Upper tract urothelial carcinoma (UTUC) represents 5 to 10% of urothelial carcinoma. Their mutational profile is different as compared to bladder urothelial carcinoma (UC). While immune checkpoint inhibitors are now part of the therapeutic landscape of urothelial carcinoma, data concerning their use in UTUC patient’s treatment remain scarce. We reviewed the latest molecular characterization data and proposed an insight for future therapeutic strategies based on molecular alteration profiles.
Trial | Drug | Study Design | Line | Overall pts n, UTUC pts n. (%) | Outcomes (Primary Endpoint) |
---|---|---|---|---|---|
IMvigor 010 [15] | Atezolizumab | Phase 3 RCT | Adjuvant | 809; 54 (6.7%) | Median disease-free survival, 19.4 months (95% CI 15.9–24.8) |
Checkmate 274 [16] | Nivolumab | KEYNOTE 052 Phase 3 RCT | Adjuvant | 709; 149 (21%) | Median disease-free survival 20.8 months (95% confidence interval [CI], 16.5 to 27.6) |
NCT02690558 [17] | Cisplatin, gemcitabine, pembrolizumab | Phase 2 | Neoadjuvant | 39; na |
Trial | Drug/Control Arm | Study Design |
Line | Overall pts n, UTUC pts n. (%) | Outcomes (Primary Endpoint) |
---|---|---|---|---|---|
[ | |||||
23] | Pembrolizumab |
Trial Identification |
Drugs | Comparative Arm | Administration | Study Design | Line | Primary Endpoint |
---|---|---|---|---|---|---|
NCT03513952 | Atezolizumab/CYT107 | Atezolizumab | IV | Phase 2 | ≥2 | ORR |
pCR:36% | ||||||
POUT [18] | Cisplatin or carboplatin + gemcitabine | Phase 3 RCT | Adjuvant | 261 | Disease-free survival (hazard ratio 0.45, 95% CI 0.30–0.68; p = 0.0001) |
JAVELIN-100 [21] | Avelumab/BSC | Phase 3 RCT | 1L | 700, 187 (27%) | median OS: 21.4 months vs. 14.3 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.86; p = 0.001 | |||||||
Phase 2 | 1L | 370, 69 (19%) | ORR: 24%, 95% CI 20–29) | |||||||||
NCT03237780 | Atezolizumab/eribulin | Eribulin | IV | Phase 2 | >2 | ORR | IMvigor 130 [24] | Atezolizumab + platinum-based chemotherapy (A)/Atezolizumab (B)/Platinum-based chemotherapy | Phase 3 RCT | 1L | 1213, 312 (26%) | median PFS: 8.2 months (95% CI 6.5–8.3) in group A and 6.3 months (6.2–7.0) in group C (stratified hazard ratio [HR] 0.82, 95% CI 0.70–0.96; one-sided |
NCT02496208 | Cabozantinib/Nivolumab ± Ipilimumab | NA | p | PO/IV | = 0.007). median OS: 16.0 months (13.9–18.9) in group A and 13.4 months (12.0–15.2) in group C (0.83, 0.69–1.00; one-sided p = 0.027). Median overall survival was 15.7 months (13.1–17.8) for group B and 13.1 months (11.7–15.1) for group C (1.02, 0.83–1.24) | |||||||
Phase 1 | >1 | KEYNOTE 361 [25] | Cisplatin or Carboplatin + Gemcitabine + Pembrolizumab/Pembrolizumab/Cisplatin or Carboplatin + Gemcitabine | Phase 3 RCT | 1L | 1010, 211 (21%) | median OS: 17·0 months (14.5–19.5) in the pembrolizumab plus chemotherapy group versus 14.3 months (12.3–16.7) in the chemotherapy group (0.86, 0.72–1.02; p = 0.0407) median PFS: 8.3 months (95% CI 7.5–8.5) in the pembrolizumab plus chemotherapy group versus 7.1 months (6.4–7.9) in the chemotherapy group (hazard ratio [HR] 0.78, 95% CI 0.65–0.93; p = 0.0033) | |||||
RP2D/safety | ||||||||||||
NCT04940299 | Tocilizumab/Ipilimumab/Nivolumab | NA | IV | Phase 2 | 1 | Safety/DLT | KEYNOTE-045 [26] | Pembrolizumab/Paclitaxel or Docetaxel or Vinflunine | Phase 3 RCT | 2L | 748, 75 (10%) | median OS: 10.3 months (95% CI 8.0 to 11.8) vs. 7.4 months (95% CI, 6.1 to 8.3) (hazard ratio for death, 0.73; 95% CI, 0.59 to 0.91; p = 0.002) median PFS: 2.1 months (95% CI, 2.0 to 2.2) vs. 3.3 months (95% CI, 2.3 to 3.5) (HR 0.98; 95% CI, 0.81 to 1.19; p = 0.42) |
NCT03606174 | Sitravatinib/Nivolumab and Sitravatinib/Pembrolizumab/Enfortumab vedotin | NA | PO/IV and PO/IV/IV | Phase 2 | 1, ≥2 | ORR | IMvigor 211 [27] | Atezolizumab/Paclitaxel or Docetaxel or Vinflunine | Phase 3 RCT | 2L | 931, 236 (25%) | median OS: 11.1 (95% CI 8.6–15.5) vs. 10.6 months (95% CI 8.4–12.2) p |
NCT04602078 | = 0.41 | |||||||||||
Atezolizumab/Gemcitabine/Cisplatin | IMvigor 210 [22] | Atezolizumab | Phase 2 | 2L | 119, 33 (28%) | ORR: 23% (95% CI 16–31) |
NA | |
IV | |
Phase 2 | |
1 | ORR |