Novartis has 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% (95% confidence interval [CI], 41% - 62%), among 93 evaluable patients who were followed for at least 3 months or discontinued earlier. A complete response (CR) was achieved in 40% of patients and 12% achieved a partial response (PR). Of the patients in CR at month 3, 83% remained in CR at month 12, and the median duration of response was not reached, indicating sustainability of response. These data presented in an oral presentation at the 23rd annual congress of the European Haematology 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% (95% CI, 49%-78%). In fact, 54% (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% CI, 17.9-NE). The OS rate at 12 months was 49% 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.

"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% of patients (14% grade 3; 8% grade 4). Fifteen per cent of patients received tocilizumab for treatment of CRS, including only 3% of patients with Grade 2 CRS and 50% 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% 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%, 20% and 15% 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's Perelman school of medicine and director of the lymphoma programme 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%) 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.

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.

DLBCL is the most common form of non-Hodgkin lymphoma, a cancer of the lymphatic system, accounting for up to 40% of all NHL cases globally. An estimated 27,650 new cases of DLBCL were diagnosed in the US in 2016. The crude incidence of DLBCL in Europe per year is 3.8 cases per 100,000 people, and incidence increases with age and varies considerably across Europe. Roughly one-third of patients with DLBCL relapse after receiving first-line treatment. Out of those patients diagnosed with DLBCL, about 10% have refractory disease and about 75% of patients who relapse or are refractory to treatment are ineligible for ASCT. For patients who relapse or don't respond to initial therapy, there are limited treatment options that provide durable responses and median life expectancy is approximately six months.

Kymriah is manufactured for each individual patient using their own cells at the Novartis Morris Plains, New Jersey facility. The reliable and integrated manufacturing and supply chain platform for Kymriah allows for an individualized treatment approach on a global scale. The process includes cryopreservation of a patient's harvested (or leukapheresed) cells, giving treating physicians and centers the flexibility to initiate therapy with Kymriah based on the individual patient's condition. Novartis has significant CAR-T manufacturing experience and has demonstrated a reproducible product. Novartis has manufactured CAR-T cells for more than 300 patients from 11 countries. Novartis continues to advance its CAR-T manufacturing expertise in Morris Plains.