A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial

Pal, Sumanta K.; Tangen, Catherine M.; Thompson, Ian M.; Balzer-Haas, Naomi; George, Daniel J.; Heng, Daniel Y.C.; Shuch, Brian; Stein, Mark N.; Tretiakova, Maria; Humphrey, Peter A.; Adeniran, Adebowale; Narayan, Vivek; Bjarnason, Georg A.; Vaishampayan, Ulka N.; Alva, Ajjai; Zhang, Tian; Cole, Scott Wesley; Plets, Melissa; Wright, John J.; Lara, Primo N.

doi:10.1016/s0140-6736(21)00152-5

Cited by 181 publications

(153 citation statements)

References 26 publications

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“… 58 Results from the randomized Phase II SWOG 1500 study (NCT02761057) demonstrated that cabozantinib treatment significantly increased PFS when compared to sunitinib in patients with metastatic papillary RCC (9 months with cabozantinib versus 5.6 months with sunitinib; hazard ratio 0.60; 95% confidence interval 0.37–0.97; 1-sided p = 0.019). 59 However, it is highly likely that NCCRCC patients will develop resistance to single-agent cabozantinib, either due to short-term signaling adaptations (e.g., bypass tracks) or longer-term selection of resistance variants (e.g., gatekeeper mutations). Combination studies with cabozantinib need to be considered, and our data suggest that either dasatinib or a MEK inhibitor would be suitable (e.g., cobimetinib, since it is undergoing combination studies in RCC [+azetolizumab, NCT03264066]).…”

Section: Discussionmentioning

confidence: 99%

Cabozantinib and dasatinib synergize to induce tumor regression in non-clear cell renal cell carcinoma

Lue

Derrick

Rao

et al. 2021

Cell Reports Medicine

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Summary The lack of effective treatment options for advanced non-clear cell renal cell carcinoma (NCCRCC) is a critical unmet clinical need. Applying a high-throughput drug screen to multiple human kidney cancer cells, we identify the combination of the VEGFR-MET inhibitor cabozantinib and the SRC inhibitor dasatinib acts synergistically in cells to markedly reduce cell viability. Importantly, the combination is well tolerated and causes tumor regression in vivo . Transcriptional and phosphoproteomic profiling reveals that the combination converges to downregulate the MAPK-ERK signaling pathway, a result not predicted by single-agent analysis alone. Correspondingly, the addition of a MEK inhibitor synergizes with either dasatinib or cabozantinib to increase its efficacy. This study, by using approved, clinically relevant drugs, provides the rationale for the design of effective combination treatments in NCCRCC that can be rapidly translated to the clinic.

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Section: Discussionmentioning

confidence: 99%

Cabozantinib and dasatinib synergize to induce tumor regression in non-clear cell renal cell carcinoma

Lue

Derrick

Rao

et al. 2021

Cell Reports Medicine

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“…This data was presented at the 2021 ASCO Genitourinary Cancers Symposium and concurrently published. 15,16 PFS was the primary endpoint. Initially, patients were randomized to one of four arms: cabozantinib, crizotinib, savolitinib, or Canil et al sunitinib.…”

Section: Non-clear-cell Histologymentioning

confidence: 99%

“…Two exceptions are the late addition of data from the CLEAR and PAPMET studies, which were presented at the ASCO Genitourinary Cancers Symposium on February 13, 2021 and concurrently published. [13][14][15][16] The results of these trials were reviewed by all co-authors and there was agreement to include the findings in this publication to ensure the most contemporary document and recommendations possible. As new data become available, treatment options will invariably change, and members of the KCRNC intend to update these recommendations on a regular basis moving forward.…”

Section: Introductionmentioning

confidence: 99%

Management of advanced kidney cancer: Kidney Cancer Research Network of Canada (KCRNC) consensus update 2021

Canil¹,

Kapoor²,

Basappa³

et al. 2021

CUAJ

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To answer the multiple-choice questions associated with this article, go to: www.cuasection3credits.org/cuajapril2021. This program is an Accredited Self-Assess-ment Program (Section 3) as defined by the Maintenance of Certification Program of The Royal College of Physicians & Surgeons of Canada, and approved by the Canadian Urological Association. Remember to visit MAINPORT (www.mainport.org/mainport/) to record your learning and outcomes. You may claim a maximum of 1 hour of credit.

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“…The final results of the SWOG-1500 phase II trial (also known as PAPMET) have been recently presented by Pal and colleagues at the American Society of Clinical Oncology Genito-urinary (ASCO GU) Cancers Symposium 2021 [92]. In this study, the clinical activity of the current standard-of-care sunitinib was compared to multi-kinase inhibitors cabozantinib, crizotinib, and savolitinib in 152 patients with metastatic pRCC (up to one prior systemic therapy was permitted).…”

Section: Met Pathwaymentioning

confidence: 99%

“…On the other side, the enrollment in the other two arms of savolitinib and crizotinib was stopped in advance on the basis of a preplanned futility analysis. These findings suggested a key role of both VEGF-and MET-signaling pathways in pRCC's oncogenesis, thereby explaining its higher responsiveness to a dual VEGF/MET inhibitor such as cabozantinib than to more selective MET inhibitors as crizotinib or savolitinib [92]. Therefore, cabozantinib may be considered as a novel practice changing strategy for metastatic pRCC patients (Table 2).…”

Section: Met Pathwaymentioning

confidence: 99%

The Molecular Characteristics of Non-Clear Cell Renal Cell Carcinoma: What’s the Story Morning Glory?

Marchetti

Rosellini

Mollica

et al. 2021

IJMS

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Non-clear cell renal cell carcinomas are a miscellaneous group of tumors that include different histological subtypes, each one characterized by peculiarity in terms of genetic alteration, clinical behavior, prognosis, and treatment response. Because of their low incidence and poor enrollment in clinical trials, alongside their heterogeneity, additional efforts are required to better unveil the pathogenetic mechanisms and, consequently, to improve the treatment algorithm. Nowadays, tyrosine kinase inhibitors, mTOR and MET inhibitors, and even cisplatin-based chemotherapy and immunotherapy are potential weapons that are still under evaluation in this setting. Various biomarkers have been evaluated for detecting progression and monitoring renal cell carcinoma, but more studies are necessary to improve this field. In this review, we provide an overview on the molecular characteristics of this group of tumors and the recently published trials, giving an insight into what might become the future therapeutic standard in this complex world of non-clear cell kidney cancers.

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A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial

Cited by 181 publications

References 26 publications

Cabozantinib and dasatinib synergize to induce tumor regression in non-clear cell renal cell carcinoma

Cabozantinib and dasatinib synergize to induce tumor regression in non-clear cell renal cell carcinoma

Management of advanced kidney cancer: Kidney Cancer Research Network of Canada (KCRNC) consensus update 2021

The Molecular Characteristics of Non-Clear Cell Renal Cell Carcinoma: What’s the Story Morning Glory?

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