The prognosis of metastatic urothelial carcinoma (mUC) patients (pts) after platinum-based chemotherapy and anti-PD-(L)1 is poor. Taxanes can provide disease control and may affect the tumor micro-environment. Clinical activity of anti-CTLA4 has been reported previously and may be dose-dependent. We evaluated whether paclitaxel (P) with tremelimumab (T), with or without durvalumab (D), could induce response in therapy-refractory mUC pts.
ICRA is an open-label, randomized, multicenter phase I/II study in pts with mUC who relapsed after platinum-based chemotherapy and anti-PD-(L)1. In the safety run-in phase (n=15), we tested weekly P (70mg/m2; day 1, 8, and 15 for 6 cycles (C)) plus either T75mg, T225mg or T750mg (C2-8 every 4 weeks), or P combined with D (C2-12 every 4 weeks) plus either T75mg (C2-5 every 4 weeks) or T300mg once (C2). In the expansion phase (n=12 per arm), pts received (A) P (C1-6) plus T750mg (C2-8); (B) P (C1-6) plus T300mg once (C2) plus D1500mg (C2-12); or (C) T750mg (C1-7). Arm A was extended to n=20 based on 2 responses. The primary endpoint was the objective response rate (ORR) according to RECIST1.1, with a target ORR 30% and aim to exclude 10% (Simon’s optimal two-stage design, α=0.12, power=0.85). Safety was assessed according to the CTCAEv5.
The primary endpoint was met with an ORR of 26% (88%CI 14-37%; 5/19 evaluable pts) in arm A. The ORR was 8% in arms B and C. Median OS (95%CI) was 16.0 (4.4-27.5), 13.9 (9.5-18.3), and 6.6 (0.0-14.8) months in arms A, B, and C, respectively (p=0.68). Median PFS was 5.7 (4.0-7.3), 6.5 (3.7-9.4), and 2.8 (0.0-5.7) months in arms A, B, and C, respectively (p=0.27). Toxicities are summarized in the Table. Table: LBA103
Toxicity
| R1 (P+T75) | R2 (P+T225) | R3B (P+T75+D1500) | A (P+T750)1 | B (P+T300+D)1 | C (T750) | |||||||
| n=3 | n=3 | n=3 | n=20 | n=12 | n=12 | |||||||
| Grade 1-2 | Grade ≥3 | Grade 1-2 | Grade ≥3 | Grade 1-2 | Grade ≥3 | Grade 1-2 | Grade ≥3 | Grade 1-2 | Grade ≥3 | Grade 1-2 | Grade ≥3 | |
| Therapy-related AEs (n, %) | 3 (100) | 1 (33) | 3 (100) | 1 (33) | 3 (100) | 0 (0) | 20 (100) | 11 (55) | 11 (92) | 8 (67) | 11 (92) | 4 (33) |
| Immune-related AEs (n, %) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 2 (67) | 0 (0) | 16 (80) | 6 (30) | 9 (75) | 3 (25) | 11 (92) | 4 (33) |
| Chemo-related AEs (n, %) | 3 (100) | 1 (33) | 3 (100) | 1 (33) | 3 (100) | 0 (0) | 19 (95) | 6 (30) | 11 (92) | 8 (67) | n.a. | n.a. |
AEs=adverse events; D=durvalumab; P=paclitaxel; R=run-in arm; T=tremelimumab 1. Run-in arms 3A and 4 were included in arms A and B of the expansion phase, respectively.
In heavily pretreated patients with mUC, P+T750mg showed a manageable safety profile and encouraging antitumor activity, suggesting a potential synergistic effect of taxanes and high-dose anti-CTLA4.