Lenvatinib in combination with everolimus in patients with advanced or metastatic renal cell carcinoma: A phase 1 study

Matsubara, Nobuaki; Naito, Yoichi; Nakano, Kenji; Fujiwara, Yutaka; Ikezawa, Hiroki; Yusa, Wataru; Namiki, Masayuki; Okude, Takashi; Takahashi, Shunji

doi:10.1111/iju.13776

Cited by 15 publications

(17 citation statements)

References 26 publications

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“…TRAEs in this study were consistent with the typical class effects of VEGFR and mTOR inhibitors without new safety signals. The grade 3/4 AEs for sunitinib included increased lipase (13%), lymphopenia (12%), neutropenia (11%), hypertension (8%), fatigue (7%), diarrhea (5%), hand-foot syndrome (5%), vomiting (4%) [54], renal AEs were not common in everolimus plus sunitinib [26]. With similar structural features of sunitinib, renal toxicity was also not frequently seen in our study with the exception of proteinuria.…”

Section: Discussionsupporting

confidence: 49%

Phase 1 trial of vorolanib (CM082) in combination with everolimus in patients with advanced clear-cell renal cell carcinoma

et al. 2020

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Background: Vorolanib (X-82, CM082) is a multi-target tyrosine kinase inhibitor. This study aimed to evaluate the tolerability, safety, pharmacokinetics and antitumor activities of vorolanib plus everolimus (an inhibitor of mammalian target of rapamycin). Methods: Patients had histologically or cytologically confirmed advanced RCC and failed with standard therapy were eligible for this study. Dose-escalated combinations of vorolanib (100, 150 or 200 mg once daily) with everolimus (5 mg once daily) were administered on 28-day cycles until disease progression or unacceptable toxicity using a conventional 3 + 3 dose-escalation design. Findings: 22 patients (100 mg n = 4, 150 mg n = 3, 200 mg n = 15) were enrolled. Only one patient experienced dose-limiting toxicity (DLT, grade 4 thrombocytopenia) in the vorolanib 200 mg combination cohort, and the maximum tolerated dose (MTD) was not reached. The most common treatment-related adverse events were proteinuria (100%), leukopenia (77%), hypercholesterolaemia (77%), increased low-density lipoprotein (68%), hypertriglyceridaemia (64%), hyperglycaemia (59%), and fatigue (55%). Most treatment-related adverse events were grade 1 to 2, with grade 3 or higher toxicities mostly seen in the 200 mg cohort. Single dosing of vorolanib demonstrated dose-proportional increases in the C max and AUC, and observed short t 1/2z ranging from 4.74 §1.44 to 12.89 §7.49 h. The pharmacokinetic parameters for everolimus were similar among all cohorts. Of 19 evaluable patients, the ORR and DCR was 32% (n = 6, 95% CI, 13À57%) and 100% (95% CI, 82À100%), respectively. Interpretation: Combination therapy of vorolanib 200 mg plus everolimus 5 mg once daily is potentially effective with potential activity. Further evaluation of the combination in advanced RCC patients is ongoing (NCT03095040).

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Section: Discussionsupporting

confidence: 49%

Phase 1 trial of vorolanib (CM082) in combination with everolimus in patients with advanced clear-cell renal cell carcinoma

et al. 2020

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“…Everolimus has also been tested in cervical cancer cell lines with a remarkable ability to inactivate efficiently the HPV16 E7 oncoprotein inhibiting cell proliferation (202). The capacity of everolimus-based combinations to inhibit cell proliferation from several cancer types has been reported for breast cancer (203,204), renal cell carcinoma (205,206), and thyroid cancer (207) in clinical trials.…”

Section: Mtorc1 As a Therapeutic Targetmentioning

confidence: 99%

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

et al. 2019

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Continuous proliferation of tumor cells requires constant adaptations of energy metabolism to rapidly fuel cell growth and division. This energetic adaptation often comprises deregulated glucose uptake and lactate production in the presence of oxygen, a process known as the "Warburg effect." For many years it was thought that the Warburg effect was a result of mitochondrial damage, however, unlike this proposal tumor cell mitochondria maintain their functionality, and is essential for integrating a variety of signals and adapting the metabolic activity of the tumor cell. The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of numerous cellular processes implicated in proliferation, metabolism, and cell growth. mTORC1 controls cellular metabolism mainly by regulating the translation and transcription of metabolic genes, such as peroxisome proliferator activated receptor γ coactivator-1 α (PGC-1α), sterol regulatory element-binding protein 1/2 (SREBP1/2), and hypoxia inducible factor-1 α (HIF-1α). Interestingly it has been shown that mTORC1 regulates mitochondrial metabolism, thus representing an important regulator in mitochondrial function. Here we present an overview on the role of mTORC1 in the regulation of mitochondrial functions in cancer, considering new evidences showing that mTORC1 regulates the translation of nucleus-encoded mitochondrial mRNAs that result in an increased ATP mitochondrial production. Moreover, we discuss the relationship between mTORC1 and glutaminolysis, as well as mitochondrial metabolites. In addition, mitochondrial fission processes regulated by mTORC1 and its impact on cancer are discussed. Finally, we also review the therapeutic efficacy of mTORC1 inhibitors in cancer treatments, considering its use in combination with other drugs, with particular focus on cellular metabolism inhibitors, that could help improve their anti neoplastic effect and eliminate cancer cells in patients. de la Cruz López et al. mTORC1 and Mitochondrial Functions Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The handling editor declared a shared affiliation, though no other collaboration, with with several of the authors AG and KC.

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“…The introduction of tyrosine kinase inhibitors and immunotherapies has remarkably improved the survival of mRCC patients. [1][2][3][4][5][6][7][8][9][10][11][12] Randomized studies suggested the efficacy of first-line nivolumab plus ipilimumab in patients belonging to the intermediate-and poor-risk groups of the IMDC. [13][14][15] However, the efficacy and safety of the first-line nivolumab plus ipilimumab for mRCC patients need to be validated in actual practice, 14 and CheckMate 214 trial only enrolled a limited number of Japanese patients.…”

Section: Introductionmentioning

confidence: 99%

“…The introduction of tyrosine kinase inhibitors and immunotherapies has remarkably improved the survival of mRCC patients 1–12 . Randomized studies suggested the efficacy of first‐line nivolumab plus ipilimumab in patients belonging to the intermediate‐ and poor‐risk groups of the IMDC 13–15 .…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of first‐line nivolumab plus ipilimumab in patients with metastatic renal cell carcinoma: A multicenter retrospective study

Tanaka¹,

Hatakeyama²,

Numakura³

et al. 2020

Int J of Urology

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To investigate the efficacy and safety of first-line nivolumab plus ipilimumab for patients treated with metastatic renal cell carcinoma. Methods: We retrospectively evaluated 52 metastatic renal cell carcinoma patients who were treated with nivolumab plus ipilimumab between August 2015 and January 2020. Data on patient characteristics, treatment parameters and adverse events were obtained. Oncological outcomes were assessed according to the International Metastatic Renal Cell Carcinoma Database Consortium prognostic model. Furthermore, differences in treatment parameters between patients with objective response (responders) and non-responders were compared. Results: The median age and follow-up periods were 69 years and 8.2 months, respectively. The 1-year progression-free survival and overall survival rates were 55% and 75%, respectively. The objective response rate was 39%, and it was significantly different between the International Metastatic Renal Cell Carcinoma Database Consortium intermediate-and poor-risk groups (52% vs 24%). We observed 36 (69%) any immunerelated adverse events, and 19 (37%) severe immune-related adverse events (grades III-V). The International Metastatic Renal Cell Carcinoma Database Consortium poor-risk group and higher value of initial C-reactive protein (≥1.0 mg/dL) were significantly associated with non-responders. Patients with two factors (the International Metastatic Renal Cell Carcinoma Database Consortium poor-risk group plus C-reactive protein ≥1.0 mg/dL) had a significantly poor overall survival than those with none or a single factor. Conclusions: In our experience, treatment response to nivolumab plus ipilimumab is comparable with that of the CheckMate 214 clinical trial, but the incidence of treatmentrelated adverse events is lower. The International Metastatic Renal Cell Carcinoma Database Consortium poor-risk group and initial C-reactive protein value might have a prognostic value for poor survival.

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Lenvatinib in combination with everolimus in patients with advanced or metastatic renal cell carcinoma: A phase 1 study

Cited by 15 publications

References 26 publications

Phase 1 trial of vorolanib (CM082) in combination with everolimus in patients with advanced clear-cell renal cell carcinoma

Phase 1 trial of vorolanib (CM082) in combination with everolimus in patients with advanced clear-cell renal cell carcinoma

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

Efficacy and safety of first‐line nivolumab plus ipilimumab in patients with metastatic renal cell carcinoma: A multicenter retrospective study

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