ASCO 2021 Recap: CAR T-Cell Therapy

Studies Offer Promising Data on CAR T-Cell Therapy in B-ALL, Multiple Myeloma

Two abstracts presented recently at the American Society of Clinical Oncology annual meeting offered promising data for 2 chimeric antigen receptor (CAR) T-cell therapies, one in relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and one in R/R multiple myeloma. Approved in 2020 for patients with R/R mantle cell lymphoma, brexucabtagene autoleucel (brexu-cel), sold as Tecartus, is now being studied as well in patients with R/R B-ALL, and the recent conference data suggest that the treatment offers clinical benefit in these patients.¹

After a median follow-up of 16.4 months, median overall survival was not reached among the patients who responded to brexu-cel. These patients had a mean relapse-free survival of 14.2 months. Across the 55 patients receiving brexu-cel, 71% achieved a complete response (CR) or CR with incomplete hematologic recovery (CRi), 97% of whom were negative for minimal residual disease. The patients included in the study were heavily pretreated: 45%, 22%, and 42% had previously received blinatumomab, inotuzumab ozogamicin, and allogeneic stem cell transplant, respectively. Ninety-five percent of patients experienced grade ≥3 adverse events (AEs), the most common of which included anemia (49%) and neutropenia (49%).

Grade ≥3 cytokine release syndrome and neurologic AEs—commonly reported among patients treated with CAR T-cell therapies—were reported in 24% and 25% of patients, respectively, with a median time to onset of 5 days and 9 days, respectively. According to the researchers, they were generally reversible.

NOVEL THERAPY IN MULTIPLE MYELOMA. During the conference, researchers also offered data from 2 different time points of an ongoing phase 1 study of CART-ddBCMA in R/R multiple myeloma. CARTddBCMA is an autologous CAR T-cell therapy that uses a novel binding domain to target B-cell maturation antigen (BCMA), and it is designed to reduce the risk of immunogenicity and have high stability.

As of January 29, 2021, there were 9 evaluable patients, all of whom had responded to CARTddBCMA. Four patients had achieved a stringent CR (sCR), 1 a very good partial response (VGPR), and 4 a PR. One of the patients who achieved a PR had disease relapse and was retreated, while the rest of the patients had ongoing responses.²

Similar findings were seen as of April 2021,³ with all 12 evaluable patients achieving a response,
including 5 sCRs, 1 CR, 3 VGPRs, and 3 PRs.

Eleven of these responses are ongoing, and study data suggest that responses deepen over time.
According to the researchers, despite previously progressing on BCMA-targeted therapy, 1 patient
still achieved a VGPR.

All 12 of these patients have received at least 3 prior lines of therapy, and 10 were pentarefractory.

References

1. Shah BD, Ghobadi A, Oluwole OO, et al. Phase 2 results of the ZUMA-3 study evaluating KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adult patients (pts) with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). J Clin Oncol. 2021;39(Suppl 15):abstr 7002. doi:10.1200/JCO.2021.39.15_suppl.7002
2. Frigault M, O’Donnell E, Raje NS, et al. Phase 1 study of CART-ddBCMA, a CAR-T therapy utilizing a novel synthetic binding domain, for the treatment of subjects with relapsed and refractory multiple myeloma. J Clin Oncol. 2021;39(Suppl 15):abstr 8015. doi:10.1200/JCO.2021.39.15_
suppl.8015
3. Arcellx announces presentation of positive clinical results from ongoing phase 1 study of CART-ddBCMA at the 2021 ASCO Annual Meeting. News release. Arcellx; June 4, 2021. Accessed July 2, 2021. https://arcellx.com/arcellx-announces-presentation-of-positive-clinical-results-from-ongoing-phase-1-study-of-cart-ddbcma-at-the-2021-asco-annual-meeting/

ASCO Clinical Spotlight: Larry Anderson, MD, PhD, Discusses High Response Rates of Ide-Cel in Multiple Myeloma, Protocols During COVID-19

LARRY D. ANDERSON, MD, PHD, is the director of the Myeloma, Waldenström’s, and Amyloidosis
Program and associate professor, Internal Medicine, Division of Hematology/Oncology, UT
Southwestern Medical Center in Dallas, Texas.

Findings indicate an overall response rate of 73% for the chimeric antigen receptor (CAR) T-cell therapy idecabtagene vicleucel (ide-cel) in the treatment of relapsed or refractory multiple myeloma, with the safety profile remaining consistent regardless of the number of prior
lines of therapy, said Larry D. Anderson Jr, MD, PhD. Evidenced-Based Oncology™️ (EBO) spoke with Anderson during the 2021 American Society of Clinical Oncology (ASCO) annual meeting, as
updated data were being presented for KarMMa (NCT03361748), a pivotal trial involving ide-cel,¹ and prior to the presentation of phase 2 data from CARTITUDE-2, a study of a different CAR T-cell
therapy, ciltacabtagene autoleucel (cilta-cel).² This interview is edited lightly for clarity.

EBO: Can you discuss the long-term data on ide-cel that were presented at the 2021 ASCO Annual Meeting?

ANDERSON: This is an updated analysis from the KarMMa study presented at ASCO 2021 that shows longer-term efficacy and safety results in patients treated with ide-cel in the KarMMa trial overall, and broken down by number of prior lines of therapy of 3 vs 4 or more, [because] the FDA label is requiring at least 4 prior lines of therapy and the study only required 3.

Our results showed a 24.8-month median overall survival in triple class–exposed, relapsed refractory multiple myeloma now at a median follow-up of 24.8 months, the longest follow-up to date for a global clinical trial of CAR T-cell therapy for myeloma.

Overall survival was similar after 3 vs 4 or more prior lines of therapy. And of note, it was over 20 months for those with extramedullary disease and with triple class refractory. Overall, 128 patients were infused with ide-cel in this study, with a range of 150 [million] to 450 million CAR T-cells infused. These were patients that had received a median of 6 prior lines of therapy, ranging from 3 to 16.

The overall response rate was 73%. Median progression-free survival [PFS] was 8.6 months. This study showed an average response rate that wasn’t affected by the number of prior lines of therapy. However, the patients that received the highest target dose of 450 million CAR T-cells did have higher response rates of 81% and the complete response rate was higher at 39% and the median PFS was 12.2 months.

Responses were durable, with a median duration of response of 10.9 months among all ide-cel–treated patients [and] an increase with depth of response to 21.5 months of duration of response for those achieving complete response.

Although 84% of patients in this study experienced some level of cytokine release syndrome, only 6% had grade 3 or higher, and fortunately, only 18% of patients in the study experienced any grade
of neurotoxicity, with only 4% experiencing grade 3 and no grade 4 or 5 neurotoxicity.

So, the safety profile in this study was similar regardless of the number of prior lines of therapy [and] remained consistent with longer follow up, with similar rates of infections, second primary malignancies, and no unexpected gene therapy–related toxicities. And based on this study, the ide-cel product has now been FDA approved for patients with relapsed refractory multiple myeloma who have received at least 4 prior lines of therapy.

EBO: What are the key points of separation between the long-term KarMMa data of ide-cel and the data of cilta-cel seen thus far? What do the long-term data tell us about adverse events?

ANDERSON: First of all, the long-term data tells us it tells us that we’re not seeing any increasing long-term side effects of CAR T-cell therapy for myeloma, no gene therapy related [adverse] effects, no unexpected higher incidence of second malignancies, and no late neurotoxicity. But as far as comparing products, we really don’t have any data to compare between ide-cel versus cilta-cel at this point. …

One other thing of a note, certainly with the ide-cel patients in the KarMMa study where, as I mentioned, we’re only seeing about 18% neuropathy with very low risk of severe neuropathy. Certainly, the studies presented to date with cilta-cel do show some non [central nervous system] neurotoxicity that we’re anxious to follow up on, and see how that pans out with further follow up and see what the true incidence and outcomes are for those patients.

EBO: One of the issues with payers over the cost of CAR T-cell therapy generally has been that even when patients have a good response, they may relapse. Given that the median duration of response for patients with a complete response is still less than 2 years, what have you learned from KarMMa about patient selection to ensure that the best candidates receive ide-cel, and that conditions are optimal for good results?

ANDERSON: Right now, all we can say is that there were similar results if patients had received 3 lines of private therapy versus 4 or more. Certainly, we would like to know more about exactly which patients are going to have a complete response. Obviously, that translates into better outcomes. And in those patients with a complete response, they have a duration of response of 21.5 months; of those with [near complete response], 41% are still in remission at 2 years, and some still in remission, and currently at 3 years. But we don’t have any data yet on trying to pin down which patients specifically are going to be predicted to have the better responses and longer remissions, unfortunately.

So, right now, just compared to all the other options that we have for these patients that provide a very short survival with most other products, certainly, this is still a really good option for these patients. What we’re suspecting though, is that if we can give these CAR T cells even earlier in the course of therapy, when the T cells are more functional or less dysfunctional, we’re hoping that can make even more difference on the outcomes in these patients.

EBO: How to do response rates for CAR T-cell therapies given multiple myeloma compare with those given for leukemia and lymphoma?

ANDERSON: Certainly, the data for leukemia and lymphoma are more mature and have longer follow up. And it does appear that a fair percentage of those patients may have long-term remissions, whereas, so far in myeloma studies, while we’re not able to confirm yet if we see
any true long-term remissions or cures, we’re still hopeful. Right now, it does look like a higher percentage of patients are relapsing within two years and the myeloma studies as compared with the lymphoma and leukemia. That gets back to the biology—we already can potentially
cure leukemia and lymphoma with other therapies, allergenic transplant, or high dose chemo. Whereas with myeloma, most of our studies have shown that any other product that we’ve tried to use to cure patients has not been able to do that so far, although certainly further follow up
and long-term outcomes are needed before we can really decide.

EBO: Were patients given ide-cel during the COVID-19 pandemic? If so, can you describe the protocols and what you have learned? Should patients with refractory multiple myeloma be vaccinated if CAR T-cell therapy is contemplated?

ANDERSON: Certainly, we have been giving CAR T-cell [therapy] during the pandemic. We did have a pause for a couple months at the very beginning of the pandemic when we didn’t really know which way things were going. So, everything was on hold for a couple months last year, but since then we’ve been moving forward.

We do have a lot of protocols in place to ensure the safety of our patients. We’ll screen them with a swab for coronavirus before their infusion, before their collection, and then usually we’ll admit them to a cell therapy unit where all the other patients are also screened for coronavirus so that these patients don’t come down with coronavirus during their period of low immune system.

We will recommend revaccination against coronavirus starting around 3 months out from CAR T-cell therapy. So, even if they’ve had a prior vaccine before, just because of the possible dysfunction of the residual immunity, we’ll recommend repeating that vaccination starting about 3 months out, but certainly if patients are not immediately about to go through their CAR T-cell therapy, just thinking about it in the next few months, then certainly would also recommend going ahead and getting that coronavirus vaccine to build up some immunity that might help protect them during their procedure as well.

References

1. Anderson LD, Munshi NC, Shah N, et al. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, in relapsed and refractory multiple myeloma: Updated KarMMa results. J Clin Oncol. 2021; 39(suppl 15):abstr 8016. DOI: 10.1200/JCO.2021.39.15_suppl.8016
2. Agha ME, Cohen AD, Madduri D, et al. CAR TITUDE-2: Efficacy and safety of ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR T-cell therapy, in patients with progressive multiple myeloma (MM) after one to three prior lines of therapy. J Clin Oncol. 2021;39(suppl 15): abstract 8013.