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Page 10 of 25 Lue et al. J Cancer Metastasis Treat 2022;8:11 https://dx.doi.org/10.20517/2394-4722.2021.193

Ab CR: 30% (DLBCL)
(NCT02953509)
[147,
Mosunetuzumab CD3-CD20 BsAb Phase I/Ib ORR: 37%
148]
CR: 19%
(NCT02500407)

Phase Ib/II N/A
Mosunetuzumab+CHOP or (NCT03677141)
Polatuzumab+CHP
Odronexatamab [149] CD3-CD20 BsAb Phase I ORR: 60% (CAR T-cell Naïve)
CR: 60% (CAR T-cell Naïve)
ORR: 33.3% (Refractory CAR T-cell)
CR: 23.8% (Refractory CAR T-cell)
(NCT02290951)
[150]
Epicoritamab CD3-CD20 BsAb Phase I/II ORR: 100% (DLBCL) at 48mg
CR: 28.6% (2/7)
PR: 71.4% (5/7)
(NCT03625037)
Glofitamab [151,152] 2:1 CD20-C3 BsAb Phase I/Ib ORR: 50% (aggressive NHL)
CR: 29.2%
(NCT03075696)
[153]
CMG1A46 Trispecific Ab: CD19- Pending N/A
CD20-CD3
[170]
Selinexor XPO-1 Mediated Nuclear Phase 2 ORR: 28%
Transport Inhibitor CR:12%
(NCT02227251)
Ab: Antibody; BR: Bendamustine+Rituximab; BsAb: bispecific antibody; CR: complete response; DLBCL: diffuse large B-cell lymphoma; FL:
follicular lymphoma; ITT: intent to treat; PR: partial response; MMAE: monomethyl auristatin E; NHL: non-Hodgkin lymphoma; PROTAC:
proteolysis targeting chimera; PI3K: phosphoinositide 3-kinase (PI3K) inhibitor; R-CHP: Rituximab, Cyclophosphamide, Doxorubicin, Prednisone;
R-CHOP: Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone; R/R: relapsed/refractory.

BTK, demonstrated single-agent activity in patients with R/R DLBCL with an ORR of 37% (14/38) in ABC-
DLBCL patients, and a more impressive response in patients with dual mutations in MYD88 and CD79A/B,
[66]
[64]
albeit a small sample size (ORR 80%, 4/5) . Phelan et al. elucidated a possible mechanism driving
ibrutinib responses in ABC-DLBCL, describing a My-T-BCR complex comprising MYD88-TLR9-BCR that
interacts with mTOR within endolysosomes to activate downstream NFkB signaling. The My-T-BCR
complex was found to be present in ABC-DLBCL cell lines as well as primary patient tumors that responded
to ibrutinib, and responses were also noted in the absence of dual mutations in MYD88 and CD79A/B.
Given these promising pre-clinical and clinical data, a phase III randomized clinical trial was launched in
patients with non-GC DLBCL but failed to demonstrate any additive benefit to R-CHOP . In a pre-
[49]
planned analysis, patients younger than 60 years of age benefited based on an improved PFS and event-free
survival (EFS); on the other hand, those older than 60 years of age suffered from increased toxicity leading
to reduced intensity therapy, likely contributing to reduced efficacy. One can also postulate that using a less
robust strategy of IHC to identify high-risk patients as non-GC DLBCL may have also impacted the results.
Nonetheless, retrospective GEP analyses of available tumor samples from the PHOENIX trial were also
analyzed, and there was no improvement of EFS, PFS or OS when adding ibrutinib to R-CHOP. Next-
generation BTK inhibitors are in the investigation for the treatment of DLBCL, including the less toxic
acalabrutinib. In the relapsed/refractory (R/R) setting, acalabrutinib has been evaluated as a single agent
(ORR of 24%, 5/21) and more recently in a 4-arm Phase I study (PRISM) that evaluates acalabrutinib in
[67]
combination with one of the following: AZD9150, an antisense oligonucleotide against STAT3 mRNA;
AZD6738, an inhibitor of ATR; magrolimab (anti-CD47) and rituximab; or AZD5153, a BRD4 inhibitor .
[68]
Acalabrutinib is also being studied in the upfront setting (NCT0400294, NCT03571308) in combination
with R-CHOP or DA-R-EPOCH. Unlike ibrutinib, early data suggests that acalabrutinib does not
compromise the ability to administer R-CHOP regardless of age [69,70] .