CAR T Progress: Global Submissions for Kymriah, 42% Ongoing Response With Yescarta in ZUMA-1 Patients

A much-anticipated session on the second day of the 59th Annual Meeting and Exposition of the American Society of Hematology (ASH) in Atlanta, Georgia, provided long-term

updates on trials evaluating 2 chimeric antigen receptor (CAR) T-cell treatments: tisagenlecleucel, or CTL019 (Kymriah), for the treatment of adult relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL), and axicabtagene ciloleucel (Yescarta), which was evaluated in patients with refractory aggressive non-Hodgkin lymphoma (NHL).

Tisagenlecleucel was the first CAR T-cell treatment to be approved in certain pediatric and young adult patients with B-cell precursor acute lymphoblastic leukemia. Results from

the single-arm, open-label, multicenter, global, pivotal phase 2 JULIET trial of CTL019 in adults with r/r DLBCL were presented by Stephen Schuster, MD, professor, Division of Hematology/Oncology, Perelman School of Medicine, University of Pennsylvania.¹ Conducted in 27 study centers located in 10 countries around the world, the CAR T cells were manufactured in the United States and Germany.

The primary objective was met at the interim analysis, with the best overall response rate (ORR) of 59%, Schuster reminded the audience. His presentation provided results from the primary analysis of JULIET data, with the primary endpoint defined as best ORR (complete response [CR] + partial response [PR]) per independent review committee.

Eligibility criteria for JULIET included age 18 or older with r/r DLBCL, progression after receiving at least 2 lines of chemotherapy, and ineligible for or failed autologous stem cell transplant. Shuster shared a flow chart depicting the study status for JULIET, which had a data cutoff of March 8, 2017. Of the 147 patients who initially enrolled in the trial, 43 patients left the trial prior to infusion and 5 were pending infusion. Of the 99 who received a single CTL019 infusion, 81 were evaluable for response, 89 had received bridging chemotherapy, and 92 had received lymphodepleting chemotherapy (73% received fludarabine 25 mg/m² and cyclophosphamide 250 mg/m²/day for 3 days; 19% received bendamustine 90 mg/m²/day for 2 days).

The best ORR in the 81 patients was 53%, with 40% achieving a CR and 14% achieving a PR. The 3-month ORR was 38% (32% CR + 6% PR) and ORR at 6 months was 37% (30% CR + 7% PR). “The durability off the CTL019 response is shown by the stability between the 3- and 6-month response rates,” Schuster pointed out, adding that the 3-month response hints at a more long-term benefit of this treatment.

Subgroup analysis also showed consistent ORR across the various cohorts:

• All patients: 53.1% (95% CI, 41.7%-64.3%)

• Age

<65 years: 50.0% (95% CI, 37.2%-62.8%)

≥65 years: 64.7% (38.3%-85.8%)

• Gender

Female: 62.1% (95% CI, 42.3%-79.3%)

Male: 48.1% (95% CI, 34.0%-68.5%)

• Prior neoplastic therapy

≤2 lines: 53.7% (95% CI, 37.4%-69.3%)

>2 lines: 52.5% (95% CI, 36.1%-68.5%)

“The median duration of response and median overall survival had not been reached at data cutoff,” Schuster said. He also indicated that 74% of patients were relapse free at 6

months and almost all patients who had a CR at 3 months remained relapse-free. “Patients who responded with either a CR or a PR did not proceed to receive allogenic- or auto-stem

cell transplant,” he added.

Overall, 86% of patients had grade 3 or 4 adverse events (AEs). Cytokine release syndrome (CRS) occurred in 58% of infused patients: 15% were grade 3 and 8% were grade 4. About 15% of patients received anti-IL6 therapy (tocilizumab) for CRS management, with good response, and 11% of patients received corticosteroids. Other grade 3 or 4 AEs included neurologic AEs (12%, managed with supportive care), cytopenias lasting longer than 28 days (27%), infections (20%), and febrile neutropenia (13%).

Three patients died within 30 days of infusion, all due to disease progression. No deaths were attributed to CTL019, CRS, or neurologic events.

Of the 26 (26%) patients in the study who received outpatient infusion, 20 (77%) remained on outpatient status for at least 3 days following infusion, “which means tisagenlecleucel can be safely administered in both the inpatient and the outpatient settings,” Schuster concluded.

Speaking during a press briefing in advance of the annual meeting, 2017 ASH President Kenneth C. Anderson, MD, highlighted the international scope of the JULIET trial, which he said indicates a much broader reach of this treatment.

The future plans for JULIET include:

• Ongoing global regulatory submissions

• Large-scale production of tisagenlecleucel

• A 22-day manufacturing time in the commercial setting

The second study was a 15.4-month follow-up on ZUMA-1, which is designed to evaluate axicabtagene ciloleucel (Axi-cel, Yescarta) in patients with refractory aggressive NHL.² Axi-cel became the second approved CAR T-cell treatment, in October, for adult patients with DLBCL. The results were presented by Sattva S. Neelapu, MD, professor in the Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center.

The results were simultaneously published in the New England Journal of Medicine.³ The primary analysis of ZUMA-1 demonstrated positive results, Neelapu said, with an ORR of 82% and a CR rate of 54% after a single infusion of axicel. The treatment had a manageable safety profile as well: grade ≥3 CRS and neurologic events were generally reversible and reported in 13% and 28% of patients, respectively. “At a median follow-up of 8.7 months, 44% of patients in ZUMA-1 had an ongoing response,” Neelapu indicated.

The study population included patients with refractory DLBCL (n = 77), and transformed follicular lymphoma or primary mediastinal large B cell lymphoma (total n = 24). Patients were

treated with cyclophosphamide (500 mg/m2) plus fludarabine (30 mg/m2) for 3 days to condition the body prior to treatment with 2x106 CAR-positive T cells/kg.

“While the CAR T-cell product was successfully manufactured in 99% of enrolled patients, only 91% received the infusion,” Neelapu said. Eligibility criteria included:

• Refractory disease, defined as progressive disease or stable disease as best response to last line of therapy

• Relapse ≤12 months after autologous stem cell transplant

• Prior anti-CD20 antibody and an anthracycline-containing regimen

The primary endpoint was ORR and secondary endpoints included duration of response (DOR), overall survival (OS), and incidence of AEs. A key exploratory endpoint was to investigate the mechanisms of resistance using posttreatment tumor biopsies obtained at time of relapse or progression. “To date, no patients have been lost to follow-up,

and all patients who are alive remain in disease and survival follow-up,” Neelapu told the audience.

Following analysis of results from the trial, at a data cut-off date of August 11, 2017, which was a 15.4-month follow-up, the best ORR was 82%, with a CR rate of 58%. Neelapu noted that patients who had a PR at the first tumor assessment (which was 1 month post infusion) had a CR up to 15 months post infusion, without need for additional treatment. The median time for conversion from PR to CR was 64 days (range, 49-424).

Overall DOR was 11.1 months (range, 3.9-not reached), CR was not reached, and PR was 1.9 months (range, 1.4-2.1). “Forty-three percent of phase 1 patients have an ongoing CR

at 24 months,” he said. The following are the 15.4-month survival updates from the study:

• Median progression-free survival: 5.8 months (range, 3.2-not reached)

• Median OS: not reached (range, 12.0-not reached)

With respect to AEs, Neelapu said that 95% of patients had grade 3 or higher AEs (43% of which were serious adverse events [SAEs]) in the primary analysis, which increased to 97% in the updated analysis (46% SAEs). Grade 3 or higher CRS was noted in 13% of patients following the primary analysis and 12% with the update; 28% of patients experienced

neurologic toxicities at the point of the primary analysis, which increased to 31% by the time of the current updated analysis. Grade 5 AEs were also documented in a small proportion of patients. Further, infections were the most common new-onset treatment-emergent SAEs at 6 months, but were resolved by the time of data cut off in August.

Biomarker clues were investigated by the ZUMA-1 researchers who identified several serum biomarkers associated with neurologic events and CRS of grade 3 or higher (including IL-6, IL-10, IL-15, IL-2Rα, and granzyme B). IL-2, granulocyte-macrophage colony-stimulating factor, and ferritin were significantly associated only with neurologic events of grade 3 or higher.

Based on these findings, Neelapu concluded that although a median DOR or OS had not been reached, durable response was observed in both patients who had detectable persistent CAR T cells and those who did not, which he said could be attributed to CD19 loss or immune checkpoint activation, according to some preliminary observations

by the study group.References

1. Schuster SJ, Bishop MR, Tam CS, et al. Primary analysis of JULIET: a

global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or

refractory diffuse large B-cell lymphoma. In: Proceedings from the 59th

Annual Meeting and Exposition of the American Society of Hematology;

December 9-12, 2017; Atlanta, GA. Abstract 577.

2. Neelapu SS, Locke FL, Bartlett NL, et al. Long-term follow-up ZUMA-1:

a pivotal trial of axicabtagene cilolueucel (Axi-Cel; KTE-C19) in patients

with refractory aggressive non-Hodgkin lymphoma (NHL). In: Proceedings

from the 59th Annual Meeting and Exposition of the American Society of

Hematology; December 9-12, 2017; Atlanta, GA. Abstract 578.

3. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR

T-cell therapy in refractory large B-cell lymphoma [published online

December 10, 2017]. N Engl J Med. doi: 10.1056/NEJMoa1707447.