James N. Kochenderfer, MD
Remedy with the BCMA-directed CAR T-cell remedy bb2121 induced full remissions (CRs) for 56% of sufferers with relapsed/refractory a number of myeloma, in keeping with up to date findings from a dose escalation trial introduced on the 2017 ASH Annual Assembly.
The target response fee (ORR) for bb2121 was 94%, which consisted of an excellent partial response or higher for 89% of sufferers. After 40 weeks of follow-up, the median progression-free survival (PFS) had not but been reached. The 9-month PFS fee was 71%. The therapy was usually well-tolerated and the manufacturing success fee was 100%, in keeping with the senior examine writer James N. Kochenderfer, MD.
“We’re excited concerning the early ends in a affected person inhabitants with very superior myeloma for whom earlier therapies have failed,” Kochenderfer, of the Heart for Most cancers Analysis on the Nationwide Most cancers Institute in Bethesda, mentioned in an announcement. “We’ve sufferers who’ve a sustained response and have been in a position to go for over a 12 months with no extra myeloma remedy and tolerable adversarial results.”
The second-generation CAR T-cell remedy bb2121 consists of a Four-1BB costimulatory area with an anti-BCMA scFv and CD3 zeta T cell activation area. Based mostly on an earlier evaluation of the dose escalation trial, bb2121 was granted a breakthrough remedy designation in November 2017.
The examine utilized a wide range of doses, with a spread of 150 to 300 × 106 CAR+ T cells recognized for future examine. The bottom dose (50 x 106) was not proven to have scientific exercise. Previous to infusion of the CAR T-cell remedy, sufferers obtained conditioning with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2).
The trial enrolled 21 sufferers at a median age of 58 years (vary, 37-74) following a median of seven prior strains of remedy, with 29% of sufferers being refractory to bortezomib, lenalidomide, carfilzomib, pomalidomide, and daratumumab. The time since analysis was Four years and sufferers had an ECOG efficiency standing of zero (48%) or 1 (52%). Forty-three % of sufferers had high-risk cytogenetics. All sufferers had obtained prior autologous stem cell transplantation.
Exercise was reported for these handled with an lively dose of bb2121. On the median follow-up of 40 weeks, 9 of 10 evaluable sufferers examined unfavorable for minimal residual illness. The period of response was not but reached however sturdy responses had been seen, a few of which lasted over 1 12 months. Typically, the responses continued to enhance as late as month 15, Kochenderfer mentioned.
The median time to first response was 1.02 months and the median time to finest response was three.74 months. The median time to CR was three.84 months.
“To see a lot of these responses after one therapy with bb2121 in a closely pretreated affected person inhabitants could be very promising, and we’re hopeful that CAR T remedy with bb2121 might turn out to be an necessary remedy within the struggle in opposition to a number of myeloma, which stays an insidious and incurable illness,” mentioned Kochenderfer.
Fourteen of the 21 sufferers skilled a minimum of 1 critical adversarial occasion. Cytokine launch syndrome (CRS) was skilled by 71% of sufferers, with 2 having a grade ≥three occasion. Neurotoxicity was skilled by 21% of sufferers, with 1 having a grade Four occasion related to tumor lysis syndrome and CRS. Grade ≥three neutropenia was skilled by 86% of sufferers, and grade ≥three thrombocytopenia and anemia had been skilled by 43% and 57% of sufferers, respectively.
Cytopenias seen within the trial had been principally related to the conditioning chemotherapy, Kochenderfer mentioned. Most grade 1 or 2 cytopenias resolved 2 months following infusion. There have been 5 deaths within the trial, three on account of illness development, 1 from cardiac arrest, and 1 from myelodysplastic syndrome following therapy discontinuation.
“Thus far, the protection profile of bb2121 has been manageable,” mentioned Kochenderfer. “The two reported occasions of grade three CRS resolved inside 24 hours.”
A worldwide section II KarMMa trial is at present open for enrollment, and can function the premise for a regulatory submission for bb2121. The trial plans to enroll 94 sufferers with relapsed/refractory a number of myeloma. The first endpoint of the examine is response. The estimated major completion date for the trial is November 2023.
Berdeja JG, Lin Y, Raje N, et al. Sturdy Scientific Responses in Closely Pretreated Sufferers with Relapsed/Refractory A number of Myeloma: Up to date Outcomes from a Multicenter Research of bb2121 Anti-Bcma CAR T Cell Remedy. Introduced at: ASH Annual Assembly and Exposition; Dec. 9-12, 2017; Atlanta. Summary 740.