Gilead puts its Car-T money where its mouth is

It’s one thing to claim you’ve got a better asset on your hands than a first-generation version, but another actually to put this to the test. Yet this is precisely the bold move Gilead is to undertake: a just published clinicaltrials.gov listing reveals that the company is planning to test its Car-T contender KITE-753 in a pivotal trial head to head against Yescarta.

Gilead’s Yescarta sold $1.5bn last year, but KITE-753 is said to have a couple of advantages over it, targeting CD20 as well as CD19, and using a shortened manufacturing process designed to generate younger and fitter T cells. The move into phase 3 development also formalises Gilead’s prioritisation of KITE-753 over a structurally identical Car-T project coded KITE-363.

KITE-753 and KITE-363 are bicystronic anti-CD19 x CD20 Car-T constructs, their only difference being that the former uses the novel, rapid manufacturing method, while the latter employs a traditional technique. Formally Gilead has made no public statement about which is being prioritised, but it became pretty clear recently that KITE-753 was winning out, at least in oncology.

First-in-human data at ASH showed similar activity for both assets in Car-naive B-cell lymphoma patients, but KITE-753 achieved this at about a one tenth of the dose of KITE-363. KITE-363 is being taken forward in immunology, but so far no pivotal trial plans for it in haematological cancer have been disclosed.

KITE-753 wins

The pivotal honour thus goes to KITE-753, which according to clinicaltrials.gov will begin its phase 3 trial, in 550 chemo-refractory large B-cell lymphoma patients, in August.

This study will compare KITE-753, administered after standard cy-flu lymphodepletion, against Yescarta, and measure event-free survival and six-month complete response rate as co-primary endpoints. Use of Yescarta as an active control is a nod to the emergence of this Car-T therapy as a second-line standard of care, following its 2022 approval on the back of the Zuma-7 trial.

As such, Zuma-7 provides a benchmark for KITE-753 to beat, assuming that Yescarta control performs roughly in line with its registrational study. In Zuma-7, a phase 3 study using a broadly similar definition of chemo-refractory disease to first-line therapy, Yescarta scored 8.3 months of median EFS, and a best CR rate of 65%.

One difference was that Zuma-7 had a sole primary endpoint, EFS, and the secondary response rate metric related not to best CR rate but to ORR. As for other secondary endpoints, Yescarta showed 14.9 months of median PFS, while the median wasn’t reached for OS; patients in Zuma-7’s control cohort got salvage chemotherapy.

It’s also notable that Yescarta isn’t the only Car-T therapy available for second-line DLBCL, with Bristol Myers Squibb’s Breyanzi scoring this US green light shortly after the Gilead therapy. That was based on the phase 3 Transform study, which showed slightly higher median EFS (10.1 months), but otherwise seemed pretty similar to Zuma-7 on efficacy.

As such, it’s probably not too important that Gilead’s new phase 3 will compare KITE-753 versus only Yescarta, rather than a choice of Yescarta or Breyanzi. But Gilead will be mindful of the fact that if KITE-753 fails to beat Yescarta this would call into question the logic of rapid manufacturing; if it succeeds it could put in jeopardy its Yescarta blockbuster.

Some benchmarks for KITE-753 to clear in 2nd-line DLBCL

Source: prescribing information.