Promising Road Lies Ahead for Bispecific Antibody Combinations in Hematologic Malignancies

Microscopic images of red blood cells activated platelets and white blood cells are showcased in the photographs as a result of leukemia: © AkuAku - stock.adobe.com

The emergence of bispecific antibodies (BsAb) in the treatment of B-cell and T-cell hematologic malignancies represents a significant advancement in the management of the disease. As a monotherapy, the agents have demonstrated antitumor activity in heavily pretreated patients, but much work is needed to determine the optimal setting, including their use in combination therapy, ways to minimize toxicity, and mitigating the development of resistance mechanisms.¹

Overall, these agents offer high efficacy and response rates coupled with manageable toxicity profiles. But their use as a potential off-the-shelf approach that avoids logistical and financial constraints that are associated with other cellular therapies, such as chimeric antigen receptor therapy, is an appealing treatment option for oncologists and hematologists. The following is an overview of combination therapies evaluating bispecific antibodies across hematologic malignancies.

Diffuse Large B-Cell Lymphoma

CHOP

In the frontline setting, the combination of BsAbs with CHOP (cyclophosphamide, doxorubicin hydrochloride [hydroxydaunomycin], vincristine [Oncovin], prednisolone) has been explored in several trials. Response rates of mosunetuzumab-axgb (Lunsumio), a novel CD20/CD3 BsAb, in combination with CHOP were explored in a phase 1/2 study (NCT03677141) in patients with relapsed/refractory non-Hodgkin lymphoma (R/R NHL) and newly diagnosed diffuse large B-cell lymphoma (DLBCL).² In the trial, patients received six 21-day cycles of mosunetuzumab and CHOP (M-CHOP). The combination was delivered in step-up doses on day 1 (1 mg), day 8 (2 mg), and day 15 (13.5 mg and 30 mg in patients with R/R NHL and 30 mg in patients with DLBCL).

A total of 43 patients received the combination; this included 7 with R/R NHL and 36 with newly diagnosed DLBCL. In patients with R/R NHL, the overall response rate (ORR) was 86%, with 71% of patients reaching complete response (CR). In patients with DLBCL, the ORR was 96% with a CR rate of 85%. Patients with DLBCL began treatment at least 3 months prior to June 3, 2020.²

The majority (86%) of patients experienced grade 3 or greater adverse events (AEs) and serious AEs in 44% of patients. Two patients with R/R NHL, 1 case of grade 1 and 1 case with grade 2, experienced cytokine release syndrome (CRS) and one patient required tocilizumab (Actemra). In contrast, 19 patients with DLBCL (53%) experienced CRS events and ranged from grade 1 (14 patients) to grade 2 (5 patients). Among this group, 1 patient received tocilizumab.

The investigators reported that all CRS events occurred during the first cycle of treatment and resolved. CRS events did not result in discontinuation or delay of treatment. The investigators also noted no cases of immune effector cell–associated neurotoxicity syndrome (ICANS) events.²

Two patients with R/R NHL experienced neutropenia (29%) and 2 experienced grade 4 neutropenia. In patients with DLBCL, 64% developed neutropenia; 3 had grade 3 and 20 had grade 4. Two patients (29%) with R/R NHL had febrile neutropenia and 6 patients (17%) with DLBCL developed the AE. One death was reported due to pneumonia and 2 patients withdrew from the study treatment due to AEs. Investigators concluded that mosunetuzumab combined with CHOP delivers high response rates and a manageable safety profile in patients with R/R NHL and DLBCL (TABLE).²

A phase 1b trial (NCT03467373)3 evaluating glofitamab-gxbm (Columvi) in combination with obinutuzumab (Gazyva) or rituximab (Rituxan), and CHOP; or polatuzumab vedotin (Polivy) plus rituximab and CHP (Pola-R-CHP) in patients with non-Hodgkin lymphoma or DLBCL demonstrated promising efficacy in patients who received glofitamab and Pola-R-CHP. Investigators reported that patients received Pola-R-CHP on day 1 of each 21-day cycle, with subsequent treatment of glofitamab during cycles 2 to 6.

After a median follow-up of 5.1 months (range, 3-8), complete metabolic response (CMR) was 76.5% with an ORR of 100%. Fifteen (63%) patients reported grade 3 or higher AEs; among patients who were treated with glofitamab, 9 (38%) reported grade 3 or higher AEs. Twelve (50%) of patients reported serious AEs and in the glofitamab-treated group, there were 4 (17%) patients. Dose interruption in the glofitamab group occurred in 5 (21%) of patients.³

Regarding CRS, 3 (13%) patients reported grade 1 AEs. This did not require treatment or hospitalization. Neurological AEs were reported in 11 (46%) of patients and neutropenia was reported in 12 (50%) of patients. Investigators wrote that these data suggest that the combination of glofitamab plus Pola-R-CHOP in the first-line setting demonstrated promising efficacy and a safety profile that was similar to Pola-R-CHP and glofitamab plus R-CHOP for first-line DLBCL treatment.

Another trial evaluating glofitamab is a phase 1b/2 study evaluating the agent in combination with atezolizumab (Tecentriq) or polatuzumab vedotin in patients with R/R NHL (NCT03533283).

The single-arm, multicenter trial will determine the maximum tolerated dose and the recommended phase 2 dose for the combination. Safety, tolerability, pharmacokinetics and preliminary antitumor activity will be explored.

Follicular Lymphoma

EPCORE NHL-2

The combination of lenalidomide (Revlimid) and rituximab (R2) with CD3/CD20 bispecific antibodies has been investigated in the frontline and relapsed settings. The safety and efficacy of epcoritamab-bysp (Epkinly), a subcutaneous CD3/CD20 bispecific antibody, has been explored in combination with R2 in 66 patients with relapsed follicular lymphoma (FL) and 36 with previously untreated FL (grades 1 to 3A) in the phase 1/2 EPCORE NHL-2 trial (NCT04663347).⁴ All patients received epcoritamab as monotherapy or in combination in 10 regimen arms.

At the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting,⁵ a pooled analysis from cohorts 2a and 2b from EPCORE NHL-2 were presented. These cohorts included patients with relapsed/refractory FL.

No synergistic toxicity was observed, investigators reported. However, CR rates were 80% or higher, independent from the line of therapy.

“Adding epcoritamab to the R2 regimen led to deep and durable remissions in R/R FL, including POD24 patients. High overall and complete responses were observed across patient subgroups,” lead author Reid W. Merryman, MD, said during the presentation.⁵ Merryman is a physician at Dana-Farber Cancer Institute and instructor of medicine at Harvard Medical School in Boston, Massachusetts.

In a previous study, subcutaneous epcoritamab showed durable responses and manageable safety in EPCORE NHL-1 (NCT03625037). Findings from this trial led to the agent’s approval in patients with certain R/R B-cell NHLs after 2 or more lines of systemic therapy.

In EPCORE NHL-2, efficacy evaluable patients (n = 104) treated with epcoritamab at 48 mg plus R2 demonstrated an ORR of 98%; ORR to the immediate prior therapy was 85% at the data cutoff of January 31, 2023 (median follow-up, 11.4 months). The CMR was 87% and 58% for current therapy with epcoritamab and immediate prior therapy, respectively. Investigators reported that the partial metabolic response (PMR) was 12% and 27%, stable disease 1% and 5%, and progressive disease 1% and 7%, in each arm.⁵

Across subgroups, high ORR and CMR rates were also observed, with 95% or greater ORR in all groups. There was 75.0% CMR and 22.5% PMR for POD24 patients (n = 40), and a 98% ORR in this group. In primary refractory patients (n = 37), 83.8% and 16.2% had CMR and PMR, respectively. There was a CMR/PMR of 80.9%/14.9% in patients refractory to prior anti-CD20 (n = 47), 75.7%/18.9% for those who were double refractory (n = 37), 86.7%/11.7% in those with high Follicular Lymphoma International Prognostic Index (FLIPI) score, and 90.0%/10.0% for those with non–high-risk disease.⁵

The ORR for patients with and without POD24 receiving epcoritamab was identical, at 98%. For POD24 patients receiving study treatment in the second line, the ORR was 100% and CMR was 86%. In the third line or later, the ORR was 85% and CMR was 63% for POD24 patients.

Multiple Myeloma

Monoclonal Antibodies

In the TRIMM-2 study (NCT04108195),⁶ investigators evaluated daratumumab in combination with 2 bispecific antibodies. The objective was to establish the recommended phase 2 doses for daratumumab plus talquetamab-tgvs (Talvey) and teclistamab-cqyv (Tecvayli) plus daratumumab in patients with multiple myeloma. Patients with a multiple myeloma diagnosis and who had been treated with 3 or more prior lines of therapy, including a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), or were double refractory to a PI and IMiD were eligible.⁶

AEs were manageable with 97.0% of patients experiencing 1 or more AEs of any grade with two-thirds (66.7%) of patients experiencing grade 3/4 AEs. CRS was the most common AE reported (54.5%), with a median time to onset of 2 days (range, 1-6) and a median duration of 2 days (range, 1-7).⁶

Other AEs of note included neutropenia (36.4%; all grade 3/4), thrombocytopenia (36.4%; grade 3/4, 33.3%), and anemia (36.4%; grade 3/4, 24.2%).⁶

Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia

Venetoclax

A phase 1b/2 dose-escalation and dose-expansion study, EPCORE CLL-1 (NCT04623541), is evaluating the safety and efficacy of epcoritamab as monotherapy and in combination with venetoclax (Venclexta). In the expansion phase, investigators plan to evaluate the preliminary efficacy, safety, and tolerability profiles of the monotherapy and combination therapy at the recommended phase 2 dose.

The regimen arms will explore epcoritamab in combination with venetoclax, lenalidomide, or R-CHOP in patients with R/R CLL/small lymphocytic lymphoma (SLL) and patients with Richter syndrome.

Antibody-Drug Conjugates

Various formats of BsAbs have been developed, all with unique designs, development needs, and production challenges. Antibody-drug conjugates (ADCs) also have production and development issues that involve linker chemistry, conjugation site specificity, and potency of payload. Despite these challenges, a number of BsAbs and ADCs have been approved and many promising combinations are undergoing evaluation.⁷

Advances in ADC and BsAb (Bs-ADC) technology have made significant inroads and a recent study reported on the coadministration of BsAb with anti–HER2 ADC. This combination has yet to be approved and several candidates are in the early stages of clinical development. Investigators hypothesize that Bs-ADC technology helps increase the specificity of ADCs or the internalization and killing ability of BsAbs. A recent study explored this combination and reported enhanced cytotoxic activity of the ADC and a significant decrease in effective concentration against a HER2 cell line.⁸ Exploratory studies that evaluate BsAbs as monotherapy and in combination across hematologic cancers are ongoing with promising results being reported. With a manageable toxicity profile and their availability for convenient dosing, they represent a formidable approach in cancer treatments.

REFERENCES:

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2. Phillips TJ, Olzsewski AJ, Munoz J, et al. Mosunetuzumab, a novel cd20/cd3 bispecific antibody, in combination with chop confers high response rates in patients with diffuse large B-cell lymphoma. Blood. 2020;136(suppl 1):37-38. doi:10.1182/blood-2020-136295

3. Dickinson M, Viardot A, Marks R, et al. Glofitamab + Pola-R-CHP in patients with previously untreated diffuse large B-cell lymphoma (DLBCL): results from a phase Ib study. J Clin Oncol. 2023;41(suppl 16):7549-7549. doi:10.1200/ JCO.2023.41.16_suppl.7549

4. Falchi L, Abrisqueta P, Nijland M, et al. Subcutaneous epcoritamab with rituximab + lenalidomide in patients with relapsed or refractory follicular lymphoma: phase 1/2 trial update. Blood. 2022;140(suppl 1):1464-1466. doi:10.1182/ blood-2022-158203

5. Merryman R, Belada D, Sureda A, et al. Epcoritamab + R2 regimen and responses in high-risk follicular lymphoma, regardless of POD24 status. J Clin Oncol. 2023;41(suppl 16):7506. doi:10.1200/JCO.2023.41.16_suppl.7506

6. Rodriguez-Otero P, Dholaria B, Askari E, et al. subcutaneous teclistamab in combination with daratumumab for the treatment of patients with relapsed/refractory multiple myeloma: results from a phase 1b multicohort study. Blood. 2021;138(suppl 1):1647. doi:10.1182/blood-2021-148723

7. Shim H. Bispecific antibodies and antibody-drug conjugates for cancer therapy: technological considerations. Biomolecules. 2020;10(3):360. doi:10.3390/biom10030360

8. Andreev J, Thambi N, Perez Bay AE, et al. Bispecific antibodies and antibody-drug conjugates (ADCs) bridging HER2 and prolactin receptor improve efficacy of HER2 ADCs. Mol Cancer Ther. 2017;16(4):681-693. doi:10.1158/1535-7163. MCT-16-0658