ASH 2020: Dr. Anthony Mato on LOXO-305 A Next Generation Highly Selective Non-Covalent BTK inhibitor.

In an oral presentation during ASH 2020, Dr. Anthony Mato discussed LOXO-305, a new generation BTKi (Bruton Tyrosine Kinase Inhibitor) that blocks a key step in the B cell receptor (BCR) pathway. In doing so, it blocks pro-survival and “homing” messages to the CLL cells, forcing the cancer cells to leave their protective niches in the lymph nodes and bone marrow, and float out into the blood stream, eventually dying.

Ibrutinib was the first approved BTKi and it revolutionized the treatment of CLL because of its ability to provide a durable response in most patients, including those with high-risk features such as del 17p or TP53.

However, especially in the relapsed and refractory setting, some CLL cells may eventually be able to escape inhibition from ibrutinib and other similar BTKis such as acalabrutinib and zanabrutinib (not approved for CLL at the time of this writing). The most common way this happens is by a mutation in the drug’s binding site at C481 preventing those 1st generation BTKis from irreversibly binding to and blocking BTK, rendering those drugs largely ineffective.

LOXO-305 binds “reversibly” and does not seem to be affected by changes in the C481 binding site. It remains able to turn off BTK when the irreversible binders are no longer effective.

Dr. Mato discusses the CLL data from the BRUIN trial, which is the first in-human trial of LOXO-305 for CLL and NHL (Non-Hodgkin Lymphomas)

• 170 CLL patients were studied.
  • 80% had received ibrutinib or acalabrutinib.
• 200 mg is the daily dose.
• Fatigue, diarrhea, and bruising were the only side effects above 10%.
• < 1% had atrial fibrillation.
• Response rate for all 63%. If one looked at just the patients who were assessed at > 6 months or greater giving the medicine some time to work, the response rate went up to 86%.
• 94% of those who responded are still on drug.
• Patients responded well even they failed multiple other drugs and were running out of options.
• First study of one BTK inhibitor after failing another BKI inhibitor.

Conclusions:

Blocking the BTK pathway works amazing well for CLL patients, so when patients relapse on a first generation BTK inhibitor, there is good sense in trying another drug that uses a different mechanism to block the B cell receptors through BTK inhibition. Early data from the BRUIN trial suggest that LOXO-305 seems is a promising new option with regard to efficacy and tolerability and deserves further study to assess it in larger numbers of patients.

Here is a link to the actual trial on Clinicaltrials.gov that Dr. Mato describes in our ASH interview: A Study of Oral LOXO-305 in Patients With Previously Treated CLL/SLL or NHL.

Please enjoy our interview:

Here is the ASH abstract: LOXO-305, A Next Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated CLL/SLL: Results from the Phase 1/2 BRUIN Study.

Stay strong.  We are all in this together.

Brian

Brian Koffman MDCM (retired) MS Ed

ASH 2020: Dr. Arnon Nagler on Safety and Efficacy of CD19-CAR T Cells in Richter’s Transformation After Targeted Therapy for Chronic Lymphocytic Leukemia (CLL)

At the virtual ASH 2020 Annual Conference and Exposition, Dr. John Pagel of Swedish Hospital and one of CLL Society’s directors interviewed Dr. Arnon Nagler of Sheba Medical Center in Israel concerning using “in-house” CAR-T cells made locally at his medical center for Richter’s Transformation patients.

 

Richter’s Transformation (RT) is usually an aggressive transformation of chronic lymphocytic leukemia into a fast-moving lymphoma, usually clonally related, DLBCL (diffuse large B-cell lymphoma). RT is associated with a very poor response to most therapies and has a discouraging prognosis.

 

It remains one of the most pressing unmet needs in CLL patients.

 

That is why when the Israeli group showed that six of nine Richter’s patients responded to CAR-T therapy, their research was recognized for its importance and given a slot as one of the six oral CLL clinical presentations at ASH 2020.

 

Take Aways:

·      These were mostly heavily pretreated patients, all having progressed on ibrutinib and/or venetoclax

·      Del 17p/TP53 was found in 83% (five out of six) of those tested

·      Despite these poor markers and their aggressive disease, six of nine patients had complete remissions

·      Only two of these six progressed within a year, including one who went on to have a bone marrow transplant

·      One significant advantage of an “in-house” CAR-T is that the waiting time to manufacture the CAR-T is only ten days, so “bridging therapy” to keep the fast-moving Richter’s under control while waiting for the cells is less likely to be needed

·      No new problems or adverse events were noted in this Richter’s population. Just the usual three that are seen in most CAR-T treatments:

1.     Cytokine release syndrome (CRS): An acute systemic inflammatory syndrome characterized by fever, flu-like symptoms, and has the potential for low blood pressure and multiple organ dysfunction. It is usually of short duration, is now well understood, and can be safely managed in nearly all cases.

2.     Neurotoxicity: Might include headache, confusion, delirium, language disturbance, coma, seizures, and rarely acute brain swelling. It is usually mild and is almost always fully reversible.

3.     Low blood counts: May include anemia, low neutrophils, low platelets, and low lymphocytes. It can be persistent, but counts do recover over time.

 

Conclusions:

 

These results give us clear proof that CAR-T cellular therapy can work in Richter’s Transformation, and that is much-needed good news. The numbers are small, so larger studies will be needed, and I am sure will be done to confirm the promising findings.

 

But there remain many unanswered questions.

 

Can CAR-T be curative for some? For at least some patients, there is reason to be hopeful this might be the case.

 

Should it be used as a bridge to an allogeneic stem cell (bone marrow) transplant for RT patients to “consolidate” their response? We know the transplants (while high-risk and not perfect) still offer the best, most durable responses in Richter’s to those who are well enough to undergo the procedure.

 

Here is Dr. Pagel’s interview with Professor Nagler from ASH 2020: https://youtu.be/yFOWNR0x-u0

 

A transcript of the interview is being provided, as some of the interview is difficult to understand. We ask you to rely on the abstract linked below for study details, as we are not certain of the accuracy of every word in the transcript.

 

Here is the ASH abstract: Safety and Efficacy of CD19-CAR T Cells in Richter’s Transformation after Targeted Therapy for Chronic Lymphocytic Leukemia

 

EHA 2021: Dr. Anthony Mato on pirtobrutinib (LOXO-305) for Richter’s transformation in chronic lymphocytic leukemia (CLL)

Richter’s transformation (a.k.a. Richter’s syndrome) is a rare complication of chronic lymphocytic leukemia (CLL) where the cancer cells transform into a much more aggressive lymphoma. It occurs in 2-10% of CLL patients, and it is associated with very rapid disease progression, limited therapeutic options, and poor survival. Outcomes have generally been poor because the lymphoma does not respond well to traditional treatments. While chemotherapy is often used to treat Richter’s transformation, it is not very effective. 

 

At the annual meeting of the European Hematology Association (EHA) 2021,I interviewed Dr. Anthony Mato, Director of the CLL Program at Memorial Sloan Kettering Cancer Center. They discussed preliminary results from a clinical trial of pirtobrutinib (formerly LOXO-305) in a subset of patients with Richter’s transformation.

 

Takeaways:

·      This is a phase 1/2 clinical trial of pirtobrutinib, which is a highly-selective, reversible (non-covalent) Bruton’s tyrosine kinase (BTK) inhibitor we have previously discussed here.

·      The trial is currently ongoing, and this portion of the trial is enrolling patients with previously treated Richter’s syndrome.

·      Thus far, 17 patients with Richter’s transformation have been enrolled in the trial. 

·      These patients have already been heavily treated. The median number of prior therapies for CLL was 6, and the median number of prior therapies specifically for Richter’s transformation was 2.

·      Thus far, 15 patients have had a response assessment, and 67% (2 out of 3) responded to treatment.

·      Though it is still early on, some patients have continued to respond after 6+ months of follow-up.

·      Pirtobrutinib is probably not a cure for Richter’s transformation, but it may help stabilize the disease, improve quality of life, and potentially serve as a bridge to other therapies such as CAR-T therapy or stem cell transplant.

·      Thus far, pirtobrutinib has been well-tolerated with very few serious adverse events.

 

Conclusions:

There is a large unmet need for effective treatments for Richter’s transformation. Even though these results are only in a small number of patients with a short follow-up period, pirtobrutinib seems like a promising candidate thus far. This is encouraging news for patients who have few options, and we hope that we continue to see positive results with longer term follow up in more patients. If you are interested in participating, the trial is still ongoing at multiple sites in the United States and worldwide. More information can be found here.

 

Please enjoy this brief interview with Dr. Mato from the virtual EHA meeting which was held June 2021.

 

<Video link> https://youtu.be/OOV7myAT4aA 

 

You can read the actual abstract here: Pirtobrutinib (LOXO-305), a next generation, highly-selective, non-covalent BTK inhibitor in previously treated Richter transformation: results from the phase 1/2 BRUIN study

ASH 2020: Dr. Peter Hillmen on the CLARITY Trial of Ibrutinib Plus Venetoclax for Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

 

 

The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib and BCL2 inhibitor venetoclax have been very successful as individual therapies for treating chronic lymphocytic leukemia (CLL), but on their own they rarely lead to the eradication of measurable (a.k.a. minimal) residual disease (MRD). Researchers have been very interested in whether they can combine these therapies to improve outcomes for patients and achieve better remissions. They also want to determine how long would patients need to take the combination for to achieve deep remissions.

 

At the annual meeting of the American Society of Hematology (ASH) 2020, Dr. John Pagel of the CLL Society Board of Directors interviewed Dr. Peter Hillmen, Professor of Experimental Hematology at the University of Leeds in the United Kingdom. They discussed updates to the phase II CLARITY trial which has been evaluating the efficacy of combination ibrutinib + venetoclax in patients with relapsed/refractory CLL.

 

Takeaways:

·      The CLARITY trial is a phase II study testing the combination of ibrutinib + venetoclax in patients with relapsed/refractory CLL. The primary endpoint the researchers were evaluating was undetectable measurable residual disease (uMRD) after one year, and those results have been published here.

·      Almost all patients (89%) responded to treatment.

·      Responses continued to improve after the first year of combination treatment with 24/50 (48%) patients achieving uMRD in the bone marrow at month 26 compared to 20/50 (40%) at month 14.

·      After 3 years, responses to ibrutinib + venetoclax were sustained even though many patients had discontinued treatment due to achieving uMRD.

·      Patients who had not yet achieved uMRD by year 2 were allowed to extend combination treatment duration for and additional year.

·      While there was some benefit in year 3, most of the benefit occurs earlier on. This suggests that patients who respond probably only need a limited duration of therapy, and more is not necessarily better.

·      The response to treatment in the first 2-3 months seems to predict who will achieve uMRD. Thus, clinicians might want to alter the treatment plan if a patient doesn’t respond to ibrutinib + venetoclax early on.

 

Conclusions:

These results show that combination therapy with ibrutinib + venetoclax can produce deep remissions with eradication of MRD in many but not all patients with difficult to treat relapsed/refractory CLL. Thus far, these responses seem to be sustained even with planned treatment discontinuation once uMRD is achieved, and researchers continue to follow these patients.

 

The logical extension of this research is to see if ibrutinib + venetoclax can be used as a first line treatment. We know that the best responses are with first line treatment, and some phase II trials of ibrutinib + venetoclax as a first line treatment for CLL have shown promising results. However, phase II trials usually do not have a comparator group so the results can’t be directly compared to other treatments. To address this gap in knowledge, a large clinical trial is currently underway to test ibrutinib + venetoclax as a first line therapy vs. ibrutinib alone or FCR chemoimmunotherapy.

 

Please enjoy this brief interview with Dr. Hillmen from the virtual ASH meeting which was held December 2020.

 

<Video link> https://youtu.be/05oooiOKGDw 

 

You can read the actual abstract here: Continued Long Term Responses to Ibrutinib + Venetoclax Treatment for Relapsed/Refractory CLL in the Blood Cancer UK TAP Clarity Trial