ASH First Look: CAR-T Therapies Against BCMA, CD19 And More

CAR-T therapies from Janssen, Celgene and others will get a lot of attention at the annual hematology meeting, including candidates with novel constructs and targets. 

BCMA CAR-T still is a hot topic, but novel therapies advance at ASH.

T-cell therapies once again will be a hot topic at this year’s American Society of Hematology annual meeting 7-10 December in Orlando, FL, ranging from the latest round of BCMA-targeting chimeric antigen receptor T-cell therapy results in multiple myeloma to very early first-in-human results for the first CRISPR/Cas9 gene-edited T-cell therapy.

BCMA Candidates: J&J And Celgene CAR-Ts, Regeneron Bispecific

Data for CAR-T therapies, bispecific antibodies and other candidates targeting B-cell maturation antigen (BCMA) for the treatment of multiple myeloma were a highlight of last year’s ASH meeting, including results from the most advanced program – Celgene Corp. and bluebird bio Inc.’s bb2121, which was challenged by JNJ-4528 (LCAR-B38M) from Legend Biotech Corp. and Johnson & Johnson’s Janssen Pharmaceutical Cos. (Also see "Poseida, Legend/Janssen Look To Snag Celgene/Bluebird's BCMA Crown" - Scrip, 4 Dec, 2018.)

This year, Celgene and bluebird aren’t presenting updated results for bb2121, which they expect to submit for US Food and Drug Administration review in the first half of 2020, but they will have updated results for the follow-on BCMA-targeting CAR-T, bb21217. Approval of bb2121 by 31 March 2021 is one of the three drug approvals needed for Celgene investors to earn a $9 per share contingent value right from Bristol-Myers Squibb Co., which is buying the company for $74bn up front plus the CVR. (Also see "Bristol Values Celgene's Hematology, Immunology Portfolio At $74bn, But Does It Price In Risk?" - Scrip, 3 Jan, 2019.) 

However, Janssen will present the first results from its Phase Ib/II CARTITUDE-1 study of JNJ-4528 in relapsed or refractory multiple myeloma after data from Legend’s Phase I/II LEGEND-2 trial were presented at last year’s meeting. 

According to the CARTITUDE-1 ASH abstract, a reduction in tumor burden was observed among all 21 patients treated with JNJ-4528 and evaluated as of the 24 June data cutoff. With a median follow-up of three months, the overall response rate was 91%, including four stringent complete responses (sCRs), two complete responses, seven very good partial responses (VGPRs) and six partial responses (PRs). Among 15 of the evaluable patients, 10 were minimal residual disease-negative – MRD negativity generally is associated with a good prognosis.

The rate of cytokine release syndrome, which can be severe for CAR-T-treated patients, was 88% among the 25 patients who received JNJ-4528 as of the data cut-off date. Most cases of CRS were grade 1 and 2 (80%), with one grade 3 and one grade 5 event. Three patients experienced neurotoxicity, another potentially severe side effect often associated with CAR-T therapies, including two grade 1 neurotoxicity cases and one grade 3 event, but all cases resolved within one or two days.

Updated results from 57 patients treated in LEGEND-2 show that the CRS rate was 90%, but most cases were grade 1 (45%) or grade 2 (37%) with four grade 3 events (7%) and no grade 4 or 5 CRS. There was one case of grade 1 neurotoxicity.

The median duration of follow-up as of 31 December in Legend’s study was 19 months and median overall survival had not been reached, but the OS rate at 18 months was 68% and the median duration of response was 22 months. Median progression-free survival (PFS) was 20 months and 26 patients (46%) were progression-free at the data cut-off date. The study has had 17 deaths, including 11 attributed to progressive disease.

Last year’s early results for Celgene and bluebird’s bb21217 showed an 83% ORR with 10 of 12 evaluable patients responding to treatment. Rates of CRS and neurotoxicity were 67% and 25%, respectively.

Now, according to the ASH 2019 abstract, ORR still is 83% based on responses in 15 of 18 evaluable patients assessed after at least two months after treatment, but only nine continued to respond as of a 20 April cut-off. Thirteen of the full 22 patients treated through the cut-off date experienced CRS and five developed neurotoxicity, including one grade 3 and one grade 4 event.

All of the BCMA-targeting CAR-T therapies presented at ASH in 2018 and in 2019 are autologous therapies, which require extraction of patients’ own T-cells, which are reengineered to target a specific antigen then infused back into the same patients. Many off-the-shelf allogeneic, or donor-derived, CAR-T therapies still are largely preclinical programs.

Outside of CAR-T therapies, Regeneron Pharmaceuticals Inc. also will report results at this year’s ASH from the Phase I portion of its Phase I/II study in relapsed or refractory multiple myeloma for REGN5458, which is a bispecific antibody targeting BCMA and CD3. The ASH abstract has data for just three patients treated with REGN5458 as of the 12 July cut-off, including one man with a PR that improved to a VGPR, a woman whose disease progressed and another woman who achieved stable disease.

Jefferies analyst Biren Amin said in a 6 November note that the JNJ-4528 data from the LEGEND-2 study improve upon Legend’s previously presented data, while the bb21217 data are consistent in terms of ORR with previously disclosed results, but data showing durable responses are eagerly awaited. Amin also noted that Regeneron’s updated REGN5458 data, while early, are not as robust as those reported last year for Amgen Inc.’s bispecific T-cell engager AMG 420. (Also see "ASH Preview: BCMA-Targeting CAR-Ts And Bispecifics Hog The Spotlight" - Scrip, 28 Nov, 2018.)

GlaxoSmithKline PLC is far ahead of most companies with a BCMA-targeting therapy for multiple myeloma. It intends to seek approval for its antibody-drug conjugate (ADC) belantamab mafodotin (GSK2857916) before the end of this year. (Also see "DREAMM-2 Put GSK’s BCMA Drug In Pole Position In Multiple Myeloma " - Scrip, 23 Aug, 2019.)

CD19 CAR-T Therapy: Beyond Yescarta And Kymriah

Arguably Celgene’s most important CAR-T candidate with data at ASH this year is the CD19-targeting therapy JCAR017 (lisocabtagene maraleucel, or liso-cel) with final results from the TRANSCEND NHL 001 study in relapsed or refractory non-Hodgkin lymphoma. Celgene, which acquired JCAR017 with its $9bn purchase of Juno Therapeutics Inc. in January 2018, hopes to deliver a CAR-T therapy against CD19 that’s safer than its predecessors. (Also see "Celgene Seeks CAR-T Leadership, Hematology Diversification With Juno Buy" - Scrip, 22 Jan, 2018.)

Celgene plans to submit JCAR017 to the US FDA in the fourth quarter of this year; approval by the end of 2020 is required as one of the three components for the CVR payout under Bristol's acquisition of the company.

The first two CD19-targeting CAR-T therapies approved in the US are the diffuse large B-cell lymphoma treatment Yescarta (axicabtagene ciloleucel) from the Gilead Sciences Inc. subsidiary Kite Pharma Inc. and Novartis AG’s Kymriah (tisagenlecleucel) for adults with DLBCL and pediatric acute lymphoblastic leukemia. Both have struggled to achieve significant sales due to the cost and complexity of the autologous therapies and various reimbursement challenges. (Also see "Gilead Says Sluggish Yescarta Business Will Continue To Fluctuate" - Scrip, 24 Oct, 2019.)

The ASH abstract for the pivotal study of JCAR017 in large B-cell lymphomas, including NHL, showed a 73% ORR among 255 evaluable patients with a 53% CR rate. The median duration of response was 13.3 months, median PFS was 6.8 months and median OS was 19.9 months. The abstract notes that “overall, PFS after liso-cel infusion was substantially longer than PFS from the immediate prior therapy.”

Grade 3 or higher treatment-related adverse events (TEAEs) were observed in 79% of patients, primarily neutropenia, anemia and thrombocytopenia. CRS was experienced by 42% of patients (2% of cases were grade 3 or higher) and 30% had neurotoxicity (10% of cases were grade 3 or higher).

“The abstract calls out four deaths (i.e., grade 5 TEAEs related to liso-cel). The most important thing to remember is that Yescarta and Kymriah had deaths too, and still got approved,” Mizuho Securiteis analyst Salim Syed said in a 6 November report.

He noted that the Yescarta label describes four deaths for patients who experienced CRS. Meanwhile, the Kymriah label points out that five deaths occurred within 30 days of Kymriah infusion due to CRS or disease progression in ALL, while three adults with DLBCL who developed CRS died.

Syed said JCAR017 looks comparable to its rivals on efficacy with lower rates of grade 3 and 4 CRS and neurotoxicity.

Kite will have updated results for Yescarta and for a next-generation CD19-targeting CAR-T therapy known as KTE-X19 in mantle cell lymphoma (MCL).

Autolus Ltd. will present early results at ASH for its CD19-targeting CAR-T therapy AUTO1 in pediatric and adult ALL as well as for AUTO3, a programmed T-cell therapy that targets CD19 and CD22, in DLBCL and pediatric ALL. Data for a third candidate, AUTO2 targeting BCMA and TACI, but the company has discontinued development of that multiple myeloma candidate.

“Overall, we believe AUTO1 continues to show a strong efficacy and safety profile in adult ALL patients, with no patients reporting grade 3 or higher CRS,” William Blair analyst Matt Phipps wrote on 6 November, noting that there is not enough data yet to determine whether AUTO3 is a competitive candidate.

Early-Stage T-Cell, NK Cell Therapies

There will be an abundance of earlier-stage data at ASH for novel T-cell and natural killer (NK) cell therapies, including:

• Results from the first three patients infused with T-cells gene-edited with CRISPR/Cas9 technology show the therapy is safe, so far. Researchers at the Abramson Cancer Center of the University of Pennsylvania (UPenn) used CRISPR/Cas9 editing to remove a T-cell’s natural receptors and remove the checkpoint PD-1 before using a lentivirus to insert a T-cell receptor (TCR) targeting the antigen NY-ESO-1. The private biopharma firm Tmunity Therapeutics Inc. and the Parker Institute for Cancer Immunotherapy are partnered with the UPenn researchers.

• Celyad SA will present Phase I results for its autologous NKG2D-based CAR-T candidates CYAD-01 and CYAD-02, including Phase I does-escalation data from THINK study and interim results from the DEPLETHINK trial, both for CYAD-01 in relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), and preclinical results for CYAD-02. (Also see "All To Play For: CAR-T Specialist Celyad’s Big Year" - Scrip, 10 May, 2019.)

• Celularity Inc.’s presentations for its allogeneic cell therapies derived from donated placental cells will include Phase I data for the NK cell therapy PNK-007 in multiple myeloma. (Also see "Venture Funding Deals: Celularity Launches With $250m; Generation Bio Grabs $100m Series B" - Scrip, 5 Mar, 2018.)

• Gamida Cell Ltd. also has an allogeneic NK cell-based therapy, GDA-201, for which it will present Phase I results in NHL and multiple myeloma. The therapy comes from its nicotinamide-based cell-expansion technology platform.

• Initial Phase I/IIa results in NHL, MCL and DLBCL will be presented for Precision BioSciences Inc.’s lead allogeneic CAR-T candidate PBCAR0191, which targets CD19 and is being developed with partner Servier SA.