Final results from a phase I trial and expansion cohorts of cabozantinib and nivolumab (CaboNivo) alone or with ipilimumab (CaboNivoIpi) for metastatic genitourinary tumors.
Authors: Apolo Andrea B. , Girardi Daniel da Motta , Niglio Scot Anthony , Nadal Rosa Maria , Cordes Lisa M. , Steinberg Seth M. , Costello Rene , Trepel Jane B , Lee Sunmin , Lee Min-Jung , Cao Liang , Gulley James L. , Bottaro Donald P. , Saraiya Biren , Pal Sumanta K. , Quinn David I. , Lara Primo "Lucky" N. , Parnes Howard L. , Dahut William L. , Mortazavi Amir 
Published: March 2021

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Background: CaboNivo and CaboNivoIpi showed promising efficacy and safety in a dose-escalation phase I study in patients (pts) with metastatic genitourinary (mGU) tumors. We now report the final results from a pooled analysis of the phase I dose-finding and 7 subsequent expansion cohorts. Methods: Pts with mGU tumors in the phase I cohort received 8 escalating doses of CaboNivo or CaboNivoIpi. In the 7 expansion cohorts, pts received the recommended phase II dose for CaboNivo (cabo 40mg qd + nivo 3mg/kg q2wks in 28-day cycles) and for CaboNivoIpi (CaboNivo same dose + ipi 1mg/kg q3wks in 21-day cycles x 4 cycles followed by CaboNivo). The CaboNivo expansion cohorts included pts with urothelial carcinoma (UC); clear cell renal cell carcinoma (RCC), bladder adenocarcinoma (BlaAdeno), and other rare mGU tumors. The CaboNivoIpi expansion cohorts included, UC, RCC, and penile carcinoma (penile). The objectives of the study were to determine the clinical activity, safety and tolerability of both combinations. A secondary objective was the detection of EpCAM+ circulating tumor cells (CTCs). Biomarker correlatives of plasma VEGFA/VEGFR2, PIGF, and inflammatory cytokines will be presented. Results: A total of 120 pts (median age 59; range 20-82) were enrolled: 54 in the phase I and 66 in the dose expansion cohorts. 64 pts received CaboNivo and 56 CaboNivoIpi. Median follow-up was 40.4 months (range 2.2-62.2 months). The ORR 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%). The ORRs for the following mGU tumors 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); BlaAdeno 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); 24.9 months (95% CI: 11.8-41.6) for pts with UC (n=39); and 38.6 months (95% CI: 19.4-not estimable) for RCC (n=16). Median duration of response was 22.8 months (95% CI: 18.3-40.1 months) for all pts, 32.1 months [95% CI: 20.3-NE)] for the UC pts and 20.1 months (95% CI: 5.8-NE) for RCC pts. Grade 3 or 4 treatment related adverse events (AEs) occurred in 84% and 80% of pts treated with CaboNivo and CaboNivoIpi pts respectively, and 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%). One pt had Grade 5 pneumonitis on CaboNivoIpi. Baseline EpCAM+ CTC count of < 5 vs. > 5, was associated with longer median OS (24.3 vs. 12.3 months p=0.037). Conclusions: CaboNivo and CaboNivoIpi demonstrated promising clinical activity and manageable safety in many mGU histologies including rare tumors. Clinical trial information: NCT02496208.