The approval of BAVENCIO in combination with INLYTA was based on positive results from the Phase III JAVELIN Renal 101 study (NCT02684006), in which the combination significantly improved median progression-free survival (PFS) compared with sunitinib by more than five months in the intent-to-treat (ITT) patient population (HR: 0.69 [95% CI: 0.56–0.84]; 2-sided p-value=0.0002; median PFS for BAVENCIO in combination with INLYTA: 13.8 months [95% CI: 11.1-NE]; sunitinib: 8.4 months [95% CI: 6.9-11.1]). The ITT population included patients regardless of PD-L1 expression and across IMDC (International Metastatic Renal Cell Carcinoma Database) prognostic risk groups (favorable 21%, intermediate 62% and poor 16%). 
"As we look to continue to improve outcomes for people with advanced RCC, new treatment approaches have the potential to benefit patients," said Robert J. Motzer, M.D., Jack and Dorothy Byrne Chair in Clinical Oncology, Memorial Sloan Kettering Cancer Center, New York, US, and principal investigator for JAVELIN Renal 101. "With today's FDA approval of avelumab in combination with axitinib, we can now offer patients with advanced RCC a first-line treatment option that combines a PD-L1 immunotherapy with a well-known VEGFR TKI to provide a significant reduction in the risk of disease progression or death and doubling of the response rate compared with sunitinib."RCC is a type of cancer where PD-L1 expression may contribute to inhibition of the immune response against the tumor.  It is also a highly vascular tumor, in which vascular endothelial growth factor (VEGF) plays a key role.
"A kidney cancer diagnosis is life-changing for both patients and their loved ones, and having a treatment strategy for their disease quickly becomes a priority," said Dena Battle, President, KCCure. "The approval of new treatments such as BAVENCIO in combination with INLYTA gives patients with advanced RCC much-needed options."There is a significant unmet need for first-line treatments that delay progression and have an acceptable safety profile. Approximately 20% to 30% of patients are first diagnosed with RCC at the advanced stage, and 30% of patients treated for an earlier stage go on to develop metastases.4,5 About half of patients living with advanced RCC do not go on to receive additional treatment after first-line therapy, [6,7] for reasons that may include poor performance status or adverse events from their initial treatment. [6,8,9]
"Today's approval of BAVENCIO in combination with INLYTA builds on Pfizer's long heritage in bringing innovation to the RCC community with the hopes of making a significant and meaningful impact on the lives of patients," said Andy Schmeltz, Global President, Pfizer Oncology. "For more than 12 years, Pfizer has led the field in its commitment to developing new treatments for patients with advanced kidney cancer."
"With today's FDA approval of BAVENCIO in combination with INLYTA, we feel privileged that we can offer patients with first-line advanced renal cell carcinoma a new treatment option," said Rehan Verjee, President, EMD Serono, and Global Head of Innovative Medicine Franchises, Merck KGaA, Darmstadt, Germany.In JAVELIN Renal 101, the objective response rate (ORR) was doubled in the ITT population with BAVENCIO in combination with INLYTA versus sunitinib (51.4% [95% CI: 46.6-56.1] vs. 25.7% [95% CI: 21.7-30.0]). With a median overall survival (OS) follow-up of 19 months, data for the trial's other primary endpoint of OS were immature, with 27% of deaths in the ITT population, and the trial is continuing as planned. The most common adverse reactions (≥20%) were diarrhea, fatigue, hypertension, musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia, dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal pain, and headache. Serious adverse reactions occurred in 35% of patients receiving BAVENCIO in combination with INLYTA. The incidence of major adverse cardiovascular events (MACE) was higher with BAVENCIO in combination with INLYTA versus sunitinib.1 Findings from the study have been published in The New England Journal of Medicine.
The European Medicines Agency (EMA) validated the Type II variation application for BAVENCIO in combination with INLYTA in advanced RCC in March 2019, and a supplemental application for BAVENCIO in combination with INLYTA in unresectable or metastatic RCC was submitted in Japan in January 2019.
About Renal Cell Carcinoma:
In 2019, an estimated 73,820 new cases of kidney cancer will be diagnosed in the US, and approximately 14,770 people will die from the disease. RCC is the most common form of kidney cancer, accounting for about 2% to 3% of all cancers in adults.[12,13] Approximately 20% to 30% of patients with kidney cancer are first diagnosed at the advanced stage.4 The five-year survival rate for patients with metastatic RCC is approximately 12%. 
About the JAVELIN Renal 101 study:
The Phase III JAVELIN Renal 101 study is a randomized (1:1), multicenter, open-label study of BAVENCIO in combination with INLYTA in 886 patients with untreated advanced RCC regardless of tumor PD-L1 expression [intent-to-treat (ITT) population]. Patients with autoimmune disease or conditions requiring systemic immunosuppression were excluded. The major efficacy outcome measures were PFS as assessed by a Blinded Independent Central Review (BICR) using RECIST v1.1 and OS in patients with PD-L1-positive tumors using a clinical trial assay (PD-L1 expression level ≥1%). If PFS was statistically significant in patients with PD-L1-positive tumors, it was then tested in the ITT population. The hazard ratio for PFS in patients with PD-L1-positive tumors was HR 0.61 (95% CI: 0.48, 0.79). PFS and OS in the ITT population, overall response and safety are included as secondary endpoints. The study is continuing for OS.
About BAVENCIO® (avelumab):
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. [15-17] BAVENCIO has also been shown to induce NK cell-mediated direct tumor cell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. [17-19] In November 2014, EMD Serono and Pfizer announced a strategic alliance to co-develop and co-commercialize BAVENCIO.
1. BAVENCIO Prescribing Information. Rockland, MA: EMD Serono Inc.; 2019.
2. Weinstock M and McDermott D. Targeting PD-1/PD-L1 in the treatment of metastatic renal cell carcinoma. Therapeutic Advances in Urology. 2015;7(6):365-377.
3. Roskoski R Jr. Vascular endothelial growth factor (VEGF) and VEGF receptor inhibitors in the treatment of renal cell carcinomas. Pharmacological Research. 2017;120:116-132.
4. Ljungberg B, Campbell S and Cho H. The Epidemiology of renal cell carcinoma. European Urology. 2011;60:615-621.
5. Klatte T, Rossi SH, Stewart GD. Prognostic factors and prognostic models for renal cell carcinoma: a literature review. World Journal of Urology. 2018;36(12):1943-1952.
6. Eggers H, Ivanyi P, Hornig M and Grünwald V. Predictive Factors for Second-Line Therapy in Metastatic Renal cell Carcinoma: A Retrospective Analysis. Journal of Kidney Cancer and VHL. 2017;4(1):8-15.
7. Motzer R, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. The New England Journal of Medicine. 2018;378:1277-1290.
8. Eichelberg C, et al. SWITCH: A Randomised, Sequential, Open-label Study to Evaluate the Efficacy and Safety of Sorafenib-sunitinib Versus Sunitinib-sorafenib in the Treatment of Metastatic Renal Cell Cancer. European Urology. 2015;68:837-847.
9. Motzer R, et al. Phase II Randomized Trial Comparing Sequential First-Line Everolimus and Second-Line Sunitinib Versus First-Line Sunitinib and Second-Line Everolimus in Patients With Metastatic Renal Cell Carcinoma. Journal of Clinical Oncology. 2014;32:2765-2772.
10. Motzer R, et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal Cell Carcinoma. The New England Journal of Medicine. 2019;380:1103-1115.
11. American Cancer Society: Key Statistics about Kidney Cancer. Available from: https://www.cancer.org/cancer/kidney-cancer/about/key-statistics.html. Accessed May 2019.
12. American Cancer Society: What is Kidney Cancer? Available from: https://www.cancer.org/cancer/kidney-cancer/about/what-is-kidney-cancer.html. Accessed May 2019.
13. Ljungberg B, et al. European Association of Urology Guidelines on Renal Cell Carcinoma: The 2019 Update. European Urology. 2019 Feb.
14. National Cancer Institute: SEER Cancer Stat Fact Sheets: Kidney and Renal Pelvis. Available from: https://seer.cancer.gov/statfacts/html/kidrp.html. Accessed May 2019.
15. Dolan DE, Gupta S. PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy. Cancer Control. 2014;21(3):231-237.
16. Dahan R, Sega E, Engelhardt J, Selby M, Korman AJ, Ravetch JV. FcγRs modulate the anti-tumor activity of antibodies targeting the PD-1/PD-L1 axis. Cancer Cell. 2015;28(3):285-295.
17. Boyerinas B, Jochems C, Fantini M, et al. Antibody-dependent cellular cytotoxicity activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells. Cancer Immunology Research. 2015;3(10):1148-1157.
18. Kohrt HE, Houot R, Marabelle A, et al. Combination strategies to enhance antitumor ADCC. Immunotherapy. 2012;4(5):511-527.
19. Hamilton G, Rath B. Avelumab: combining immune checkpoint inhibition and antibody-dependent cytotoxicity. Expert Opinion on Biological Therapy. 2017;17(4):515-523.
Source: Merck KGaA