Efficacy-toxicity relationship analysis of cabozantinib (CABO) plus durvalumab (DURVA) in patients (pts) with advanced urothelial carcinoma (UC) or non-UC variant histologies (VH) after platinum chemotherapy (CT): Interim results from the phase 2 ARCADIA trial.

Background: Combining multitargeted receptor TKI with checkpoint inhibitors has shown synergistic effect in pts with UC due to the immunomodulatory propriety of VEGFR inhibitors. We investigated the potential relationship between toxicity of CABO and DURVA in pts with advanced UC and non-UC histology (VHs) in a phase II study (NCT03824691) and patient characteristics and outcome. Patients and Methods: Patients affected by UC and VHs recurred or progressed after failure of at least one line of platinum-based CT for metastatic disease have been treated with CABO 40 mg daily, orally, and are administered DURVA 1500 mg IV, q28 days, until disease progression (PD, by RECIST 1.1) or onset of unacceptable toxicity. The primary endpoint was OS.Secondary endpoints included safety (CTCAE v.4.03), objective response-rate (ORR), duration of response (DoR), progression-free survival (PFS). Results: Between September 2019 and April 28, 2023, the ARCADIA study enrolled 71 pts: this is an interim analysis from 62 pts. The median follow-up was 21.9 mos (15.6–27.3 mos). Overall, 39 (62.9%) of 62 pts had all-grade treatment-related adverse events (TRAEs): among them, 7 pts (16.7%) reported grade = 3 TRAEs; the most common TRAEs are summarized in Table 1. Dose-reductions of CABO were needed in 26 pts (41.9%). The incidence of TRAEs affects positively both PFS (HR 0.24; 95% CI, 0.1195 - 0.4803; p value < 0.0001) and OS (HR 0.28; 95% CI, 0.1393 - 0.5662; p value = 0.000385). Conclusions: CABO in combination with DURVA toxicity appears to be associated with improved PFS and OS in UC and in non-UC VH. Proactive toxicity driven/individualized dose modification strategies for CABO plus DURVA may help to mitigate AEs while maintaining efficacy. Table 1 Safety Summary (n=62) Grade, n (%) Any 1-2 3-4 AE All-causes AEs 41 (100) 35 (85) 6 (15) TRAEs 39 (95) 32 (82) 7 (18) Cabozantinib related AEs 36 (92) 31 (86) 7 (18) Durvalumab related AEs 18 (8) 17 (94) 1 (6) TRAEs unclear attribution 2 (5) 0 2 (100) Serious AEs 5 (12) 1 (20) 4 (80) AEs leading discontinuation Cabozantinib discontinuation 2 (5) 1 (50) 1(50) Durvalumab discontinuation 1 (2) 0 1 (100) AEs leading CABO dose reduction 26 (63) 21 (81) 5 (19) TRAEs Fatigue 10 (26) 10 (26) 0 Diarrhea 8 (20) 8 (20) 0 Dysphonia 4 (10) 4 (10) 0 Hypertension 6 (15) 6 (15) 0 Dysgeusia 2 (5) 2(5) 0 AST/ALT increase 9 (23) 8 (20) 1 (2) Creatinine increase 2 (5) 1 (2) 1 (2) Stomatitis 8 (20) 8 (20) 0 Thrombocytopenia 2 (5) 2 (5) 0 Arthralgia 1 (2) 1 (2) 0 Hand-foot syndrome 8 (20) 8 (20) 0 Hypothyroidism 5 (12) 5 (12) 0 Dyspepsia 4 (10) 4 (10) 0 Xerostomia 5 (12) 5 (12) 0