As Novartis preps for first CAR-T FDA AdComm, Juliet data revealed

It’s been a big week for CAR-T: Novartis, Juno, Kite, Bluebird Bio and Nanjing Legend Biotech all posted positive data for the cutting-edge experimental cancer class at ASCO, and now Novartis has revealed the long-awaited interim Juliet data for its CAR-T candidate at a Swiss conference.

The FDA ‘breakthrough’ tagged Juliet data, which many have been waiting for to see how well it could stack up against rival Kite Pharma, was assessing CTL019 (a.k.a tisagenlecleucel) in 51 relapsing/remitting diffuse large B-cell lymphoma (r/r DLBCL) patients who had already received a series of treatments.

Revealed for the first time today, Novartis says the single-arm, open-label pivotal phase 2 trial hit its primary endpoint, showing a 3-month overall response rate (ORR) of 45% (23 of the 51 patients evaluated), with 37% achieving a complete response (CR) and 8% achieving a partial response (PR), respectively. In all, 141 patients were enrolled, but only 51 were evaluated. 

The Swiss Big Pharma said that CR also “remained stable” from 3 months through data cut-off among the patient group. And among the 51 patients with 3 months or more of follow-up or earlier discontinuation, best ORR was 59% (p<0.0001), with 43% achieving CR and 16% achieving PR.

Secondary endpoints from the study include overall survival, duration of response and progression-free survival, although Novartis tells me these are not yet mature enough to assess.

The new data are set to be presented at the International Conference on Malignant Lymphoma (ICML) meeting in Lugano, Switzerland.

This is broadly comparable to Kite Pharma’s data, which tested its rival CAR-T axicabtagene ciloleucel (a.k.a. KTE-C19) in non-Hodgkin’s lymphoma. Cohort 1 of the Zuma-1 phase 2 trial, posted last September, saw 51 patients with chemorefractory DLBCL being treated with the therapy.

At 3 months, data showed an ORR of 39% and a CR of 33%. In Februrary this year it also published longer data, in 77 DLBCL patients, that at 6 months showed a 36% ORR and 31% CR. Novartis told FierceBiotech it would not be comparing the two, but said it was pleased with its own data.

DLBCL is the most common form of lymphoma and accounts for about 30% of all non-Hodgkin lymphoma cases. Around 10 to 15% of DLBCL patients fail to respond to initial therapy or relapse within 3 months of treatment, with an additional 20% to 25% relapse after initial response to therapy.

Novartis also said in terms of safety that 57% of all treated patients (85 in total) experienced any grade cytokine release syndrome (CRS), a known complication of CAR-T therapy, and 26% experienced grade 3/4 CRS.

There were however no deaths coming out of the trial from CRS or cerebral edema, and no incidents of cerebral edema were reported in the study. This is an important point, given that 5 patients died in a Juno trial of its then-leading CAR-T med JCAR015 from cerebral edema. There were 3 deaths, but the Big Pharma said these were from “disease progression within 30 days of infusion.”

Novartis adds that 13% of patients had grade 3/4 neurologic adverse events, but said these “were managed with supportive care.”

“The overall response rate seen in this early analysis is impressive for these heavily pretreated patients with relapsed/refractory DLBCL, who have limited treatment options,” said Juliet lead investigator, Stephen Schuster, M.D., Professor of hematology/oncology in the Perelman School of Medicine at the University of Pennsylvania and Penn’s Abramson Cancer Center.

“The goal for these patients is achieving durable response. The most promising aspect of these data is that, at the time of this interim analysis, all patients with complete response at three months have remained in complete response.”

On the safety side for Kite, from its non-Hodgkin lymphoma trial data from February, the most common grade 3 or higher adverse events included anemia (43%) and neutropenia (39%).

The grade 3 or higher CRS was 13% and neurologic events 28%, but it initially said it had no cases of cerebral edema. There were 3 deaths not due to disease progression in the study, with Kite saying 2 events, one hemophagocytic lymphohistiocytosis and one cardiac arrest in the setting of CRS, “were deemed related to axicabtagene ciloleucel”. The third case, a pulmonary embolism, was deemed unrelated.

But in May, the biotech revealed that a month before there had in fact been the death of a patient from cerebral edema in the non-Hodgkin’s lymphoma test. At the time, the company told FierceBiotech: “This was a singular event and as you know, Grade 5 events [i.e., deaths] are not unexpected in studies involving patients who are suffering from rapidly progressing cancer that is refractory to treatments. The Safety Expansion Cohort was initiated after the close of the registrational trial.”

Novartis, which has developed its med with Penn University and has U.K. biotech Oxford BioMedica manufacturing the lentiviral vector expressing CTL019, said the full rundown of the Juliet will be posted later this year, with it being used as the basis for its submissions to the FDA and the EMA.

In May, Kite was given an FDA priority review for its med in aggressive non-Hodgkin lymphoma, with a PDUFA date of November 29, based on its Zuma-1 phase 2 data.

Novartis will clearly be behind Kite in that indication, but looks on course to be the first to gain a CAR-T approval, as it also said this week that there will be an AdComm with the FDA on 12 July for CTL019 and its proposed indication for the treatment of r/r pediatric and young adult patients with B-cell acute lymphoblastic leukemia (a smaller patient population than r/r DLBCL). Should things go well, this indication could get approval by September.

Cowen questions

Some of the data were released early this morning by Cowen and shared on Twitter (ahead of an embargo), which questioned why so many patients were not evaluated in Juliet, and also raised questions about the manufacturing of the med, and how quickly it can be produced and why some patients couldn't use the med due to manufacturing problems.

Novartis told FierceBiotech in response to Cowen’s questions: “Of the patients who discontinued the trial before infusion, the majority were due to rapid progression of their disease or deterioration in their clinical status. This reflects the acute and progressive nature of the disease of the patients. We had factored in a high dropout rate due to the aggressive nature of this disease.

“Only 6% (9 of 141) of enrolled patients were discontinued 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.

“In Juliet, patients could receive bridging chemotherapy, reflecting the aggressive nature of disease in patients with r/r DLBCL, so even patients in poor condition could be enrolled and infused. The cryopreserved leukapheresis used in Juliet gives physicians the flexibility to schedule apheresis at a time that is in the best interest of their patients, including times far in advance of manufacturing. The trial design and population infused reflects the real-world challenges in treating patients with an aggressive cancer such as r/r DLBCL.

“As for manufacturing, we are confident we will be able to meet the required manufacturing demands moving forward. The actual cell processing time is 10-12 days. We anticipate that the time from manufacture start to product release (including quality assessments) will be 22 days at the time of commercial launch. We have a rigorous quality assessment process to ensure a GMP compliant product is released to patients.”

It also added that its commercial manufacturing for CTL019 "will build on its extensive experience in our Morris Plains facility, which has already manufactured CTL019 for hundreds of patients in global clinical trials."

It went on: "Novartis believes that hands-on experience matters in cell therapy manufacturing, and the experience at Morris Plains will be a foundation for manufacturing for commercial purposes and future CAR-T therapies. Novartis has made and continues to make significant investments in capacity and turnaround time and is committed to meeting the needs of CTL019 patients in the future." 

This comes after Karen Walker left her role as VP of global, head cell and gene therapies technical development and manufacturing at Novartis a few months back, moving over to Seattle Genetics.  

Novartis was slightly down late morning by 0.4%, while Kite was up 6.5%.