, et al. Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype. J Clin Invest. 1992;89(5):1517-1522.

    • Lee YC, Chen JY, Huang CJ, et al. Detection of NTRK1/3 rearrangements in papillary thyroid carcinoma using immunohistochemistry, fluorescent in situ hybridization, and next-generation sequencing. Endocr Pathol. 2020;31(4):348-358.

      Lee YC, Chen JY, Huang CJ, et al. Detection of NTRK1/3 rearrangements in papillary thyroid carcinoma using immunohistochemistry, fluorescent in situ hybridization, and next-generation sequencing. Endocr Pathol. 2020;31(4):348-358.

    • Panebianco F, Nikitski AV, Nikiforova MN, et al. Characterization of thyroid cancer driven by known and novel ALK fusions. Endocr Relat Cancer. 2019;26(11):803-814.

      Panebianco F, Nikitski AV, Nikiforova MN, et al. Characterization of thyroid cancer driven by known and novel ALK fusions. Endocr Relat Cancer. 2019;26(11):803-814.

    • Prasad ML, Vyas M, Horne MJ, et al. NTRK fusion oncogenes in pediatric papillary thyroid carcinoma in Northeast United States. Cancer. 2016:1097-1107.

      Prasad ML, Vyas M, Horne MJ, et al. NTRK fusion oncogenes in pediatric papillary thyroid carcinoma in Northeast United States. Cancer. 2016:1097-1107.

    • Romei C, Ciampi R, Casella F, et al. RET mutation heterogeneity in primary advanced medullary thyroid cancers and their metastases. Oncotarget. 2018;9(11):9875-9884.

      Romei C, Ciampi R, Casella F, et al. RET mutation heterogeneity in primary advanced medullary thyroid cancers and their metastases. Oncotarget. 2018;9(11):9875-9884.

    • Priya SR, Dravid CS, Digumarti R, Dandekar M. Targeted therapy for medullary thyroid cancer: a review. Front Oncol. 2017;7:238.

      Priya SR, Dravid CS, Digumarti R, Dandekar M. Targeted therapy for medullary thyroid cancer: a review. Front Oncol. 2017;7:238.

    • Subbiah V, Gainor JF, Rahal R. Precision targeted therapy with BLU-667 for RET-driven cancers. Cancer Discov. 2018;8(7):836-849.

      Subbiah V, Gainor JF, Rahal R. Precision targeted therapy with BLU-667 for RET-driven cancers. Cancer Discov. 2018;8(7):836-849.

    • Krampitz GW, Norton JA. RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma. Cancer. 2014;120:1920-1931.

      Krampitz GW, Norton JA. RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma. Cancer. 2014;120:1920-1931.

    • Fulciniti F, Campanile AC, Malzone MG, et al. Impact of ultrasonographic features, cytomorphology and mutational testing on malignant and indeterminate thyroid nodules on diagnostic accuracy of fine needle cytology samples: A prospective analysis of 141 patients. Clin Endocrinol (Oxf). 2019;91(6):851-859.

      Fulciniti F, Campanile AC, Malzone MG, et al. Impact of ultrasonographic features, cytomorphology and mutational testing on malignant and indeterminate thyroid nodules on diagnostic accuracy of fine needle cytology samples: A prospective analysis of 141 patients. Clin Endocrinol (Oxf). 2019;91(6):851-859.

    • Belli C, Penault-Llorca F, Norman N, et al. ESMO recommendations on the standard methods to detect RET fusions and mutations in daily practice and clinical research. Ann Oncol. 2021;32(3):337-350.

      Belli C, Penault-Llorca F, Norman N, et al. ESMO recommendations on the standard methods to detect RET fusions and mutations in daily practice and clinical research. Ann Oncol. 2021;32(3):337-350.

    • US Food & Drug Administration. In: Orange Book: Approved Drug Products With Therapeutic Equivalence Evaluations. https://www.accessdata.fda.gov/scripts/cder/ob/results_product.cfm?Appl_Type=N&Appl_No=213246#37862. Accessed January 23, 2022.

      US Food & Drug Administration. In: Orange Book: Approved Drug Products With Therapeutic Equivalence Evaluations. https://www.accessdata.fda.gov/scripts/cder/ob/results_product.cfm?Appl_Type=N&Appl_No=213246#37862. Accessed January 23, 2022.

    • Hess LM, Han Y, Zhu YE, Bhandari NR, Sireci A. Characteristics and outcomes of patients with RET-fusion positive non-small lung cancer in real-world practice in the United States. BMC Cancer. 2021;21(28):1-12.

      Hess LM, Han Y, Zhu YE, Bhandari NR, Sireci A. Characteristics and outcomes of patients with RET-fusion positive non-small lung cancer in real-world practice in the United States. BMC Cancer. 2021;21(28):1-12.

    • Data on file. Blueprint Medicines Corporation. Cambridge, MA; 2020.

      Data on file. Blueprint Medicines Corporation. Cambridge, MA; 2020.

    • Gainor JF, Curigliano G, Kim DW, et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol. 2021;22(7):959-969.

      Gainor JF, Curigliano G, Kim DW, et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol. 2021;22(7):959-969.

    • 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.

      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.

    • Phase 1/2 study of the highly-selective RET inhibitor, pralsetinib (BLU-667), in patients with thyroid cancer, non-small cell lung cancer, and other advanced solid tumors (ARROW). https://clinicaltrials.gov/ct2/show/NCT03037385. Accessed September 20, 2021.

      Phase 1/2 study of the highly-selective RET inhibitor, pralsetinib (BLU-667), in patients with thyroid cancer, non-small cell lung cancer, and other advanced solid tumors (ARROW). https://clinicaltrials.gov/ct2/show/NCT03037385. Accessed September 20, 2021.

    • Subbiah V, Hu M, Wirith 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.

      Subbiah V, Hu M, Wirith 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.