Car-T comes full circle

Chronic lymphocytic leukaemia was an early avenue for Car-T research, but efforts then shifted to other blood cancer types, such as large B-cell lymphoma and acute lymphoblastic leukaemia. Now CLL is back on the agenda, with Bristol Myers Squibb starting a phase 3 trial this week with its Juno-originated therapy Breyanzi.

Breyanzi is already awaiting an FDA approval decision in CLL, based on the phase 1/2 Transcend CLL 004 trial. In this leukaemia subset, Bristol is well ahead of its Car-T rivals, an analysis of OncologyPipeline shows.

Indeed, the other established players, Novartis and Gilead, no longer appear to be active here. Novartis said in 2019 that it had discontinued the planned pivotal CLL programme for Kymriah, while Gilead has gone quiet since reporting data from the Zuma-8 trial at the 2022 ASH meeting.

This leaves a couple of early hopefuls as Bristol’s main competition: Galapagos, which had phase 1 data on its project GLPG5201 at last year’s ASH, and Allogene, which announced plans to go into CLL early this year with its allogeneic contender cemacabtagene ansegedleucel. 

Notable Car-T trials in CLL

*Among pts progressed on BTK inhibitor & Venclexta, treated with 100m CAR-T cells. Source: OncologyPipeline.

Allogeneic therapies could have an edge in CLL; because this disease often occurs during or after middle age, patients tend to have poor-quality T cells of their own. Car-T had also been seen as too harsh for a relatively indolent disease like CLL, although centres are getting more used to managing adverse events like cytokine-release syndrome.

Meanwhile, Galapagos’s claim to fame with GLPG5201 is a median vein-to-vein time of seven days, although the importance of fast manufacturing is still up for debate. The company's presence in cell therapy derives from a 2022 double acquisition of CellPoint and AboundBio.

Galapagos is starting phase 2 expansion cohorts with GLPG5201, but Bristol looks to be some way ahead, with a PDUFA date of 14 March for Breyanzi in CLL.

Transcend

The most recent data from the Transcend CLL 004 trial, presented at ASH 2023, showed a 20% complete response rate among a prespecified subset of 50 patients who had previously progressed on BTK inhibitors and Venclexta, and had received a dose of 100 million Car-T cells.

Presenting the data, Dr Tanya Siddiqi of City of Hope said this result compared favourably against historical CR rates of 0-5%. She added that efficacy outcomes were similar in the full study population.

Meanwhile, Galapagos posted a more impressive 57% CR rate with GLPG5201, albeit among only 14 patients. In addition, not all subjects in that trial had received BTK inhibitors or Venclexta, a BCL2 inhibitor.

When asked how to improve the response rate with Breyanzi, Siddiqi mentioned a potential avenue already being evaluated: a phase 1 cohort in Transcend CLL 004 is testing the Car-T therapy alongside AbbVie and Johnson & Johnson’s BTK inhibitor Imbruvica, and data could come this year.

Bristol’s recently-begun phase 3 – which presumably will fulfil the role of confirmatory trial – will enrol patients who have previously failed on BTK and BCL2 inhibitors, and will compare Breyanzi versus investigator’s choice of Zydelig plus Rituxan or bendamustine chemo plus Rituxan. The primary endpoint is progression-free survival.

Before the study yields data Breyanzi might have become the first Car-T therapy approved for CLL, 14 years after the first patient with this blood cancer was treated with the technology.