Target on the Move

The goal of modern cancer treatment is to provide targeted and personalized care. For more than 20 years, precision therapies have revolutionized the treatment of many cancer types, including hematologic malignancies. The targets have varied over the years—growth signal inhibitors, angiogenesis inhibitors, cell cycle inhibitors—and so have their success.

The gold standard for targeted treatments has long been the tyrosine kinase inhibitors developed to target BCR-ABL that changed the disease course of patients with chronic myeloid leukemia. Unfortunately, some other targeted therapies have been less effective and less successful. For example, the BCMA-targeting antibody-drug conjugate belantamab mafodotin-blmf, which was granted accelerated approval for relapsed or refractory multiple myeloma (MM), was withdrawn from the US market in late 2022 after disappointing results of a confirmatory trial.¹

Although many of these targeted therapies have improved tumor responses, progression-free survival, and sometimes overall survival for patients, few, if any, are curative. The eventual acquired resistance to these precision therapies means that one thing has remained constant: the need for novel targets. Blood Cancers Today recently spoke with several researchers and clinicians about novel targets being investigated in several types of hematologic malignancies.

GPRC5D

Despite the withdrawal of the BCMA-targeting antibody-drug conjugate, other therapies targeting BCMA, which is highly expressed in mature B-lymphocytes and plasma cells, have been more successful in the treatment of MM, including two chimeric antigen receptor (CAR) T-cell therapies (ciltacabtagene autoleucel and idecabtagene vicleucel) and a T-cell engager (teclistamab).^2,3

BCMA-directed CAR T cells have shown deep responses in some patients with advanced MM, but most patients are likely to eventually relapse. One of the targets being explored for patients with relapsed or recurrent disease, or those who have progressed after BCMA-targeting therapies, is orphan G protein-coupled receptor, class C, group 5, member D (GPRC5D).

In 2019, Eric L. Smith, MD, PhD, of the Memorial Sloan Kettering Cancer Center, and colleagues published a paper detailing that the GPRC5D protein, which is normally expressed in the hair follicle, was expressed in MM cells independently of BCMA. Experiments in mouse models showed that targeting GPRC5D eradicated MM and led to long-term survival.⁴

“We don’t know a lot about its activity or the mechanism of how it helps myeloma cells survive,” said Saad Z. Usmani, MD, MBA, FACP, Chief of the Myeloma Service at the Memorial Sloan Kettering Cancer Center. “What we do know it that it is highly expressed on myeloma cells and more preferentially expressed in plasma cells compared to other cell types.”

Drs. Smith and Usmani were both part of a team of researchers who published results of a first-in-human, phase I, dose-escalation study looking at GPRC5D-targeted CAR T-cell therapy in patients with heavily pretreated MM, including some with prior BCMA CAR T-cell therapy.⁵

The study looked at four different dose levels: 25×10⁶, 50×10⁶, 150×10⁶, and 450×10⁶ total CAR T cells. The maximum tolerated dose was identified at 150×10⁶.

“It is important to note that the overall response rate (ORR) for the entire cohort was 71%, which included a majority of patients who had prior BCMA treatment,” Dr. Usmani said. “Seven of the nine patients with prior BCMA treatment responded.”

Data indicated that the therapy was safe. Cytokine release syndrome (CRS) was mostly grade 1 or 2, with one patient experiencing grade 4 CRS and neurotoxicity.

Targeting GPRC5D is also being explored in the form of a bispecific T-cell engager antibody that targets both GPRC5D and CD3. The drug, talquetamab, was granted US Food and Drug Administration (FDA) Breakthrough Therapy Designation in June 2022.⁶

In December 2022, results of a phase I study of talquetamab as treatment for patients with heavily pretreated relapsed or refractory MM were published in the New England Journal of Medicine. ⁷ Patients received talquetamab either intravenously weekly or every other week or subcutaneously weekly, every other week, or monthly, with two subcutaneous doses recommended for phase II study (405 μg/kg weekly and 800 μg/kg every other week).

At follow-up, patients treated with 405 μg/kg weekly had a response rate of 70%; patients treated with 800 μg/kg every other week had a response rate of 64%. Median durations of response were 10.2 and 7.8 months, respectively, for the two doses.

Dr. Usmani noted that the GPRC5D bispecific antibody did have a different safety profile compared with the CAR T-cell therapy.

In addition to mostly grade 1 or 2 CRS, skin-related events occurred in 67% and 70% of patients at the two dose levels, respectively, and dysgeusia occurred in 63% and 57%. One dose-limiting grade 3 rash was also reported at the higher dose. Bispecific antibodies, in general, are also associated with increased infection risk, Dr. Usmani noted.

“The advantage of CAR T-cell therapy is that you give a single dose and let the patients recover,” Dr. Usmani said. “There is not any consolidation or maintenance treatment.”

In contrast, talquetamab is given on a regular basis.

“The skin- and nail-related changes are a quality-of-life concern, of course,” Dr. Usmani said. “Right now, the strategy with bispecifics is to focus on giving less treatment to mitigate these side effects. We want to see if patients get a good response if you can back off treatment frequency.”

There are also other GPRC5D bispecific antibodies in development, like RG6234 (Regeneron), which also showed response rates of approximately 70%.⁸

In addition, researchers are looking into the feasibility and efficacy of a CAR T-cell therapy simultaneously targeting BCMA and GPRC5D. If these GPRC5D-targeting therapies prove effective and gain regulatory approval, the next step will be to determine the appropriate sequencing of these drugs.

IRAK4

Another area of hematologic malignancies in need of new targets is myelodysplastic syndromes (MDS). Although many patients diagnosed with MDS will have lower-risk disease, those with higher-risk disease need effective strategies. Right now, most patients who undergo first-line treatment for MDS will eventually experience relapse or resistance, according to Guillermo Garcia-Manero, MD, Chief of the Section of MDS in the Department of Leukemia at the University of Texas MD Anderson Cancer Center.

“The therapies we have for MDS are, at best, very limited,” Dr. Garcia-Manero said. “We need new, effective therapies.”

Molecular diagnostics have helped researchers to identify several gene mutations in MDS, including genes responsible for epigenetic regulation, RNA splicing, DNA damage response, transcriptional regulation, and signal transduction.⁹ A recent area of interest involves the role of interleukin (IL) 1 receptor-associated kinases (IRAKs), which are involved in multiple inflammatory pathways implicated in hematologic malignancies.

“Over the last decade or so, there has been an effort to understand the molecular pathogenesis of MDS,” Dr. Garcia-Manero said. “A number of investigators, including our group, discovered that a pathway that we refer to as innate immunity signaling is overexpressed in a large fraction of patients, particularly those with lower-risk disease.”

Dr. Garcia-Manero said this signaling starts with activation of certain receptors, like toll-like receptors, which leads to activation of the NF-κB pathway. Overactivity of the NF-κB signaling pathway is implicated in the development of both MDS and acute myeloid leukemia (AML).

These and related discoveries have spurred interest in targeting IRAKs.

“The idea is that if you block this IRAK4, for instance, you may dampen signaling via NF-κB and decrease production of inhibitory cytokines such as IL-1 and IL-6 and potentially restore hematopoiesis,” Dr. Garcia-Manero said.

There are a few compounds targeting IRAK4 currently under investigation. These drugs may have activity in both lower- and higher-risk disease.

In 2022, Dr. Garcia-Manero presented data at the European Hematology Association Annual Meeting on emavusertib (CA-4948; Curis), which is a novel inhibitor of both IRAK4 and FLT3. The open-label, phase I/IIa trial established a phase II dose of the drug (300 mg twice daily) and showed efficacy in the group of patients with heavily pretreated AML and high-risk MDS. In the five patients with AML, 40% achieved complete response (CR) or CR with incomplete hematologic recovery. In the seven patients with high-risk MDS, 57% reached bone marrow CR.¹⁰

German researchers are also investigating the use of emavusertib for the treatment of anemia in patients with very low-, low-, or intermediate-risk MDS.¹¹

In December 2022, Rigel Pharmaceuticals announced it was launching a phase Ib study of its dual IRAK1/4 inhibitor R289 in patients with lower-risk refractory or resistant MDS.¹² One concern with targeting IRAK4, Dr. Garcia-Manero said, is that innate immunity is part of our natural defense mechanism used to defend against infection.

“One potential problem with targeting that pathway is that you also inhibit the physiological mechanisms of defense and patients are more prone to infection,” he said, adding that the issue is more theoretical and has not yet been seen in trials of other drugs that disturb this pathway. “There is quite a bit of interest in these agents, but we need to figure out the proper dose and schedule in higher-risk disease and eventually in low-risk disease,” Dr. Garcia-Manero said. “A next step would also be to find a subset of patients who are vulnerable to this type of drug.”

Data from several groups have suggested that leukemias with splicing mutations may be vulnerable to this kind of intervention. Dr. Garcia-Manero also mentioned that the innate immunity signaling pathway is quite redundant, with many receptors that could trigger activation.

“In my mind, there will be a need for some type of combination treatment to make these compounds more effective,” he said.

EZH2

Another novel target that may have some interaction with the immune system is EZH2, an enzymatic catalytic subunit of polycomb repressive complex 2 (PRC2). PRC2 controls the organization of chromatin in many cells, including in germinal center B cells where follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) originate, according to Gilles Salles, MD, PhD, Chief of the Lymphoma Service at the Memorial Sloan Kettering Cancer Center.

“EZH2 was one of the first genes found to be mutated in FL and some DLBCL more than 10 years ago,” Dr. Salles said. “Interestingly, these mutations, which are present in up to 20% of FL, are activating mutations that lead to overexpression of the protein, and experimental data suggest that this contributes to the malignant process.”

Early data indicated that inhibiting EZH2, whether it is mutated or unmutated, would be a reasonable target in patients with FL.

“Based on this target identification, it was tempting to try to develop an inhibitor of EZH2, and tazemetostat was the first oral inhibitor developed and tested in patients with B-cell lymphoma,” Dr. Salles said.

In 2020, tazemetostat was granted FDA accelerated approval based on data out of two open-label, single-arm cohorts.¹³ Eligible patients were treated with tazemetostat 800 mg twice daily for 28-day cycles. Among patients with FL with EZH2 mutations, the objective response rate was 69%; among those with EZH2 wild-type disease, it was 35%.¹⁴

“The duration of the response of both cohorts, with and without the mutations, was found to be about one year,” said Dr. Salles, who was a researcher on the study. “Based on these data, the drug was approved by the FDA with two distinct indications.”

In patients with the EZH2 mutation, tazemetostat should be used as a third-line therapy in patients who have failed at least two lines of therapy and in patients without characterization with relapsed or refractory FL who have no other alternative treatment options, noted Dr. Salles.

Given that the drug is an oral agent and was well-tolerated, Dr. Salles said that he considers it a “useful tool, but not a magical tool.”

According to Dr. Salles, EZH2 inhibition also leads to the expression of a couple of molecules on the surface of the B cell that may participate with immune interaction with T cells. Because of this interaction, researchers are curious to try combining tazemetostat with some immunotherapy regimens.

In December 2022, Dr. Salles presented the results of the phase Ib SYMPHONY-1 trial that tested tazemetostat in combination with lenalidomide and rituximab (R²) in patients with relapsed or refractory FL.¹⁵ The ORR among evaluable patients was 97.6%, with a little more than half (51.2%) achieving CR and a little less than half (46.3%) achieving partial response.

“The results appear to be very promising and may be superior to those we observed when using R² alone,” Dr. Salles said, adding that the populations are not comparable.

The tolerability of the combination was satisfactory, he said, with side effects similar to those seen with R².

“It really acts on an interesting pathway given that it affects the intimate molecular level of FL biology but also has some more broad immune effects,” Dr. Salles said. “I will, however, add a word of caution about targeting epigenetics. The potential long-term effects of this modification of epigenetic machinery on other cell types, including hematopoietic stem cells, are unknown, and we need to continue to follow patients exposed to molecules of this family.”

PLK4

Another potential drug class was developed with potential synergy with immunotherapy, according to Gautam Borthakur, MD, a Professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center.

PLK4 is a novel target of interest in the management of leukemia. PLK4—or polo-like kinase 4—is a member of the polo-like kinase family of serine/threonine kinases, which are linked to cell cycle regulation. PLK4 is linked specifically with the regulation of centriole duplication during cell division and has been shown to be overexpressed in a number of human cancers.¹⁶

In addition, its expression has been linked with poor outcomes, Dr. Borthakur noted.

“PLK4 is interesting in that its function does not have a redundancy, whereas other PLKs can have redundancy,” Dr. Borthakur said. “That means that as a target, if you hit it, there is not a compensatory mechanism that can take over.”

According to Dr. Borthakur, there is a substantial unmet need for new options in patients with high-risk AML.

“Despite the introduction of venetoclax, and the improved outcomes seen with the drug, there is still a large percentage of patients whose responses don’t last,” he said.

In 2020, researchers from Toronto published an abstract with preliminary results of a phase I study of an oral PLK4 inhibitor—CFI-400945—tested in patients with AML and high-risk MDS.¹⁷

“In this investigator-initiated study, responses were seen in patients with high-risk AML with complex cytogenetics, supporting the idea that maybe PLK4 inhibition would be effective in patients with p53 mutations or other complex cytogenetics,” Dr. Borthakur said.

Late last year, a poster presentation included preliminary results of the dose optimization of the TWT-202 trial of CFI-400945 in advanced leukemias.¹⁸

It is still too early to tell what patient populations might benefit most from a PLK4 inhibitor, Dr. Borthakur said. At the end of the day, it must still be determined if this type of drug is best delivered as a single agent or in combination with other agents. For example, there is interest in combining a PLK4 inhibitor with hypomethylating agents to see if that would enhance activity in patients with high-risk AML.

One of the biggest remaining questions, according to Dr. Borthakur, is what toxicities will be seen with drugs targeting PLK4.

“There are cells in our body that are mitotically active, particularly those in the gut and normal cells in the bone marrow, so there is a question about toxicities,” he said. “This is also an area where research into combinations would help. We may not need to push a single agent to the maximum-tolerated dose if we use a multipronged strategy to hit similar targets.”

Leah Lawrence is a freelance health writer and editor based in Delaware.

References

1. GSK provides an update on Blenrep (belantamab mafodotin-blmf) US marketing authorization. GSK. November 22, 2022. Accessed March 8, 2023. https://www.gsk.com/en-gb/media/press-releases/gsk-provides-update-on-blenrep-us-marketing-authorisation/
2. Mullard A. FDA approves second BCMA-targeted CAR-T cell therapy. Nat Rev Drug Discov. 2022;21(4):249. doi:10.1038/ d41573-022-00048-8
3. FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. U.S. Food and Drug Administration. October 25, 2022. Accessed March 10, 2023. https://www.fda.gov/ drugs/resources-information-approved-drugs/fda-approves-teclistamab-cqyv-relapsed-or-refractory-multiple-myeloma
4. Smith EL, Harrington K, Staehr M, et al. GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells. Sci Transl Med. 2019;11(485):eaau7746. doi:10.1126/scitranslmed.aau7746
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6. Janssen announces U.S. FDA Breakthrough Therapy Designation granted for talquetamab for the treatment of relapsed or refractory multiple myeloma. Johnson & Johnson. June 29, 2022. Accessed March 10, 2023. https://www.jnj.com/janssen-announces-u-s-fda-breakthrough-therapy-designation-granted-for-talquetamab-for-the-treatment-of-relapsed-or-refractory-multiple-myeloma
7. Chari A, Minnema MC, Berdeja JG, et al. Talquetamab, a T-cell–redirecting GPRC5D bispecific antibody for multiple myeloma. N Engl J Med. 2022;387(24):2232-2244. doi:10.1056/NEJMoa2204591
8. Carlo-Stella C, Mazza R, Manier S, et al. RG6234, a GPRC5DxCD3 T-cell engaging bispecific antibody, is highly active in patients (pts) with relapsed/refractory multiple myeloma (RRMM): updated intravenous (IV) and first subcutaneous (SC) results from a phase I dose-escalation study. Abstract #161. Presented at the 64th ASH Annual Meeting and Exposition; December 10, 2022; New Orleans, Louisiana.
9. Platzbecker U, Kubasch AS, Homer-Bouthiette C, Prebet T. Current challenges and unmet medical needs in myelodysplastic syndromes. Leukemia. 2021;35(8):2182-2198. doi:10.1038/s41375-021-01265-7
10. Garcia-Manero G, Winer ES, DeAngelo DJ, et al. TAKEAIM Leukemia- a phase 1/2a study of the IRAK4 inhibitor emavusertib (CA-4948) as monotherapy or in combination with azacitidine or venetoclax in relapsed/refractory AML or MDS. Abstract #S129. Presented at EHA 2022; June 11, 2022; Vienna, Austria.
11. Curis announces initiation of investigator-sponsored phase 2 LUCAS study of CA-4948 for the treatment of anemia in patients with very low, low, or intermediate-risk myelodysplastic syndromes. Curis. February 2, 2021. Accessed March 10, 2023. https://investors.curis.com/2021-02-02-Curis-Announces-Initiation-of-Investigator-Sponsored-Phase-2-LUCAS-Study-of-CA-4948-for-the-Treatment-of-Anemia-in-Patients-with-Very-Low-Low-or-Intermediate-Risk-Myelodysplastic-Syndromes
12. Rigel doses first patient in phase 1b study of R289 for the treatment of lower-risk myelodysplastic syndromes. Rigel. December 15, 2022. Accessed March 10, 2023. https://www.rigel.com/news-media/press-releases/detail/350/rigel-doses-first-patient-in-phase-1b-study-of-r289-for-the
13. FDA granted accelerated approval to tazemetostat for follicular lymphoma. U.S. Food and Drug Administration. June 18, 2020. Accessed March 10, 2023. https://www.fda.gov/drugs/fda-granted-accelerated-approval-tazemetostat-follicular-lymphoma
14. Morschhauser F, Tilly H, Chaidos A, et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol. 2020;21(11):1433-1442. doi:10.1016/S1470-2045(20)30441-1
15. Batlevi CL, Salles G, Park SI, et al. Tazemetostat in combination with lenalidomide and rituximab in patients with relapsed/refractory follicular lymphoma: phase 1b results of Symphony-1. Abstract #954. Presented at the 64th ASH Annual Meeting and Exposition; December 12, 2022; New Orleans, Louisiana.
16. Garvey DR, Chhabra G, Ndiaye MA, Ahmad N. Role of polo-like kinase 4 (PLK4) in epithelial cancers and recent progress in its small molecule targeting for cancer management. Mol Cancer Ther. 2021;20(4):632-640. doi:10.1158/1535-7163. MCT-20-0741
17. Murphy T, Leber B, Bray MR, et al. Preliminary results from a phase 1 study of CFI-400495, a PLK4 inhibitor, in patients with acute myeloid leukemia and high risk MDS. Abstract #1050. Presented at the 62nd ASH Annual Meeting and Exposition; December 5, 2020; Virtual.
18. Treadwell Therapeutics announces a presentation at the 2022 ASH Annual Meeting featuring a clinical trial update on CFI-400945, an oral PLK4 inhibitor. Treadwell Therapeutics. December 13, 2022. Accessed March 10, 2023. https://treadwelltx.com/news/treadwell-therapeutics-announces-a-presentation-at-the-2022-ash-annual-meeting-featuring-a-clinical-trial-update-on-cfi-400945-an-oral-plk4-inhibitor