There is a new targeted drug in Clinical Trials that may offer a new treatment option for us CLLers—Nemtabrutinib.
For the entire article on this drug go to cancer.osu.edu and scroll down to “First in human trial of new drug raises hopes for patients with relapsed blood cancer” dated 11/06/2023.
The gist of the article is this. “Nemtabrutinib was designed to bind to BTK even in the presence of common mutations that make other BTK inhibitors stop working. It also binds to a number of proteins besides BTK that are important in B cell cancers”.
Number 5 on my list of BTKis, nemtabrutinib was previously known as ARQ 531 or MK1026. healthunlocked.com/cllsuppo... Importantly it's a non-covalent BTKi like pirtobrutinib, so as you pointed out, "Nemtabrutinib was designed to bind to BTK even in the presence of common mutations that make other (covalent) BTK inhibitors (e.g. acalabrutinib, ibrutinib or zanubrutinib) stop working"
The article Varney referenced is light on, noting only that "Nemtabrutinib was designed to bind to BTK even in the presence of common mutations that make other BTK inhibitors stop working. It also binds to a number of proteins besides BTK that are important in B cell cancers." The last sentence is intriguing and while there's much more technical detail in this ASH article ashpublications.org/blood/a... there's nothing to indicate that it might work after CLL becomes refractory to both covalent BTKi and the non-covalent BTKi pirtobrutinib.
and concluded "Nemtabrutinib shows promising antitumor activity and a manageable safety profile in highly relapsed/refractory patients with CLL / SLL. The hope is that noncovalent BTK inhibitors such as nemtabrutinib and pirtobrutinib will be able to rescue many but not all of those with double refractory disease (meaning they failed both a covalent BTK inhibitor and a BCL2 inhibitor). While noncovalent BTK inhibitors are probably not a curative, they may help stabilize disease, improve quality of life, and potentially serve as a bridge to other therapies."
There doesn't appear to be much in the way of opportunity for dose adjustment, but pleasingly, per the article Varney referenced , it's only "one pill of nemtabrutinib (65mg) every day".
Further to the excellent information you and SeymourB have provided, Neil, an ASH 2023 abstract provides some information about a Phase 3 trial (NCT05947851) of venetoclax + nemtabrutinib versus venetoclax + rituximab in relapsed/refractory CLL.
The clinicaltrials.gov search result using the link provided in SeymourB 's reply includes an entry for this trial that details site locations. Here is an excerpt from the ASH 2023 abstract:
"#3287 Bellwave-010: Phase 3, Open-Label, Randomized Study of Nemtabrutinib Plus Venetoclax Versus Venetoclax Plus Rituximab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Following at Least One Prior Therapy"
"Background: Venetoclax + rituximab (VR) is a standard therapy among patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who have relapsed after at least 1 line of prior therapy. However, there is an unmet need for more effective treatments. Bruton’s tyrosine kinase (BTK) is a critical signaling molecule in the pathogenesis of CLL, and inhibitors of BTK have resulted in significant improvements in survival for patients with CLL. Nemtabrutinib is a noncovalent, reversible, competitive inhibitor of BTK that does not require the C481 residue of BTK for binding and inhibition of kinase activity. As a result, nemtabrutinib can target both wild-type and C481-mutant forms of BTK. Results from the ongoing BELLWAVE-001 study have demonstrated manageable safety and durable antitumor activity of nemtabrutinib in patients with CLL/SLL with and without C481 mutations. The randomized, active-controlled, open-label, phase 3 BELLWAVE-010 study (NCT05947851) is designed to investigate the efficacy and safety of nemtabrutinib + venetoclax versus VR as second-line (2L) or later treatment for patients with relapsed/refractory (R/R) CLL/SLL."
Thank you for this info Varney , CLLerinOz , AussieNeil & SeymourB . I missed this post a couple months ago and am catching up. Today, my CLL specialist brought up the possibility of the Bellwave-010 trial as an option. (To recap from above: it's a randomized trial of venetoclax + nemtabrutinib vs venetoclax + rituximab in relapsed/refractory CLL)
My doc has been discussing V+O for the past year, but when I mentioned that I'm starting to navigate Medicare pricing plans for next year, he brought up this trial as an option. ClinicalTrials.gov doesn't list Oregon as a location, but he says they'll be offering it. clinicaltrials.gov/search?c... As I get closer to treatment, I'll get an updated FISH test to see if I qualify.
It comes down to this complicated issue: having done a clinical trial in 2015/16, I learned that the study did not pay for the required CT scans (2), bone marrow biopsies (2), many extra blood labs, & prophylactic drugs like steroids & allopurinol, etc.. (My insurance paid for most of it, but several cohort members in the study were not so lucky.) I'm all for scientific research, but at this point, I'm looking for the most cost-effective treatment. If I end up in the VR arm (venetoclax + rituximab, both of which are already FDA approved), would my out of pocket co-pays be less outside the study (with Medicare during 2024)? Even if it's a wash, do I really want more CT scan radiation and BMBs if I can avoid them?
Lastly, if V+R or V+O do turn out to be the most cost-effective tx for now, would it be better to save BTKi options for for later?
Varney, my apologies for hijacking your post. Perhaps this should be a separate post. But there is a wealth of great info about nemtabrutinib shared here that I thought it might make more sense within this context.
Thank you all for any thoughts. Also Happy New Year!
It depends on the study, exactly what is paid. The last trial I did, even the office visit $50 copay I usually pay was covered by the trial. They paid CT copays, most everything.
The Clinical Trial Coordinator for the practice will know or be able to obtain, what your part to pay is, for any study. It did seem I paid more before Medicare. But that could simply be the other study offered to pay less. A good study coordinator will be hooked into the "free or reduced cost drug" resources. Mine told me (when I was considering ULTRA-V) one of the first things she does is look at drug costs for the patients, and secure funding if possible. Before I had Medicare, the specialty pharmacy did all the initial work finding copay funding. So you probably would not have to navigate this yourself.
There isn't anywhere near enough data at this point in time to state "which will definitely be most cost effective" IMO. If you can't tolerate a treatment and have to switch, you have to switch! Your insurance can estimate any costs associated with routine V&R. Ask what their policy regarding Medicare approved clinical trials is.
My understanding of the current protocols and recommendations, is that overall a series of time limited treatments will be the most cost effective for a patient. As opposed to continuous therapy. With the new NGS testing, it seems to me the profession is looking to tamp the disease down quickly but long enough to definitely get uMRD, then give a patient a "drug holiday" where their system gets a break from the immune suppressing and other side effects. Then the same treatment may be considered, if the patient wishes. Resistance risk is low with time limited treatments, and making sure patients actually are uMRD (instead of some protocol stating X amount of time) will make sure no one is discontinued before remission is reached. But some here haven't reached uMRD, or they need continuous treatment, their doc has them on continuous BTK or venetoclax. No way to know ahead of time if this will apply to you.
I'll mention I went off venetoclax after 2 years even though I still had low level disease, 12 cells per million. That number did not change from year 1 to year 2. My partial remission has lasted about a year, my count is still technically uMRD4 but the CLL has started growing. It's slowed down compared to other times I "came out of remission", so we'll see if I can wait 2 or more years before needing to treat again. I probably will ask for a repeat of venetoclax, since I had very few side effects. If I can go 2 hears on, 2 or more off, that's very desirable for me/my variant!
IDK if your plan has outpatient infusion/clinic fees as a straight copay, or percentage. There should not be a "drug copay" on an infusion or injectable medication administered in a clinic or hospital. Outpatient infusions are usually billed similarly to inpatient infusions, the drug is a line item on the total bill, with you being responsible for some copay or percentage. The specific coverage of your particular plan will dictate if each drug item administered technically as an outpatient, even though it must be done in an infusion center or clinic, is covered. Copays generally don't apply to these types of meds.
I think that trial admins need to address all the billing much more up front. I, too, experienced trouble on my trial at M.D.Anderson. They said that my insurance would cover everything, but they failed to note that my insurance was out of network, and covered only 60% instead of 80%. At least they didn't force the balance billing on me. The testing before the official beginning of the trial was also not covered by my Out of Network Exception. So I like to remind them every chance I get that I am underwriting this trial, and I kid them about stock options and mentions in the study papers.
As far as the BTKi vs BCL2, now or later, I haven't seen where one is inherently better than the other. Much has to do with duration. I think getting BTKi+BCL2 over a long time would build less resistance that BTKi or BCL2 alone over the same duration. But I don't know how long is long. I only know that in my trial, I'm only doing 13 cycles of BTKi+BCL2 and 6 cycles of Obinutuzumab, and resistance is not expected to develop at all. I have the sense that the 2 durations we commonly see for venetoclax - 13 cycles vs 26 cycles (1 vs 2 years) were chosen with resistance in mind. But I can't point to a clear statement that says so.
Another issue that's barely been researched is non-covalent BTKi before covalent-BTKi as far as resistance goes. There seems to be much more attention to covalent first, because so many people have already been treated with it. But I have a list of papers on this, since I am on a treatment naive non-covalent BTKi (pirtobrutinib).
I would want the researchers to answer, "Based on your current understanding of current therapies, what are my choices of therapies after this trial?"
Important thing is that they are trying to stay one step ahead of this disease giving us hopefully longer and longer remissions and options. The ultimate will be to repair the chromosomal abnormalities so may be no drugs are involved at all.
I don't know that repair of chromosome or gene abnormalities will ever be possible because there's so many different ones, and they have to be both detected and repaired.
So while waiting for that, I hope to see therapies that somehow focus only on detecting the CLL cells, and not all B-cells.
The problem till now is that the outer markers of CLL cells are complex combinations. An monoclonal, multispecific antibody that could simultaneously bind CD5, CD19, and CD23 (bare minimum CLL markers) plus CD3 (T-cell) or CD56 (NK cell) or some other NK cell surface molecule might be nice.
First in human trial of new drug raises hopes for patients with relapsed blood cancer
NOVEMBER 6, 2023
"The study found more than 75% of the patients with relapsed CLL responded to the drug, at an optimal dose of 65mg. These included patients who had mutations in BTK. Most patients remained cancer free for at least 16 months during the trial. While all patients experienced some side effects—which is common with chemotherapeutic drugs—many of these were minor and manageable, proving that the drug was also very safe."
Some earlier articles refered to initial results of the BELLWAVE trial, which I think were preliminary, and from a small group. There are multiple BELLWAVE trials.
Efficacy and Safety of Nemtabrutinib, a Wild-Type and C481S-Mutated Bruton Tyrosine Kinase Inhibitor for B-Cell Malignancies: Updated Analysis of the Open-Label Phase 1/2 Dose-Expansion Bellwave-001 Study
Blood (2022) 140 (Supplement 1): 7004–7006.
The article below cites the 2022 Blood article in regards to Nemtabrutinib:
Next-Generation Sequencing—Optimal Sequencing of Therapies in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)
Curr Oncol Rep. 2023; 25(10): 1181–1189.
re: Pirtobrutinib:
"ORR was 82.2% for all 247 patients and 79.0 % for double-exposed patients (n=100, inhibitors of both BTK and BCL2) when PR with lymphocytosis was included. With a median follow-up of 19.4 months, median PFS was 19.6 months for the entire cohort, 16.8 months for double-exposed patients, and 13.8 months for those who had been treated with CIT, BTKI and inhibitors of BCL2 and PI3K. ORR and PFS estimates appeared independent from BTK C481 mutation status and 56% of patients with a PLCG2 mutation achieved a response. Eighteen-month OS was 80.5% for the entire cohort at a median follow-up of 22.6 months."
re: Nemtabrutinib:
"With a relatively short follow up of 8.1 months ORR was 56% and estimated median duration of response was 24.4 months. ... Longer follow-up and increased patient numbers are needed to better define the role of nemtabrutinib next to pirtobrutinib."
I think the comparing ORR is often misleading, because it allows PR (partial remission) with more than one symptom to out of remission - it makes the drug look better than it is. Most of us really want CR (complete remission), but may take a PR if it stays stable. I was uMRD6 ( <1 CLL cell out of 1 million WBC's) at end of Cycle 7 (of 13 planned cycles), but was in PR due to a single node still being 1.5cm. I won't have another CT to check that node till end of Cycle 13.
I would like to see more work done on analyzing WHO does better on which drug. What is in the person's inherited genetics, case history, and markers that might let us pick or choose between multiple options? We need more univariate analysis, I think. Of course, such analysis requires adequate numbers of patients to make the stats meaningful. But we could have done that by now with the older BTKi's, and possibly saved many people some trouble.
ClinicalTrials.gov has 7 trials listed for Nemtabrutinib as of today (Nov. 8, 2023:
Interesting, because I was on an ARQ531 trial for a little over a year, so is this an improved ARQ and then renamed? When I was on it, my numbers went down very very slowly, never reaching normal numbers after a year. Then I had to go off it for 2 weeks due to high lipase and during that break my numbers started shooting up. Due to this it was decided to move on to V and O which has me in CR now and may get to go off it next May after 2 years.
Interesting. I know nothing about this drug other than the article I forwarded from OSU. It is in Clinical Trial so maybe their expectations of the drug will exceed its performance, but I guess that is why you have trials. Wishing you the best.
Content on HealthUnlocked does not replace the relationship between you and doctors or other healthcare professionals nor the advice you receive from them.
Never delay seeking advice or dialling emergency services because of something that you have read on HealthUnlocked.
New Years Good News
New Dana Farber Research 
Time-Limited Triplet Emerges as a Potential Standard in Relapsed/Refractory CLL
New Clinical Trial of Ibrutinib + Venetoclax for people relapsing on Ibrutinib 
Ibrutinib denied to new patients
