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CAR T-Cell Therapy Update

CAR T-Cell Therapy Update

CAR T-Cell therapy updates presented at the American Society of Clinical Oncology's Annual Meeting held June 2018.

ZUMA-1: Response to Axi-cel at 3 Months Prognostic for Remission in B-cell Lymphoma

Surabhi Dangi Garimella, PhD

A long-term follow-up of patients with B-cell lymphoma treated with axicabtagene ciloleucel (axi-cel), a chimeric antigen receptor (CAR) T-cell therapy, was presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting. Results indicate that a response at 3 months may be prognostic for long-term remission in those patients.

An autologous anti-CD19 CAR T-cell therapy developed by Kite Pharma, axi-cel was granted priority review following interim results showing that 82% of patients had met the primary end point of an objective response rate at 8.7 months of follow-up. Subsequently, the drug was approved within 5 months by the FDA for the treatment of adult patients with relapsed/refractory large B-cell lymphoma whose disease has progressed on at least 2 lines of systemic therapy.1

At ASCO, Frederick Locke, MD, program co-leader in immunology at the Moffitt Cancer Center and Research Institute in Tampa, Florida, presented the longer-term update. Patients (n = 101) with refractory large B-cell lymphoma received 2 × 106 CAR T cells/kg after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine.2 The best objective response rates (ORRs) were analyzed by both the local investigators and by an independent review committee (IRC).3

Results collected at a median follow-up of 15.4 months showed that while the best ORR was 82% at primary analysis (median follow-up of 8.7 months) it remained consistent in the longer term, with follow-up by local doctors (median 15.4 months). The complete response (CR) rates increased from 54% to 58%. Of the 34 patients who had a partial response (PR) at 3 months, 18 (44%) converted to a CR by the long-term follow-up cut off.

The researchers report observing a high concordance (77%-79%) for ORRs between local investigators and the IRC at all times assessed.

Locke emphasized that patients who responded at 3 months had an 80% likelihood of a durable response at 12 months. Analysis of progression-free survival (PFS) by local investigators found that most of the 60 patients with disease control (stable disease or better) at 3 months had prolonged disease control a year out and a PFS of 78% at the benchmarked 6, 9, and 12 months.

Among patients who had a CR, 88% had a CR at 6 months, 83% at 9 months, and 79% at 12 months.

Adverse events, primarily cytokine release syndrome (CRS) and neurologic events, were observed at a similar rate across all response groups, Locke said. CRS was observed in all 9 patients with PR, but all instances were low grade (<3); 39 CR patients experienced CRS, of which 5 instances were grade 3 or higher. In total, 7 PR patients experienced neurologic events, 3 of which were grade 3 or higher; 28 CR patients had neurologic adverse events, of which 15 were grade 3 or higher.

The authors concluded that based on the ORR and increasing CR rates during the long-term follow-up, patients can achieve CR even 1 year out following infusion of the axi-cel CAR T-cell treatment, which suggests that responses deepen over time.

“Patients who are in response at 3 months are 80% likely to maintain their response to the treatment at 12 months,” Locke said. He emphasized that a PR or CR at 3 months following the infusion can serve as a prognostic marker for long-term remission in patients with B-cell lymphoma who are administered axi-cel.

References:
  1. FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma [press release]. Silver Spring, MD: FDA; October 18, 2017. fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm581216.htm. Accessed June 5, 2018.
  2. Locke FL, Ghobadi A, Jacobson CA, et al. Durability of response in ZUMA-1, the pivotal phase 2 study of axicabtagene ciloleucel (Axi-Cel) in patients (Pts) with refractory large B-cell lymphoma. J Clin Oncol. 2018;36 (suppl; abstr 3003). abstracts.asco.org/214/Abst- View_214_211541.html.
  3. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544. doi: 10.1056/ NEJMoa1707447.


Promising Early-Phase Results With bb2121 CAR T Treatment in Relapsed Refractory Myeloma

Surabhi Dangi-Garimella, PhD

Innovation around developing safe and effective chimeric antigen receptor (CAR) T cells to treat cancer continues, and at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, Noopur S. Raje, MD, director, Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, Boston, presented results from the phase 1 multicenter study with a second-generation CAR T-cell therapy called bb2121.

The therapy, which uses biomarker-directed targeting of T cells to recognize and kill malignant myeloma cells in patients diagnosed with multiple myeloma, was tested for safety and efficacy in a dose-escalation phase of the CRB-401 trial. Raje reported updated safety and efficacy results in 43 patients enrolled in this ongoing study. The modified T cells were devised to target the B-cell maturation antigen (BCMA). Raje confirmed that based on preclinical results, bb2121 is not inhibited by high levels of soluble BCMA in serum by myeloma cells.

Patients with relapsed/refractory multiple myeloma who were selected for the dose-escalation treatment had received at least 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or were double refractory. BCMA expression on plasma cells was 50% or higher. Patients in the dose-expansion phase were required to have been treated with daratumumab, and they were refractory to their last line of therapy; BCMA expression was not required. A single infusion of bb2121 was administered to the patients following a 3-day lymphodepletion procedure with fludarabine (30 mg/m2)/cytarabine (300 mg/m2) given daily for 3 days.1

Safety concerns with CAR T-cell administration have lingered— cytokine release syndrome (CRS) and neurotoxicity CAR T cell– related encephalopathy syndrome are frequently documented in this patient population.2 For instance, one CAR T-cell therapy that was being developed to treat acute lymphocytic leukemia registered 5 fatalities following patients’ cerebral edema, and development had to be terminated.3 ROCKET was initially halted following an FDA directive, and the company made changes to its preconditioning regimen (leukapheresis), eliminating fludarabine from the preconditioning process. This, however, did not prove an effective solution and the trial was shelved.

When the abstract about bb2121 was submitted in October 2017 for presentation at this year’s ASCO annual meeting, 21 patients at that point had received bb2121 in the 4 dose-escalation cohorts, and the median follow-up was 35 weeks. The majority of patients were male and the median age was 58 years. All 21 patients had received a prior autologous stem cell transplant (ASCT) and a median 7 prior lines of treatments (range, 3-14).

As of October, the authors had observed no dose-limiting toxicities and no grade 3 or higher neurotoxicities. However, grade 1-2 CRS was reported in 15 patients (71%), 2 of whom had grade ≥3 CRS that resolved in 24 hours.

Surprisingly, 2 patients died, even though they had achieved a complete response (CR) and their disease had not progressed. Of the remaining 19 evaluable patients, the overall response rate in the dose escalation cohorts, who received at least 150×106 CAR T cells, was 94%: 10 of 18 patients (56%) patients had CR or unconfirmed CR; 9 of 10 evaluable patients were minimal residual disease–negative.

At a median follow-up of 40 weeks (in October), in the 150×106 or greater dose-escalation cohorts, median response duration and progression-free survival (PFS) had not been reached. PFS rates at 6 and 9 months were 81% and 71%, respectively. In the expansion phase, patients were administered 150 to 300×106 CAR T cells.

At ASCO, Raje also presented results of 22 patients who were in the dose-expansion cohort—10 had <50% BCMA expression and 12 had ≥50% BCMA expression. The majority of patients in this cohort were male, as well, and the patients’ median age was 65 years. Nineteen of these patients had received prior ASCT and had received a median 8 lines of treatment (range, 3-23).

In the updated results presented at the meeting, Raje showed that 27 of the total 43 patients experienced CRS, of which 2 incidences were grade 3 or higher. Only 9 patients needed treatment with tocilizumab for their CRS. Fourteen patients experienced neurotoxicity, 35 had neutropenia, 26 had thrombocytopenia, and 24 had anemia. There were no grade 4 CRS events.

The overall response rate (ORR) was 33.3% in the low-dose patients (50x106), 57.1% in patients who received the 150x106 dose, and 95.5% in those who received an even higher dose. ORR was not significantly different between low–BCMA- expressing patients (100%) versus high–BCMA-expressing patients (91%).

Finally, Raje discussed the significant improvement in PFS in patients receiving a high dose of bb2121. Median PFS in 18 patients in the dose-escalation phase was 11.8 months, while it was 17.7 months in 16 subjects who were negative for minimal residual disease.

A lingering question with the approved CAR T-cell treatments—tisagenlecleucel (Kymriah; Novartis) and axicabtagene ciloleucel (Yescarta; Kite Pharma/Gilead)—surrounds their costs. The treatment cycle of tisagenlecleucel costs $475,000 for B-cell acute lymphoblastic leukemia, while axicabtagene ciloleucel costs $373,000. While these numbers may seem steep, the Institute for Clinical and Economic Review released a report earlier this year on their price analysis; the Institute concluded that the prices align with the clinical value that both treatments present.4

Novartis, meanwhile, has negotiated a value-based contract with CMS for tisagenlecleucel.

References:
  1. Raje NS, Berdeja JG, Lin Y, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: updated results from a multicenter phase I study. J Clin Oncol. 2018;36,(suppl; abstr 8007). abstracts.asco.org/214/AbstView_214_211179.html.
  2. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47-62. doi: 10.1038/ nrclinonc.2017.148.
  3. Dangi-Garimella S. Juno’s ROCKET trial, evaluating CAR-T treatment in leukemia patients, shelved. The American Journal of Managed Care® website. ajmc.com/newsroom/junos-rock- et-trial-evaluating-car-t-treatment-in leukemia-patients-shelved. Published March 2, 2017. Accessed June 5, 2018.
  4. Tice JA. Chimeric antigen receptor T-cell therapy for B-cell cancers: effectiveness and value evidence report. Institute for Clinical and Economic Review website. icer-review.org/wp-content/uploads/2017/07/ICER_CAR_T_Evidence_Report_021518.pdf. Published February 15, 2018. Accessed June 4, 2018.

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