ASCO GU 2021: Final Results From a Phase I Trial and Expansion Cohorts of Cabozantinib and Nivolumab Alone or With Ipilimumab For Metastatic Genitourinary Tumors

( Cabozantinib, nivolumab, and ipilimumab have been increasingly utilized for a number of genitourinary malignancies, most prominently in renal cell carcinoma. In a dose-escalation study, combinations of cabozantinib and nivolumab (CaboNivo) and cabozantinib, nivolumab, and ipilimumab (CaboNivoIpi) demonstrated promising efficacy and safety in a dose-escalation phase I study. In a plenary abstract presentation in the Rapid Abstract Session: Urothelial Carcinoma and Rare Tumors session at the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), Dr. Apolo presented results from a pooled analysis of the phase I dose-finding and 7 subsequent expansion cohorts among patients with metastatic genitourinary (mGU) tumors.

In the expansion cohorts, the authors enrolled patients with urothelial carcinoma (UC); clear cell renal cell carcinoma (RCC), bladder adenocarcinoma (BlaAdeno), and other rare mGU tumors (CaboNivo expansion) and patients with UC, RCC, and penile carcinoma (penile) (CaboNivoIpi expansion).

In the phase I cohort, patients received 8 escalating doses of CaboNivo or CaboNivoIpi. Subsequently, in the 7 expansion cohorts, patients received the recommended phase II dose for CaboNivo (cabozantinib 40mg daily + nivolumab 3mg/kg q2wks in 28-day cycles) and CaboNivoIpi (same dose of cabozantinib and nivolumab + ipilimumab 1mg/kg q3wks in 21-day cycles x 4 cycles followed by CaboNivo). 


The authors sought primarily to assess clinical activity, safety, and tolerability of both combinations. A secondary objective was the detection of EpCAM+ circulating tumor cells (CTCs) and biomarker correlatives.

The authors enrolled a total of 120 patients (median age 59; range 20-82), of whom 54 were in the phase I portion of the trial and 66 of whom were in the dose expansion cohorts. 64 pts received CaboNivo and 56 received CaboNivoIpi. Notably, 83% of patients had visceral disease.

Over a median follow-up of 40.4 months (range 2.2-62.2 months), the objective response rate for 108 evaluable pts was 38% (95% CI: 28.8-47.8%) with 12 complete responses (CRs) (11.1%) and 29 partial responses (26.9%). 


Stratified by tumor type, the objective response rates were: 
-UC 42.4% (n=33) with CR=21.2%; 
-RCC 62.5% (n=16); 
-prostate cancer 11.1% (n=9); 
-germ cell tumor no responses (n=6); 
-bladder adenocarcinoma 20% (n=15); 
-penile 44.4% (n=9); 
-bladder squamous 85.7 (n=7); 
-renal medullary 50% (n=2); 
-bladder small cell 33.1 (n=3). 



The median overall survival for the entire population was 15.9 months (95% CI: 11.6-23.9) with differences between tumor types: medial overall survival was 24.9 months (95% CI: 11.8-41.6) for patients with UC (n=39) and 38.6 months (95% CI: 19.4-not estimable) for patients with RCC (n=16). The median duration of response was 22.8 months (95% CI: 18.3-40.1 months) among all comers, again with variation between tumor types with a median duration of response of 32.1 months [95% CI: 20.3-NE)] for patients with UC and 20.1 months (95% CI: 5.8-NE) for patients with RCC. 

Toxicity was relatively common with grade 3 or 4 treatment related adverse events (AEs) occurring in 84% and 80% of patients treated with CaboNivo and CaboNivoIpi, respectively. These included hypophosphatemia (25% and 16%), lipase elevation (20% and 20%), fatigue (20% and 18%), ALT elevation (5% and 14%), AST elevation (9% and 11%), diarrhea (9% and 11%), and thromboembolic event (11% and 4%) for patients treated with CaboNivo and CaboNivoIpi, respectively. One patient receiving CaboNivoIpi had grade 5 pneumonitis. 

In terms of biomarker correlates, baseline EpCAM+ CTC count of < 5 vs. > 5 was associated with longer median OS (24.3 vs. 12.3 months p=0.037) in this cohort.

The authors conclude that both CaboNivo and CaboNivoIpi demonstrated promising clinical activity and manageable safety in patients with a variety of advanced genitourinary malignancies. Based on these data, a number of phase II and III trials are ongoing.



Presented by: Andrea B. Apolo, MD, Medical Oncologist, Genitourinary Malignancies Branch, NIH Lasker Clinical Research Scholar, Head, Bladder Cancer Section, Center for Cancer Research
National Cancer Institute

Co-Authors: Daniel da Motta Girardi, Scot Anthony Niglio, Rosa Maria Nadal, Lisa M. Cordes, Seth M. Steinberg, Rene Costello, Jane B Trepel, Sunmin Lee, Min-Jung Lee, Liang Cao, James L. Gulley, Donald P. Bottaro, Biren Saraiya, Sumanta K. Pal, David I. Quinn, Primo "Lucky" N. Lara, Howard L. Parnes, William L. Dahut, Amir Mortazavi

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center, @WallisCJD on Twitter during the 2021 ASCO Genitourinary Cancers Symposium (ASCO GU), February 11th to 13th, 2021

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