ASH 2019: CAR T

CE / CME

My Take on Key Studies in CAR T-Cell Therapy From ASH 2019

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Released: January 31, 2020

Expiration: January 30, 2021

Michael R. Bishop
Michael R. Bishop, MD

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Several exciting reports related to CAR T-cell therapy were presented the 2019 ASH annual meeting. In this commentary, I discuss 4 of the studies that I found to be of greatest interest at the meeting.

ZUMA-2: KTE-X19 for Mantle Cell Lymphoma (MCL)
Patients with MCL that have progressed despite targeted salvage therapy have a particularly poor prognosis. The phase II ZUMA-2 study investigated the use of the anti-CD19 CAR T-cell product KTE-X19 in patients with relapsed/refractory (R/R) MCL. KTE-X19 has the same construct as axicabtagene ciloleucel; however, the manufacturing process differs in that KTE-X19 manufacturing includes a white blood cell enrichment step. Twenty-eight patients with R/R MCL received a single dose of 2 x 106 CAR T-cells/kg following lymphodepleting chemotherapy; patients in the study had received a median of 4 previous lines of therapy. After a median follow-up of 13 months, the ORR was 86%, of which 57% were CRs. These responses were durable, with 75% of responders maintaining their response. The 12-month OS rate was approximately 86%. Using the Lee criteria for cytokine-release syndrome (CRS), 18% of patients receiving KTE-X19 experienced grade ≥ 3 CRS. Grade ≥ 3 neurologic events were observed in 46% of patients. Median time to onset of CRS and neurologic events was 2 days and 6 days, respectively. These compelling results indicate that KTE-X19 may provide an important treatment option for patients with R/R MCL.

TRANSCEND NHL 001: Lisocabtagene Maraleucel for Large B-Cell Lymphomas
Fewer than one half of patients with R/R large B-cell lymphoma respond to standard therapies after second-line treatment fails. The pivotal phase I TRANSCEND NHL 001 study investigated the anti-CD19 CAR T-cell product lisocabtagene maraleucel in patients with R/R large B-cell lymphomas, predominantly diffuse large B-cell lymphoma. In contrast to other anti-CD19 CAR T-cell therapies, lisocabtagene maraleucel has a defined proportion (1:1) of CD4+ and CD8+ CAR T-cells. At ASH 2019, data were presented on 268 patients who received doses of 50, 100, or 150 x 106 CAR T-cells. In total, 255 patients were evaluable for efficacy, and the ORR was 73%, with 53% of patients achieving a CR. The median duration of response for all patients was 13.3 months, and median duration of response had not been reached for patients who were in CR. The median PFS and OS rates were 6.8 months and 19.9 months, respectively. Any-grade CRS or neurotoxicity occurred in 42% and 30% of patients, respectively. Only 2% had grade ≥ 3 CRS, and 10% of patients experienced grade ≥ 3 neurotoxicity. Although there are no head-to-head trials comparing CAR T-cell products, it would appear that lisocabtagene maraleucel may provide relatively equal efficacy with less toxicity as compared with other anti-CD19 CAR T-cell products for patients with R/R large B-cell lymphomas.

TRANSCEND CLL 004: Lisocabtagene Maraleucel for Chronic Lymphocytic Leukemia (CLL)
Lisocabtagene maraleucel is also under investigation for treating patients with R/R CLL, and data from TRANSCEND CLL 004 trial were presented at ASH 2019. Twenty-three patients with R/R CLL, all of whom had been treated previously with ibrutinib, received dose levels of 50 and 100 x 106 CAR T-cells. The ORR was 82%, and 46% achieved a CR; 65% of evaluable patients were reported to have had undetectable measurable residual disease. Continuing responses were observed in 83% of patients achieving CR or PR at 9 months. Two patients experienced grade 3 CRS, and 5 patients experienced grade ≥ 3 neurotoxicity. Median time to onset for both CRS and neurotoxicity was 4 days. The phase II portion of this study is currently accruing and testing the efficacy and safety of the 100 x 106 CAR T-cell dose level. 

CARTITUDE-1: JNJ-4528 for Multiple Myeloma (MM)
Several BCMA-targeted CAR T-cell therapies are now in clinical development for patients with R/R MM, with idecabtagene vicleucel having been the subject of a successful phase I study and now being evaluated in the randomized phase III KarMMa-3 trial in this population. At ASH 2019, results were presented from the ongoing CARTITUDE-1 study investigating JNJ-4528—a CAR T-cell therapy comprised of 2 BCMA-targeting domains—in patients with R/R MM. It should be noted that JNJ-4528 is identical to LCAR-B38M. For the 21 patients evaluable for efficacy in CARTITUDE-1, the ORR was 91%. No patient had progressed at data cutoff, and responses were seen regardless of baseline BCMA expression. CRS occurred at a median of 7 days after CAR T-cell infusion. Based on these encouraging results, which are nearly identical to those observed in the LCAR-B38M trial, the phase II CARTITUDE-2 trial has been initiated.

Your Thoughts
What are your thoughts on the new CAR T-cell therapy data presented at ASH 2019? I encourage you to answer the polling question and join the conversation in the comment box.

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Which of the following topics related to CAR T-cell therapies that were discussed at ASH 2019 was of most interest to you?
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