TY - JOUR
T1 - A Single-arm, Multicenter, Phase 2 Study of Lenvatinib Plus Everolimus in Patients with Advanced Non-Clear Cell Renal Cell Carcinoma
AU - Hutson, Thomas E.
AU - Michaelson, M. Dror
AU - Kuzel, Timothy M.
AU - Agarwal, Neeraj
AU - Molina, Ana M.
AU - Hsieh, James J.
AU - Vaishampayan, Ulka N.
AU - Xie, Ran
AU - Bapat, Urmi
AU - Ye, Weifei
AU - Jain, Rohit K.
AU - Fishman, Mayer N.
N1 - Funding Information:
Funding/Support and role of the sponsor: This study was funded by Eisai Inc. , Woodcliff Lake, NJ, USA , and Merck Sharp & Dohme Corp. , a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Eisai Inc. offered input towards the design and conduct of the study; and participated in the collection, management, and analysis of the data. Both sponsors (Eisai Inc. and Merck Sharp & Dohme Corp, a subsidiary of Merck & Co., Kenilworth, NJ, USA) participated in interpretation of the data; and in the preparation, review, and approval of the manuscript. However, the academic authors and lead/senior authors had full access to the data and control of the final approval and decision to submit the manuscript. Medical writing support was provided by Tarah M. Connolly, PhD of Oxford PharmaGenesis Inc, Newtown, PA, USA, and funded by Eisai Inc. and Merck Sharp & Dohme Corp, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Funding Information:
Financial disclosures: Thomas E. Hutson certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Thomas E. Hutson has acted in a consulting or advisory role for Bayer/Onyx, Pfizer, Novartis, J&J, BMS, Astellas Pharma, Eisai, and Exelixis; has participated in speaker bureaus for Pfizer, J&J, Eisai, Exelixis, Astellas Pharma, and BMS; has received honoraria from Pfizer, Astellas Pharma, BMS, Exelixis, Eisai, Novartis, J&J, and Bayer/Onyx; and has received research funding from Pfizer, J&J, Exelixis, Eisai, and BMS. M. Dror Michaelson has an immediate family member employed by Cullinan Oncology; has acted in a consulting or advisory role for Exelixis, Novartis, Pfizer, and Merck; has an immediate family member with stock or other ownership interests in Jounce Therapeutics; has received honoraria from Pfizer, Exelixis, and Merck; and has received research funding from Pfizer, Eisai, Exelixis, and Millennium. Timothy M. Kuzel has received honoraria from Merck, Tyme, and Amgen; has acted in a consulting or advisory role for Novartis, Janssen, Eisai, Cardinal Health, BMS, Seattle Genetics, Pfizer, and Array BioPharma; has received research funding from Eisai, NCI, and the Prostate Cancer Foundation; and has participated in a speaker bureau for Sanofi Aventis. Neeraj Agarwal has acted in a consulting or advisory role for Astellas, Astra Zeneca, Bayer, Bristol Myers Squibb, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Janssen, Merck, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics; and has received institutional research funding from AstraZeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, GlaxoSmithKline, Immunomedics, Janssen, Medivation, Merck, Nektar, New Link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon. Ana M. Molina has acted in a consulting or advisory role for Eisai, Exelixis, Novartis, and Janssen; and has received honoraria from ASCO. James J. Hsieh has acted in a consulting or advisory role for Eisai and BostonGene; and has received research funding from BMS, Merck, AstraZeneca, Exelixis, SillaJen, and BostonGene. Ulka N. Vaishampayan has acted in a consulting or advisory role for BMS, Eisai, Pfizer, Exelixis, Bayer, Merck, and Alkermes; has received honoraria from Bayer, Sanofi, BMS, and Exelixis; and has received research funding from Astellas Pharma, Exelixis, and BMS. Ran Xie and Weifei Ye are employed by Eisai. Urmi Bapat is employed by Eisai and has stock or other ownership interests in BMS. Rohit K. Jain has acted in a consulting or advisory role for Pfizer and Taiho Oncology (immediate family member); has received honoraria from DAVA Oncology; and has participated in speaker bureaus for Astellas/Seattle Genetics. Mayer N. Fishman has acted in a consulting or advisory role for Novartis, Pfizer, Eisai, Merck, Clinigen, and Merck KgA; has participated in speaker bureaus for or been paid for presentation by Exelixis, Ipsen, Medivation, EMD Serono, and BMS; has received research funding from Prometheus/Clinigen, Argos Therapeutics, Genentech/Roche, AstraZeneca, Alkermes, Eisai, Merck, Nektar, Pfizer, BMS, and Acceleron Pharma; and holds an interest in patent #10,300,245 held by the Moffitt Cancer Center.
Publisher Copyright:
© 2021 The Authors
PY - 2021/8
Y1 - 2021/8
N2 - Background: Non-clear cell renal cell carcinoma (nccRCC) accounts for ≤20% of RCC cases. Lenvatinib (a multitargeted tyrosine kinase inhibitor) in combination with everolimus (an mTOR inhibitor) is approved for the treatment of advanced RCC after one prior antiangiogenic therapy. Objective: To determine the safety and efficacy of lenvatinib plus everolimus as a first-line treatment for patients with advanced nccRCC. Design, setting, and participants: This open-label, single-arm, multicenter, phase 2 study enrolled patients with unresectable advanced or metastatic nccRCC and no prior anticancer therapy for advanced disease. Intervention: Lenvatinib (18 mg) plus everolimus (5 mg) orally once daily. Outcome measurements and statistical analysis: The primary endpoint was the objective response rate (ORR) as assessed by investigators according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety assessments. The 95% confidence intervals (CIs) for ORRs were calculated using the two-sided Clopper-Pearson method. Median PFS and median OS were estimated using the Kaplan-Meier product-limit method and their 95% CIs were estimated via a generalized Brookmeyer and Crowley method. Results and limitations: The study (start date: February 20, 2017) enrolled 31 patients with nccRCC (papillary, n = 20; chromophobe, n = 9; unclassified, n = 2). At the data cutoff date (July 17, 2019), the best overall response was a partial response (eight patients: papillary, n = 3; chromophobe, n = 4; unclassified, n = 1) for an overall ORR of 26% (95% CI 12–45). Median PFS was 9.2 mo (95% CI 5.5–not estimable), and median OS was 15.6 mo (95% CI 9.2–not estimable). The most common treatment-emergent adverse events were fatigue (71%), diarrhea (58%), decreased appetite (55%), nausea (55%), and vomiting (52%). Limitations include the small sample size and single-arm design. Conclusions: Lenvatinib plus everolimus showed promising anticancer activity in patients with advanced nccRCC with an ORR of 26% and is worthy of further study. The safety profile was consistent with the established profile of the study-drug combination. Patient summary: We examined the combination of lenvatinib plus everolimus as the first therapy for 31 patients who had advanced nccRCC. We found that this treatment seemed effective, because most patients had a decrease in tumor size and manageable treatment-related side effects. Clinical registration: This trial is registered at ClinicalTrials.Gov as NCT02915783.
AB - Background: Non-clear cell renal cell carcinoma (nccRCC) accounts for ≤20% of RCC cases. Lenvatinib (a multitargeted tyrosine kinase inhibitor) in combination with everolimus (an mTOR inhibitor) is approved for the treatment of advanced RCC after one prior antiangiogenic therapy. Objective: To determine the safety and efficacy of lenvatinib plus everolimus as a first-line treatment for patients with advanced nccRCC. Design, setting, and participants: This open-label, single-arm, multicenter, phase 2 study enrolled patients with unresectable advanced or metastatic nccRCC and no prior anticancer therapy for advanced disease. Intervention: Lenvatinib (18 mg) plus everolimus (5 mg) orally once daily. Outcome measurements and statistical analysis: The primary endpoint was the objective response rate (ORR) as assessed by investigators according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety assessments. The 95% confidence intervals (CIs) for ORRs were calculated using the two-sided Clopper-Pearson method. Median PFS and median OS were estimated using the Kaplan-Meier product-limit method and their 95% CIs were estimated via a generalized Brookmeyer and Crowley method. Results and limitations: The study (start date: February 20, 2017) enrolled 31 patients with nccRCC (papillary, n = 20; chromophobe, n = 9; unclassified, n = 2). At the data cutoff date (July 17, 2019), the best overall response was a partial response (eight patients: papillary, n = 3; chromophobe, n = 4; unclassified, n = 1) for an overall ORR of 26% (95% CI 12–45). Median PFS was 9.2 mo (95% CI 5.5–not estimable), and median OS was 15.6 mo (95% CI 9.2–not estimable). The most common treatment-emergent adverse events were fatigue (71%), diarrhea (58%), decreased appetite (55%), nausea (55%), and vomiting (52%). Limitations include the small sample size and single-arm design. Conclusions: Lenvatinib plus everolimus showed promising anticancer activity in patients with advanced nccRCC with an ORR of 26% and is worthy of further study. The safety profile was consistent with the established profile of the study-drug combination. Patient summary: We examined the combination of lenvatinib plus everolimus as the first therapy for 31 patients who had advanced nccRCC. We found that this treatment seemed effective, because most patients had a decrease in tumor size and manageable treatment-related side effects. Clinical registration: This trial is registered at ClinicalTrials.Gov as NCT02915783.
KW - Chromophobe
KW - Everolimus
KW - First-line treatment
KW - Lenvatinib
KW - Non-clear cell renal cell carcinoma
KW - Papillary
UR - http://www.scopus.com/inward/record.url?scp=85104345130&partnerID=8YFLogxK
U2 - 10.1016/j.eururo.2021.03.015
DO - 10.1016/j.eururo.2021.03.015
M3 - Article
C2 - 33867192
AN - SCOPUS:85104345130
SN - 0302-2838
VL - 80
SP - 162
EP - 170
JO - European Urology
JF - European Urology
IS - 2
ER -