LBA103 - ICRA: Efficacy of paclitaxel with tremelimumab +/- durvalumab in metastatic urothelial carcinoma after progression on platinum chemotherapy and anti-PD-(L)1

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

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.