Merck/Pfizer Bavencio Maintenance Treatment Phase III Is Significantly Better Than Standard Care, Prolonging Patient Survival!

- Jun 22, 2020-

Pfizer and partner Merck KGaA recently announced the anti-PD-L1 therapy Bavencio (avelumab) first-line maintenance treatment for locally advanced or metastatic urothelial carcinoma (UC) phase III JAVELIN Bladder 100 study (NCT02603432) mid-term Analysis of overall survival (OS) results. The data shows that the study reached the primary endpoint: Bavencio combined with BSC significantly prolonged the OS compared to best supportive care (BSC). It is worth mentioning that the JAVELIN Bladder 100 study marked the first time in a phase III trial that there was an immunotherapy showing first-line treatment of locally advanced or metastatic UC with OS data superior to standard care.

Bavencio is an immuno-oncology drug jointly developed by Pfizer and Merck. It was approved by the US FDA in May 2017 for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC), specifically: (1) containing Patients whose disease progressed during or after platinum chemotherapy; (2) Patients who underwent platinum-based chemotherapy before surgery (neoadjuvant therapy) or after surgery (adjuvant therapy) within 12 months. The approval is based on tumor response data and duration of response.

The JAVELIN Bladder 100 study is a confirmatory phase III study designed to support the transition from accelerated approval to full approval of Bavencio's treatment of UC indications. In April of this year, based on the positive results of the mid-term analysis of the study, Pfizer and Merck submitted a supplementary biological product license application (sBLA) to the US FDA: Bavencio was used as first-line maintenance treatment for patients with locally advanced or metastatic UC. At the same time, FDA has granted Bavencio a breakthrough drug qualification (BTD) for this indication, and the sBLA is currently under review by the FDA under the real-time oncology review (RTOR) pilot project.

JAVELIN Bladder 100 is a multi-center, multi-country, randomized, open-label, parallel group study conducted in patients with locally advanced or metastatic UC who have not progressed after completing first-line platinum-containing chemotherapy and evaluated Bavencio in conjunction with best supportive care ( BSC) and BSC alone are used to maintain the efficacy and safety of first-line maintenance therapy. In the study, a total of 700 patients who did not progress after induction chemotherapy (according to RECIST v1.1 evaluation) were randomly assigned to the Bavencio+BSC treatment group or the BSC treatment group. The primary end point was the overall survival (OS) in all randomized patients and patients with PD-L1 positive tumors.

In this study, BSC will be implemented by the treating doctor as appropriate, and may include antibiotic treatment, nutritional support, correction of metabolic disorders, optimal symptom control and pain management (including palliative radiotherapy). BSC does not include any active anti-tumor treatment, but localized radiation therapy for dividends is acceptable for isolated lesions.

The results showed that at the mid-term analysis, the study had reached the primary endpoint of OS: in 2 co-primary groups (all randomized patients, PD-L1-positive tumor patients), compared with BSC, Bavencio+BSC made OS statistical Significant improvement in meaning. The specific data are: in all randomized patients, compared with the BSC group, the median OS in the Bavencio+BSC group was significantly prolonged (21.4 months vs 14.3 months), and the risk of death was reduced by 31% (HR=0.69; 95% CI: 0.56-0.86; p<0.001), 12-month survival rate (71% vs 58%) and 18-month survival rate (61% vs 44%) have increased significantly. Among patients with PD-L1 positive tumors, Bavencio+BSC showed a greater OS benefit and reduced the risk of death by 44% compared with BSC. In this study, the safety of Bavencio was consistent with the JAVELIN single drug clinical development project.

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

Globally, bladder cancer is the tenth most common cancer. In 2018, there were more than 500,000 newly diagnosed bladder cancer cases, and about 200,000 people worldwide died from bladder cancer. Urothelial carcinoma (UC) accounts for approximately 90% of bladder cancers. When bladder cancer metastasizes, the 5-year survival rate is only 5%. Combination chemotherapy is currently the first-line standard for the treatment of advanced disease. Although the initial response rate is high, sustained and complete remission after first-line chemotherapy is not common. Most patients will eventually develop disease within 9 months after starting treatment. Considering the poor progression of patients with advanced bladder cancer after first-line chemotherapy, additional treatment options are urgently needed to improve overall survival.

Bavencio belongs to PD-(L)1 tumor immunotherapy, which is currently a high-profile type of tumor immunotherapy, which aims to use the body's own immune system to resist cancer and block cancer by blocking the PD-1/PD-L1 signaling pathway. Cell death has the potential to treat many types of tumors. Bavencio has been shown to participate in both adaptive immunity and innate immune function in preclinical models. By blocking the interaction between PD-L1 and PD-1 receptors, Bavencio has been shown to release inhibitory effects on T cell-mediated anti-tumor immune responses in preclinical models.

Pfizer and Merck signed an agreement of up to 2.85 billion US dollars in November 2014 to enter the PD-(L)1 field. Currently, both parties are advancing the JAVELIN clinical development project, which involves more than 10,000 patients with more than 15 different types of tumors. In addition to the gastric/gastroesophageal junction adenocarcinoma, these tumor types also include: ovarian cancer, breast cancer, head and neck cancer, Merkel cell carcinoma, non-small cell lung cancer, renal cell carcinoma, and urothelial carcinoma.

In the United States, Bavencio received accelerated FDA approval in March 2017 for the treatment of pediatric and adult metastatic Merkel cell carcinoma (mMCC) aged 12 years and older. This approval makes the drug the world’s first treatment of mMCC Tumor immunotherapy, which is an aggressive skin cancer with a worse prognosis than melanoma. In May 2017, Bavencio received accelerated approval from the US FDA for: (1) patients with locally advanced or metastatic urothelial carcinoma (mUC) who progressed during or after platinum-containing chemotherapy; (2) before surgery (new Adjuvant therapy) or after surgery (adjuvant therapy) patients with locally advanced or metastatic urothelial carcinoma (mUC) who received platinum-containing chemotherapy within 12 months of progression. In May 2019, the combined treatment plan of Bavencio and tyrosine kinase inhibitor Inlyta (axitinib, axitinib) was approved by the FDA for the first-line treatment of patients with advanced renal cell carcinoma (RCC).