Gilead’s ZUMA-3 study shows continued efficacy, and results from tweaks to side effect management

The company presented end-of-Phase I data from the trial, on KTE-X19, at the ASCO meeting in Chicago Saturday.

New data from a Phase I/II CAR-T study show that more than 80 percent of adult leukemia patients receiving the cell therapy at the dose that will be used for the Phase II portion went into remission.

On Saturday, Gilead Sciences subsidiary Kite Pharma presented end-of-Phase I data on the Phase I/II ZUMA-3 study of KTE-X19 in adults with relapsed or refractory acute lymphoblastic leukemia (ALL) at the American Society of Clinical Oncology annual meeting in Chicago. Among the 19 of 23 patients receiving the Phase II dose of 1 million cells per kilogram of body weight, 84 percent achieved complete remission or complete remission without full recovery of blood counts, known as the CR/CRi rate. Of those, 75 percent remained in remission at data cut-off, with a median duration of remission of 12.9 months. All the patients who responded had achieved minimal residual disease negativity, meaning no detectable disease. The Phase I portion had also tested two other dose levels, 500,000 and 2 million cells per kilogram.

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“Going down to [1 million cells], we weren’t seeing MRD positivity, so it’s very, very encouraging,” study investigator Dr. Bijal Shah, a leukemia and lymphoma specialist at the Moffitt Cancer Center in Tampa, Florida, who presented the data, said in an interview at the ASCO meeting.

KTE-X19 is similar to Gilead’s marketed CAR-T, Yescarta (axicabtagene ciloleucel), which has Food and Drug Administration approval for diffuse large B-cell lymphoma. However, it differs in terms of its manufacturing process, particularly the inclusion of enrichment of lymphocytes.

The trial is also incorporating a revised protocol for handling the side effects associated with CAR-Ts, particularly cytokine release syndrome (CRS) and neurological toxicity. Early on, there were two deaths in the study attributable to CRS, one in a patient who had a stroke, and another in a patient who suffered multi-organ failure.

Among nine of the patients receiving the 1 million-cell dose, the trial incorporated two changes to management of CRS and neurotoxicity. First, Actemra (tocilizumab) – a Roche drug used for autoimmune diseases and approved for CRS – was given only in response to CRS-related symptoms instead of prophylactically. Second, corticosteroids were given at the onset of moderate or worse neurotoxicity, rather than when neurotoxicity was more serious.

Among those nine patients, two had serious – though not life-threatening – CRS, while one had serious neurotoxicity. By contrast, under the previous protocol, 26 percent had CRS, and 43 percent had neurotoxicity that was serious or life-threatening. However, Shah noted that no additional patients died from those side effects.

“We not only saw that neurotoxicity was reduced in terms of significance – the duration of neurotoxicity was substantially reduced, from 20.5 days to 11 days,” Shah said.

The Phase II portion will incorporate the protocol revisions.

Shah also noted that 42 percent of patients in the study had received prior treatment with Amgen’s drug Blincyto (blinatumomab), which like KTE-X19, Yescarta and Novartis CAR-T Kymriah (tisagenlecleucel) targets the CD19 antigen. Although treatment with either CD19-directed CAR-Ts or Blincyto can lead to patients relapsing without expressing the antigen – thereby making them ineligible for treatment with CD19-directed therapy – Amgen has stated the rate of that happening is 10-15 percent, while Shah put the figure at 6 percent.

“We don’t need to be as worried about antigen loss from [Blincyto] as a reason for CAR-T failure,” Shah said.

Photo: Alaric DeArment, MedCity News