Spectacular early results for Novartis’ CAR-T combined with Imbruvica

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A combination of Novartis’ 'next generation' CAR-T drug CTL119 with Janssen and AbbVie's Imbruvica has cleared all signs of chronic lymphocytic leukaemia from eight out of nine patients in a pilot study.

This complete remission was seen three months into treatment in patients with hard-to-treat variants of the disease, and is an eye-catching result for Novartis and the whole CAR-T field.

The results could herald a step change in treating CLL, which current treatments can hold in abeyance, but not cure. The true test of the combination will come in larger and longer-lasting studies – but if the combination can keep patients disease free for years, it could be a major breakthrough.

However the combination did also produce side-effects in all the study participants, including three serious cases of cytokine release syndrome (CRS), so safety will also be a major question for later trials.

Novartis has unveiled the results ahead of a special investor event in Cambridge, Mass today, and a week ahead of ASCO, the year’s biggest cancer congress, with the hope of convincing investors it has the upper hand in this key field.

The company is playing catch-up in oncology, but is hoping to be the leader in the cutting-edge CAR-T market.  The drug in the latest study, CTL119, is a humanised CD19-directed CAR-T drug, making it a further step on from the mouse-derived CTL019 which the company has filed with regulators.

Novartis filed CTL109 in March for paediatric patients with acute lymphoblastic leukaemia (ALL), and is in a neck-and-neck race for approval with Kite and its rival CAR-T candidate KTE-C19.

The new pilot study is also remarkable because it is the first clear proof that CAR-Ts can work in combination with other cancer treatments.

James Bradner, president of the Novartis Institutes for BioMedical Research said the trial population were high risk CLL patients who were otherwise unlikely to achieve complete remission on ibrutinib (Imbruvica) alone.

The patients in the study all had relapsed/refractory chronic lymphocytic leukemia (CLL) and had been taking Imbruvica for at least six months and were not in complete remission. All study patients had to have failed at least one prior regimen before ibrutinib or carried high-risk cytogenetics or mutations.

Eight out of nine patients showed no signs of the disease at three months, as tested by flow cytometry and/or analysis for minimal residual disease (MRD), which measures residual abnormalities in the blood and bone marrow at the molecular level.

A number of patients also saw improvement in the burden of disease on their spleens and lymph nodes, which are also affected by the disease.

Cytokine release syndrome

The trial wasn’t without some serious side-effects however, a recurrent concern in CAR-T drugs.

While Novartis presented data from a total of nine patients, there was a total of 10 in the study, but one did not produce evaluable data.

The Novartis release states that 10 patients – all of the patients in the study - experienced cytokine release syndrome (CRS), a potentially very serious immune response, two of which were grade 3.

However, the company says no patients required treatment with Roche’s Actemra (which helps dampen down this response) and all patients recovered from CRS. In addition, one patient developed tumor lysis syndrome and two patients had febrile neutropenia.

Safety problems have recently hit Kite, after it revealed a patient taking its KTE-C19 in a trial had died.

The full CTL119 + Imbruvica study will be presented at ASCO in Chicago on Monday by Saar Gill, MD, PhD, an assistant professor of Hematology-Oncology in the Perelman School of Medicine and the Abramson Cancer Center of the University of Pennsylvania.

Other companies in the CAR-T field are also expected to unveil new data at ASCO, including Bluebird and little-known Nanjing Legend biotech, which has a late-breaker presentation, both targeting multiple myeloma.

Please note this story has been updated to clarify the distinction between CTL119 and CTL109.

Andrew McConaghie

31 May, 2017