Novartis announced updated results from the JULIET clinical trial demonstrating sustained responses with Kymriah (tisagenlecleucel) suspension for intravenous infusion, formerly CTL019, in adult patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL).

The data from this pivotal trial, led by researchers from the University of Pennsylvania (Penn), show an overall response rate (ORR) of 53% (95% confidence interval [CI], 42% - 64%; p<0.0001), with 40% achieving a complete response (CR) and 14% achieving a partial response (PR) among 81 infused patients with three or more months of follow-up or earlier discontinuation. At six months from infusion, the ORR was 37% with a CR rate of 30%. The median duration of response was not reached. Results from this study of Kymriah, the first-ever FDA-approved chimeric antigen receptor T cell (CAR-T) therapy, were included in the US and EU regulatory filings for Kymriah in r/r DLBCL and presented in an oral presentation at the 59th American Society of Hematology (ASH) annual meeting.

“At the time of trial enrollment, these patients with DLBCL had been through multiple rounds of chemotherapy and many had unsuccessful stem cell transplants, leaving them with few options and a poor prognosis,” said the study’s principal investigator Stephen J. Schuster, MD, the Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma Clinical Care and Research in the University of Pennsylvania’s (Penn) Perelman School of Medicine and director of the Lymphoma Program at the Abramson Cancer Center. “With tisagenlecleucel, we have been able to significantly increase their chance of achieving and maintaining a sustained response without stem cell transplant, demonstrating the therapy’s benefit in the treatment of this lethal blood cancer.”

At month three, the CR rate was 32% and the PR rate was 6%, which remained consistent to month six (30% CR, 7% PR). Response rates were also consistent among prognostic subgroups, including patients who received prior autologous stem cell transplant (ASCT) and those with a subtype of DLBCL known as double-hit lymphoma, who historically have poor outcomes. No patients in response following treatment with Kymriah proceeded to stem cell transplant.

In the JULIET study, the relapse-free probability at six months after first response was 74% (95% CI, 52%-87%), and median duration of response was not reached. Median overall survival was also not reached (95% CI: 6.5 months to NE [not estimable]), and the median time from infusion to data cutoff was 5.6 months.

“While immediate response to treatment is a marker for efficacy, patients and physicians need treatment options that provide sustained responses over time with a consistent safety profile,” said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. “We look forward to continuing to work with health authorities to bring Kymriah to patients with relapsed or refractory DLBCL.”

In the JULIET study, cytokine release syndrome (CRS) occurred in 58% of all treated patients, with 23% of patients experiencing grade 3/4 CRS (15% grade 3; 8% grade 4) using the Penn Grading Scale, a rigorous scale for grading 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.

Twenty one per cent of patients experienced any grade neurologic events, and 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 27%, 20% and 13% of patients, respectively. Three patients died from disease progression within 30 days of infusion. There were no deaths attributed to Kymriah, CRS or neurological events. No cerebral edema events were reported.

In the JULIET trial, 26 patients (26%) were infused in the outpatient setting; of those, 20 patients (77%) remained outpatient for three or more days after infusion. Forty-three patients discontinued before infusion and the majority did so due to rapid progression of their disease or deterioration in their clinical status. This reflects the acute and progressive nature of relapsed or refractory DLBCL. Only 9 of 147 (6.1%) enrolled patients could not be infused due to inability to manufacture an adequate dose of CAR-T cells. Over the course of JULIET, with continuous process improvements, manufacturing success rate improved to 97% for the last 30 patients.

JULIET is the first multi-center global registration study for Kymriah in adult patients with r/r DLBCL and the second global CAR-T cell therapy trial, following the Novartis ELIANA study of Kymriah in children and young adults with r/r B-cell acute lymphoblastic leukemia (ALL). JULIET was conducted in collaboration with Penn and enrolled patients from 27 sites in 10 countries across the US, Canada, Europe, Australia and Japan. 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.

The results from JULIET build upon a pilot study of Kymriah in r/r DLBCL and follicular lymphoma published online in the New England Journal of Medicine, which was led by and conducted at Penn and supported by Novartis and grants from the National Institutes of Health, as well as through philanthropic support. Among patients with r/r DLBCL, the study demonstrated an ORR and safety profile similar to results seen in JULIET. The study demonstrated sustained remissions at a follow up of 28.6 months among patients who responded at six months.

In April 2017, the US Food and Drug Administration (FDA) granted Breakthrough Therapy designation to Kymriah based on data from the JULIET study. In October 2017, Novartis submitted an application to the FDA for Kymriah in adult patients with r/r DLBCL who are ineligible for or relapse after ASCT, followed shortly by an application to the European Medicines Agency (EMA) in November for Kymriah for the treatment of adult patients with r/r DLBCL who are ineligible for ASCT, and for children and young adults with r/r B-cell ALL. Additional filings beyond the US and EU are anticipated in 2018.

In August 2017, Kymriah became the first available chimeric antigen receptor T cell (CAR-T) therapy when it received FDA approval for children and young adults with B-cell acute lymphoblastic leukemia (ALL) that is refractory or has relapsed at least twice. Kymriah is a novel immunocellular therapy and a one-time treatment that uses a patient’s own T cells to fight cancer. Kymriah uses the 4-1BB costimulatory domain in its chimeric antigen receptor to enhance cellular expansion and persistence.

Kymriah will be manufactured for each individual patient using their own cells at the Novartis Morris Plains, New Jersey facility. Novartis has successfully demonstrated a 22-day turnaround time for manufacturing Kymriah in the commercial setting, and this will continue to be the target. 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. Building on the company’s experience, having manufactured CAR-T cells for over 250 patients from 11 countries across various indications in clinical trials, it has demonstrated a high-quality and reproducible product. Novartis continues to advance its CAR-T manufacturing expertise and make investments to support the anticipated demand to meet the needs of patients.

DLBCL is the most common form of non-Hodgkin lymphoma, a cancer of the lymphatic system, with an estimated 27,650 new cases diagnosed in 2016,. Ten to 15% of DLBCL patients fail to respond to initial therapy or relapse within three months of treatment, and an additional 20% to 25% relapse after initial response to therapy. Nearly 40% of patients with DLBCL will die of relapsed or refractory disease.

Kymriah (tisagenlecleucel) Important Safety information (for pediatric and young adult patients with B-cell precursor acute lymphoblastic leukemia).