Ash 2018 – The JCAR017 development path takes another twist

Ash presentations suggest that the lead asset Celgene acquired through its $9bn takeover of Juno is undergoing a shift of focus.

Almost a year after Celgene’s $9bn swoop on Juno a definitive path forward for the target’s lead, JCAR017, is conspicuous by its absence. Juno had touted the possibility of having JCAR017 approved for lymphoma this year, but from Celgene there has been little firm guidance as to when it would be filed or for what use.

Celgene’s focus seems to have switched back to its multiple myeloma comfort zone, and at Ash it played up its BCMA-targeting assets, with the emphasis on JCAR017 shifting to chronic lymphoblastic leukaemia (CLL). Transcend-NHL – the JCAR017 lymphoma study that Juno had called registrational – was relegated to a low-key poster.

Celgene told Vantage that lymphoma was still the lead indication, but that it was "looking ahead to a timeline of potential US approval ... in mid-2020". The group might be taking a conservative stance for commercial reasons: Gilead’s Yescarta and Novartis’s Kymriah are both approved in lymphoma, generating modest sales, so Celgene might well think that for CAR-T this setting is saturated.

Perhaps for this reason JCAR017 is now being positioned in CLL, an indication with no approved CAR-T therapies. Indeed, at Celgene’s third-quarter financials call the group’s chief executive, Mark Alles, said: “Not only do we have JCAR017 for diffuse large B-cell lymphoma and other subsets of lymphoma, but here it is coming forward in CLL.”

Too harsh?

Today, presenting data from the Transcend-CLL trial of JCAR017 in post-Imbruvica relapsed disease, City of Hope’s Dr Tanya Siddiqi said CAR-T had traditionally been seen as “too harsh” for this type of indolent disease, but with manageable toxicity even the second-line setting could in future be targeted.

In 16 subjects she reported an 81% overall response rate, holding up well at three months, and relatively low 6.3% and 18.8% rates of grade 3 cytokine storm and neurotoxicity respectively. The trial will proceed to its phase II portion next year, and a JCAR017 plus Imbruvica cohort will also get under way, she said.

The idea of concurrent dosing – never mind how much this would cost – was given support by a separate Imbruvica combo study presentation at Ash, though this featured JCAR014, an asset that uses the same construct as JCAR017 but includes an additional manufacturing step whereby cells are incubated with Epstein-Barr virus-immortalised lymphoblasts.

The trial detailed a retrospective analysis of 43 patients in two relapsed/refractory CLL cohorts, one given JCAR014 post-Imbruvica and the other given the two treatments concurrently. Overall remission was 65% and 83% respectively, but the biggest difference seemed to be toxicity: respective rates of severe cytokine storm were 25% and 0%.

Juno had previously stated that the added manufacturing complexity made JCAR014 a non-commercialisable asset, hence the focus on JCAR017. Dr Jordan Gauthier, from the Fred Hutchinson Cancer Center, told an Ash press briefing yesterday that it had also been hypothesised that driving the cells to a differentiated effector state in this way, potentially making them more powerful, might have resulted in added toxicity.

There were two deaths in the JCAR014 trial, one Imbruvica-related but the other due to cytokine release and neurotoxicity at day 11 in the post-Imbruvica cohort.

Defined cells

JCAR014 and JCAR017 both use a defined 1:1 population of CD4+ and CD8+ T cells that aims to result in the delivery of a more controllable CAR-T product than the likes of Kymriah or Yescarta.

But the plan for JCAR017’s development has chopped and changed. Juno had initially aimed to use Transcend-NHL as a dose-finding trial, and to begin a separate pivotal study. But a year ago it began talking about Transcend-NHL as a pivotal trial, thanks to a new cohort comprising the most aggressive lymphomas and the higher of two doses, 100 million cells.

At last year’s Ash Juno said approval was thus possible as early as the end of 2018 (Ash 2017 – Transcend fails to prevent Juno’s second collapse, December 12, 2017). And this is where the bullish rhetoric ended, with Celgene now looking much further down the road at a mid-2020 approval.

At the Transcend-CLL presentation Dr Siddiqi said: “We’re on the hunt for a cure; maybe CAR-T cells will be that.” But the once all-important Transcend-NHL trial, last updated at Asco, did not get an oral presentation slot at Ash, and features only in a poster on healthcare resource utilisation.

Over to Celgene.

Study Detail Trial ID
Transcend-NHL JCAR017 in 274 relapsed/refractory B-cell lymphoma pts NCT02631044
Transcend-CLL JCAR017 +/- Imbruvica in 400 Imbruvica failed/ineligible CLL pts NCT03331198
JCAR014 +/- Imbruciva in post-Imbruvica CLL pts  NCT01865617

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