LOXO-305 is a “next-generation” investigational drug that demonstrates a high degree of selectivity for Bruton’s Tyrosine Kinase (BTK), a protein overexpressed by CLL cells.
Dr. Anthony R. Mato, M.D.,MSCE, the CLL Program Director at Memorial Sloan Kettering Comprehensive Cancer Center, presented results from the Phase I/II BRUIN study at ASH2020.
Background
Bruton’s Tyrosine Kinase inhibitor (BTKi) drugs such as ibrutinib (Imbruvica®) and acalabrutinib (Calquence®) have radically changed how we treat and control Chronic Lymphocytic Leukemia (CLL). These first and second-generation BTKi drugs bind covalently and irreversibly to BTK. BTK is part of a pathway that controls the b-cell antigen receptor (BCR) function, which is virtually the “business end” of mature b-cells. The BCR is the receptor that binds to pathogens such as bacteria and viruses that invade our bodies. When BCR binds to an antigen, a cascade of signals follows that promotes the cell’s prolonged survival. We now know that CLL cells ‘over-express” BTK resulting in their prolonged survival.
Currently available BTKi drugs approved for CLL (ibrutinib and acalabrutinib) fall into the category of irreversible agents. Irreversible means that when a molecule of these drugs binds to BTK, the BTK signaling protein is no longer functional. CLL cells will continue to produce BTK, which is why patients must take these drugs continuously. CLL cells with the BTK signal turned off no longer live for an extended time, and regular cell death occurs. In CLL, there is an “addiction” of the CLL cell to BTK. BTK does not appear to the same extent in non-CLL cells making the signaling inhibition of the BTKi rather specific to CLL and other b-cell malignancies.
Despite the dramatic efficacy of the covalent BTKi drugs, treatment failure can occur through the development of resistance or discontinuation for adverse events. Any patient can develop BTKi resistance; however, patients with higher-risk genomics have more of a tendency to mutate around BTK blockade and build resistance to the irreversible BTKi. These mutations result in changes to the BTK molecule that no longer allow the drug to bind to BTK, restoring the proliferation pathway.
At this point, the drug is no longer useful, and the patient may again begin to experience CLL symptoms. To understand how this mutation blocks the binding, you should consider that the binding site where the drug and protein meet as a lock and key. Only your key (medicine) will open your lock with (BTK). If the lock is changed (mutation), your key no longer works. Essentially the BTK protein develops a way to change the lock. The two most common mutations that result in BTKi resistance are (C481S) and PLCG2. C481S alone accounts for 50-60% of mutations, and many patients experience both C481S and PLCG2 simultaneously.
Reversible BTKi drugs, such as LOXO-305, ARQ531, and vecabrutinib, represent the next-generation BTK inhibitor, and were developed “pre-clinically” (animal trials) to take advantage of better pharmacokinetics {the formal study of the absorption, distribution, metabolism, and excretion (ADME) of medicinal products}. In particular, these drugs demonstrate longer “half-lives,” which means that these drugs stay in the body longer than the irreversible agents. These drugs can also move in and out of the “kinase pocket,” the site where binding occurs in CLL. Both LOXO-305 and ARQ531 continue to be studied; however, vecabrutinib did not show adequate efficacy to continue in clinical trials at this time.
Because LOXO-305 demonstrates a greater than 300-fold selectivity for BTK compared to the 370+ other kinases, it is currently the “most-selective” BTKi drug available either commercially or in a clinical trial. The hope is that this higher selectivity will translate into a lower incidence of side effects. Many adverse effects of ibrutinib and acalabrutinib result from the interaction of those drugs with other kinases. The phenomenon of the drug’s affinity to other kinases and the resulting side effects are known as “off-target” effects.
The two adjoining figures are known as kinome trees. Kinome trees graphically demonstrate the interaction of medicinal molecules with the family of kinases found in the human body. The larger the red dot, the higher the effect on that kinase. Fewer red dots indicate higher selectivity.
Notice the multiple red dots for ibrutinib on the left (above on mobile devices) that show it affects multiple kinases. It is the lack of selectivity of ibrutinib that is believed to be responsible for “off-target” adverse events.
LOXO-305 can affect other kinases but the affinity for BTK is so great that they cannot be shown graphically.
Do not compare the sizes of dots on these diagrams because they are from different sources.
Methods - BRUIN Phase I/II Study of LOXO-305 a Next-Generation BTK Inhibitor
BRUIN is a multicenter Phase I/II trial (NCT03740529) that enrolled patients with advanced b-cell malignancies. These patients have received at least two prior therapies and had active disease requiring treatment.
The median number of past systemic therapies was three for the group overall (range: 1-11). Patients who had prior BTKi use had a median of four prior therapies (1-11).
As with all Phase I trials, the primary goal is to determine the medication’s safety being tested and determine the dose for continuing phases of the study. The dosage for later trial phases is called the MTD/2P2D. The 2P2D dose is that dose that produces about 20% dose-limiting toxicities. In North America, the Maximum Tolerated Dose (MTD) is equal to the 2P2D dose, while in other parts of the world, the MTD is the next higher dose above 2P2D.
Assessment of Patient response occurred every eight weeks beginning after the end of the third 28-day cycle and then moved to every 12 weeks after cycle 13. “Efficacy Evaluable” Patients were those who underwent their first efficacy assessment (cycle 3) or who discontinued therapy.
The safety of LOXO-305 was assessed in all patients (CLL/SLL and Non-Hodgkins Lymphoma (NHL), n=186). The iwCLL (International Workshop on CLL) 2018 criteria was the standard used to measure response. Responses included: partial response (PR) and partial response with lymphocytosis (high lymphocyte count) (PR-L.)
Further, the group shows a significant presence of patients with high-risk characteristics shown in the lower chart above on the right.
Phase I of this trial was a standard 3+3 dose-escalation study that evaluated dosages from 25mg to 300mg. The graphic below illustrates how a 3+3 trial is structured. The dosage selected for Phase II and beyond was 200mg daily.
The graphic to the right (below on mobile devices) illustrates a 3+3 dose-escalation trial. DLT= dose limiting toxicity.
Results - BRUIN Phase I/II Study of LOXO-305 a Next-Generation BTK Inhibitor
Responses were seen in patients at even the initial dose of 25mg daily. The dosage selected for future studies (RP2D) was 200mg once daily.
The median follow-up time was six months for CLL/SLL patients and 6.7 months for those patients who responded to the drug. Among all CLL/SLL patients (as of 9/27/2020), the overall response rate was 63% and 67% among participants who had become resistant to a prior BTKi. Overall response improved over time with patients who had reached ten months of follow-up, showing an ORR of 84 percent (21/25).
As expected with BTK inhibitors, no patients experienced a complete response. Of note, in patients who harbored the BTK C481S mutation (n=24), the objective response rate was 71% compared to those without the modification at 61% (n=65). Researchers hope that this will potentially allow patients who fail a covalent BTKi due to the C481S mutation to continue with another BTKi and preserve other options for the future if and when needed. In patients with deletion 17p, a TP53 mutation, or both (n=28), the ORR was 79%. Also, overall response rates increased over time. The longest followed patient remains on LOXO-305 at 17.8 months.
The very best CLL Specialists are those who not only treat a large proportion of patients with Chronic Lymphocytic Leukemia (CLL) but those who engage in active clinical research, like Dr. Anthony MATO who represented 25 other practicing physicians in presenting this information at ASH2020.
Read our blog post “6 Reasons CLL Specialists Help Patients Live Longer.”
If you have previously used the e-mail opt-in to the left (above on mobile devices) to receive the CLL Pharmacist List of CLL Specialists, your old link will still bring you to the updated list or you can e-mail me at [email protected]
Conclusions - BRUIN Phase I/II Study of LOXO-305 a Next-Generation BTK Inhibitor
The data presented by Dr. Mato in the ASH2020 abstract 542 – LOXO-305, A Next Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated CLL/SLL: Results for the Phase I/II BRUIN Study is very encouraging.
Like all early clinical trials (Phase I or II), the numbers are small; however, the data on this next-generation BTKi show a consistent safety and efficacy profile.
BRUIN Study subjects are a heavily pre-treated population where therapy responses are often significantly lower than shown in this trial.
If this next-generation BTK inhibitor succeeds in the upcoming Phase III portion of the trial, it is possible that we may see a commercial product approved. Dr. Mato said, “We are increasingly in need of new therapies for patients that have been previously treated with a covalent BTK inhibitor, and LOXO-305 may allow us to continue treating patients in the same biologic class before attempting more complicated therapeutic approaches.”
This clinical trial is not randomized.
A phase III randomized trial BRUIN CLL-321 (NCT04666038) should begin in the first quarter of 2021. In this trial, patients will be randomized to receive LOXO-305 as continuous therapy or the investigator’s choice of idelalisib (Zydelig®)/rituximab (Idel/R) or bendamustine/rituximab BR. Investigator’s choice would occur if the patient is randomized to the non-LOXO arm of the trial, and the study doctor would choose the appropriate treatment. Both Idel/R and BR are considered standards of care for relapsed/refractory CLL.
Another phase III randomized trial BRUIN CLL-322 is planning to enroll patients in the second quarter of 2021. Patients in this trial will be randomized to LOXO-305 + venetoclax (Venclexta®) + rituximab or venetoclax + rituximab alone.
Sometime later, in 2021, an additional international Phase III comparing LOXO-305 to ibrutinib in treatment-naïve patients is expected.
The current BRUIN trial continues to recruit. To learn more about clinical trials in general, visit our partner CLL Society, Inc. HERE