Durvalumab With or Without Tremelimumab Fails to Meet OS Endpoints in Urothelial Cancer

Thomas Powles, MBBS, MRCP, MD

The co-primary end points of overall survival in patients with metastatic urothelial cancer (UC) were not met in the phase 3 DANUBE trial of durvalumab in combination with tremelimumab and durvalumab (Imfinzi) monotherapy, according to results presented at the 2020 ESMO Virtual Congress.¹

Neither monotherapy with durvalumab (Imfinzi) or combination treatment with durvalumab plus tremelimumab met co-primary end points of overall survival versus chemotherapy for the treatment of metastatic urothelial cancer (UC).

However, secondary analyses suggested that tremelimumab bolstered the anti-tumor activity of durvalumab, particularly in patients whose tumors had high PD-L1 expression.

In introducing the DANUBE study, investigator Thomas Powles, MBBS, MRCP, MD, explained that although platinum-based chemotherapy yields initial high responses as first-line treatment for metastatic urothelial cancer, “patients relapse, and long-term, durable remissions are rare.

“Both atezolizumab [Tecentriq] and pembrolizumab [Keytruda] are approved in the cisplatin-ineligible, PD-L1-positive population in this frontline space. Their approval is based off 2 single-arm trials with relatively modest numbers.^2,3 We don't currently have any mature, randomized overall survival data in this setting,” added Powles, professor of genitourinary oncology, director of Barts Cancer Centre, Queen Mary University of London, United Kingdom.

Durvalumab is approved by the FDA for the treatment of platinum-refractory, metastatic UC. Previous research has indicated that tremelimumab alone and the combination of durvalumab plus tremelimumab shows activity in platinum-refractory, metastatic UC regardless of PD-L1 expression.^4,5

The DANUBE trial evaluated durvalumab, with or without tremelimumab, vs platinum-based chemotherapy, as first-line treatment for metastatic UC (NCT02516241). The study included 1032 patients with untreated, unresectable, locally advanced, or metastatic UC.

Patients were randomized 1:1:1 to receive 1500 mg durvalumab IV once monthly until progression (n = 346); 1500 mg durvalumab IV once monthly until progression plus 75 mg tremelimumab once monthly for up to 4 doses (n = 342); and a standard-of-care chemotherapy regimen of gemcitabine plus cisplatin or carboplatin up to 6 cycles (n = 344). Randomization was stratified by cisplatin eligibility, PD-L1 status (high or low), and presence or absence of liver and/or lung metastases.

Baseline characteristics such as age, region, and pure transitional cell carcinoma were generally well balanced among the treatment groups.

Co-primary end points consisted of overall survival (OS) for durvaluamb vs chemotherapy in patients with high PD-L1 expression and OS for durvalumab plus tremelimumab vs chemotherapy in the intention-to-treat (ITT) population.

The minimum follow-up time was 34 months, and median follow-up for survival was 41.2 months for all patients.

Median OS for patients in the durvalumab-only group was 14.4 months vs 12.1 months for the chemotherapy group (HR, 0.89; 95% CI, 0.71-1.11) In the durvalumab plus tremelimumab cohort. Median OS was 15.1 months vs 12.1 months for the chemotherapy group (HR, 0.85; 95% CI, 0.72-1.02).

In regards to anti-tumor activity, median duration of response in the ITT population for patients in the durvalumab-only, durvalumab plus tremelimumab, and chemotherapy groups was 9.3 months (95% CI, 5.8-20.5), 11.1 months (95% CI, 7.9-18.5), and 5.7 months (95% CI, 5.6-6.2), respectively.

Median duration of response in the PD-L1-high population in the durvalumab only, durvalumab plus tremelimumab, and chemotherapy groups was 18.5 months (95% CI, 7.6-not estimable), 10.0 months (95% CI, 7.4-18.7), and 5.8 months (95% CI, 5.1-7.0), respectively.

Treatment-related adverse events occurred in 56% of the durvalumab cohort, 75% of the durvalumab plus tremelimumab cohort, and 90% of the chemotherapy cohort. Both durvalumab monotherapy and durvalumab/tremelimumab had manageable safety profiles, and no new safety signals were observed.

Reflecting on the results, Powles commented, “Overall, with a median survival 41 months, this DANUBE data has the most robust data set to date. I think it gives a good impression of the role of both monotherapy and the combination in this environment.”

He added, “While the trial was negative, it does give us some provocative data…for future trials."

_References:

_{1. Powles TB, van der Heijden MS, Gauna Castellano D, et al. A phase III, randomized, open-label study of first-line durvalumab (D) with or without tremelimumab (T) vs standard of care chemotherapy in patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE). Paper presented at: European Society of Medical Oncology virtual congress; September 19-21, 2020. Abstract 697O.}

_{2. Balar AV, Castellano D, O’Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(11):1483-1492. doi:10.1016/S1470-2045(17)30616-2}

_{3. Balar AV, Galsky MD, Rosenberg JE, IMvigor 210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017; 389(10064)67-76. doi: 10.1016/S0140-6736(16)32455-2}

_{4. Sharma P, Sohn J, Shin SJ, et al. Efficacy and tolerability of tremelimumab in locally advanced or metastatic urothelial carcinoma patients who have failed first-line platinum-based chemotherapy. Clin Cancer Res. 2020;26-61-70. doi:10.1158/1078-0432.CCR-19-1635}

_{5. Balar AV, Mahipal A, Grande E, et al. Durvalumab + tremelimumab in patients with metastatic urothelial cancer. Paper presented at: 2018 American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago, IL.}