Late Breaking Abstract – ESMO 2018 First Line BAVENCIO® plus INLYTA® Highly Effective in Advanced Renal Cell Carcinoma

SUMMARY: The American Cancer Society estimates that 73,820 new cases of kidney and renal pelvis cancers will be diagnosed in the United States in 2019 and about 14,770 people will die from the disease. Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer and is about twice as common in men as in women. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five year survival of patients with advanced RCC is less than 10% and there is significant unmet need for improved therapies for this disease. SUTENT® (Sunitinib) is a MultiKinase Inhibitor (MKI) which simultaneously targets the tumor cell wall, vascular endothelial cell wall as well as the pericyte/fibroblast/vascular/ smooth vessel cell wall and is capable of specifically binding to tyrosine kinases, inhibiting the earlier signaling events and thereby inhibits phosphorylation of VEGF receptor, PDGF receptor, FLT-3 and c-KIT. SUTENT® is the standard first-line intervention for treatment naïve patients with advanced RCC. In a large, multi-center, randomized, phase III study, the median Progression Free Survival (PFS) with SUTENT® was 9.5 months, the Objective Response Rate (ORR) was 25%, and the median Overall Survival was 29.3 months, when compared with Interferon Alfa, in patients with treatment-naïve Renal Cell Carcinoma. This was however associated with a high rate of hematological toxicities.International-Metastatic-RCC-Database-Consortium-(IMDC)

BAVENCIO® (Avelumab) is a human, immunoglobulin G1 lambda, PD-L1 targeted monoclonal antibody that binds to PD-L1 and blocks the interaction between PD-L1 and its receptors PD-1. This in turn negates the inhibitory effects of PD-L1 on the immune response by unleashing the immune system and restoring antitumor immune responses. In addition, BAVENCIO® induces Antibody Dependent Cell-mediated Cytotoxicity (ADCC). INLYTA® (Axitinib) is a kinase inhibitor and inhibits receptor tyrosine kinases including Vascular Endothelial Growth Factor Receptors (VEGFR)-1, VEGFR-2, and VEGFR-3. These receptors have been implicated in pathologic angiogenesis, tumor growth, and cancer progression. INLYTA® is approved by the FDA for the treatment of advanced Renal Cell Carcinoma (RCC) after failure of one prior systemic therapy. The rationale behind combining these two agents was that BAVENCIO® stimulates the immune system while INLYTA® inhibits tumor neoangiogenesis by preventing VEGF activity. Preclinical data suggested that combining these two agents is effective, as their mechanisms of action complement each other. A combination of BAVENCIO® and INLYTA® also showed encouraging antitumor activity among patients with advanced RCC in a phase 1b trial.Unleashing-T-Cell-Function-with-PD-1-and-PD-L1-Antibodies

JAVELIN Renal 101 is a global, randomized phase III trial in which 886 patients with clear cell advanced Renal Cell Carcinoma who had no prior systemic therapy, were randomly assigned in a 1:1 to receive BAVENCIO® 10 mg/kg IV every 2 weeks along with INLYTA® 5 mg orally twice daily, in 6 week cycles (N=442) or SUTENT® 50 mg orally daily, 4 weeks on followed by 2 weeks off (N=444). This study included all MSKCC (Memorial Sloan Kettering Cancer Center) prognostic subgroups (good, intermediate, and poor risk). According to the IMDC (International Metastatic RCC Database Consortium), 21% were in the favorable risk group, 62% were in the Intermediate risk group and 16% were in the poor risk group. Among the enrolled patients, 63.2% (N=560) patients were PD-L1positive (1% or more positive immune cells) of whom 270 patients received the BAVENCIO® and INLYTA® combination whereas 290 patients received SUTENT®. The Primary endpoints were Progression Free Survival (PFS) and Overall Survival (OS) in the PD-L1 positive group and Secondary endpoints included PFS and OS irrespective of PD-L1 expression, Objective Response Rate (ORR) and Safety.

It was noted that in the patient group with PD-L1 positive tumors, the median PFS was 13.8 months in the combination group compared to 7.2 months in the single agent SUTENT® group (HR=0.61; P<0.0001). The median PFS in patients irrespective of PD-L1 expression was 13.8 months with the combination treatment compared to 8.4 months with SUTENT® (HR=0.69; P=0.0001). The confirmed Objective Response Rate (ORR) among those with PD-L1 positive tumors was 55.2% in the combination group and 25.5% in the SUTENT® group. The benefit with combination treatment was noted in all prognostic risk groups. The OS data were immature at the time of data cutoff. Grade 3 or more treatment related adverse events were similar in both treatment groups and led to discontinuation of drug in 22.8% of patients in the combination group versus 13.4% in the SUTENT® group.

It was concluded that a combination of BAVENCIO® given along with INLYTA® significantly improved Progression Free Survival as well as Objective Response Rate, irrespective of PD-L1 expression, and across all prognostic risk groups. The authors added that these results support this combination as a potential new first line standard of care for patients with advanced Renal Cell Carcinoma. JAVELIN Renal 101: a randomized, phase III study of avelumab + axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma (aRCC). Motzer RJ, Penkov K, Hannen JBAG, et al. Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA6_PR.