(UroToday.com) The 2023 ESMO annual meeting included a session on urothelial carcinoma, featuring a presentation by Dr. Sarah Einerhand discussing ICRA, a trial assessing the efficacy of paclitaxel with tremelimumab +/- durvalumab in metastatic urothelial carcinoma after progression on platinum chemotherapy and anti-PD-(L)1. The prognosis of metastatic urothelial carcinoma patients after platinum-based chemotherapy and anti-PD-(L)1 is poor. Furthermore, the first line platinum based chemotherapy median OS remains 12-15 months, with only durable responses to second line anti-PD-(L)-1 in a minority of patients. There are limited treatment options for patients after platinum chemotherapy and anti-PD-(L)1, including vinflunine, taxanes, and enfortumab vedotin (which is now standard third line treatment). As such, there is an unmet clinical need for new therapeutic strategies remaining. Dr. Einerhand and colleagues evaluated whether paclitaxel with tremelimumab, with or without durvalumab, could induce response in therapy-refractory metastatic urothelial carcinoma patients.
ICRA (Improved Checkpoint-blockade Response in Advanced urothelial carcinoma) is an open-label, randomized, multicenter phase I/II study in patients with metastatic urothelial carcinoma who relapsed after platinum-based chemotherapy and anti-PD-(L)1. In the safety run-in phase (n = 15), they tested weekly paclitaxel (70mg/m2; day 1, 8, and 15 for 6 cycles) + either tremelimumab 75 mg, tremelimumab 225 mg or tremelimumab 750 mg (cycles 2-8 every 4 weeks), or paclitaxel combined with durvalumab (cycles 2-12 every 4 weeks) plus either tremelimumab 75 mg (cycles 2-5 every 4 weeks) or tremelimumab 300 mg once (cycle 2):
In the expansion phase (n = 12 per arm), patients received (Arm A) paclitaxel (cycle 1-6) + tremelimumab 750 mg (cycle 2-8); (Arm B) paclitaxel (cycle 1-6) plus tremelimumab 300 mg once (cycle 2) plus durvalumab 1500 mg (cycle 2-12); or (Arm C) tremelimumab 750 mg (cycle 1-7):
Arm A was extended to n=20 based on two 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 complete baseline characteristics are as follows:
There were two grade 3 treatment-related adverse events in the run in phase (blood transfusions for anemia), and the most common any grade immune-related adverse events in the entire study were rash/pruritus, hypothyroidism, and colitis. The most common any grade chemotherapy related adverse events were nausea, fatigue, anemia, and neuropathy. A summary of grade 3 and 4 adverse events is as follows:
The primary endpoint was met with an ORR of 26% (88% CI 14-37%; 5/19 evaluable patients) in arm A; the ORR was 8% in arms B and C. There was tumor reduction in 50% of patients in arm A, 67% in arm B, and 17% in arm C:
Median OS was 16.0 (95%CI 4.4-27.5), 13.9 (95%CI 9.5-18.3), and 6.6 (95%CI 0.0-14.8) months in arms A, B, and C, respectively (p=0.68):
Median PFS was 5.7 (95%CI 4.0-7.3), 6.5 (95%CI 3.7-9.4), and 2.8 (95%CI 0.0-5.7) months in arms A, B, and C, respectively (p=0.27):
Dr. Einerhand concluded her presentation by discussing the ICRA trial assessing the efficacy of paclitaxel with tremelimumab +/- durvalumab in metastatic urothelial carcinoma after progression on platinum chemotherapy and anti-PD-(L)1 with the following take-home points:
- The primary endpoint was met with an ORR of 26% in paclitaxel + tremelimumab 750 mg
- Tremelimumab can induce response in some patients post-anti-PD-(L)1, with the combination with paclitaxel appearing to be more active than the anti-CTLA4 monotherapy arm
- The safety profile was consistent with previously reported for tremelimumab and/or durvalumab
- Novel agents with better initial tumor control are in the development for metastatic urothelial carcinoma
- Future studies could explore new combinations with high dose anti-CTLA4 for synergy
Presented by: Sarah M.H. Einerhand, Netherlands Cancer Institute, Amsterdam, Netherlands
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 European Society of Medical Oncology (ESMO) Annual Meeting, Madrid, Spain, Fri, Oct 20 – Tues, Oct 24, 2023.