TY - JOUR
T1 - A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma
T2 - a randomised, open-label, phase 2 trial
AU - Pal, Sumanta K.
AU - Tangen, Catherine
AU - Thompson, Ian M.
AU - Balzer-Haas, Naomi
AU - George, Daniel J.
AU - Heng, Daniel Y.C.
AU - Shuch, Brian
AU - Stein, Mark
AU - Tretiakova, Maria
AU - Humphrey, Peter
AU - Adeniran, Adebowale
AU - Narayan, Vivek
AU - Bjarnason, Georg A.
AU - Vaishampayan, Ulka
AU - Alva, Ajjai
AU - Zhang, Tian
AU - Cole, Scott
AU - Plets, Melissa
AU - Wright, John
AU - Lara, Primo N.
N1 - Funding Information:
SWOG 1500 was supported by NIH/National Cancer Institute grants CA180888, CA180819, CA180820, CA180821, CA180863, and CA180868. UV was affiliated with Wayne State University (Detroit, MI, USA) during the conduct of the trial.
Funding Information:
SKP reports personal fees from Genentech, Aveo, Eisai, Roche, Pfizer, Novartis, Exelixis, Ipsen, Bristol Myers Squibb, and Astellas, outside the submitted work. IMTJ reports grants from SWOG—National Institutes of Health (NIH)/NCI grant, during the conduct of the study. NB-H reports personal fees from Exelixis, outside the submitted work. DJG reports personal fees from the American Association for Cancer Research, Axess Oncology, Bristol Myers Squibb, Capio Biosciences, Constellation Pharmaceuticals, EMD Serono, Flatrion, Ipsen, Merck, Michael J Hennessey Assoc, Millennium Medical Publishing, Modra Pharmaceitucals, Myovant Sciences, NCI Genitourinary SC member, Nektar Therapeutics, Physician Education Resource, Propella TX, UroGPO, and Vizuri Health Sciences; grants from Calithera and Novartis; grants and personal fees from Astellas, AstraZeneca, Janssen Pharmaceuticals, and Pfizer; personal fees and other support from Bayer and UroToday; and grants, personal fees, and other support from Exelixis and Sanofi, outside the submitted work. DYCH reports grants from the Canadian Clinical Trials Group during the conduct of the study; personal fees from Pfizer, Ipsen, AstraZeneca, Bristol Myers Squibb, and Merck, outside the submitted work. MS reports grants from Janssen Oncology, Advaxis, Harpoon, Bristol Myers Squibb, Genocea Biosciences, Lilly, Nektar, Tmunity Therapeutics, and Exelixis; personal fees from Merck Sharp & Dohme; and grants and personal fees from Xencor, outside the submitted work. VN reports grants and personal fees from Pfizer and Janssen; grants from Merck and Bristol Myers Squibb; and personal fees from Myovant Sciences and Regeneron, outside the submitted work. GAB reports personal fees from Pfizer, Bristol Myers Squibb, Ipsen, and Merck, outside the submitted work. UV reports grants and personal fees from Bristol Myers Squibb, Exelixis, Alkermes, and Merck; and personal fees from Bayer, Sanofi, and Pfizer, outside the submitted work. AAl reports grants and personal fees from AstraZeneca, and personal fees from Pfizer, outside the submitted work. TZ reports grants from Acerta, Novartis, Merrimack, AbbVie/Stemcentrx, Regeneron, Mirati Therapeutics, Omniseq, and PGDx; personal fees from Genentech Roche, Exelixis, Amgen, Bristol Myers Squibb, Sanofi-Aventis, Pharmacyclics, Foundation Medicine, MJH Life Sciences, Calithera Biosciences, Dendreon, and Nanorobotics; grants and personal fees from Merck, Janssen, AstraZeneca, Pfizer, and SeaGen; and other support from Capio Biosciences and Archimmune Therapeutics, outside the submitted work. All other authors declare no competing interests.
Funding Information:
SWOG 1500 was supported by NIH/National Cancer Institute grants CA180888, CA180819, CA180820, CA180821, CA180863, and CA180868. UV was affiliated with Wayne State University (Detroit, MI, USA) during the conduct of the trial.
Publisher Copyright:
© 2021 Elsevier Ltd
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/2/20
Y1 - 2021/2/20
N2 - Background: MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic PRCC exists, we aimed to compare an existing standard of care, sunitinib, with the MET kinase inhibitors cabozantinib, crizotinib, and savolitinib for treatment of patients with PRCC. Methods: We did a randomised, open-label, phase 2 trial done in 65 centres in the USA and Canada. Eligible patients were aged 18 years or older with metastatic PRCC who had received up to one previous therapy (excluding vascular endothelial growth factor-directed and MET-directed agents). Patients were randomly assigned to receive sunitinib, cabozantinib, crizotinib, or savolitinib, with stratification by receipt of previous therapy and PRCC subtype. All drug doses were administered orally: sunitinib 50 mg, 4 weeks on and 2 weeks off (dose reductions to 37·5 mg and 25 mg allowed); cabozantinib 60 mg daily (reductions to 40 mg and 20 mg allowed); crizotinib 250 mg twice daily (reductions to 200 mg twice daily and 250 mg once daily allowed); and savolitinib 600 mg daily (reductions to 400 mg and 200 mg allowed). Progression-free survival (PFS) was the primary endpoint. Analyses were done in an intention-to-treat population, with patients who did not receive protocol therapy excluded from safety analyses. This trial is registered with ClinicalTrials.gov, NCT02761057. Findings: Between April 5, 2016, and Dec 15, 2019, 152 patients were randomly assigned to one of four study groups. Five patients were identified as ineligible post-randomisation and were excluded from these analyses, resulting in 147 eligible patients. Assignment to the savolitinib (29 patients) and crizotinib (28 patients) groups was halted after a prespecified futility analysis; planned accrual was completed for both sunitinib (46 patients) and cabozantinib (44 patients) groups. PFS was longer in patients in the cabozantinib group (median 9·0 months, 95% CI 6–12) than in the sunitinib group (5·6 months, 3–7; hazard ratio for progression or death 0·60, 0·37–0·97, one-sided p=0·019). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p=0·010). Savolitinib and crizotinib did not improve PFS compared with sunitinib. Grade 3 or 4 adverse events occurred in 31 (69%) of 45 patients receiving sunitinib, 32 (74%) of 43 receiving cabozantinib, ten (37%) of 27 receiving crizotinib, and 11 (39%) of 28 receiving savolitinib; one grade 5 thromboembolic event was recorded in the cabozantinib group. Interpretation: Cabozantinib treatment resulted in significantly longer PFS compared with sunitinib in patients with metastatic PRCC. Funding: National Institutes of Health and National Cancer Institute.
AB - Background: MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic PRCC exists, we aimed to compare an existing standard of care, sunitinib, with the MET kinase inhibitors cabozantinib, crizotinib, and savolitinib for treatment of patients with PRCC. Methods: We did a randomised, open-label, phase 2 trial done in 65 centres in the USA and Canada. Eligible patients were aged 18 years or older with metastatic PRCC who had received up to one previous therapy (excluding vascular endothelial growth factor-directed and MET-directed agents). Patients were randomly assigned to receive sunitinib, cabozantinib, crizotinib, or savolitinib, with stratification by receipt of previous therapy and PRCC subtype. All drug doses were administered orally: sunitinib 50 mg, 4 weeks on and 2 weeks off (dose reductions to 37·5 mg and 25 mg allowed); cabozantinib 60 mg daily (reductions to 40 mg and 20 mg allowed); crizotinib 250 mg twice daily (reductions to 200 mg twice daily and 250 mg once daily allowed); and savolitinib 600 mg daily (reductions to 400 mg and 200 mg allowed). Progression-free survival (PFS) was the primary endpoint. Analyses were done in an intention-to-treat population, with patients who did not receive protocol therapy excluded from safety analyses. This trial is registered with ClinicalTrials.gov, NCT02761057. Findings: Between April 5, 2016, and Dec 15, 2019, 152 patients were randomly assigned to one of four study groups. Five patients were identified as ineligible post-randomisation and were excluded from these analyses, resulting in 147 eligible patients. Assignment to the savolitinib (29 patients) and crizotinib (28 patients) groups was halted after a prespecified futility analysis; planned accrual was completed for both sunitinib (46 patients) and cabozantinib (44 patients) groups. PFS was longer in patients in the cabozantinib group (median 9·0 months, 95% CI 6–12) than in the sunitinib group (5·6 months, 3–7; hazard ratio for progression or death 0·60, 0·37–0·97, one-sided p=0·019). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p=0·010). Savolitinib and crizotinib did not improve PFS compared with sunitinib. Grade 3 or 4 adverse events occurred in 31 (69%) of 45 patients receiving sunitinib, 32 (74%) of 43 receiving cabozantinib, ten (37%) of 27 receiving crizotinib, and 11 (39%) of 28 receiving savolitinib; one grade 5 thromboembolic event was recorded in the cabozantinib group. Interpretation: Cabozantinib treatment resulted in significantly longer PFS compared with sunitinib in patients with metastatic PRCC. Funding: National Institutes of Health and National Cancer Institute.
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U2 - 10.1016/S0140-6736(21)00152-5
DO - 10.1016/S0140-6736(21)00152-5
M3 - Article
C2 - 33592176
AN - SCOPUS:85100894384
VL - 397
SP - 695
EP - 703
JO - The Lancet
JF - The Lancet
SN - 0140-6736
IS - 10275
ER -