Multiple myeloma patients treated with BCMA-directed CAR T-cell therapy have high response rate
Prof Deepu Madduri - Mount Sinai, New York, USA
I’m very excited here to share some of the data that we’re very enthusiastic about. This is the CARTITUDE-1 study which is a phase Ib/II study of JNJ-4528 in relapsed and refractory multiple myeloma patients. As we know, multiple myeloma is a rare blood cancer that is the third most common blood cancer accounting for about 10% of all haematological malignancies. There are 160,000 new cases worldwide per year, that’s about 1% of worldwide new care cancers. In the US there are about 25,000 new patients diagnosed with a mortality of 13,000. We know that there have been a lot of advances in the last few years over multiple myeloma drugs and so people are living longer, however, if you are a patient who has failed all available classes of therapy your median overall survival is less than 12 months.
So we really need a product that we can give to patients that hopefully we can cause deep, sustained responses. CAR
T initially was thought that this is going to cure the patients but we’ve found that maybe cure is not the right word yet but maybe we can give a one-time treatment for these patients who, as you know from myeloma patients, they’re coming once a week or sometimes two times a week to get infusions.
JNJ-4528, what’s unique about it is it’s structurally distinct, it’s a second generation chimeric antigen T-cell therapy with two BCMA targeting single domains. The CARTITUDE-1 study is a dose confirmation study based on the phase ILEGEND-2 study but it was done in a slightly different population. The primary objective of the phase Ib, as are most phase I studies, to characterise the safety and confirm the phase II dose, as I mentioned, informed by the LEGEND-2 study. The phase II portion is to evaluate efficacy.
Some of the key eligibility criteria are here. You can see the patients have progressive myeloma. So all patients must be progressing, they have to have measurable disease in their blood or bone marrow so you have to be able to see an M protein or serum free light chains. They must have had at least three prior therapies and received all classes of available agent, so a PI, at least one PI, one IMiD and an anti-CD38. To the right you see actually the study design.
After the patients were enrolled they all got themselves aphorised, this gets sent off to the manufacturing company and it takes about 4-5 weeks to get these cells remanufactured. During this time, as you know, these patients are heavily pre-treated so we were able to give them bridging therapy to keep them stable before the patients are infused with their cells. Then the patient gets lymphodepleting chemotherapy with fludarabine and Cytoxan. What this does is wipes out their T-cells so that when you can reinfuse the new manufactured engineered cells they can do their job.
The target dose is 0.75 million CAR T-cells per kilogram of bodyweight. I want to point that out as some of the CAR Ts are a flat dose of 300 million, 450 million, but here you’re giving CAR T-cells per kilogram of body weight. The median administered dose was 0.73 million CAR T-cells per kilogram of bodyweight which is very close to the target dose.
Today we’ll only be talking about the phase Ib portion of the study which had a median follow-up at data cut-off of six months. In the phase Ib portion we treated 29 patients with a median age of 60 and half of them were female. All patients were heavily pre-treated. As you can see, the prior lines of therapy was five and it ranged anywhere from three to eighteen, eighteen is quite high. So these patients are quite refractory. 100% of these patients are triple exposed, meaning that they’ve had exposure to three different classes, such as PI, IMiD and a CD38. 86% of those patients were triple refractory to those classes and 72% of the patients were penta exposed, meaning they’ve been exposed to two. PIs, two IMiDs and an anti-CD38 and 31% of the patients are refractory to all five drugs.
Here we report the safety data of the study. As you can see, the most common grade 3 or 4 adverse event was haematological, which is as expected, and non-haematological AEs are very uncommon. We only had two patients who had increased AST, which is a lab abnormality, one patient with ALT and one patient had diarrhoea. In terms of cytokine release syndrome all but two patients had cytokine release syndrome with 86% of the patients having mostly grade 1 or 2 CRS. One patient had a grade 3 CRS event and one patient had a prolonged dose limiting toxicity of grade 4 CRS which converted to a grade 5 event and the patient passed away from complications at day 99.
In terms of neurotoxicity it was quite uncommon, only three patients, or 10% of the patients, had any grade of neurotoxicity with one patient who had a grade 3 neurotoxic event which happened concurrently with her grade 3 CRS event, both of which resolved within a day after the administration of tocilizumab and steroids. The one thing I want to point out with this CAR T that’s different from the others is the median time of onset of CRS. This was seven days with 90% between five and nine days. Most of the products have rapid expansion and you notice CRS happening within the first couple of days but in this one they’re slow expansion causing the CRS to happen closer to seven days.
As we mentioned, these are very heavily pre-treated patients and so getting early and deep responses is quite amazing. Every single patient on this study responded so we had 100% overall response rate. Every single patient had a reduction in their paraprotein. If you break that 100% response rate down further you can see 69% of the patients were in complete response, meaning that they had no evidence of myeloma cells in their bone marrow or in their blood. 86% of the patients were very good partial remission or better.
The median time to first response was one month, as was the median time of CR. We had 17 evaluable patients which is what we look for is MRD negative status and all 17 patients were MRD negative. 27 of the 29 patients are still progression free at six months follow-up.
Here we’re going to discuss briefly about the pharmacokinetics of this study. As I mentioned, every single patient expanded their T-cells and they were consistent. So the peak happened around day 10, ranging between day 10 to 14 with CRS preceding about three days prior. So you started having CRS, you had the slow expansion of these T-cells and, as you can see on the right, what we think makes this product a little bit more unique is the preferential expansion of the CD8 central memory phenotype. What that means is CD8 cells are used to kill your myeloma cells but these central memory cells have a way, we think, of not getting exhausted as often and having sustained effector function.
In conclusion, the CARTITUDE-1 study confirmed the recommended phase II dose of 0.75 million CAR T-cells per kilogram of bodyweight. It was a very safe and tolerated product. Like I said, 86% of the patients had mostly grade 1 and 2 CRS with very rare neurotoxicity. There were early and deep responses observed in these heavily pre-treated patients with 100% overall response rate and CR rates of 69%. Out of the 29 patients 27 patients are still progression free at a median of six months follow-up. All 100% of the patients who were MRD evaluable were MRD negative. JNJ-4528 exhibits this preferential expansion of the CD8 central memory phenotype.
So in conclusion, the safety and efficacy results are very consistent with the LEGEND-2 study. The phase II portion of the study has been fully enrolled and the phase II and III studies have been initiated. Just yesterday the FDA actually gave JNJ-4528 breakthrough designation for relapsed refractory myeloma patients. Thank you.