Merck/Pfizer’s Anti-PD-L1 Therapy Bavencio Under Regulatory Review in US, EU, and Japan for First-Line Maintenance Treatment of Locally Advanced or Metastatic Urothelial Carcinoma

June 23, 2020 /Bio ValleyBIOON/ --Pfizer(Pfizer) and its partner Merck KGaA recently announced that the European Medicines Agency (EMA) has accepted a Class II variation application for the anti-PD-L1 therapy Bavencio (avelumab): first-line maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC). The EMA has now initiated the review process.

Earlier this year, the U.S. Food and Drug Administration (FDA) accepted the supplemental Biologics License Application (sBLA) for the above-mentioned indications of Bavencio, which is currently undergoing real-timeTumorPriority review for the Real-Time Oncology Review (RTOR) pilot program. Previously,FDABavencio was also granted Breakthrough Therapy Designation (BTD) for the aforementioned indications. Furthermore, the Japanese Ministry of Health, Labour and Welfare (MHLW) has accepted the supplemental New Drug Application (sNDA) for Bavencio for these indications.

This application is based on the results of the Phase III JAVELIN Bladder 100 study (NCT02603432). The data showed that the study met its primary endpoint: compared with the best supportive care (BSC) group, the Bavencio plus BSC group demonstrated a statistically significant improvement in overall survival (OS). The study data have been presented at the ASCO 2020 Virtual ScientificConferencepublished above. Notably, the JAVELIN Bladder 100 study marked the first time in a Phase III trial that an immunotherapy demonstrated superior overall survival (OS) data compared with standard of care for first-line treatment of locally advanced or metastatic urothelial carcinoma (UC).

Bavencio is an immuno-oncology drug co-developed by Pfizer and Merck, approved in the United States in May 2017FDAAccelerated approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC), specifically: (1) patients who have disease progression during or following platinum-containing chemotherapy; (2) patients who have disease progression within 12 months of receiving platinum-containing chemotherapy in the neoadjuvant or adjuvant setting. This approval is based onTumorRelief Data and Duration of Relief.

The JAVELIN Bladder 100 study is a confirmatory Phase III trial designed to support the conversion of Bavencio’s indication for urothelial carcinoma (UC) from accelerated approval to full approval.

Bladder Cancer (Image source: medscape.com)

JAVELIN Bladder 100 is a multicenter, multinational, randomized, open-label, parallel-group study conducted in patients with locally advanced or metastatic urothelial carcinoma (UC) who did not experience disease progression after first-line platinum-based chemotherapy, to evaluate the efficacy and safety of Bavencio combined with best supportive care (BSC) versus BSC alone as first-line maintenance therapy. In the study, a total of 700 patients who did not experience disease progression after induction chemotherapy (assessed according to RECIST v1.1) were randomly assigned to either the Bavencio plus BSC group or the BSC-alone group. The primary endpoint was overall survival in all randomized patients and in PD-L1-positiveTumorOverall Survival (OS) in Patients.

In this study, BSC will be implemented at the discretion of the treating physician and may includeAntibioticsTreatment, nutritional support, correction of metabolic disorders, optimization of symptom control and pain management (including palliative radiotherapy), etc. BSC does not include any active anti-TumorTreatment, but localized radiation therapy for isolated lesions is acceptable.

The results showed that at the interim analysis, the study had reached its primary endpoint of OS: in two co-primary populations (all randomized patients and patients with PD-L1-positive tumors), Bavencio plus BSC resulted in a statistically significant improvement in OS compared to BSC alone. Specifically, among all randomized patients, the median OS was significantly prolonged in the Bavencio plus BSC group compared to the BSC group (21.4 months vs. 14.3 months), with a 31% reduction in the risk of death (HR=0.69; 95% CI: 0.56–0.86; p<0.001). The 12-month survival rate (71% vs. 58%) and 18-month survival rate (61% vs. 44%) were also substantially improved. In PD-L1-positiveTumorAmong patients, Bavencio + BSC demonstrated a greater OS benefit compared with BSC alone, reducing the risk of death by 44%. In this study, the safety profile of Bavencio was consistent with that observed in the JAVELIN monotherapy clinical development program.

According to the study, Bavencio is the firstClinical TrialsThe first-line immunotherapy for advanced UC in China to achieve statistically significant improvement in OS. For the past 30 years, chemotherapy has been the standard of care as first-line treatment for patients with advanced urothelial carcinoma. Although this is an effective short-term option for many patients, most will eventually experience disease progression, highlighting the need for more treatment options. Based on the positive overall survival (OS) results from the JAVENLIN Bladder 100 study, Bavencio has the potential to change clinical practice.

Bladder cancer is the tenth most common cancer worldwide. In 2018, there were over 500,000 newly diagnosed cases of bladder cancer, and approximately 200,000 people died from the disease globally. Urothelial carcinoma (UC) accounts for about 90% of bladder cancers. When bladder cancer metastasizes, the 5-year survival rate is only 5%. Combination chemotherapy is currently the first-line standard of care for advanced disease; however, although initial response rates are high, durable and complete responses after first-line chemotherapy are uncommon, with most patients ultimately experiencing disease progression within 9 months of initiating treatment. Given the poor prognosis and disease progression in patients with advanced bladder cancer following first-line chemotherapy, there is an urgent need for additional therapeutic options to improve overall survival.

Bavencio belongs to the class of PD-(L)1 tumor immunotherapies, a currently highly regarded category of cancer immunotherapy designed to harness the body’s own immune system to combat cancer. By blocking the PD-1/PD-L1 signaling pathway, it induces cancer cell death and holds potential for treating various types of tumors. Bavencio has been demonstrated in preclinical models to engage both adaptive and innate immune responses. By blocking the interaction between PD-L1 and the PD-1 receptor, Bavencio has been shown in preclinical models to release T cell-mediated anti-TumorInhibitory Effect on Immune Response.

In November 2014, Pfizer entered into an agreement worth up to $2.85 billion with Merck KGaA to enter the PD-(L)1 field. Currently, both parties are advancing the JAVELIN clinical development program, which involves more than 15 different types of tumors and over 10,000 patients. In addition to gastric/gastroesophageal junction adenocarcinoma, theseTumorTypes also include: ovarian cancer,Breast Cancer, head and neck cancer, Merkel cell carcinoma, non-small cell lung cancer, renal cell carcinoma, and urothelial carcinoma, etc.

In the United States, Bavencio was approved in March 2017FDAAccelerated approval for the treatment of metastatic Merkel cell carcinoma (mMCC) in pediatric patients aged 12 years and older and adults, making this drug the first globally approved therapy for mMCC.TumorImmunotherapy, a type of therapy that is moreMelanomaAggressive skin cancer with a poorer prognosis. In May 2017, Bavencio received accelerated approval from the U.S. FDA for: (1) patients with locally advanced or metastatic urothelial carcinoma (mUC) who experienced disease progression during or after platinum-containing chemotherapy; and (2) patients with locally advanced or metastatic urothelial carcinoma (mUC) who experienced disease progression within 12 months of receiving platinum-containing chemotherapy in the neoadjuvant (pre-surgical) or adjuvant (post-surgical) setting. In May 2019, the combination regimen of Bavencio and the tyrosine kinase inhibitor Inlyta (axitinib) was approvedFDAApproved for the first-line treatment of patients with advanced renal cell carcinoma (RCC). (Bioon.com)

Original source: European Medicines Agency Validatesapplication for BAVENCIO® (avelumab) for First-Line Maintenance Treatment of Locally Advanced or Metastatic Urothelial Carcinoma