Cabozantinib in patients with platinum-refractory metastatic urothelial carcinoma: an open-label, single-centre, phase 2 trial

Apolo, Andrea B.; Nadal, Rosa; Tomita, Yusuke; Davarpanah, Nicole N.; Cordes, Lisa; Steinberg, Seth M.; Cao, Liang; Parnes, Howard L.; Costello, Rene; Merino, María J.; Folio, Les; Lindenberg, Liza; Raffeld, Mark; Lin, Jeffrey; Lee, Min-Jung; Lee, Sunmin; Alarcon, Sylvia V.; Yuno, Akira; Dawson, Nancy A.; Allette, Kimaada; Roy, Arpita Singha; Silva, Dinuka De; Lee, Molly M.; Sissung, Tristan M.; Figg, William D.; Agarwal, Piyush K.; Wright, John J.; Ning, Yang‐Min; Gulley, James L.; Dahut, William L.; Bottaro, Donald P.; Trepel, Jane B.

doi:10.1016/s1470-2045(20)30202-3

Cited by 62 publications

(44 citation statements)

References 33 publications

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“…8 Cabozantinib may promote an immune-permissive environment that enhances response to ICIs. [17][18][19][20] In preclinical models, cabozantinib synergized with ICIs to inhibit tumor growth and mitigate immunosuppression 18 ; and in clinical studies, cabozantinib increased the numbers of tumorinfiltrating cytotoxic T cells and reduced immunosuppressive cells. 17,20 These studies provided the rationale to combine cabozantinib with immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

“…[17][18][19][20] In preclinical models, cabozantinib synergized with ICIs to inhibit tumor growth and mitigate immunosuppression 18 ; and in clinical studies, cabozantinib increased the numbers of tumorinfiltrating cytotoxic T cells and reduced immunosuppressive cells. 17,20 These studies provided the rationale to combine cabozantinib with immunotherapy. 21 Recently, cabozantinib in combination with the programmed cell death protein-1 inhibitor nivolumab was approved as a firstline therapy for patients with advanced ccRCC based on outcomes from the phase III CheckMate 9ER study, which showed improved PFS, overall survival, and ORR with the combination therapy versus sunitinib.…”

Section: Introductionmentioning

confidence: 99%

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Cabozantinib in Combination With Atezolizumab for Advanced Renal Cell Carcinoma: Results From the COSMIC-021 Study

Pal

McGregor

Suárez

et al. 2021

JCO

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PURPOSE COSMIC-021 is evaluating cabozantinib plus atezolizumab in patients with solid tumors. We report results from patients with advanced clear cell (cc) and non–clear cell (ncc) renal cell carcinoma (RCC). METHODS This phase Ib study ( NCT03170960 ) enrolled patients age ≥ 18 years with advanced RCC. A dose-escalation stage was followed by expansion cohorts. For cohort expansion, prior systemic therapy was not permitted for ccRCC but allowed for nccRCC. Patients received oral cabozantinib 40 mg once a day (ccRCC and nccRCC) or 60 mg once a day (ccRCC only) plus atezolizumab (1,200 mg intravenously, once every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1; the secondary end point was safety. RESULTS A total of 102 patients were enrolled. Median follow-up was 25.8, 15.3, and 13.3 months for the 40-mg ccRCC, 60-mg ccRCC, and nccRCC groups, respectively. ORR was 53% (80% CI, 41 to 65) in the 40-mg ccRCC group (n = 34) and 58% (80% CI, 46 to 70) in the 60-mg ccRCC group (n = 36), 3% and 11%, respectively, with complete response; median progression-free survival (exploratory end point) was 19.5 and 15.1 months, respectively. In nccRCC (n = 32), ORR was 31% (80% CI, 20 to 44), all partial responses; median progression-free survival was 9.5 months. Grade 3 or 4 treatment-related adverse events (TRAEs) were reported by 71% of patients in the 40-mg ccRCC group, 67% in the 60-mg ccRCC group, and 38% in the nccRCC group; TRAEs leading to discontinuation of both agents occurred in 15%, 6%, and 3% of patients, respectively. There were no grade 5 TRAEs. CONCLUSION The novel combination of cabozantinib plus atezolizumab demonstrated encouraging clinical activity and acceptable tolerability in patients with advanced ccRCC and nccRCC. Disease control was observed across dose levels and histologic subtypes.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cabozantinib in Combination With Atezolizumab for Advanced Renal Cell Carcinoma: Results From the COSMIC-021 Study

Pal

McGregor

Suárez

et al. 2021

JCO

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“…13,14 Preclinical models have suggested that the MET pathway mediates resistance to VEGF-targeted therapy in several cancers, including RCC, 15,16 and multiple clinical trials investigating cabozantinib in GU tumors have shown clinical activity. [17][18][19] ICIs are now part of the standard of care for mUC and mRCC 7,10 and have been investigated in CRPC and metastatic germ cell tumors (mGCTs). 20,21 Nivolumab is a monoclonal antibody against the programmed cell death protein 1 (PD-1) cell surface membrane receptor.…”

Section: Introductionmentioning

confidence: 99%

Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors

Apolo

Nadal

Girardi

et al. 2020

JCO

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PURPOSE We assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) and CaboNivo plus ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignances. PATIENTS AND METHODS Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase II dose (RP2D). Secondary objectives included objective response rate (ORR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS). RESULTS Fifty-four patients were enrolled at eight dose levels with a median follow-up time of 44.6 months; data cutoff was January 20, 2020. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 75% and 87% of patients treated with CaboNivo and CaboNivoIpi, respectively, and included fatigue (17% and 10%, respectively), diarrhea (4% and 7%, respectively), and hypertension (21% and 10%, respectively); grade 3 or 4 immune-related AEs included hepatitis (0% and 13%, respectively) and colitis (0% and 7%, respectively). The RP2D was cabozantinib 40 mg/d plus nivolumab 3 mg/kg for CaboNivo and cabozantinib 40 mg/d, nivolumab 3 mg/kg, and ipilimumab 1 mg/kg for CaboNivoIpi. ORR was 30.6% (95% CI, 20.0% to 47.5%) for all patients and 38.5% (95% CI, 13.9% to 68.4%) for patients with mUC. Median DoR was 21.0 months (95% CI, 5.4 to 24.1 months) for all patients and not reached for patients with mUC. Median PFS was 5.1 months (95% CI, 3.5 to 6.9 months) for all patients and 12.8 months (95% CI, 1.8 to 24.1 months) for patients with mUC. Median OS was 12.6 months (95% CI, 6.9 to 18.8 months) for all patients and 25.4 months (95% CI, 5.7 to 41.6 months) for patients with mUC. CONCLUSION CaboNivo and CaboNivoIpi demonstrated manageable toxicities with durable responses and encouraging survival in patients with mUC and other GU tumors. Multiple phase II and III trials are ongoing for these combinations.

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“…In a phase II trial involving patients with metastatic UC refractory to platinum-based therapy, cabozantinib was well-tolerated and produced an ORR of 19%. Among 68 patients, the most common grade 3-4 AEs were fatigue [6(9%)], hypertension [5(7%)], proteinuria [4(6%)], and hypophosphatemia [4(6%)] ( 86 ).…”

Section: Future Perspectives For Bladder Cancer Treatmentmentioning

confidence: 99%

Elucidation of Novel Molecular Targets for Therapeutic Strategies in Urothelial Carcinoma: A Literature Review

2021

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Urothelial carcinoma therapy is a rapidly evolving and expanding field. Traditional cytotoxic chemotherapy regimens have not produced optimal long-term outcomes, and many urothelial cancer patients have comorbidities that disqualify them as chemotherapy candidates. In recent years, a plethora of novel therapeutic agents that target diverse molecular pathways has emerged as alternative treatment modalities for not only metastatic urothelial carcinoma, but also for muscle-invasive bladder cancer and non-muscle invasive bladder cancer in adjuvant and definitive settings. This review paper aims to discuss the various categories of therapeutic agents for these different types of urothelial cancer, discussing immunotherapy, antibody-drug conjugates, kinase inhibitors, CAR-T cell therapy, peptide vaccination, and other drugs targeting pathways such as angiogenesis, DNA synthesis, mTOR/PI3K/AKT, and EGFR/HER-2.

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Cabozantinib in patients with platinum-refractory metastatic urothelial carcinoma: an open-label, single-centre, phase 2 trial

Cited by 62 publications

References 33 publications

Cabozantinib in Combination With Atezolizumab for Advanced Renal Cell Carcinoma: Results From the COSMIC-021 Study

Cabozantinib in Combination With Atezolizumab for Advanced Renal Cell Carcinoma: Results From the COSMIC-021 Study

Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors

Elucidation of Novel Molecular Targets for Therapeutic Strategies in Urothelial Carcinoma: A Literature Review

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