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Cabozantinib plus Nivolumab in metastatic urothelial carcinoma patients with progressive disease following immune checkpoint inhibitor therapy: phase I expansion study


Previous treatment with immune checkpoint inhibitor ( ICI ) is more common in clinical practice since recent FDA-approval of 5 ICIs in second-line and 2 in first-line for metastatic urothelial carcinoma ( mUC ).
There is lack of data regarding the use of immune checkpoint inhibitor after progression on a prior ICI.
Cabozantinib ( Cabometyx ) has been shown to have immunomodulatory properties and may have synergistic effect with immune checkpoint inhibitor.

This is a phase I expansion cohort of patients with metastatic urothelial carcinoma, who received prior immune checkpoint inhibitor, treated with Cabozantinib 40 mg daily and Nivolumab 3 mg/kg every 2 weeks ( CaboNivo ) until disease progression / unacceptable toxicity.

The primary objective was to determine the efficacy and tolerability of the combination of Cabozantinib and Nivolumab.

Twenty-nine patients with metastatic urothelial carcinoma were treated. Median follow-up was 14.1 months. The majority of patients were male ( 75.8% ); 27 were white ( 93.1% ), and 2 were asian ( 6.9% ).
Primary tumor was bladder in 21 patients ( 72.4% ) and upper tract in 8 ( 27.6% ).
Twenty-two patients ( 75.9% ) had visceral metastasis, 4 ( 13.8% ) had lymph node only metastasis and 13 ( 44.8%) had liver metastasis.
The median number of prior lines of treatment for metastatic urothelial carcinoma was 2 ( range 0-8 ) with 17 patients ( 58.6% ) receiving 2 prior lines of treatment. The majority of patients ( 86.2% ) received prior chemotherapy for metastatic urothelial carcinoma and all patients received prior immune checkpoint inhibitor.
The median number of cycles of prior immune checkpoint inhibitor was 7 ( range 1-20 ) and median time between previous immune checkpoint inhibitor and Cabozantinib + Nivolumab was 2.5 months ( range 1-18 ).

The best response to previous immune checkpoint inhibitor was partial response ( PR ) in 1 patient ( 3.4% ), stable disease ( SD ) in 13 ( 44.9% ), progressive disease ( PD ) in 14 ( 48.3% ) and one ( 3.4% ) was not evaluable ( NE ).

The overall response rate ( ORR ) for Cabozantinib + Nivolumab was 13.8% with 4 patients achieving partial response ( 13.8% ), 15 stable disease ( 51.7% ), 7 PD ( 24.2% ) and 3 not-evaluable ( 10.3% ).
Responses were seen in the liver, lung, and lymph nodes.
Among 4 patients with partial response, 2 were primary refractory to previous immune checkpoint inhibitor and 2 had stable disease.

At cutoff date the median duration of response was not reached and 3 partial responses were still ongoing: 1 had just began and the other 2 were ongoing at 12.3 and 26.4 months.
Among 15 patients with stable disease, 4 had stable disease for more than 6 months, and 2 were still ongoing at 8.1 and 25.1 months.
Median progression-free survival ( PFS ) was 3.6 months ( 95% CI: 2.1 – 5.3 months ) and median overall survival was 10 months ( 95% CI: 5.8 – 16.7 months ).

Grade 1/ 2 treatment related adverse events occurred in 28 patients ( 97% ) and more than grade 3 adverse effects occurred in 14 patients ( 48% ).
The most common more than grade 3 adverse events were: fatigue ( 14% ), hypophosphatemia ( 14% ), lymphocyte count decrease ( 14% ), hypertension ( 7% ) and hyponatremia ( 7% ).

In conclusion, the combination of Cabozantinib and Nivolumab is clinically active and safe in heavily pretreated patients with progressive metastatic urothelial carcinoma following immune checkpoint inhibitor. ( Xagena )

Source: American Society of Clinical Oncology ( ASCO ) Virtual Meeting, 2020

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