Novartis JULIET Trial of Kymriah Demonstrates More Than 1-year Durability of Responses

Novartis announced 14-month results from the pivotal JULIET clinical trial showing ongoing durable responses are achievable with Kymriah (tisagenlecleucel) when administered to adult patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL). The overall response rate (ORR) was 52 percent (95 percent confidence interval [CI], 41 percent – 62 percent), among 93 evaluable patients who were followed for at least 3 months or discontinued earlier. A complete response (CR) was achieved in 40 percent of patients and 12 percent achieved a partial response (PR). Of the patients in CR at month 3, 83 percent remained in CR at month 12, and the median duration of response was not reached, indicating sustainability of response. These data will be presented in an oral presentation at the 23rd Annual Congress of the European Hematology Association (EHA).

“Advanced aggressive lymphoma patients who once faced a poor prognosis now have the possibility of sustained remission after a single course of therapy – a previously unimaginable and revolutionary breakthrough,” said the lead author of the updated JULIET analysis Peter Borchmann, MD, Department of Internal Medicine, University Hospital of Cologne, Germany. “With 14 months of data from JULIET, we are seeing that Kymriah may continue to redefine outcomes for patients with relapsed or refractory DLBCL.” In the JULIET study, the relapse-free probability at 12 months after a patient’s first response (n=48) was 65 percent (95 percent CI, 49 percent-78 percent). In fact, 54 percent (13/24) of patients who had achieved a PR converted to CR, including two patients between months 9 and 12. Median overall survival (OS) was not reached for patients in CR (95 percent CI, 17.9-NE). The OS rate at 12 months was 49 percent and median OS was 11.7 months among all infused patients (n=111) (95 percent CI, 6.6-NE). The median time from infusion to data cut off was 14 months with a maximum time from infusion of 23 months. At the time of data cut-off, no patients in response following treatment with Kymriah proceeded to stem cell transplant.

“These results from JULIET continue to show Kymriah delivers strong efficacy with durable responses, and a predictable and consistent safety profile more than a year after infused in patients with advanced DLBCL,” said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. “Novartis is committed to bringing this important and innovative treatment option to more patients around the world.” Within eight weeks of infusion with Kymriah, Grade 3/4 cytokine release syndrome (CRS), as defined by the Penn Grading Scale – a rigorous scale for grading CRS –, was reported in 22 percent of patients (14 percent grade 3; 8 percent grade 4). Fifteen percent of patients received tocilizumab for treatment of CRS, including only 3 percent of patients with Grade 2 CRS and 50 percent of patients with Grade 3 CRS. CRS is a known complication of CAR-T therapy that may occur when the engineered cells become activated in the patient’s body. CRS was managed globally using prior site education on implementation of the CRS treatment algorithm. No deaths due to cerebral edema were reported. In this analysis, 12 percent of patients had grade 3/4 neurologic adverse events, which were managed with supportive care. Grade 3/4 cytopenias lasting more than 28 days, grade 3/4 infections and grade 3/4 febrile neutropenia occurred in 32 percent, 20 percent and 15 percent of patients, respectively.

“When we continued follow-up with DLBCL patients in the global JULIET study, we were extremely pleased that response rates were maintained a year or more after infusion with Kymriah, which was consistent with the durable responses seen in the pilot studies conducted at Penn,” said Stephen J. Schuster, MD, the Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma Clinical Care and Research in Penn’sPerelman School of Medicine and director of the Lymphoma Program at the Abramson Cancer Center. “We look forward to continuing to follow these patients who we hope will remain in remission from their disease.” Analyses to better characterize and predict severe CRS and neurologic events, including relationships with baseline clinical and laboratory parameters, dose and cellular kinetics will also be presented. Fifty patients discontinued before infusion and the majority did so due to rapid progression of their disease or deterioration in their clinical status reflecting the acute and progressive nature of r/r DLBCL. Twelve out of 165 (7.3 percent) enrolled patients could not be infused due to inability to manufacture an adequate dose of CAR-T cells.

In May 2018, the US Food and Drug Administration (FDA) approved Kymriah for the treatment of adult patients with r/r large B-cell lymphoma after two or more lines of systemic therapy including DLBCL, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma based on data from the JULIET study. Kymriah is not approved for the treatment of patients with primary central nervous system lymphoma. The European Medicines Agency (EMA) is evaluating the Marketing Authorization Application (MAA) for Kymriah for the treatment of children and young adults with r/r B-cell acute lymphoblastic leukemia (ALL) and for adult patients with r/r DLBCL. – Medical Buyer Bureau