In this video, Dr Wang discusses the use of LOXO-305, a highly selective BTK inhibitor, in patients with pretreated MCL, WM, and other NHLs.

Transcript

My name is Michael Wang, I am the Puddin Clarke Endowed Professor, at MD Anderson Cancer Center in the lymphoma service. It is my great pleasure to introduce to you our clinical trial on LOXO-305, the first-in-human, Phase 1 clinical trial in relapsed and non-Hodgkin lymphomas.

This clinical trial is the first-in-human trial with one of the most advanced BTK inhibitors, the third-generation BTK inhibitor. As we all know, the BTK is a very good target to treat B-cell lymphomas. Many inhibitors have been FDA approved including the first generation, ibrutinib, the second generation acalabrutinib, and zanubrutinib.

All the first and the second generation of BTK inhibitors are covalent or irreversible inhibitors of BTK. They all bind to the same C481 site pocket, where if one drug caused resistance, the other drug binding to the same pocket will also be resistant and not be able to overcome the drug resistance caused by the other, so we have cross-resistance among the three drugs that's FDA-approved for mantle cell lymphoma.

LOXO-305 is the new third-generation BTK inhibitor. In contrast to the first and second generation that is covalent, irreversible, the third-generation LOXO-305 is non-covalent binding and reversible, so just the opposite.

Theoretically, according to the in vitro laboratory data and in vivo animal data, we have evidence to show that LOXO-305 was able to overcome resistance caused by the first and the second-generation BTK inhibitors, both in cultured cells and in PDX models.

Carryall, the preclinical data, we translated that in the clinical trial, first in human. We treated 303 patients in the trial. The trial have roughly four cohorts. The CLL and SLL cohort is the largest cohort. We have three other cohorts including mantle cell lymphoma, Waldenstrom's, B-cell lymphomas, such as Richter's transformation, mantle cell lymphoma, marginal lymphoma, and large cell lymphoma.

The first cohort including CLL and SLL will be presented by my colleague, Dr. Anthony Mato, in another oral presentation. This one,I presented at ASH. 

I am in charge of presenting an oral presentation in the cohort including mantle cell lymphoma, Waldenstrom's, follicular lymphoma, Richter's transformation, marginal zone lymphoma, and diffuse large B-cell lymphoma.

First of all, the blog design is a part-three design with a Phase 1 cohort. After the Phase 1 expansion cohort, we added additional cohorts on mantle cell lymphoma, Waldenstrom's, and other lymphomas. Please remember, for the mantle cell lymphoma and Waldenstrom's lymphoma, the prior lines of therapy was three. These are first-line therapies for mantle cell lymphoma and in Waldenstrom's.

For the other lymphomas, including follicular, Richter's, marginal zone lymphoma and large-cell lymphoma, the primary prior lines of therapy was four. This is the first-line therapy for Richter's transformation, follicular, marginal and diffuse large B-cell lymphomas.

Please remember for both the mantle cell and the Waldenstrom's and other lymphomas, the patients are heavily pretreated. The drug is very well tolerated with the asking doses of LOXO-305 giving orally daily in 28, eight day cycles. We did not find any BOT.

We have to, according to the drug the plasma exposure of the IC90, we have to choose the optimal dosage as MTD for the next cohort, for the expansion cohorts and probably for three clinical trials in the near future.

At the dosage of 100 milligrams daily orally, the drug plasma exposure is very high. If we go lower 200 milligrams per day, we are afraid that we will be hitting a lot of off-kinase activities. So, we choose 200 milligrams daily for all the non-CLL and lymphoma cohorts -- again mantle, Waldenstrom's, follicular, Richter's, marginal and large-cell lymphomas.

The drug is very well tolerated. There is only a few phase three or four toxicities. The majority are grade one or two. Most common ones including fatigue, diarrhea and those are very commonly seen in BTK inhibitors.

Other BTK-inhibitor-induced side effects via the first and second generation BTK inhibitors including, bleeding, rash, atrial fibrillation, hemorrhage, infections, arthralgias are very rarely seen with LOXO-305.

Let's come to the most exciting part of the data is that the overall responses for mantle cell lymphoma at the first-line therapy with 93 of them already exposed to prior BTK inhibitors, the overall response rate by Lugano criteria is 52 percent.

Please remember, this include 93 percent of the population already exposed to prior BTK inhibitors. In our opinion, this is a very significant efficacy data, so ORR against the 50 percent, the CR 25 percent.

Please remember, those patients who received the prior BTK inhibitors, they only have around eight months of a time to live whatever therapy including tough chemotherapies we give them, their response does not exceed the 45 percent.

This single drug LOXO-305 cost a significant response of over 50 percent. This is a very significant. It's going to be leading practical changes in our way to manage mantle cell lymphoma patients post BTK inhibitors.

I also want to emphasize that two out of two patients who received the CAR T-Cell therapy for mantle cell lymphoma also responded to LOXO-305, indicating that LOXO-305 not only able to overcome BTK inhibitors from first and second generation BTK inhibitors, but also potentially useful in the post CAR T relapse patients.

Among the Waldenstrom's patients, 73 of them were already exposed or received prior BTK inhibitors as a fourth-line therapy with 73 percent received the BTK inhibitors. The response rate was 68 percent. This is very, very significant for Waldenstrom's.

Going on for the next therapies, the next cohort for the Non-Hodgkin lymphomas including Richter's, follicular, marginal and large-cell lymphoma, please remember, the prior lines of a therapy was four. Therefore, for those lymphomas, our therapy with LOXO-305 is the fifth line of therapy in which the overall response rate for Richter's transformation was 75 percent.

For follicular lymphoma, it was 50 percent, for marginal lymphoma, it was 22 percent, and for large-cell lymphoma as a fifth line of therapy the response rate is 24 percent. In my opinion, this is very, very significant data.

In conclusion, I must point out the limitations of this clinical trial. Data that we are presenting, the limitations that we have relatively shorter follow-up period. Our median follow-up period for all is about six months, but the data looks so good already. That's why we are presenting this.

I am very confident the responses shall be durable because many of my patients who received therapies more than a year is still reading response in my clinic where I treated many patients on this clinical trial.

In conclusion, the third generation BTK Inhibitor that is non-covalent reversible induced a high response rate that is potentially durable. The side effect profile is very durable. With only a few, three or four, severe toxicities.

I really think this agent is very promising.

It is going to change our practice if the longer follow-up hold could keep the high response rate and durability. In the real-world application is that we continue to improve on this protocol and planning for potential FDA approval and in which case it will be used in real world in patients with the relapse mantle cell lymphoma.