Pivotal trial data from first-ever FDA-approved chimeric antigen receptor T cell (CAR-T) therapy presented at ASH 2017

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 will be presented in an oral presentation at the 59th American Society of Hematology (ASH) annual meeting (Abstract #577; Monday, December 11, 7:00 AM EST)

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.

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 percent 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.

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.

A cost effective analysis presented at ASH, showed that, based on the current US list price of $475,000, Kymriah is cost-effective compared to standard of care. The analysis compared the life years and quality-adjusted life years gained with Kymriah compared to clofarabine monotherapy, clofarabine combination therapy, blinatumomab, other salvage chemotherapies and allogeneic stem cell transplant. Quality-adjusted life years is a measure of value of health outcomes based on disease burden, including both the quality and quantity of life lived. In addition, results of another analysis to determine the potential societal value of Kymriah to patients with r/r ALL in the United Kingdom were presented in a poster presentation at the meeting (Abstract #1330; Saturday, December 9, 5:30 PM EST) .To quantify the societal value of Kymriah, the analysis looked at the economic value of the incremental quality adjusted life years gained along with the patient's expected productivity using nationally representative data on employment rates and earnings. Results show that therapies such as Kymriah have the potential to provide benefit to patients and society, particularly through gains in survival, contributing to productivity.

See- Schuster S., et al. "Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma". 59th American Society of Hematology Annual Meeting and Exposition. Abstract #577".

Schuster S., et al. CAR-T cells (CTL019) in Refractory B-cell Lymphomas. N Engl J Med. December 28, 2017. doi: 10.1056/NEJMoa1708566.