Tremelimumab Plus Paclitaxel Generates Responses in Refractory Metastatic Urothelial Cancer

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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