Merck (MRK) Reports Pivotal Phase III Data for BAVENCIO (avelumab) Plus INLYTA (axitinib) in Advanced RCC Published in New England Journal of Medicine (Earlier)

February 19, 2019 5:54 AM

Merck (NYSE: MRK) which operates its biopharmaceutical business as EMD Serono in the US and Canada, and Pfizer Inc. (NYSE: PFE) today announced the publication of results from an interim analysis of the pivotal JAVELIN Renal 101 trial online in the New England Journal of Medicine.1 The combination of BAVENCIO® (avelumab) and INLYTA® (axitinib)* significantly extended median progression-free survival (PFS) by more than five months compared with SUTENT® (sunitinib) as a first-line treatment for patients with advanced renal cell carcinoma (RCC), irrespective of PD-L1 expression (HR: 0.69 [95% CI: 0.56–0.84]; BAVENCIO+INLYTA: 13.8 months [95% CI: 11.1-NE]; SUTENT: 8.4 months [95% CI: 6.9-11.1]; p<0.001). Further, the objective response rate (ORR) was doubled with BAVENCIO+INLYTA versus SUTENT in this population (51.4% [95% CI: 46.6-56.1] vs. 25.7% [95% CI: 21.7-30.0]). The study is continuing for the other primary endpoint of overall survival (OS).

"There is a significant need for patients with advanced RCC to prolong the time until the disease worsens beyond what tyrosine kinase inhibitors alone offer," 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. "The magnitude and consistency of PFS and response rates seen thus far across populations in the JAVELIN Renal 101 study suggest that many different types of patients, including those with a favorable prognosis, could potentially derive benefit from this particular combination."

Additional data presented today at the 2019 Genitourinary Cancers Symposium reinforce the consistency of the PFS and ORR results across patient subgroups, including patients with favorable, intermediate and poor prognoses as well as those with PD-L1-positive or negative tumors. In subgroup analyses, approximately two-thirds of patients with favorable risk (66% of patients using the Memorial Sloan Kettering Cancer Center risk model and 68% with the International Metastatic Renal Cell Carcinoma Database Consortium risk model) achieved a complete or partial response with BAVENCIO+INLYTA. Median PFS for these patients is not yet estimable. BAVENCIO+INLYTA also extended median PFS2, defined as the time from randomization to disease progression on next-line therapy (HR: 0.56 [95% CI: 0.42-0.74]; NE [95% CI: 19.9-NE] vs. 18.4 months [95% CI: 15.7-23.6]) and increased median duration of response by more than four months (95% CI: 2.9-5.1) in the overall population.

"In this study, the combination of avelumab plus axitinib not only prolonged the initial response in treated patients compared to sunitinib, but for patients who went on to subsequent therapy, reduced the risk of disease progression or death on the next treatment," said Toni K. Choueiri, M.D., Director of the Lank Center for Genitourinary Oncology at Dana-Farber, Boston, US, senior and co-corresponding author of JAVELIN Renal 101, and presenter. "Together with the progression-free survival results and objective response rates, these findings show the potential of this combination regimen to be an important new treatment option for patients with advanced RCC."

The Phase III JAVELIN Renal 101 study is evaluating the combination of BAVENCIO+INLYTA compared with SUTENT in 886 patients with previously untreated advanced RCC. BAVENCIO+INLYTA significantly reduced the risk of disease progression or death by 39% in patients with PD-L1-positive (≥1%) tumors, a primary endpoint (HR: 0.61 [95% CI: 0.47–0.79], p<0.001; median PFS: 13.8 months [95% CI: 11.1-NE] vs. 7.2 months [95% CI: 5.7-9.7]). In the overall population, which was tested after achieving statistical significance for the primary endpoint, the risk was reduced by 31%. The confirmed ORR in patients with PD-L1-positive tumors was 55.2% (95% CI: 49.0-61.2) with BAVENCIO+INLYTA vs. 25.5% (95% CI: 20.6-30.9) with SUTENT.

In the BAVENCIO+INLYTA arm, 20.8% of patients received subsequent anticancer drug therapies, compared with 39.2% in the SUTENT arm. In the SUTENT arm, about two-thirds (66.7%) of patients who received subsequent anticancer therapy were known to have been treated with an anti–PD-1/PD-L1 agent.

Adverse events of grade 3 or higher during treatment (treatment-emergent adverse events [TEAEs]) occurred in 71.2% of patients in the BAVENCIO+INLYTA arm and 71.5% in the SUTENT arm; grade 3 or higher TEAEs that occurred in more than 5% of patients receiving the combination were hypertension (25.6%), diarrhea (6.7%), increased alanine aminotransferase level (6.0%) and hand–foot syndrome (5.8%). In the combination arm, 9.0% of patients experienced grade 3 or higher immune-related adverse events. Grade 5 events occurred in three patients in the BAVENCIO+INLYTA arm (myocarditis, necrotizing pancreatitis, sudden death; n=1 each); and in one patient in the SUTENT arm (intestinal perforation). There were fewer discontinuations due to adverse events that occurred during treatment with BAVENCIO+INLYTA, compared with SUTENT (7.6% vs. 13.4%).

On February 11, 2019, the alliance announced that the US Food and Drug Administration (FDA) accepted for Priority Review the supplemental Biologics License Application (sBLA) for BAVENCIO in combination with INLYTA for patients with advanced RCC. The application has been given a target action date in June 2019. A supplemental application for BAVENCIO+INLYTA in unresectable or metastatic RCC was submitted in Japan on January 30, 2019. In December 2017, the FDA granted Breakthrough Therapy Designation for BAVENCIO in combination with INLYTA for treatment-naïve patients with advanced RCC. Despite available therapies, the outlook for patients with advanced RCC remains poor.2

*The combination of BAVENCIO and INLYTA is under clinical investigation for advanced RCC, and there is no guarantee this combination will be approved for advanced RCC by any health authority worldwide. In the US, INLYTA is approved as monotherapy for the treatment of advanced RCC after failure of one prior systemic therapy. INLYTA is also approved by the European Medicines Agency (EMA) for use in the EU in adult patients with advanced RCC after failure of prior treatment with SUTENT or a cytokine.

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