DANUBE trial Failure
AstraZeneca presented its view on the failure of DANUBE Phase III trial, which evaluated Durvalumab with or without tremelimumab in metastatic Urothelial Carcinoma (UC). The study has been one of the longest follow-ups till now for a randomized trial of immunotherapy in previously untreated metastatic UC. It was analyzed that the combination of durvalumab +tremelimumab has activity, which was enhanced in patients with tumors that have high PD-L1 expression suggesting that the utilized biomarker strategy is enriched for the patient that was likely to receive benefit from durvalumab with or without tremelimumab. The company warranted further investigation in the context of all checkpoint inhibitors.
After the disappointing results from DANUBE trial, DelveInsight analyzed that the maintenance avelumab post-chemo remains the standard treatment. Despite the setback in this trial, Astrazeneca is looking forward to the results of its NILE trial, which is again evaluating Durvalumab in the 1st line metastatic setting.
Trophy U-01 trial: Antibody-drug conjugates (ADC) are undoubtedly changing the treatment paradigm of metastatic Urothelial Cancer (mUC)
Immunomedics announced compelling results from cohort 1 of cisplatin-eligible patients in the pivotal Phase II TROPHY U-01 study of sacituzumab govitecan, an antibody-drug conjugate (ADC) targeting the TROP-2 receptor in metastatic urothelial cancer (mUC). The company confirmed sacituzumab govitecan’s significant activity and its safety in patients with heavily-pretreated mUC who progressed on both platinum-based chemotherapy and checkpoint inhibitors (CPI) and have reported achieving a 27 percent overall response rate(ORR), Overall Survival (OS) of 10.5 months and median PFS of 5.4 months compared with chemotherapy. As per DelveInsight analysis, these are highly promising results in the early-phase trial as sacituzumab govitecan has already received a Fast Track Designation, and it may offer a new treatment option for patients with mUC, which would certainly give hope to patients and their families. The company is further seeking guidance from the FDA on the registration pathway in third-line mUC.
IMvigor130 : Encouraging Patient-reported outcomes (PROs) from a global Phase III study
Roche was quite excited about the promising safety, efficacy results due to improved PFS in IMvigor 130 global study last year in ESMO 2019, where Atezolizumab represented the first immune checkpoint inhibitor study to show a progression-free survival benefit for first-line treatment of locally advanced and mUC patient This phase III trial evaluating atezolizumab with and without platinum-based chemotherapy, has now addressed positive patient-reported outcomes during the ESMO 2020. The study analyzed that the addition of Atezolizumab to platinum/gemcitabine resulted in PFS improvement without compromising patients' function or Quality of Life (QoL). Roche believes that these encouraging PRO when coupled with the prolonged PFS and satisfactory safety profile, support a favorable benefit-risk profile of Atezolizumab plus platinum/gemcitabine as an important new treatment option for patients with untreated metastatic Urothelial Carcinoma.
Expert Views “Imvigor130 (front line bladder chemo+atezo) is positive for PFS, with OS trending positive. PFS has not been easy to achieve previously in the bladder. I have been more confident about OS, which will get there in time. A new standard of care, I suspect."
JAVELIN Bladder-100: Further characterization of mUC patients based on a combination of biomarkers
The JAVELIN Bladder-100 results described the efficacy of BAVENCIO (avelumab) as a first-line maintenance treatment across various subgroups of patients with locally advanced or metastatic urothelial carcinoma (UC), leading to its approval. This time in ESMO 2020, the focus was on detailed results, which included exploratory biomarkers analysis as well as patient-reported outcomes in the same trial. The study mainly enabled exploratory analysis of predictive biomarkers that may identify patients who would obtain an OS benefit from avelumab 1L maintenance plus BSC vs. BSC alone. Multiple biomarkers were also identified as potentially predictive, which could be explored in future research. As per DelveInsight, the next generation trials are expected to benefit from these predictive biomarkers, enhancing the treatment decision making of the clinicians soon as these combinations of biomarkers could help further characterize patients with mUC who benefit from avelumab 1L maintenance.
It also garnered several Oncologist’s Optimistic reviews:
“Seeing the phase 3 data for bladder cancer all combined. Javelin bladder 100 maintenance avelumab still the only one to show OS benefit. Lots to come to change the landscape in met urothelial cancer.”
“This was a great team effort to establish a new standard of care in metastatic urothelial cancer.”
Keynote -361 Trial: Fails to Meet Primary Endpoints
Merck has finally confirmed that the addition of Keytruda to platinum chemotherapy in first-line UC did not improve PFS or OS: PFS 8.3 vs 7.1 months, OS 17 vs 14.3 months. It was analyzed that despite good tolerability, combo pembro/chemo did not beat chemo only in Keynote-361.
- “No improvement in outcomes despite intriguing trends for benefit with pembro”
- “Despite good tolerability, combo pembro+chemo did not beat chemo only in Keynote-361. Standard is avelumab maintenance post-chemo in bladder cancer."
Few Experts trying to compare all these trials:
“Danube phase III with dual checkpoint blockade versus standard chemo fails to improve outcomes. Keynote 361 IO vs. Chemo also negative. Perhaps Javelin 100 is positive because it's already selected patients who responded to chemo for the use of maintenance IO”
“First-line Pembrolizumab with or without chemotherapy did not improve PFS or OS in Keynote 361. Surprised yet not surprised given the modest improvements seen in IMVigor130 and negative Danube results. Of course, the details will matter.”
Considering these failures, it can be concluded that it is extremely important to understand that focus should be laid on developing a robust biomarker-based treatment approach in Urothelial Carcinoma.
Overall, we believe that it was an amalgamation of good and not so good results and assume a modification in the market forecast of Urothelial Carcinoma based on the recent insights from ESMO 2020. DelveInsight’s Urothelial Carcinoma- Market Insights, Epidemiology, and Market Forecast-2030 Report has included all these findings based on recent evidence and analysis to provide accurate estimates.