The Bottom Line:
MS-553, a protein kinase C-beta (PKCß) inhibitor, is an exciting new agent in a yet-to-be-approved class of drugs that target an area of the B-cell receptor pathway independent of Bruton tyrosine kinase (BTK) and phospholipase C gamma 2 (PLCy2) mutations which confer resistance to BTK inhibitors. This drug is demonstrating exciting promise in early-phase drug testing for treating CLL / SLL in heavily treated patient populations, potentially offering a therapeutic alternative for those who have developed resistance to BTK inhibitors. In addition, there is a significant unmet need for those with relapsed refractory disease who have developed resistance to not only BTK inhibitors but also to venetoclax, the only approved member of a second class of drugs called B-cell lymphoma 2 (BCL-2) inhibitors, which together form the backbone of CLL / SLL therapy currently. So far, in very early drug testing, MS-553 offers hope for the future for those who have become resistant to currently available treatments.
Who Performed the Research and Where Was it Presented:
In concert with colleagues, Dr. James Blachly, a research scientist, and clinical hematologist from Ohio State University, presented the results of this study at the American Society of Hematology (ASH) annual meeting in 2022.
Background:
Over decades of scientific research, the B-cell receptor pathway, a complex series of molecular interactions, is critical to the survival and proliferation of the malignant CLL / SLL cell. Treatment of CLL / SLL has been revolutionized with great success by introducing BTK inhibitors that block a crucial step in the pathway. Unfortunately, drug resistance to BTK inhibitors may arise due to a mutation at the BTK receptor site preventing binding of the inhibitor (or at a signaling protein directly downstream of BTK, called PLCy2) causing independent activation of this molecule, allowing in either case for continued cell survival. Another signaling agent downstream of PLCy2 is PKCß which is overly expressed in CLL / SLL and provides for continued cell survival. A drug to target this site has yet to be approved. However, Dr. Blachly at ASH 2022 presented exciting new early drug testing data for a novel PKCß inhibitor, MS-533, which shows encouraging potential for those who have developed resistance to BTK inhibitors.
Following the presentation at ASH, Dr. Brian Koffman interviewed Dr. James Blachly to delve deeper into the research and discuss the very encouraging results of this early-stage clinical trial.
Methods and Participants:
- The primary objectives of the study are to determine the safety and tolerability of oral daily MS-533 in 3 groups of patients:
- Cohort A – MS-533 is being tested as monotherapy for relapsed and refractory patients with CLL / SLL, including those with aggressive lymphoma.
- Cohort B – MS-533 is being tested in combination with acalabrutinib, a BTK inhibitor, in patients not previously treated with a BTK inhibitor.
- Cohort C – MS-533 is being tested in combination with both venetoclax and obinutuzumab in patients not previously treated with a Bcl-2 inhibitor.
- The study’s secondary objectives are to assess the pharmacokinetic profile, pharmacodynamic activity, and evidence of anti-tumor activity of MS-553 treatment.
- Dose expansion testing continues in cohort A.
- Dose escalation has begun determining the recommended Phase 2 dose in cohorts B and C.
Results:
- As of June 20, 2022, 45 patients had been enrolled and treated with at least one therapeutic dose.
- Overall, 72% of enrolled patients were IgHV unmutated, and 44% had del (17p) or TP53 mutations, which are high-risk features caused by genetic alterations that allow CLL cells to survive. In addition, 76% had been previously treated with one or more BTK inhibitors.
- Cohort A consists of patients treated with MS-553 alone, including 37 patients with a median number of 4 prior therapies, 92% having previously received a BTK inhibitor, 51% having previously received venetoclax, and 41% having received both a BTK inhibitor and venetoclax. Of the efficacy evaluable patients in cohort A, 10/20 patients with a median duration of therapy of 6.0 months have exhibited a partial response (PR), and 10/20 patients with a median treatment duration of 4.1 months have shown stable disease.
- Cohort B consists of patients being treated with MS-553 in combination with acalabrutinib, and to date, includes four patients with a median number of 2 prior therapies. This cohort remains in the dose escalation phase of the study. 4/4 of patients have achieved a partial response (PR) with a median time on treatment of 5.6 months.
- Cohort C consists of patients treated with MS-553 in combination with venetoclax and obinutuzumab and includes four patients with a median number of 0.5 prior therapies. The cohort remains in the dose escalation phase of the study. 2/3 patients have had a PR, and 1/3 had a complete response (CR) with a median time on therapy of 6 months.
- Responses have occurred in several ultra-high-risk patients, including those with BTK/ PLCy2/TP53 triple mutations and relapse after BTK inhibitor and venetoclax treatment and having relapsed after both covalent and non-covalent BTK inhibitors.
- Most drug-related treatment-emergent adverse events (TEAE’s) were grade 1 or 2, the most common being nausea, diarrhea, fatigue, vomiting, anemia, abdominal pain, and anorexia.
- There was only one dose-limiting grade 3 toxicity with acute kidney injury. There were a few severe, grade 3, drug-related TEAE’s, including a low white blood cell count, nausea, diarrhea, fatigue, weight loss, increase in white blood cell count, low sodium level, kidney injury, and generalized muscle weakness. There were no cases of atrial fibrillation or bleeding, which have been reported with BTK inhibitors.
Conclusions:
MS-553 is a highly selective oral non-covalent PKCß inhibitor in early drug testing and is tolerated with initial efficacy in patients having previously received multiple lines of therapy and have developed resistance to some prior treatments. In addition, MS-533, when used in combination with other therapies, has shown initial safety and tolerability.
Links and Resources:
Enjoy this interview between Dr. Brian Koffman and Dr. James Blachly from ASH:
You can read the actual ASH abstract here: Initial Results from a Phase 1/2 Dose Escalation and Expansion Study Evaluating MS-553, a Novel and Selective PKCβ Inhibitor, in Patients with CLL / SLL
Additional resources:
ClinicalTrials.gov study registration: A Study of The Selective PKC-β Inhibitor MS- 553
Clinical Trial Phases, the Drug Approval Process, and Measuring Responses
We share in this journey together,
Kim Davidson, MD
CLL patient and physician
