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Instructor of Medicine
Division of Oncology
Department of Internal Medicine
Harvard Medical School
Hematopoietic Cell Transplant and Cellular Therapy Program
Massachusetts General Hospital Cancer Center
Matthew J. Frigault, MD, has disclosed that he has received consulting fees from Arcellx, Celgene, Foundation, Kite/Gilead Sciences, Nkarta, Novartis, and Xenetic.
The 2019 ASH annual meeting will host an impressive number of presentations on CAR T-cell therapy. In this commentary, I preview the some of the abstracts that I think will be of high interest in this field.
New Data on CAR T-Cell Therapy for Diffuse Large B-Cell Lymphoma (DLBCL)
There are currently 2 CAR T-cell therapies approved for use in patients with relapsed/refractory DLBCL who have received 2 or more previous lines of therapy: axicabtagene ciloleucel and tisagenlecleucel, both of which are targeted to CD19. Numerous products are also in clinical development for lymphoma, including lisocabtagene maraleucel, which is also a CD19-targeted agent. At ASH 2019, we will see data with this therapy from the pivotal phase I TRANSCEND NHL 001 trial in patients with relapsed/refractory DLBCL. Of importance, this will be the largest investigational cohort presented to date. In the abstract, the authors reported an ORR of 73%, with a best overall CR rate of 53% (N = 268 treated). We anxiously await data on the durability of responses in this cohort. With approval of lisocabtagene maraleucel anticipated in the next 12 months as the third CD19‑specific CAR T-cell agent coming to market, it will be important to see the toxicities and breakdown of responses by disease subtype to know how these data fit in relation to the JULIET and ZUMA‑1 cohorts.
In terms of emerging strategies, we will see results utilizing novel approaches, including CD19/CD22 bispecific CAR-T constructs. One such example is AUTO3, a novel CAR T-cell therapy targeting CD19 and CD22. In a phase I/II study, 24 patients with relapsed/refractory DLBCL were treated with one of 2 doses of AUTO3 plus pembrolizumab, a PD-1 inhibitor. Per the ASH abstract, at the lowest dose level of 50 x 106 cells, the ORR was 57% and CR rate was 29%.
Another noteworthy study will highlight earlier use of steroids with axicabtagene ciloleucel in patients with relapsed/refractory DLBCL. In this trial, a nonrandomized safety expansion cohort of the ZUMA-1 trial (“cohort 4”), patients received early steroid intervention starting at grade 1 neurologic events (NEs) and cytokine-release syndrome (CRS) when no improvement was seen after 3 days with supportive care. This approach deviates from standard care, which traditionally involves steroids or tocilizumab therapy only when CRS or NEs reach grade 2, due to concerns that steroid or tocilizumab therapy may impair overall treatment efficacy. The abstract for this study suggests that earlier tocilizumab or steroid treatment initiation does not affect ORRs or durability of responses, although long‑term follow-up data are needed. Of interest, CAR T-cell expansion within this cohort was comparable to cohorts 1 and 2 of the ZUMA-1 trial (in which steroids were given later), suggesting an earlier steroid treatment approach does not impair overall expansion of CAR T-cells with axicabtagene ciloleucel, which was a primary concern. The study authors also report decreased toxicity with early steroid use; grade 3 CRS only occurred in 2% of the study group and grade ≥ 3 NEs only occurred in 17%, which is dramatically decreased compared with ZUMA-1 cohorts 1 and 2. These findings are likely to affect future practice, suggesting that early steroid use with axicabtagene ciloleucel for the prevention of serious NEs may be beneficial, with no impact on cell expansion or treatment efficacy.
A real-world evaluation of tisagenlecleucel for adults with DLBCL within the Center for International Blood and Marrow Transplant Research (CIBMTR) Cellular Therapy registry will also be presented. Although there have been real-world reports from various consortiums evaluating axicabtagene ciloleucel, this is one of the first reports to use the new CIBMTR registry to look at overall outcomes of tisagenlecleucel in the post approval setting. According to the abstract, tisagenlecleucel was associated with a CR rate of 38% and an ORR of 60% (N = 70). What is even more interesting about this dataset is that response data were subdivided by CAR T-cell viability (ie, > 80% or < 80%). When looking at the 23 patients who had viability > 80% and the 21 patients with viability < 80%, the ORR and CR rates were actually comparable across groups, suggesting that this viability cutoff may not be relevant to overall patient care, as it does not appear to affect efficacy, but rather only limits drug access by commercial means.
We will also see real-world CIBMTR data on axicabtagene ciloleucel for patients with relapsed/refractory DLBCL at ASH 2019. Similar to previously reported retrospective studies, the ORR in this series was 70%, with a CR rate of 52% (N = 295), which is generally comparable to the responses observed in ZUMA-1. Taken together, these abstracts suggest that the CIBMTR reporting mechanisms can successfully capture the patient specific data required for long-term follow-up.
CAR T-Cell Therapy for MCL
Also anticipated at ASH 2019 are interim safety and efficacy results from the phase II ZUMA‑2 trial of axicabtagene ciloleucel in patients with relapsed/refractory mantle cell lymphoma (MCL). MCL has been excluded from other CAR T-cell therapy approvals; this is an exciting study that now has more than 1 year of follow-up. The abstract reported an ORR of 86% in this cohort with highly refractory MCL, with best CR rate of 57% (N = 28). In addition, 12-month estimates of duration of response, PFS, and OS were reported to be 83%, 71%, and 86%, respectively. Regarding toxicities, the most commonly reported grade 3/4 adverse event was CRS, which occurred in 18% of patients. This rate is slightly higher than that observed in previous trials. It is important to point out that although NEs were reported in 46% of the overall cohort, there were no grade 5 NEs. We eagerly await further breakdown of the study results, including durability of response and overall toxicities.
BCMA-Targeted Therapy for Multiple Myeloma (MM)
Several BCMA-targeted CAR T-cell therapies are now in clinical development for patients with relapsed/refractory MM, with idecabtagene vicleucel having been the subject of a successful phase I study and having now reached a randomized phase III trial (KarMMa-3) in this population. At ASH 2019, we will see results from the phase Ib/II CARTITUDE‑1 study of BCMA‑specific JNJ-4528 for patients with relapsed/refractory MM. What is unique about this product compared with other BCMA-targeted CAR T-cell therapies is that JNJ-4528 binds 2 BCMA epitopes simultaneously, potentially improving efficacy and/or durability, although long-term follow-up will be needed to confirm these effects. Inclusion criteria for CARTITUDE‑1 included age older than 18 years and measurable disease as assessed by M-protein or serum-free light chain levels. Subjects were also required to either have received 3 or more previous regimens or be double refractory to proteasome inhibitors and immunomodulatory drugs and have received an anti‑CD38 antibody. The abstract reported an ORR of 91% among 21 evaluable patients (N = 25). Four stringent CRs, 2 CRs, 7 VGPRs, and 6 PRs were also reported. Among the 15 patients who were evaluable by bone marrow samples at 28 days post infusion, 10 had negative measurable residual disease (MRD) at 10‑5 sensitivity level, 2 were MRD negative at 10‑4 level, and 3 had unidentified clones. This is an important study because it addresses previous critiques of similar trials, namely that the patient populations were less extensively treated as compared with standard practice. By contrast, this study is reflective of current US-based MM treatment approaches.
Also of interest is an abstract reporting long‑term follow-up results of a phase I study of BCMA-targeted LCAR-B38M for patients with relapsed/refractory MM. The abstract for this study reported an ORR of 88%. The median PFS for all patients treated was 20 months, but the median PFS for MRD‑negative patients with CR was 28 months; these are some of the longest PFS durations observed in trials of BCMA-targeting agents to date. This product is similar to JNJ-4528, indicating that treatment focused on simultaneous binding of dual epitopes may produce durable responses.
Finally, I am looking forward to seeing results from a first-in-human assessment of feasibility and safety of multiplexed genetic engineering of autologous T-cells in advanced MM and sarcoma, as presented by Edward Stadtmauer and Carl June. This trial represents the next generation of cellular therapy for these diseases. The therapy under study is an autologous T-cell product that uses CRISPR to knock out genes encoding endogenous T-cell receptor alpha and beta chains to reduce TCR mispairing. This product also knocks out PD-1 to enhance activity and persistence in overcoming the tumor microenvironment. In this phase I study of 3 patients, the abstract reported confirmation of the safety, feasibility, expansion, and persistence of this treatment. As this is one of the newer CRISPR gene-editing products being developed, the full results are eagerly anticipated.
Emerging CAR T-Cell Therapy for Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
Lisocabtagene maraleucel is also being evaluated in patients with CLL and SLL, and at ASH we will see findings from the open-label phase I/II TRANSCEND CLL 004 trial. This study included patients with standard-risk or high-risk relapsed/refractory CLL and SLL, all of whom had received prior ibrutinib and one half of whom had failed previous venetoclax therapy as well. At a median follow-up of 9 months, the best ORR was 82% and the best CR/CR with incomplete blood count recovery (CRi) was 46% among 22 patients. In addition, 68% of subjects achieved an objective response by Day 30. Two patients had grade 2 CRS and 5 patients had grade ≥ 3 NEs, including encephalopathy in three subjects. These findings position lisocabtagene maraleucel as a potential new line of therapy for CLL/SLL.
What CAR T-cell therapy studies are you most interested in at this year’s ASH meeting? Please answer the polling question on your screen and share your thoughts in the comments box.
Attending the 2019 ASH annual meeting in Orlando? Sign up here to attend CCO’s satellite symposium, “CAR T-Cell Therapy for Leukemia, Lymphoma, and Myeloma: Where We Are and Where We Are Going,” on the evening of Friday, December 6, during which I will discuss patient case studies and current and emerging strategies in CAR T-cell therapy with our esteemed panel, including Stephen J. Schuster, MD; James K. Kochenderfer, MD; and Jae H. Park, MD.
Not attending ASH but still want to view this exciting educational event? Sign up here to watch the live simulcast from your computer. After ASH concludes, remember to check the CCO Web site for a downloadable slideset summarizing the data from these studies and more.