CAR-T Spotlight - Episode 5
At the recent meeting of the American Society of Hematology, results from several studies involved the use of chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma.
Chimeric antigen receptor (CAR) T-cell therapy is moving into to new treatment areas, as the year 2020 brough an approval in mantle cell lymphoma and the recent 62nd meeting of the American Society of Hematology (ASH) saw scientists share results for the treatment in multiple myeloma.
Among them was the December 5, 2020, virtual presentation of CARTITUDE-1, the phase 1b/2 results for ciltacabtagene autoleucel (cilta-cel), Janssen’s investigational B-cell maturation antigen (BCMA) CAR T-cell treatment for patients whose multiple myeloma has progressed after as many as 6 treatments.
Deepu Madduri, MD, of The Tisch Cancer Institute at Mount Sinai, New York, and the principal investigator of CARTITUDE-1, presented results that showed an overall response rate (ORR) of 97% and a stringent response rate of 67% with a median follow-up time of 12.4 months. Of note, median duration of response and progression-free survival (PFS) were not reached.
In an interview with The American Journal of Managed Care®(AJMC®), Madduri explained that patients with multiple myeloma have a poor prognosis if their disease progresses after 3 treatments. But in CARTITUDE-1, cilta-cel has produced deep responses in these patients.
The following interview has been edited for length and clarity.
AJMC®: In 2019 at ASH, you presented data from CARTITUDE on 29 patients. Now, there are 97 patients with data. How have patient responses remained similar to what you reported last year? Are there any new important observations about the patients who have received treatment?
Madduri: At this year's ASH, we presented the CARTITUDE-1 study, which was the combined phase 1b and phase 2 portions of the study, which had a total of 97 patients who were treated. They were heavily pretreated, as their median prior lines of therapy was 5. Despite having this heavily relapsed/refractory population—and as we know from the MAMMOTH study, patients who are penta-refractory have an overall survival of less than 6 months—we saw on the CARTITUDE study, we haven't met the median PFS [progression-free survival]. We haven't reached the median PFS yet. The overall response rate on this study was 97%, with 67% of these patients being in stringent CR [complete response] and about 93% of the patients having VGPR [very good partial response] or better. Even more exceptional is that 72% of these patients were still maintaining their response at the time of data cutoff, which was about 12.4 months.
AJMC®: What did investigators learn about adverse event (AE) occurrence in CARTITUDE-1 vs CAR T-cell treatment in general?
Madduri: In the 97 patients that were treated on this study, we had a total of 14 deaths during the study, which 5 of them were due to progressive disease; 3 were due to adverse events unrelated to treatment, such as pneumonia and acute leukemia; and 6 patients had AEs related to the treatment.
With CAR [chimeric antigen receptor] T-cell therapy, one of the known side effects is cytokine release syndrome [CRS], which is the body's reaction after the CAR T cells are infused, and this is a very known complication. And another complication is CAR T-related neurotoxicity. So, looking at the study, we actually saw mostly grade 1 and 2 CRS. And what was interesting is our median time of onset with CRS was about 7 days. And regarding the CAR T neurotoxicity, any-grade neurotoxicity was about 21%, with 10% having grade 3 or higher.
In terms of managing these toxicities, we have a lot of supportive measures we can use, particularly atezolizumab, steroids, and anakinra. And I think as investigators get more and more comfortable in managing CAR T-related symptoms and side effects, we tend to give tocilizumab much earlier now, not necessarily waiting until grade 2 CRS. So, I feel like these patients are managed very easily with the supportive care that we have, and particularly, they're not that high-grade CRS that we're managing to begin with.
AJMC®: What have investigators learned about adverse events (AEs) that may be specific to this therapy compared with CAR T-cell treatment in general? Are there strategies for preventing AEs in the future?
Madduri: With CAR T-cell therapy, one of the known side effects is cytokine release syndrome (CRS), which is the body's reaction after the CAR T cells are infused; this is a very well-known complication. Another complication is CAR T-related neurotoxicity So, in looking at the study, we actually saw mostly Grade 1 in CRS. And what was interesting is our median time of onset with CRS was about 7 days. And regarding neurotoxicity, any grade neurotoxicity was about 21% with 10% having grade 3 or higher. In terms of managing these toxicities we have a lot of supportive measures we can use, particularly tocilizumab, steroids, and anakinra. As investigators got more and more comfortable in managing CAR T-related symptoms and side effects, we tend to give tocilizumab much earlier now—not necessarily waiting until grade 2 CRS. I feel these patients are managed very easily with the supportive care that we have, and particularly, they're not that high grade CRS to begin with.
AJMC®: Minimal residual disease (MRD) was an important marker in CARTITUDE. Can you explain why it’s become an important marker for cancer therapy?
Madduri: MRD has become more of a landmark study [marker] that we do for most clinical trials in multiple myeloma, and trying to achieve MRD negativity in some studies is [now] their primary end point or secondary end point. Here in the CARTITUDE study, it was a secondary end point. Fifty-seven patients were evaluable for MRD, and 53 out of the 57 patients were MRD-negative. And that was about 93%. And this MRD was done by Adaptive [Biotechnologies], and it was 10 5.
AJMC®: One striking aspect of CARTITUDE is how many prior treatments these patients received, and yet many are still responding to treatment. Are there any differences in responses based on the type or the number of treatments patients have previously received?
Madduri: That’s a very interesting question. In the 97 patients that we treated, we had a median of 6 prior lines of therapy, and it ranged anywhere from 3 to 18 prior lines of therapy. Unfortunately, we didn't see any correlation between the number of lines of therapy that they had, whether less lines of therapy meant that they had more response. It’s just nice to actually have something to offer to these patients—who are heavily refractory [and] have a median overall survival of less than 6 months. So, I think a one-time treatment to give these deep durable responses is what we need in our myeloma patients. It's one step closer to getting a cure.
AJMC®: Are there any important differences in this study population versus that of LEGEND, which would give us insight into how CAR T-cell therapy could work for different patient populations?
Madduri: Compared with the LEGEND-2 study where the update was presented at ASH last year, we know a lot of those patients weren’t daratumumab exposed, which is what you expect in China. Not a lot of patients [in China] end up getting anti-CD38 therapy. So, in our study … we actually had 96 out of the 97 patients been exposed to anti-CD38. They’re also penta-refractory—42% of these patients are penta-refractory. ... So, in looking at the [CARTITUDE] patients, they are a little bit more heavily pretreated compared to the patients in China. But at the same time, those patients have had more than 1 transplant, or they've had a lot of different lines of therapy as well, but just not penta-refractory.
AJMC®: Data cut off was made 2020 about two months after lockdowns began in the United States due to the pandemic, how has COVID-19 affected the clinical trial process?
Madduri: As for the COVID-19 process, in particular I can speak from the experience in New York City. New York City was an epicenter; we actually had to hold all our clinical trials. And all of us were deployed into managing acutely ill COVID-19 patients. So, I think in terms of data, we adapted very quickly, we were able to do tele visits and remote visits, and patients were going to local labs and drawing their bloodwork when they needed to at their time points, and they were mailing [the bloodwork] in. So, I feel like we tried to keep up with data as much as we can during the pandemic. And the patients actually really enjoyed seeing us via video because a lot of these patients travel from far to come to an academic center to have CAR T. So, I was able to see patients in New Mexico patient at one of our patients actually went to Portugal. We were able to see him in Portugal and in Florida. I think it helped out, we are still able to collect the local labs, at least for these patients. And whenever the COVID pandemic eased up, we brought them back in. And another thing that Janssen has implemented is to do home monitoring. We’re in the process of working on a contract, where they will send somebody to draw these patients labs, so they won't miss any central labs during this pandemic.
AJMC®: Do you think this pandemic has the potential to fundamentally change medicine and patient interactions going forward?
Madduri: I think we have learned a lot from COVID-19. As I mentioned, not only [during] clinical trials, but during the initial COVID-19 phase when we didn't understand what was going on and how it was going to impact our patients. We were switching a lot of our patients to oral chemotherapy; we were switching a lot of patients to telehealth because [they had] a lot of comorbidities; they may be in the high-risk category for getting COVID. And we wanted to kind of protect our patients as well. Since the [beginning] of COVID, it has gotten a little better in New York City. Now obviously, it's getting worse again. But during the time where it's gotten better during August and September, some of our patients still continue to prefer video visits because they were still a little hesitant to come out of their house until the vaccine comes out. We were able to still take care of the patient. We're offering even more treatments because we're able to see more patients, but not restricted to New York City alone. So, we're seeing patients out of state [and even] out of the country and doing initial consultations with them, helping them guide them through their treatment. I feel like we're all learning from it and we're making the best out of what we can.