Berdeja Projects Promising Future for JNJ-4528 in Relapsed/Refractory Myeloma

The novel CAR T-cell product JNJ-4528 induced responses in 100% of patients in the phase 1b/2 CARTITUDE-1 (NCT03548207) trial, proving to be a promising agent for patients with relapsed/refractory multiple myeloma, according to Jesus G. Berdeja, MD.

Longer-term results from the trial were presented during the 2020 ASCO Virtual Scientific Program, and showed that JNJ-4528 continued to demonstrate deep and durable responses in heavily pretreated patients with relapsed/refractory disease. Results showed an overall response rate of 100% and a stringent complete response rate of 86%. Additionally, at 9 months, the progression-free survival rate reported with the CAR T-cell product was 86%.

“JNJ-4528 has received a breakthrough therapy designation by the FDA. We're hoping that that will be one of the first candidates for FDA approval in this arena, for patients with relapsed/refractory myeloma,” said Berdeja. “Phase 2 and 3 studies are now underway and they are examining this product in earlier lines of therapy and even in high-risk populations, potentially [a] frontline consolidation type [of approach], so there is lots to come with JNJ-4528.”

In an interview with OncLive, Berdeja, director of Myeloma Research at the Sarah Cannon Research Institute, further discussed other exciting trials in multiple myeloma and CAR T therapy being presented at the 2020 ASCO Virtual Scientific Program.

OncLive: Could you shed light on JNJ-4528 and the initial data at the 2020 ASH Annual Meeting?

Berdeja: JNJ-4528 is a second-generation BCMA-directed CAR T-cell product; it has a CD3-zeta signaling domain and a 4-1BB costimulatory domain, but it differs from other products in that it has 2 BCMA-targeting single-chain antibodies. These are designed to confer avidity, and hopefully, less BCMA escape. [The product is] identical to the CAR construct that was used in the LEGEND-2 study. 

At the 2019 ASH Annual Meeting, we saw the initial results of the phase 1b portion of the study. At the 2020 ASCO Meeting, we're presenting the same population with a longer median follow-up of 11.5 months.

What did those longer-term results show in terms of responses, durability, and minimal residual disease (MRD) negativity?

Twenty-nine patients were enrolled in the phase 1b portion of the trial. These were heavily pretreated patients, with a median of 5 prior lines of therapy; 86% were triple refractory. We didn't see any unexpected safety signals. The majority of patients had cytokine release syndrome (CRS) as expected, but mostly grade 1 to 2 in severity. The median time to CRS was 7 days, which is a little more delayed than some of the other CAR T-cell products out there. Neurotoxicity was rare and only 1 patient had a grade 3 event or higher. We did see significant cytopenias, but most resolved by 60 days and we didn't really see any untoward infectious complications that would not be expected in this patient population. 

The response rate with the product is still 100%. Now, we have 86% of patients in stringent complete remission (CR) and a 97% very good partial response rate at a median follow up 11.5 months. Sixteen patients were in CR who had MRD samples available; of those, 81% were MRD negative at 10^-5 or better and 69% were negative at 10^-6. The estimated PFS rate at 9 months was 86%.

What are the implications of these data and the next steps?

The phase 2 portion of the study is fully enrolled. We'll be looking to combine those data with this population. I'll remind you that even though this was a phase 1b, it was not a dose-escalation trial. We used the dose that was informed from the LEGEND trials. The patient population should be fluid, and it will be the same dose for both the phase 1b and phase 2 [trials].

I'm looking forward to seeing those data and of course, longer-term results because that's what we really want to know. How durable will these responses will be? We're very pleased with what we've seen so far.

In the abstract, it said that CAR T-cell persistence did not seem to correlate with the deepening of response. How do you interpret that?

It's actually very, very interesting. Those data were presented at the 2019 ASH Annual Meeting in a different presentation. We didn't focus on it this time but it's very different from what we're seeing with [agents, such as] idecabtagene vicleucel (ide-cel; bb2121) where you see persistence of the CAR even 1 year out. Here, for the most part, most patients don't have that persistence. However, interestingly, what seemed to happen is that the subset of cells that were expanded with memory phenotype cells. That's one theory, that perhaps we’re not seeing the cells in total persist, but maybe a subpopulation is persisting. 

The other is that perhaps you don't need to have the cells persist. This is a product that has the 2 BCMA-binding domains, so it's almost acting perhaps like a dual CAR, which means that it is binding at 2 different sites. Perhaps [there] is a more robust initial binding and less of a potential for escape and thus, you're not seeing the cells remain expanded for a longer period of time. Again, the proof will be in the duration of that response. Then, we'll sort out what that means, why they are not persisting, and whether we really need that persistence.

Is there anything else about the longer-term follow up findings that you wanted to emphasize?

One thing is that I didn’t really go into the dosing, but the dose of this CAR T-cell product is much lower than what we're seeing with some of the other products. The median administered dose was 0.75 x 10⁶ CAR T cells/kg, which if you take a 70-kg person, we're talking about 50 million CARs, which is the very low dose with which other CARs didn't [show] activity or [only had] mild activity. We're not sure what that means, but at the same time, it would be easier to not have to make so many CAR T cells. Perhaps less patients will have manufacturing failures as you start going out into a broader population.

Does that translate to less toxicity? We know that in other products, there is a dose-dependence to some of that toxicity. Also, the onset of CRS at 7 days is very intriguing. Compared with other products where you see CRS very soon after infusion of the CAR or within the first couple days, this may potentially lend itself to outpatient dosing and then just admission to the hospital for that patient who may need it. That potentially could also distinguish this product [from others].

Was any other myeloma research presented at the meeting that you wanted to highlight?

I'll just mention that this year's ASCO was great for myeloma. I was in the committee for selecting the research and we had a hard time deciding which 9 studies will actually get an oral presentation because there were so many. In the oral session, we had 3 CAR T-cell products head to head, in a way. It was a nice way to get up to date on the frontrunners and see some of the differences [between the products]. Some really interesting data were reported on some newcomers, a new CELMod, CC-480, which are looking quite impressive. Some data with belantamab mafodotin (GSK2857916) in combinations were also presented, as well as data with selinexor (Xpovio) from the BOSTON trial. 

Data with all these new drugs were presented, as well as some very intriguing data in the frontline setting in patients with high-risk myeloma. I would encourage you to stay tuned because that is a very difficult population with unmet needs. Then of course, beyond the orals, we actually had 2 myeloma abstracts that were presented during special sessions.

One was a BCMA bispecific that was presented by Saad Z. Usmani, MD, of Atrium Health. Then, the ENDURANCE trial was presented by Shaji K. Kumar, MD, of Mayo Clinic, during the plenary; it was 1 of 5 abstracts that were selected and it's the first myeloma study in a very long time to be presented during a plenary session at ASCO. This trial examined frontline therapy between carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone versus bortezomib, lenalidomide, and dexamethasone, and it will have implications for standard of care.

Reference

1. Berdeja JG, Madduri D, Usmani SZ, et al. Update of CARTITUDE-1: A phase Ib/II study of JNJ-4528, a B-cell maturation antigen (BCMA)-directed CAR-T-cell therapy, in relapsed/refractory multiple myeloma. J Clin Oncol. 2020;38(suppl 15):8505. doi:10.1200/JCO.2020.38.15_suppl.8505