Abstract LBA103
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Clinical trial identification
NCT03871036.
Editorial acknowledgement
Legal entity responsible for the study
Netherlands Cancer Institute.
Funding
AstraZeneca.
Disclosure
J. de Feijter: Financial Interests, Institutional, Advisory Board: Merck. S. Oosting: Financial Interests, Institutional, Advisory Board: Bristol Myers Squibb, Genmab; Financial Interests, Institutional, Invited Speaker: Merck; Financial Interests, Institutional, Research Grant, Investigator initiated research: Celldex; Financial Interests, Institutional, Research Grant, Investigator initiated study: Pfizer, Novartis; Financial Interests, Institutional, Research Grant, I am the principle investigator of EORTC 2120 for which EORTC has received funding from Merck.: Merck; Non-Financial Interests, Institutional, Product Samples: Celldex, Pfizer, Novartis; Other, Member of steering and safety monitoring committee, unpaid.: ALX Oncology. B.B. Suelmann: Financial Interests, Institutional, Advisory Board: Bristol Myers Squibb, Pfizer, Ipsen, Eisai, Merck, MSD; Financial Interests, Institutional, Research Grant, Investigator-initiated study: Pfizer; Financial Interests, Institutional, Research Grant: IPSEN, AstraZeneca, Merck. M.S. van der Heijden: Financial Interests, Institutional, Advisory Board: AstraZeneca, BMS, Janssen, MSD, Seagen, Pfizer; Financial Interests, Institutional, Funding, Investigator-initiated trial: BMS, Roche, AstraZeneca, 4SC; Financial Interests, Institutional, Steering Committee Member, Local PI + SSC member: BMS, AstraZeneca, MSD, Seagen; Financial Interests, Institutional, Steering Committee Member, Local PI + study co-PI: Janssen; Financial Interests, Institutional, Local PI: GSK. All other authors have declared no conflicts of interest.
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