Tremelimumab Plus Paclitaxel Generates Responses in Refractory Metastatic Urothelial Cancer

Treatment of high-dose tremelimumab (Imjudo) in combination with weekly paclitaxel led to responses in patients with metastatic urothelial cancer whose disease progressed on platinum-based chemotherapy and anti–PD-(L)1 therapy, according to updated data from the phase 1/2 ICRA trial (NCT03871036).1

Findings presented at the 2024 ESMO Immuno-Oncology Congress demonstrated that at a median follow-up of 31.6 months, patients treated with tremelimumab plus paclitaxel (n = 20) achieved a confirmed objective response rate (ORR) of 26%, meeting the study’s primary end point. Patients administered tremelimumab in combination with durvalumab (Imfinzi) and paclitaxel (n = 12) experienced a confirmed ORR of 8%, and those given tremelimumab alone (n = 12) had a confirmed ORR of 8%.

The median overall survival (OS) was 16.1 months (95% CI, 8.5-not applicable [NA]) in the tremelimumab/paclitaxel arm, 14.5 months (95% CI, 9.4-NA) in the tremelimumab/durvalumab/paclitaxel arm, and 8.3 months (95% CI, 4.7-NA) in the tremelimumab arm.

“Novel anticancer therapies combined with anti–CTLA-4 [therapy] may provide a more optimal combination for tumor response and durability of response in the therapy-refractory [urothelial cancer] population,” lead study author Hamza Ali, an MD/PhD student at the Netherland Cancer Institute, said in a presentation of the data.

ICRA Rationale and Overview

During his presentation, Ali explained that patients with metastatic urothelial cancer who experience disease progression on or after platinum-based chemotherapy and immune checkpoint inhibitors have a poor prognosis and limited treatment options.

ICRA was a single-center trial conducted at the Netherlands Cancer Institute where investigators enrolled patients at least 18 years of age with histologically or cytologically documented metastatic or unresectable urothelial carcinoma.2 Ineligibility for cisplatin-based chemotherapy or prior treatment with platinum-based chemotherapy was required. Patients also needed to have prior treatment with anti–PD-(L)1 therapy.

Other key inclusion criteria included a World Health Organization performance status of 0 or 1; a body weight of more than 30 kg; and adequate organ and bone marrow function.

During the safety run-in portion of the study, patients were assigned to 1 of 5 arms, which each included 3 patients:1,2

• Arm 1: 75 mg of tremelimumab on day 1 of cycles 2 to 6, then once every 12 weeks until week 45, plus 70 mg/m2 of paclitaxel on days 1, 8, and 15 of cycles 1 to 6
• Arm 2: 225 mg of tremelimumab on day 1 of cycles 2 to 6, then once every 12 weeks until week 45, plus 70 mg/m2 of paclitaxel on days 1, 8, and 15 of cycles 1 to 6
• Arm 3: 750 mg of tremelimumab on day 1 of cycles 2 to 6, then once every 12 weeks until week 45, plus 70 mg/m2 of paclitaxel on days 1, 8, and 15 of cycles 1 to 6
• Arm 4: 75 mg of tremelimumab on day 1 of cycles 2 to 5 plus 1500 mg of durvalumab on day 1 of cycles 1 to 12, then once every 4 weeks until week 49, and 70 mg/m2 of paclitaxel on days 1, 8, and 15 of cycles 1 to 6
• Arm 5: 300 mg of tremelimumab on day 1 of cycle 2 plus 1500 mg of durvalumab on day 1 of cycles 1 to 12, then once every 4 weeks until week 49, and 70 mg/m2 of paclitaxel on days 1, 8, and 15 of cycles 1 to 6

The main study included 3 arms:

• Arm A: 750 mg of tremelimumab on day 1 of cycles 2 to 6, then once every 12 weeks until week 45, plus 70 mg/m2 of paclitaxel on days 1, 8, and 15 of cycles 1 to 6
• Arm B: 300 mg of tremelimumab on day 1 of cycle 2 plus 1500 mg of durvalumab on day 1 of cycles 1 to 12, then once every 4 weeks until week 49, and 70 mg/m2 of paclitaxel on days 1, 8, and 15 of cycles 1 to 6
• Arm C: 750 mg of tremelimumab on day 1 of cycles 1 to 12, then every 4 weeks until week 49

In the main study, the arms were intended to include 12 patients each, and expansion to 20 patients was permitted in arms where at least 2 responses were observed.1

ORR served as the trial’s primary end point.2 Secondary end points included safety, OS, progression-free survival, and duration of response.

Translational Analysis Findings

During the 2024 ESMO Immuno-Oncology Congress, investigators also presented findings from a translational analysis, which showed that high baseline IFN-γ (P = .021) and CD8 (P = .064) signatures were associated with durable clinical benefit.1

Ali explained that durable responses were correlated with higher inflammatory signature scores.

“[Transcriptional data suggest that] anti–CTLA-4 [therapy] may still induce inflammation in the tumor microenvironment, even in patients who have already [experienced disease progression] on anti–PD-[L]1 immunotherapy,” Ali concluded.

Disclosures: Ali did not disclose any interests.

References

1. Ali H, Van Dorp J, Einerhand SMH, et al. Tremelimumab +/- durvalumab plus paclitaxel as immune induction in metastatic urothelial cancer: translational results of the ICRA trial. Ann Oncol. 2024;24(suppl 1):1-20. doi:10.1016/iotech/iotech100741
2. Improve checkpoint-blockade response in advanced urothelial cancer (ICRA). ClinicalTrials.gov. Updated February 23, 2024. Accessed December 23, 2024. https://clinicaltrials.gov/study/NCT03871036