Bispecific Antibodies and Noncovalent BTK Inhibitors Expand Horizons in DLBCL and MCL

Catherine C. Coombs, MD

In an interview with OncLive®, Catherine C. Coombs, MD, an associate professor in the Division of Hematology-Oncology in the Department of Medicine at the University of California Irvine (UCI) School of Medicine, discussed key points from an OncLive Institutional Perspectives in Cancer (IPC) webinar on leukemia and lymphoma, which she chaired.

Coombs spotlighted the bispecific antibodies approved for use in patients with diffuse large B-cell lymphoma (DLBCL), as well as the significance of the addition of polatuzumab vedotin-piiq (Polivy) to standard therapy for patients with this disease. She also explained where the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) fits into the mantle cell lymphoma (MCL) treatment paradigm and how this agent has prompted further research with noncovalent agents in this population. Coombs provided further insights from her colleagues’ presentations in another article.

OncLive: Regarding the presentation by Swetha Kambhampati, MD, of City of Hope in Duarte, California, on emerging treatments in DLBCL, how has the standard of care (SOC) evolved for patients with relapsed or refractory DLBCL?

Coombs: A lot of randomized trials are seeking to improve R-CHOP [rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, and prednisone] for patients with DLBCL. However, it’s been difficult to improve upon the excellent outcomes of R-CHOP21, which has remained the SOC for most patients with DLBCL. One study that changed [the way we use R-CHOP] was the phase 3 POLARIX trial [(NCT03274492) investigating] the combination of pola-R-CHP [rituximab, cyclophosphamide, doxorubicin, polatuzumab vedotin, and prednisone], which was found to improve progression-free survival [PFS] compared with R-CHOP.

I would call the benefit [with pola-R-CHP] modest. Pola-R-CHP demonstrated a 27% reduction in the relative risk of disease progression, relapse, or death compared with R-CHOP. At 24 months, [the estimated PFS rates were] 76.7% with pola-R-CHP vs 70.2% with R-CHOP, [translating to] an absolute change of 6.5%. However, in subgroup analyses, the PFS benefit with pola-R-CHP was perhaps a bit more notable among certain patient subgroups that admittedly the study was not powered to analyze individually. These groups, which I would always consider, are patients with IPI scores of 3 to 5, those with non-bulky disease, older male patients, and perhaps most impressively, those with the activated B-cell subtype.

Moving past the frontline setting, I’d like to mention exciting agents in the relapsed setting. There have been a lot of studies with CAR T cells, and these agents have worked their way into the standard practice for most patients with relapsed disease.

To move past CAR T-cell therapy, another novel therapeutic is bispecific antibodies. There have been a few FDA approvals of [bispecific antibodies]. Regarding glofitamab-gxbm [Columvi], the pivotal phase 1/2 [NP30179 study (NCT03075696)] investigated the administration of this bispecific antibody [in patients with relapsed or refractory DLBCL]. Intriguingly, glofitamab is intended to be used as a fixed-duration treatment with a maximum of 12 cycles. The responses to glofitamab in the relapsed setting are impressive and they can be durable. [In NP30179], the complete response [CR] rate with glofitamab was 39%, and the median duration of CR was long.

Another bispecific antibody that is also approved for DLBCL is epcoritamab-bysp [Epkinly]. Similarly [to glofitamab, epcoritamab is associated with] high rates of activity. [In the pivotal phase 1/2 EPCORE-NHL-1 trial (NCT03625037), the] CR rate was 39.5%, and similarly [to glofitamab, the CRs were durable], with a median duration of response [DOR] of 20.8 months.

Which of these drugs would I use? There are similarities and differences between the 2, but nonetheless, it’s encouraging to know that the response rates indicate a high degree of activity with both these agents, and it’s great to have as many options as possible for patients in this group.

Nirav N. Shah, MD, of the Medical College of Wisconsin in Milwaukee, discussed sequencing BTK inhibitors in MCL. How has the addition of pirtobrutinib to the MCL armamentarium changed treatment strategies for patients with this disease?

[MCL] is a less common lymphoma, accounting for approximately 6% of all lymphomas. It has a male predominance, and the therapeutic options are wide and depend on the fitness and [ECOG] performance status of any given patient. Many frontline regimens still incorporate chemotherapy plus or minus autologous transplant followed by rituximab maintenance.

Regarding relapsed MCL, it’s well agreed upon that BTK inhibitors are a SOC. The 2 [BTK inhibitors] that are probably used the most commonly in the United States are the newer-generation covalent BTK inhibitors acalabrutinib [Calquence] and zanubrutinib [Brukinsa], which have good activity in the [relapsed] setting. However, what happens after progression on a covalent BTK inhibitor? Prior to the availability of noncovalent BTK inhibitors, this was a challenge. Several real-world studies have demonstrated poor outcomes for patients in this subgroup.

However, matters have improved with the FDA approval of pirtobrutinib, a noncovalent BTK inhibitor, [for patients with relapsed/refractory MCL]. Interestingly, [pirtobrutinib] may have a different binding mechanism [than covalent BTK inhibitors because it is] a noncovalent or reversible binder, but it also may stabilize or maintain BTK in a closed, inactive conformation, which could block access to some upstream kinases and phosphorylation of residue Y551, which can inhibit some of the scaffolding interactions that support kinase-independent BTK signaling.

The phase 1/2 BRUIN trial [NCT03740529] permitted the inclusion of patients with pretreated MCL. We saw an overall response rate [ORR] of 57.8% in patients who had been treated with at least a prior covalent BTK inhibitor. The CR rate among these patients was 20.0% and if patients [achieved] responses, [these responses were] impressive, with a median DOR of 21.6 months. The ORRs [with pirtobrutinib] were even higher for patients who were covalent BTK inhibitor naive. Although the numbers are small, as only 14 patients [were covalent BTK inhibitor naive], the ORR in this group was 85.7%.

The ongoing [phase 3 BRUIN MCL-321 trial (NCT04662255)] is comparing pirtobrutinib with investigator’s choice of covalent BTK inhibitor: ibrutinib [Imbruvica], acalabrutinib, or zanubrutinib. I’ll be eagerly awaiting the results of this trial. Another advantage of pirtobrutinib is that it appears to have an excellent safety profile. [In the safety data from the patients with MCL] and all comers [in BRUIN], we saw low rates of discontinuation due to toxicity, as well as low rates of some of the worrisome class-type effects [associated with] BTK inhibitors, specifically low rates of atrial fibrillation.

Another noncovalent BTK inhibitor is under study, nemtabrutinib. However, the data with this agent are limited.

What is your main message for colleagues regarding the current state of treatment for patients with hematologic malignancies?

[This IPC] incorporated talks from many different investigators on a lot of different hematologic malignancies. However, the thread that goes through all our presentations is that care is changing and it’s changing for the better. I continue to be excited by the introduction of novel targeted agents [including] small molecule inhibitors, bispecific antibodies, etc. These agents have all benefited patients with hematologic malignancies, and the SOCs will continue to improve over time.