Mason’s summary is by and large accurate on my read. There is...

Mason’s summary is by and large accurate on my read. There is however significant risk in Allogene’s approach that hasn’t been addressed in the ongoing comparison on this forum.

The ALPHA3 trial is not a direct extension of the Phase 1 trials by Allogene, Cema-cell has not been tested in the context of consolidating SOC (R-CHOP) for LBCL. Phase 1 studies looked at relapsed patients who had already undertaken multiple lines of chemo. The ALPHA3 trial has changed approach from the initial trials to treat patients who have achieved CR or PR after SOC (stable with clinical intent for observation, not further treatment) and are found to be MRD+ (MRD is minimal residual disease, the cancer is non-detectable by standard detection methods). If you are MRD+ then you are likely to relapse.

What this means is they’re trying to prevent relapse by mopping up any remaining cancerous cells after SOC rather than treat relapsed disease. Their primary measure will be observed out to 60months (so circa 2031 for study completion) and it may take that long to really know if it’s worked considering they’re essentially waiting to see if patients start relapsing.

So why wouldn’t Cema-cell be even more effective on less disease, particularly as the Phase 1 data showed great promise wrt relapse figures? Well you’re treating MRD which is disease spread all over the body in minute amounts.
• Is the density of diseased cells significant enough for Cema-cell to comprehensively and completely activate over the residual disease?
• Will Cema-cell spread and reach enough of the residual disease?
• Even though patients have just undertaken SOC, given they are further up the treatment line will patients on average have a stronger immune system and clear the CAR-T cells quicker than expected?
• Will allogeneic Car-T’s have similar recurrence issues over longer observation periods, as other CAR-T treatments do, making it fundamentally unsuitable for the job?

There are also significant clinical adoption concerns if you consider you’re asking physicians to adopt a new treatment approach to patients that are stable by current standards. The results will need to be impressive enough to change minds and start treating stable patients. It would be a lower bar if CAR-T treatment was a walk in the park, but there are safety concerns with CAR-T treatments of all kinds. If you achieved a Complete Response but were MRD+ and told you have a chance at relapse, would you go through a pretty onerous and physically difficult treatment to be sure? Would you do the same if you had other options, maybe even an alternative allogeneic CAR-T treatment with encouraging results, if you did happen to relapse? Some patients may not opt for the extra cost, physically and financially.

Azer-cel by comparison is being approached as a salvage treatment on a smaller subset of patients who have tried everything else and relapsed anyway. It will be much easier to sell any improvement in a cohort of patients who have no other real options available, and much quicker to declare a CR/PR/SD from treatment than wait around for relapse. Azer-cel is behind now, but may have a significantly faster registrational trial timeline due to primary endpoints being able to be assessed much quicker (all highly variable and speculative until the FDA weighs in with what they want). If Imugene can get Azer-cel approved it *should* be easier to start climbing up the treatment ladder and adding/expanding indications down the line.

Allogene are giving themselves a much higher bar to clear with a bigger pot of gold at the end, while Imugene are taking a much more conservative and traditional approach (if they maintain the Phase 1 strategy). Yes Cema-cel can eat into Azer-cel’s market, it has a fair bit to prove before we can go around stating that unequivocally.

Not a med scientist, oncologist, medically trained, etc. and haven't followed Allogene closely so happy to be corrected.