After Monday's market close, Kite Pharma Inc. reported top-line results from a pre-planned interim analysis of the phase II portion of its ZUMA-1 trial indicated lead candidate, KTE-C19, indicating the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy met the primary endpoint, with an objective response rate (ORR) of 76 percent (p <0.0001) in patients with chemorefractory diffuse large B-cell lymphoma (DLBCL), including 47 percent complete remissions (CR).

ZUMA-1 enrolled patients with chemorefractory aggressive non-Hodgkin lymphoma (NHL) into two cohorts. Cohort 1 included the DLBCL patients, while cohort 2 enrolled patients with transformed follicular lymphoma (TFL) and primary mediastinal B-cell lymphoma (PMBCL). Kite, of Santa Monica, Calif., designed the pivotal trial with an eye to filing for approval in all three NHL subpopulations based on the combined data from both cohorts.

The interim analysis of ZUMA-1 evaluated the ORR in the first 51 patients in cohort 1 with at least three months of follow-up. The analysis also included 11 additional patients in cohort 2.

"We were pleasantly surprised with the consistency of what we have seen in the phase II study," David Chang, Kite's executive vice president of R&D and chief medical officer, told BioWorld Today – a refrain he echoed on a conference call with analysts late Monday. "This is highly consistent with our phase I data as well as what we have learned from the [National Cancer Institute] experience."

The phase I portion of ZUMA-1 and the NCI study were based on the same CAR construct – a low-dose cyclophosphamide-fludaribine conditioning regimen – and Kite's manufacturing process.

The data consistency was remarkable considering that the phase II portion of ZUMA-1 included centers without previous experience with engineered T cells, yet their performance was comparable to that of NIH investigators, added Arie Belldegrun, Kite's president and CEO.

The finding showed that "the technology can gradually come to earlier stages of the disease and to more and more centers in the country and outside," he told BioWorld Today.

The three-month ORR in 51 evaluable DLBCL patients was 39 percent, compared to 43 percent in the phase I study in seven DLBCL patients, and the three-month CR was 33 percent, compared to 43 percent in the phase I. Three-month ORR and CR rates in the TFL/PMBCL population were much higher, at 64 percent each, leading to rates for the combined populations, with 62 patients, of 44 percent and 39 percent, respectively.

Chang maintained that the company was pleased with that response.

"What we learned from the NCI study, as well as from our own experience, is that responses that last for the first three months tend to last much longer," he explained. "The fact that we had a combined complete remission rate of 39 percent at month three is a very good indication of that, especially when you consider that 39 percent is a five-fold increase over the historical data that we learned from our SCHOLAR-1 study."

That meta-analysis of outcomes from 635 patients with chemorefractory DLBCL, which Kite reported in June at the American Society of Clinical Oncology annual meeting, suggested that patients with chemorefractory disease have consistently poor outcomes regardless of refractory subgroup, line of therapy and disease stage. The ORR was 26 percent (165/635), with only 8 percent (51/635) achieving a CR.

'NOT SITTING QUIETLY AND WAITING FOR 6-MONTH DATA'

Across the combined 62 patients in ZUMA-1, the most common grade 3 or higher adverse events (AEs) included neutropenia (66 percent), anemia (40 percent), febrile neutropenia (29 percent), thrombocytopenia (29 percent) and encephalopathy (26 percent). Grade 3 or higher cytokine release syndrome (CRS) and neurological toxicity were observed in 18 percent and 34 percent of patients, respectively. Two patients died, from hemophagocytic lymphohistiocytosis and cardiac arrest, related to the use of KTE-C19.

On the call, Jeff Wiezorek, the company's senior vice president of clinical development, reminded analysts that the enrolled population represented "truly sick patients" who were refractory despite previous lines of therapy. Both deaths were "manifestations of cytokine release syndrome – a well-known side effect of CAR-T therapy that's been observed before in other studies," he said. Although no one wants to see any deaths occur during clinical trials, "the rate of treatment-related deaths was on par with what's seen with other therapies and quite a bit lower than some of the other aggressive therapies that are currently used in lymphoma."

Overall, 99 percent of patients who were enrolled in the trial – all but 1 patient – were able to receive the cell product, he added.

In terms of the larger context of the trial, "it's important to remember that this is the most challenging group of patients in hematologic cancers," Belldegrun told BioWorld Today. "We are presenting the largest study ever conducted in that space. At baseline, this is a population with, at best, an 8 percent CR. It's very unusual to take a disease that's very difficult or impossible to treat – patients who have failed two, three, four or five lines of therapy and have absolutely no options – and even in this very sick group of patients get at least a five-fold increase. That's quite significant."

Company officials were tight-lipped about other details on the conference call, responding to most questions by noting that additional data from the interim analysis will be submitted for presentation at an upcoming scientific meeting, which Chang alluded to as December's American Society of Hematology meeting in San Diego.

The primary analysis of the fully enrolled study of 101 patients with chemorefractory aggressive NHL, expected in the first quarter of 2017, will include approximately six months of follow-up. But Belldegrun told BioWorld Today that "we're not sitting quietly and waiting for the six-month data. As we disclosed before, we are planning to submit our [biologics license application] filing to the FDA at the end of this year. Obviously, we will be [meeting] with the FDA ahead of time, in a pre-BLA meeting, but our plan has not changed to submit the filing by year-end."

That timetable positions Kite for a potential launch in 2017, Belldegrun said. Kite manufactured KTE-C19 for 99 percent of patients enrolled in ZUMA-1 and is ready to take on a commercial product.

"We have a fully functioning commercial facility capable of producing up to 5,000 patient therapies," he said. "If needed, we can expand it – it's a modular design, so the patient number is not an issue."

Kite is already doing dry runs to prepare for the FDA's pre-launch inspection.

"We'll be ready whenever we get the approval," Belldegrun maintained.

And, since KTE-C19 has breakthrough indication in the U.S. for all three NHL indications – and a corresponding priority medicines designation by the EMA – "we believe there will be an expedited review here," he added.

The ZUMA-1 findings also suggested positive implications for the rest of the ZUMA program, which includes ZUMA-2, which is testing KTE-C19 in patients with relapsed or refractory mantle cell lymphoma, ZUMA-3 in 75 adults with relapsed or refractory acute lymphoblastic leukemia (ALL) and a fourth pediatric-focused study in ALL, ZUMA-4. (See BioWorld Today, Dec. 3, 2015.)

"We are very encouraged by the consistency of reproducing a single-center experience in a much larger multicenter clinical trial," Chang said. "The mechanism of action of KTE-C19 does not change. The fact that ZUMA-1 produced top-line positive results will bode very well in the remaining ZUMA studies."

In a first glance following the company's call, RBC Capital Markets analyst Michael Yee was upbeat, calling the DLBCL CR of 47 percent "strong and above expectations" and the three-month CR of 39 percent "largely consistent, very strong." He found nothing unexpected in the safety findings and pronounced the CR rate "very supportive of FDA approval."

On Monday, Kite's shares (NASDAQ:KITE) gained 41 cents to close at $54.98.