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 diffuse large B-cell lymphoma.
The overall response rate 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 was achieved in 40 percent of patients and 12 percent achieved a partial response.
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.
In the JULIET study, the relapse-free probability at 12 months after a patient’s first response (n=48) was 65 percent (95% CI, 49%-78%). 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 was not reached for patients in CR (95% 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% CI, 6.6-NE). The median time from infusion to data cutoff was 14 months with a maximum time from infusion of 23 months. At the time of data cutoff, no patients in response following treatment with Kymriah proceeded to stem cell transplant.
Within eight weeks of infusion with Kymriah, Grade III/IV cytokine release syndrome, as defined by the Penn Grading Scale, was reported in 22 percent of patients (14 percent grade III; 8 percent grade IV).
Fifteen percent of patients received tocilizumab for treatment of CRS, including only 3 percent of patients with Grade II CRS and 50 percent of patients with Grade III 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 III/IV cytopenias lasting more than 28 days, grade III/IV infections and grade III/IV febrile neutropenia occurred in 32 percent, 20 percent and 15 percent of patients, respectively.
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, 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 is evaluating the Marketing Authorization Application for Kymriah for the treatment of children and young adults with r/r B-cell acute lymphoblastic leukemia and for adult patients with r/r DLBCL.
JULIET is the first multi-center global registration study for Kymriah in adult patients with r/r DLBCL. JULIET, led by researchers at the University of Pennsylvania, is the largest and only globally conducted study examining a CAR-T cell therapy in DLBCL, enrolling patients from 27 sites in 10 countries across the US, Canada, Australia, Japan and Europe, including Austria, France, Germany, Italy, Norway and the Netherlands. In 2012, Novartis and Penn entered into a global collaboration to further research, develop and commercialize CAR-T cell therapies, including Kymriah, for the investigational treatment of cancers.
