BiTE Therapies Spark Lymphoma Treatment

A presentation on the expanding potential of bispecific T-cell engager (BiTE) therapy was presented by L. Elizabeth Budde, MD, during the National Comprehensive Cancer Center (NCCN) 2023 Annual Congress: Hematologic Malignancies, held in San Francisco, California, and virtually, September 22 to 23, 2023.¹ BiTE therapies have gained attention for their immediate availability, recruitment of immune cell capability, lack of gene modification requirements, and fixability for repetitive dosing. With beneficial response rates in certain cases, they present an avenue to revolutionize hematologic cancer treatment for multiple blood-related cancers, including lymphoma, leukemia, and multiple myeloma (MM). However, the need for wider accessibility, equity, and affordability are significant factors to consider for advancement of these treatments.

“Blood cancer treatment is like a journey for immunotherapy development,” Budde explained. “When you put a bispecific antibody into the patient, it can then grab the T cells and redirect their specificity regardless of the T-cell receptor’s compensation. The bispecific will recognize the protein antigen on the surface of cancer cells and bring [the] T cell into close proximity. An effective synapse will occur, and the T cells will secrete granzyme to kill the targeted cells and then the bispecific antibody can be released and move on to [the] next target.”

There are 7 bispecific T-cell engagers that have gained FDA approval for the treatment of various blood-related cancers. Blinatumomab (Blincyto) was first, gaining FDA approval based on the results of the phase 3 TOWER trial (NCT02013167) for the treatment of B-cell acute lymphoblastic leukemia (ALL).² The study evaluated blinatumomab vs standard-of-care chemotherapy and reported that the median overall survival, in months, was 7.7 (95% CI, 5.6-9.6) vs 4.0 (95% CI, 2.9-5.3), respectively. The HR was 0.71 (95% CI, 0.55-0.93; P = .01) with a complete response (CR) of 43.9% (85% CI, 37.9-50.0) vs 24.6% (85% CI, 17.6-32.8), respectively.

Most recently the talquetamab (Talvey) BiTE treatment, which is an igG-like, subcutaneous treatment that targets G protein-coupled receptor class C group 5 member D (GRPC5D), gained approval this year in August through the phase 1/2 MonumenTAL-1 trial (NCT04634552, NCT03399799) for patients with relapsed or refractory (r/r) MM.³ Both groups reached ORR and CR, one (n = 143) receiving a 0.04 mg/kg dose of talquetamab weekly (ORR 74% and CR 34%) and the other (n = 145) receiving 0.08 mg/kg every 2 weeks (ORR 73% and CR 32%).³

When comparing talquetamab with teclistamab (Tecvayli) and elranatamab (Elrexfio), targeting B-cell maturation antigen and not GRPC5D, the ORR was 63% and the CR was 46% for te clistamab (n = 165), and for elranatamab, the ORR was 61% and the CR was 35% (n = 123). Although these results are favorable for each treatment choice, the infection rates for teclistamab and elranatamab are very high: For teclistamab, any infection was 80% and grade 3 or more was 55%; for elranatamab, any infection was 70% and grade 3 or more was 40%. With the talquetamab treatment, infections vary slightly per dosing: For the every-week dose, any infection was 57% and grade 3 or more was 17%; for the every-other-week dose, any infection was reported at 50% and grade 3 or more was 12%.

Future steps for BiTEs include pushing for earlier use in first-line treatment and trial designs to evaluate efficacy on which treatment sequence or treatment combination is most beneficial: administering bispecific treatment before or after CAR T-cell treatment; evaluating the sequence with other therapeutics such as conjugates, PD-1 inhibitors, or other targeted therapies; and combining different types of BiTEs that target different antigens or increase signal to include targets CD28 and 4-1BB.¹

An ongoing phase 1/2 trial (NCT03512405)⁴ evaluates the use of the PD-1 blockade pembrolizumab (Keytruda) with blinatumomab for patients with r/r ALL. The interim results report a CR of 79%, and the combination was shown to be safe.⁴

Future challenges include expanding access of bispecifics for various demographics, to make them more available and affordable.

REFERENCES:

1. NCCN 2023 Annual Congress: Hematologic Malignancies. NCCN. Published September 23, 2023. Accessed September 24, 2023. https://nccn.digitellinc.com/live/23/page/609

2. Dombret H, Topp MS, Schuh AC, et al. Blinatumomab versus chemotherapy in first salvage or in later salvage for B-cell precursor acute lymphoblastic leukemia. Leuk Lymphoma. 2019;60(9):2214-2222. doi:10.1080/10428194.2019.1576872

3. Budde LE, Sehn LH, Matasar M, et al. Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study. Lancet Oncol. 2022;23(8):1055-1065. doi:10.1016/S1470-2045(22)00335-7

4. Schinke CD, Touzeau C, Minnema MC, et al. Pivotal phase 2 MonumenTAL-1 results of talquetamab (tal), a GPRC5DxCD3 bispecific antibody (BsAb), for relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2023;41(suppl 16):8036-8036. doi:10.1200/jco.2023.41.16_suppl.8036

5. Sandhu KS, Macias A, Del Real M, et al. Interim results of a phase 1/2 study of pembrolizumab combined with blinatumomab in patients with relapsed/refractory (r/r) ALL. Blood. 2022;140(suppl 1):8985-8986. doi:10.1182/blood-2022-170279