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Page 12 of 25 Lue et al. J Cancer Metastasis Treat 2022;8:11 https://dx.doi.org/10.20517/2394-4722.2021.193

doses ( 200mg BID), a range of tumor reduction was observed (5-67%). Twenty of the 31 patients enrolled
had available information for MYD88 status, and of the 20, two harbored an MYD88 mutation, with one
patient achieving a partial response. Based on a synergistic relationship observed in vivo, the combination of
ibrutinib in conjunction with CA-4948 is currently being evaluated in a multicentered, phase I study in
patients with R/R NHL [74,75] .

Another novel method of targeting IRAK4, has been the development of Proteolysis Targeting Chimeras
against IRAK4. These small molecules target specific proteins for degradation by cross-linking pathogenic
proteins to E3 ubiquitin ligases, leading to ubiquitination of the target protein. This serves as a rationale
mechanistic approach to eliminate oncogenic signaling. These first-in-class heterobifunctional degraders
represent an innovative approach that could revolutionize cancer therapy. In contrast to IRAK4 kinase
inhibitors, a strategy of targeting IRAK4 degradation would completely nullify the protein’s dual role as
both a kinase and scaffolding protein, and potentially circumnavigate internal resistance. First-in-class
[76]
heterobifunctional selective IRAK4 degrader, KYM-001 , demonstrated potent efficacy in MYD88-
mutated lymphomas. IRAKIMiDs, which are novel IRAK4 degraders that utilize a cereblon binder leading
to dual targeting of IRAK4 degradation and capitalizing on immunomodulatory(IMiD) biology, also
demonstrates activity in MYD88 mutant DLBCL . In pre-clinical models, IRAKIMiDs in conjunction with
[77]
[78]
ibrutinib, venetoclax and umbralisib have proven to be synergistic , suggesting a possible multidrug
platform using IRAKIMiDs as a backbone in order to potentially downregulate several oncogenic pathways
simultaneously. Further clinical studies are required to validate these promising pre-clinical data with plans
for KT-413, the lead IRAKIMiD, to enter clinical evaluation in 2022.

The development of MALT1 inhibitors is being intensively investigated and has demonstrated pre-clinical
activity in ABC-DLBCL [79-86] . BCL10 gain of function mutations, most commonly found in BN2/C1
subgroups , have been associated with increased MALT1 and NF B activity, as well as resistance to
[2,3]
[87]
ibrutinib . When exposed to JNJ-67856633, a MALT1 inhibitor, ibrutinib-resistant ABC-DLBCL cell lines
were characterized by growth inhibition, supporting the therapeutic application of MALT1 inhibitors in
ABC-DLBCL, especially those with BCL10 mutation and ibrutinib-resistance. At this time, a phase I study
[88]
(NCT03900598) is currently on-going investigating JNJ-67856633 in R/R NHL (NCT03900598) .

PD-L1 expression has been associated with inferior outcomes and found in higher expression in ABC-
DLBCL as compared to GCB-DLBCL [89,90] , and therefore has been another target for the advancement of
DLBCL treatment. It is thought that tumor cells exploit immune checkpoint pathways in order to evade the
host immune system. However, single-agent immune checkpoint inhibition (nivolumab) displayed limited
efficacy in R/R DLBCL, demonstrating an ORR of 3% and 10% for patients who relapsed after ASCT and
were ineligible for ASCT, respectively . Notably, the incidence of 9p24.1 alterations was low (16% low-level
[91]
copy gain, 3% amplification) and may partially explain the poor efficacy results after administration of
nivolumab. The addition of PD1/PD-L1 inhibitors in the upfront setting has also been evaluated,
postulating that upfront utilization may lead to better outcomes by optimizing a relatively more intact
immune system. As such, pembrolizumab (anti-PD1) in combination with R-CHOP produced an ORR of
90% (27/30) and a PFS of 83% (NCT02541565) . A Phase I/II clinical trial investigating the addition of
[92]
durvalumab (anti-PD-L1 antibody) to R-CHOP or R2CHOP [lenalidomide + R-CHOP backbone]
(NCT03003520) was initiated, however the R2-CHOP + durvalamub enrollment (Arm B) was halted due to
increased deaths in patients with Multiple Myeloma treated with durvalumab and lenalidomide [93,94] . The CR
rate at the end of induction was 54% and 67% for Arm A (n = 43) and Arm B (n = 3), respectively, with
consolidation therapy with durvalumab offered to patients who responded. Another potential platform to
incorporate immune checkpoint inhibition is the notion of sequential therapy, during which PD1/PD-L1