EMD Serono, Pfizer Receive Breakthrough Therapy Designation, Submit Application for BAVENCIO

EMD Serono, the biopharmaceutical business of Merck KGaA, Darmstadt, Germany in the US and Canada, and Pfizer announced completion of the submission of a supplemental Biologics License Application (sBLA) to the US Food and Drug Administration (FDA) for BAVENCIO® (avelumab) for first-line maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC). The FDA granted Breakthrough Therapy Designation to BAVENCIO for this indication, and the sBLA is being reviewed by the FDA under its Real-Time Oncology Review (RTOR) pilot program.

The application is based on positive results from an interim analysis of the Phase III JAVELIN Bladder 100 trial, which met its primary endpoint of overall survival (OS). In this study, BAVENCIO plus best supportive care (BSC) as first-line maintenance therapy significantly extended the survival of patients with previously untreated locally advanced or metastatic UC whose disease did not progress on induction chemotherapy, compared with BSC only. A statistically significant improvement was demonstrated in both co-primary populations: all randomized patients and patients with PD-L1–positive tumors. The safety profile for BAVENCIO in the trial was consistent with that in the JAVELIN monotherapy clinical development program. Detailed results from the JAVELIN Bladder 100 study will be presented at an upcoming medical congress.

"BAVENCIO is the first immunotherapy to demonstrate a statistically significant improvement in overall survival in a Phase III clinical trial in the first-line setting for patients with locally advanced or metastatic urothelial carcinoma," said Chris Boshoff, M.D., Ph.D., Chief Development Officer, Oncology, Pfizer Global Product Development. "Participation in the Real-Time Oncology Review program, coupled with the Breakthrough Therapy Designation, reflect the potential impact of BAVENCIO in this patient setting and provide the opportunity to work towards bringing this treatment option to patients as quickly as possible."

The RTOR program is intended to create a more efficient review process to bring safe and effective treatments to patients earlier, including drugs that are likely to demonstrate substantial improvements over currently available therapy. It allows the FDA to review clinical trial data from certain applications before the complete application is formally submitted. Review under the program does not guarantee or influence the approvability of the application.

Breakthrough Therapy Designation is a program created by the FDA to accelerate the development and review of medicines intended to treat serious or life-threatening diseases where the new treatment may be a substantial improvement over available therapy. In order to receive Breakthrough Therapy Designation, preliminary clinical evidence must indicate that the drug may demonstrate a significant improvement over available therapy on a clinically significant endpoint.

"Given the poor prognosis for patients with advanced urothelial carcinoma, there is an urgent need for additional treatment options that improve overall survival," said Luciano Rossetti, Head of Global R&D for EMD Serono. "Our data highlight the potential for a first-line maintenance treatment approach with BAVENCIO to advance the current standard of care for previously untreated patients, and we are working with urgency toward our goal of bringing this regimen to patients."

"For the past 30 years, chemotherapy has been the first-line standard of care for patients with advanced urothelial carcinoma. While this is an effective short-term option for many patients, most will ultimately experience disease progression, underscoring a need for additional treatment options," said Petros Grivas, M.D., Ph.D., one of the principal investigators in the JAVELIN Bladder 100 trial. "Based on the positive overall survival results from JAVELIN Bladder 100, I believe avelumab has the potential to be practice-changing."

In 2017, the FDA approved BAVENCIO for the treatment of patients with locally advanced or metastatic UC who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response and duration of response. JAVELIN Bladder 100 is the confirmatory study for the conversion to full approval.

BAVENCIO is under clinical investigation for the first-line maintenance treatment of advanced UC. There is no guarantee that BAVENCIO will be approved for first-line maintenance treatment of advanced UC by any health authority worldwide.

JAVELIN Bladder 100 is a Phase III, multicenter, multinational, randomized, open-label, parallel-arm study investigating first-line maintenance treatment with BAVENCIO plus BSC versus BSC alone in patients with locally advanced or metastatic UC. A total of 700 patients whose disease had not progressed after platinum-based induction chemotherapy as per RECIST v1.1 were randomized to receive either BAVENCIO plus BSC or BSC alone. The study achieved its primary endpoint of OS in each of the co-primary populations of all randomized patients and patients with PD-L1-positive tumors. Secondary endpoints include progression-free survival, anti-tumor activity, safety, pharmacokinetics, immunogenicity, predictive biomarkers and patient-reported outcomes in the co-primary populations. The safety profile for BAVENCIO in the trial was consistent with that in the JAVELIN monotherapy clinical development program.

Bladder cancer is the tenth most common cancer worldwide. In 2018, there were over half a million new cases of bladder cancer diagnosed, with around 200,000 deaths from the disease globally. UC accounts for about 90% of all bladder cancers. This subtype becomes harder to treat as it advances, spreading through the layers of the bladder wall. For patients with metastatic UC, the five-year relative survival rate is 5%. Combination chemotherapy is currently the first-line standard of care for patients with advanced disease, and while a majority of patients experience high initial response rates, most patients will ultimately experience disease progression within nine months after initiation of treatment. Given the poor prognosis for patients with advanced bladder cancer whose disease progresses after first-line chemotherapy, there is an urgent need for additional treatment options that improve overall survival.

BAVENCIO is a human anti-programmed death ligand-1 (PD-L1) antibody. BAVENCIO has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, BAVENCIO has been shown to release the suppression of the T cell-mediated antitumor immune response in preclinical models.10-12 In November 2014, Merck KGaA, Darmstadt, Germany and Pfizer announced a strategic alliance to co-develop and co-commercialize BAVENCIO.

BAVENCIO® (avelumab) in combination with axitinib is indicated in the US for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

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