ESMO Virtual Congress 2020: A Phase 3, Randomized, Open-Label Study (DANUBE) First Line Durvalumab with or without Tremelimumab vs Standard of Care Chemotherapy in Patients with Unresectable, Locally Advanced or Metastatic Urothelial Carcinoma

(UroToday.com) Immune checkpoint blockade therapy by blocking PD-1/PD-L1 axis signaling is approved in advanced urothelial cancers in a few settings: (1) first-line therapy for platinum-ineligible patients, (2) first-line therapy in cisplatin-ineligible patients with high PD-L1 expression, (3) maintenance therapy for patients who do not progress with first-line chemotherapy, and (4) as subsequent therapy for patients progressing after cisplatin-based first-line therapy. Approvals for settings #1 and #2 is based on single-arm phase 2 data, with setting #3 based on the JAVELIN-100 Bladder randomized control trial. Durvalumab, an anti-PD-L1 antibody, is one of the immunotherapy agents approved for setting #4.

Given the suggestion that combination anti-PD-L1 therapy (durvalumab) and anti-CTLA4 therapy (tremelimumab) has activity in platinum-refractory advanced urothelial carcinoma regardless of PD-L1 status, the DANUBE study was designed as a randomized phase 3 study to investigate durvalumab monotherapy versus durvalumab + tremelimumab versus platinum-based chemotherapy in the first-line setting. The schema of the trial is below. Importantly, based on prior data, the primary endpoint for the combination immunotherapy arm was overall survival (OS) in the intention-to-treat population. The primary endpoint in the durvalumab monotherapy arm was overall survival in the PD-L1 positive population. PD-L1 status was measured by either tumor or immune cell positivity.

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The statistical analysis plan entailed a split overall alpha between the durvalumab monotherapy comparison to chemotherapy and combination immunotherapy comparison to chemotherapy.

Baseline characteristics were generally well balanced between all treatment groups. 60% of patients in all arms had high PD-L1 expression.

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There was no overall survival benefit for durvalumab monotherapy in the PD-L1 high population relative to chemotherapy (HR 0.89, 0.71 – 1.11, p = 0.3039).

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There was also no overall survival benefit with combination durvalumab and tremelimumab therapy compared to chemotherapy in the intention to treat population, with a median OS of 15.1 months from combination immunotherapy and 12.1 months with chemotherapy (HR 0.85, 0.72-1.02, p = 0.0751).

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As shown in the chart below, in the intention to treat population, chemotherapy had the highest objective response rate (ORR) rate. Interestingly, in the PD-L1 high subgroup (exploratory analysis), the combination immunotherapy group had an ORR comparable to chemotherapy.

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As an exploratory secondary endpoint, combination immunotherapy in PD-L1 high patients resulted in a median overall survival of 17.9 months compared to 12.1 months with chemotherapy alone (HR 0.74, 0.59-0.93).

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Equivalent rates of patients in each treatment arm went on to receive anti-cancer therapy.

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Durvalumab monotherapy or combination immunotherapy did not have higher rates of treatment-related adverse events, though more patients receiving combination immunotherapy discontinued treatment due to adverse events. The most common grade 3+ adverse events in the immunotherapy arms was lipase elevation.

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In summary, the DANUBE trial was negative for its co-primary endpoints of overall survival in (1) durvalumab monotherapy versus chemotherapy in the PD-L1 high patient population and (2) combination durvalumab and tremelimumab versus chemotherapy in the intention-to-treat population.

The intriguing results from the secondary endpoint analysis of combination immunotherapy in the PD-L1 high population warrants further investigation. Given the longer duration of response with immunotherapy, identification of which patients are likely to benefit from immunotherapy remains a critical question for investigation moving forward.

Presented by: Thomas Powles, MBBS, MRCP, MD, Professor of Genitourinary Oncology, Lead for Solid Tumour Research at Barts Cancer Institute, Director of Barts Cancer Institute, London, United Kingdom

Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, at the European Society for Medical Oncology Virtual Congress, ESMO Virtual Congress 2020 #ESMO20, 18 Sept - 21 Sept 2020

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Durvalumab Plus Tremelimumab for Frontline, Metastatic, Urothelial Cancer, The Phase III DANUBE Trial - Thomas Powles

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