Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial

Choueiri, Toni K.; Halabi, Susan; Sanford, Ben; Hahn, Olwen; Michaelson, M. Dror; Walsh, Meghara; Feldman, Darren R.; Olencki, Thomas; Picus, Joel; Small, Eric J.; Dakhil, Shaker R.; George, Daniel J.; Morris, Michael J.

doi:10.1200/jco.2016.70.7398

Cited by 626 publications

(605 citation statements)

References 29 publications

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“…Recently, cabozantinib and the combination of lenvatinib plus everolimus have shown clinical activity in mRCC patients previously treated with TKI, including sunitinib. Moreover, cabozantinib has shown improved progression‐free survival over sunitinib in a randomized Phase II study performed in the first‐line setting . Our results show that sunitinib‐desensitized cells were more sensitive to cabozantinib and to the combination of lenvatinib and everolimus (Figs.…”

Section: Resultsmentioning

confidence: 57%

Identification of mutations associated with acquired resistance to sunitinib in renal cell cancer

Elgendy

Fusco

Segura

et al. 2019

Intl Journal of Cancer

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Sunitinib is one of the most widely used targeted therapeutics for renal cell carcinoma (RCC), but acquired resistance against targeted therapies remains a major clinical challenge. To dissect mechanisms of acquired resistance and unravel reliable predictive biomarkers for sunitinib in RCC, we sequenced the exons of 409 tumor‐suppressor genes and oncogenes in paired tumor samples from an RCC patient, obtained at baseline and after development of acquired resistance to sunitinib. From newly arising mutations, we selected, using in silico prediction models, six predicted to be deleterious, located in G6PD, LRP1B, SETD2, TET2, SYNE1, and DCC. Consistently, immunoblotting analysis of lysates derived from sunitinib‐desensitized RCC cells and their parental counterparts showed marked differences in the levels and expression pattern of the proteins encoded by these genes. Our further analysis demonstrates essential roles for these proteins in mediating sunitinib cytotoxicity and shows that their loss of function renders tumor cells resistant to sunitinib in vitro and in vivo. Finally, sunitinib resistance induced by continuous exposure or by inhibition of the six proteins was overcome by treatment with cabozantinib or a low‐dose combination of lenvatinib and everolimus. Collectively, our results unravel novel markers of acquired resistance to sunitinib and clinically relevant approaches for overcoming this resistance in RCC.

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Section: Resultsmentioning

confidence: 57%

Identification of mutations associated with acquired resistance to sunitinib in renal cell cancer

Elgendy

Fusco

Segura

et al. 2019

Intl Journal of Cancer

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“…27–31 Few studies thus far have been conducted to specifically address the efficacy of these drugs as first-line therapy in intermediate- and poor-risk patients. 4,32 …”

Section: Discussionmentioning

confidence: 99%

Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma

Motzer

Tannir

McDermott³

et al. 2018

N Engl J Med

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BACKGROUND Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma. METHODS We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk. RESULTS A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%. The median progression-free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P = 0.03, not significant per the prespecified 0.009 threshold). Treatment-related adverse events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment-related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups. CONCLUSIONS Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 214 ClinicalTrials.gov number, NCT02231749.)

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“…In a randomized phase II trial comparing cabozantinib and sunitinib in the first-line setting (CABOSUN) in 157 patients with intermediate or poor-risk mRCC [28], cabozantinib was associated with increased median PFS (8.2 v 5.6 months; HR 0.66; 95% CI, 0.46–0.95; one-sided p= .012), OS (30.3 vs 21.8 months; HR 0.8; 95% CI 0.5–1.26) and ORR (46%; 95% CI, 34–57 versus 18%; 95% CI, 10–28) with a similar incidence of grade 3–4 AEs (67% for cabozantinib and 68% for sunitinib). The comparative efficacy of cabozantinib in the first-line setting among favorable risk patients remains to be demonstrated.…”

Section: The State Of Treatment For Clear Cell Rccmentioning

confidence: 99%

Renal cell carcinoma: molecular characterization and evolving treatment paradigms

Ball¹,

Singer

Srinivasan

2017

Current Opinion in Oncology

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Purpose of review The treatment landscape of advanced renal cell carcinoma (RCC) continues to shift as both new targeted therapies and immunotherapies show efficacy in treating the disease. Contemporary insights into the molecular characterization of RCC are likely to fuel the development of additional therapies. This review summarizes recent advancements in the biologic characterization of RCC and discusses newly approved therapies and ongoing studies in the treatment of advanced RCC. Recent findings The Cancer Genome Atlas has now completed comprehensive molecular characterization of clear cell, papillary and chromophobe RCC, providing insights into the biology of these entities. Two new ‘targeted’ therapies, cabozantinib and lenvatinib, as well as a novel immune checkpoint inhibitor, the PD-1 inhibitor nivolumab, have recently been approved for the treatment of metastatic RCC. Although some of these newer therapies are associated with prolongation of survival, there are few long-term responders and the quest for more durable treatment strategies continues. Summary The addition of several new agents effective in metastatic renal cell carcinoma has resulted in improvements in overall survival; however, there are few avenues to durable responses or cure. Ongoing studies as well advances in our understanding of the molecular alterations underlying distinct forms of RCC promise further therapeutic advances and have the potential to alter the current treatment paradigm.

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Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial

Cited by 626 publications

References 29 publications

Identification of mutations associated with acquired resistance to sunitinib in renal cell cancer

Identification of mutations associated with acquired resistance to sunitinib in renal cell cancer

Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma

Renal cell carcinoma: molecular characterization and evolving treatment paradigms

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