Bladder Cancer Breakthrough: Merck/Pfizer’s Bavencio Shows Significant Overall Survival Benefit as First-Line Maintenance Therapy, Set to Transform Clinical Practice

September 22, 2020 /BioonBIOON/ -- Merck KGaA and its partnersPfizer(Pfizer) recently announced that the detailed results of the Phase III JAVELIN Bladder 100 study evaluating the anti-PD-L1 therapy Bavencio (avelumab) for the treatment of urothelial carcinoma (UC) have been published in the New England Journal of Medicine (NEJM) and presented at the 2020 European MedicalTumorsimultaneously presented at the virtual congress of the European Society for Medical Oncology (ESMO).

This June, based on the study results, the United StatesFDAApproval of Bavencio for maintenance treatment in patients with locally advanced or metastatic urothelial carcinoma (UC) whose disease has not progressed following first-line platinum-containing chemotherapy. This indication was granted through real-timeTumorThe RTOR pilot project has been granted priority review, having previously beenFDAGranted Breakthrough Therapy Designation (BTD). Currently, the aforementioned indications for Bavencio are also under regulatory review in the European Union and Japan.

It is worth noting that,Bavencio isFDAThe First Approved Phase III Trial for First-Line Maintenance Therapy in UCClinical Trialsimmunotherapy that has been demonstrated to provide a significant overall survival (OS) benefit.Data from the JAVELIN Bladder 100 study showed that, in all randomized patients andTumorIn the two major subgroups of PD-L1-positive patients, first-line maintenance therapy with Bavencio plus best supportive care (BSC) significantly prolonged overall survival (OS) and significantly improved the one-year survival rate compared with BSC alone. The clinical benefits of Bavencio were demonstrated across a range of patient populations.

Bavencio is an immuneTumorThe drug received accelerated approval from the U.S. FDA in May 2017 for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC), specifically: (1) patients who experienced disease progression during or after platinum-based chemotherapy; (2) patients who experienced disease progression within 12 months after receiving platinum-based chemotherapy in the neoadjuvant (pre-surgical) or adjuvant (post-surgical) setting. JAVELIN Bladder 100 is a confirmatory Phase III study, and based on the results of this study,FDAThe indication for Bavencio in the treatment of UC has been converted from accelerated approval to full approval.

Lead of Solid Tumour Research at the Barts Cancer Institute, Queen Mary University of London, GenitourinaryTumorProfessor Thomas Powles stated, “These data support the recentFDAThe approval and updates to the NCCN and ESMO guidelines demonstrate that first-line maintenance therapy with Bavencio can fundamentally change clinical practice in the treatment of patients with locally advanced or metastatic urothelial carcinoma. Notably, longer overall survival was observed with Bavencio maintenance therapy across all prespecified subgroups, and this improvement in overall survival was achieved without adversely affecting patients’ quality of life.

Bladder Cancer (Image source: medscape.com)

JAVELIN Bladder 100 (NCT02603432) was a multicenter, multinational, randomized, open-label, parallel-group study conducted in patients with locally advanced or metastatic urothelial carcinoma (UC) who had not experienced disease progression after first-line platinum-based chemotherapy. The study evaluated 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 whose disease had not progressed after induction chemotherapy (as assessed by RECIST v1.1) were randomly assigned to receive either Bavencio plus BSC or BSC alone. The primary endpoint was in all randomized patients and PD-L1-positiveTumorOverall Survival (OS) in Patients. In this study, Best Supportive Care (BSC) will be administered 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 local radiotherapy for isolated lesions is acceptable.

The results showed that at the interim analysis, the study had reached the primary endpoint of OS: in the two co-primary populations (all randomized patients, PD-L1 positiveTumorpatients), Bavencio + BSC resulted in a statistically significant improvement in OS compared with BSC alone.

—Among all randomized patients (n=700),Compared with the BSC group, the Bavencio + BSC group demonstrated a significantly prolonged median OS (21.4 months vs. 14.3 months), a 31% reduction in the risk of death (HR = 0.69; 95% CI: 0.56–0.86; p < 0.001), and substantially improved 12-month survival rates (71% vs. 58%) and 18-month survival rates (61% vs. 44%).

——In PD-L1-positiveTumorAmong the patients (n=358),Compared with BSC, Bavencio + BSC demonstrated a greater OS benefit, reducing the risk of death by 44% (HR=0.56; 95% CI: 0.40-0.79; p<0.001), and significantly improving the 12-month survival rate (79.1% vs 60.4%).

—Exploratory subgroup analyses demonstrated consistent efficacy outcomes with first-line maintenance treatment using Bavencio plus best supportive care (BSC) across all prespecified subgroups, including best response to first-line chemotherapy, type of chemotherapy regimen, baseline metastatic sites, and other baseline factors. Specifically: (1) Based on response to first-line chemotherapy, the hazard ratios (HRs) for overall survival (OS) were 0.69 for patients achieving complete or partial response and 0.70 for those with stable disease; (2) By first-line chemotherapy regimen, the HRs for OS were 0.69 for gemcitabine plus cisplatin and 0.66 for gemcitabine plus carboplatin.

In this study, the safety profile of Bavencio was consistent with that observed in the JAVELIN monotherapy clinical development program. According to this study, Bavencio is the firstClinical TrialThe first immunotherapy to achieve a statistically significant improvement in overall survival (OS) as first-line treatment for advanced urothelial carcinoma (UC). For the past 30 years, chemotherapy has been the standard of care 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 additional therapeutic options. Based on the positive overall survival (OS) results from the JAVELIN Bladder 100 study, Bavencio has the potential to change clinical practice.

Globally, bladder cancer is the tenth most common cancer. In 2018, there were over 500,000 newly diagnosed cases of bladder cancer, and approximately 200,000 people worldwide died from the disease. Urothelial carcinoma (UC) accounts for about 90% of bladder cancers. When bladder cancer metastasizes, the 5-year survival rate is only 5%.

Currently, platinum-based chemotherapy is the first-line standard of care for advanced urothelial carcinoma (UC). Despite high initial response rates, durable responses and complete remissions after first-line chemotherapy are uncommon, with most patients ultimately experiencing disease progression within nine months of initiating treatment. Given the poor prognosis following disease progression after first-line chemotherapy in patients with advanced UC, there is an urgent need for additional therapeutic options to prolong 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 fight 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-TumorInhibition of the 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.(Bioon.com)

Original Source: BAVENCIO PIVOTAL PHASE III JAVELIN BLADDER 100 RESULTS PUBLISHED IN THE NEW ENGLAND JOURNAL OF MEDICINE