The American Society of Hematology (ASH) welcomed its first in-person conference in two years last December, resulting in a flood of news on advancements in treating hematological cancers and rare hematological conditions like sickle cell disease, hemophilia and beta thalassemia. In this first of two posts, we report on some promising data from trials of both anti-CD38 antibodies and CAR-T treatments for patients with multiple myeloma and other indications. In our next blog post, we’ll discuss new developments in the areas of gene and cell therapy for other rare hematological conditions.
Anti-CD38 Antibodies in Multiple Myeloma
We were particularly interested by the growing faceoff between Sanofi and Johnson & Johnson (J&J) for their respective anti-CD38 antibodies, Sarclisa (isatuximab-irfc) and Darzalex (daratumumab), in multiple myeloma. Both drugs are approved for use in three-drug regimens for that cancer, and at ASH, both companies presented promising clinical data for their products’ use in four-drug regimens aimed at improving time to disease progression.
Germany’s Multiple Myeloma Multicenter Group presented Phase 3 results showing that the addition of Sarclisa to the widely used regimen of Revlimid, Velcade, and dexamethasone helped more newly diagnosed, transplant-eligible multiple myeloma patients achieve low levels of minimal residual disease (MRD) after induction therapy. MRD is a recognized marker of treatment effectiveness and considered a good prognostic for clinical outcome. The study results showed that 50.1% of the patients treated with Sarclisa achieved MRD negativity versus 35.6% of those receiving the three-drug regimen alone, marking the first time that a Phase 3 study has reported an improvement in MRD negativity post-induction for the use of a CD38 antibody in addition to Revlimid. The complete response rates were similar between the two study arms. However, the data came from analysis at the end of the induction phase, which experts consider too soon to detect an impact on complete response. Sanofi plans to file for approval of Sarclisa in the four-drug regimen in 2024 or later.
J&J presented new data in the same patient population from its Phase 2 GRIFFIN trial of Darzalex in combination with the Revlimid-containing regimen. Following two years of maintenance therapy after induction and consolidation treatment, patients receiving Darzalex maintained a higher MRD negativity rate compared to those who did not receive the drug (64.4% vs 30.1%).The durability of response was also improved with Darzalex: among MRD-negative patients, 44% kept that status for at least one year versus 13% for those who did not receive that drug as part of their treatment. A Phase 3 trial of Darzalex in the same setting is still ongoing. Both Darzalex and Sarclisa are also currently being studied in myeloma patients not eligible for transplant, with results of Phase 3 trials for each of the antibodies expected during 2022.
Despite Sarclisa’s apparent lead in trials of the four-drug regimen, Darzalez has a substantial head start in clinical development. The J&J antibody is already approved in several drug combination regimens in different cancer indications, including newly diagnosed myeloma, whereas Sarclisa does not yet have a frontline label.
Growing Survival Data for J&J’s BCMA CAR-T Therapy
J&J and its partner Legend Biotech presented striking data from the CARTITUDE-1 Phase 1b/2 myeloma study of their B-cell Maturation Antigen (BCMA) CAR-T treatment, ciltacabtagene autoleucel (cilta-cell) in heavily pre-treated patients. Patients with multiple myeloma who have failed at least three treatment regimens face a median survival of less than one year with standard therapies. Earlier results of the CARTITUDE-1 study, shared in June 2021, had shown an 80% response rate, with two thirds of all study participants alive and progression-free at 18 months. The data presented at ASH extended the patient follow-up to over 22 months, reporting that the complete response rate had risen to 83% and that the trial had yet to reach a median progression-free or overall survival figure. J&J also shared an update from another cilta-cell study, CARTITUDE-2, in patients who had received one-to-three prior lines of treatment, reporting that the complete response rate rose from 75% to 85% since initial results were announced.
Based on the strong data presented, J&J may be able to overcome Bristol-Myers Squibb’s (BMS) marketing head start with Abecma, its BCMA CAR-T product that was approved by the FDA in March 2021 for use in patients with refractory and relapsed myeloma. In the KarMMa trial of Abecma, overall progression-free survival was 8.8 months. Cilta-cel’s development had been close to a year behind that of Abecma; however, the FDA approved the J&J product, which will be marketed as Carvykti™, on February 28 for the treatment of adults with relapsed or refractory multiple myeloma (RRMM) after four or more prior lines of therapy.
Other CAR-T News
Promising CAR-T results were also presented by Gilead Sciences / Kite, Bristol Myers Squibb, and Precigen in cancer indications including non-Hodgkin’s lymphoma, large B cell lymphoma, and acute myelogenous leukemia. Of particular note, early positive efficacy and safety data was released at ASH from studies of allogeneic, off-the-shelf CAR therapies from Allogene and Fate Therapeutics.
Allogeneic CAR-T therapies offer the potential for fewer logistical challenges compared to autologous CAR-T therapies, due to the elimination of patient-specific cell processing and shorter wait periods for treatment, as well as the potential for scalable manufacturing and lower cost.
Interim results of a Phase 1, first-in-human study in multiple myeloma of ALLO-715, Allogene’s allogeneic CAR-T treatment targeting BCMA suggest that safety, response rate, and durability of response for the off-the-shelf therapy are similar to those of currently approved autologous CAR-T therapies. Forty-three evaluable patients, all of whom had failed a median of five prior therapies and 42% of whom had become non-responsive to any other treatment, were able to initiate treatment within five days of study enrollment, versus the typical vein-to-vein wait of three to four weeks for autologous CAR-T therapies. Overall response rate was 71%, and of those responders, 46% achieved a Very Good Partial Response or better (VGPR+) and 25% a Complete Response. Ninety-two percent of the patients with VGPR+ results were MRD negative. These results suggest that ALLO-715 has the potential to offer a useful on-demand therapy, especially for patients with rapidly advancing disease and limited treatment options.
Fate Therapeutics also presented positive Phase 1 data with its off-the-shelf, NK cell product, FT596, that is engineered to target three different antigens for greater specificity and anti-tumor activity. Interim results of the study showed that of 26 evaluable patients with relapsed or refractory B cell lymphoma who were treated with FT596 plus rituximab, 18 (69%) achieved an objective response following a single dose, including 12 (46%) who achieved a complete response. Nine of the 26 patients had previously been treated with an autologous CD-19 CAR-T therapy, and of those, six achieved an objective response. Notably, in the two highest dose cohorts, 9 of 12 patients achieved a complete response. The FT596 treatment regimens were well-tolerated, with no dose-limiting toxicities, and no incidents of graft-vs-host disease or immune-effector cell-associated neurotoxicity.