Cellectar Biosciences, Inc. (CLRB) Earnings Call Transcript & Summary

Good morning, and welcome to Cellectar Biosciences conference call with Dr. Yair Levy to discuss his perspective as the community-based hematologists on the top-line results of Cellectar's CLOVER-WaM pivotal study that were released last week Monday. Today's call is being recorded. Before we begin, I would like to remind everyone that statements made during this call relating to Cellectar's expected future performance, future business prospects or future events or plans are forward-looking statements as defined under the Private Securities Litigation Reform Act of 1995. Although the company believes that the expectations reflected in such forward-looking statements are based upon reasonable assumptions, actual outcomes and results are subject to risks and uncertainties that could differ materially from those forecast due to the impact of many factors beyond the control of Cellectar. The company assumes no obligation to update or supplement any forward-looking statements, whether as a result of new information, future events or otherwise. Participants are directed to the cautionary note set forth in today's press release, which is available on the Investor Relations portion of company's website as well as the risk factors set forth in Cellectar's annual reports filed with the SEC for factors that could cause actual results to differ materially from those anticipated in the forward-looking statements. Now I would like to turn the call over to Jim Caruso, President and Chief Executive Officer of Cellectar.

Thank you, operator. Good morning, and welcome, everyone. Last week, we announced the full enrollment of the CLOVER-WaM study and reported the exciting top-line results from our pivotal study evaluating iopofosine i-131 and relapsed or refractory Waldenstrom's macroglobulinemia or WM. As previously stated, we believe our pivotal study patient population is the most challenging composition of WM patients ever evaluated in a clinical study. As reported, CLOVER-WaM represents as far as we are aware, the largest study to date in relapsed or refractory WM patients, post BTKi therapy and the most refractory WM population ever tested in a clinical study. This assessment was agreed upon by top WM [ thought ] leadership at a recent advisory board commenced to review the CLOVER-WaM top-line data. Patients received a median of 4 prior lines of therapy with a range of 2 through 14. 90% were refractory to either a BTKi or a CD20 antibody, 50% were refractory to BTKis, 40% were refractory to rituximab and 27% for dual class refractory to BTKi and CD20 antibodies. In addition, approximately 30% represented mid-88 wild-type -- a genotype with a high resistance profile to BTKis. Despite this extremely challenging patient population, iopofosine i-131 achieved a 75.6% overall response rate and a 61% major response rate, which clearly exceeded the study's major response rate, statistical significance hurdle and primary endpoint of 20%. In addition, 100% of evaluable patients achieved disease control, experiencing a meaningful reduction in base IgM. Based on the biological nature of WM, iopofosine i-131's mechanism of action and demonstrated CLOVER-WaM efficacy results. We may see further improvement in the major response rate as well as the depth of these responses. To elaborate, patients experienced improved results over time. In fact, it was more than a 2x increase in the major response rates for the first 25 patients with additional follow-up between 3 and 6 months, with 18 out of the 25 patients or 72% achieving a major response. With at least 55% of the WM population being treated in the community setting, predominantly in highly organized integrated delivery networks such as Texas Oncology. We determined that it would be helpful to provide access to additional insights from the community treatment perspective versus the academic setting. To this end, we appreciate Dr. Levy's willingness to further review iopofosine's positive pivotal data and provide his perspective on its potential role in the treatment of WM patients in the community. Prior to Dr. Levy's review, Shane Lea, our Chief Commercial Officer, will provide a brief WM market assessment -- our COO, Jarrod Longcor, will discuss the next steps in the regulatory process and our commercial readiness for our manufacturing and distribution network and Dr. Andrei Shustov, our Senior Vice President and Medical Lead, will introduce Dr. Levy. I will now transition to Shane Lea for his overview of the WM landscape and patient journey. Shane?

Thank you, Jim. They are focusing positive top-line results from the CLOVER-WaM pivotal study was prominently featured in more than 20 publications. This includes coverage in major oncology and life sciences outlets included targeted oncology, cancer network, of live, cure and scrip, which helped to optimize awareness for iopofosine's impressive data in WM. The top-line data was also highly regarded by WM experts based on the impressive responses demonstrated in a heavily pretreated population. As previously stated, we believe these data highlight the unique benefits iopofosine provides for patients. In fact, our physician market research clearly identifies the need for a new mechanism of action, a fixed course of therapy and improved efficacy as the most desired product attributes for the management of WM patients. We are confident that iopopasine can address these desired attributes with a potential FDA approval in relapsed/refractory WM by delivering a much needed new mechanism of action demonstrating breadth of patient responses, deep durable responses and a short fixed course of therapy. Importantly, physicians who participated in the study were able to appreciate these key attributes in the associated impact in a heavily pretreated patient population. There are approximately 26,000 patients living with WM in the United States. Approximately 10,000 plus are relapsed or refractory, and 4,300 patients represent the third line and beyond. The annual third-line incidence is nearly 1,000 patients and 55% of all prevalent patients are managed in the community setting. There is no current standard of care in relapsed/refractory setting. Therefore, patients have limited treatment options comprised of unapproved therapies. Consequently, our market research show that many patients are treated with the same class of drugs across multiple lines of therapy. This likely means patients are required to be on continuous therapy must take additional visits to the clinic either for our treatment, blood draws or monitoring management of drug adverse events. This creates complex treatment challenges and financial burden for patients, predominantly because of the limited treatment options, there are approximately 1,000 third-line patients currently not receiving any therapy who are eligible for treatment. To date, there is no published study in a late line of dual refractory to both BTKis and anti-CD20 antibodies, a review of real-world clinical data beyond second-line treatment in the community indicates a major response rate range of 4% to 12%, which highlights the need for new therapies that provide better responses for patients. We believe iopofosine has the potential to become a new standard of care. We continue to advance our commercial strategy for iopofosine to ensure a successful launch, assuming FDA approval. Our data supports the concentrated and highly scalable nature of the WM market in the U.S. In fact, approximately 80% of WM patients reside within 15 states and 70% of patients are treated within 10% of all accounts. This patient concentration supports a targeted and efficient resource allocation to drive iopofosine use and adoption and capture the WM opportunity. To this end, our plans include establishing collaborations with large oncology community networks. We recently announced our collaboration with the American Oncology Network in addition to our previously announced partnership with Florida Cancer Specialists. These 2 organizations alone combined to treat nearly 2,000 WM patients. We look forward to highlighting additional details regarding our commercialization readiness and overall progress as we advance our strategic plan. I will now turn the call over to Jarrod Longcor to highlight our production capabilities and regulatory pathway. Jarrod?

Thank you, Shane. As many of you know, radiotherapeutic manufacturing that provides a consistent uninterrupted supply of targeted radio therapeutics has proven to be challenging. For this reason, we determined that a different strategic approach to solve the issue was required. Unlike other radiopharmaceutical drug companies, we have developed and refined our manufacturing supply chain and logistics network to provide seamless and secure access to iopofosine without the tens of millions of dollars of required investment for infrastructure along with the associated financial burden of maintaining those facilities. We have established a multi-source supply chain network that allows overlapping redundancy from select -- our selected CDMOs from isotope to finished product -- these strategies allow us to provide secure global supply with secondary supply optionality in the event of a condition impacting 1 of our contractors. In addition to this approach, providing the comfort of delivering required patient doses as planned, we have also created an extended treatment window for both patient and physician convenience. For any number of reasons, patients or physicians may be required to reschedule the planned treatment delaying dosing for a number of days. For most radio therapies, the delay would require a new dose to be provided creating a significant treatment delay. In the case of iopofosine i-131, our proprietary drug formulation creates the first ever essentially off-the-shelf product with a potential -- potentially radiopharmaceutical industry-leading 17-plus day shelf -- this provides dosing flexibility that is currently not available with targeted radiotherapies. Additionally, iopofosine is shipped and stored at room temperature as a fully finished ready-to-use product that arrives at the treatment center with no on-site compounding required. Our distribution, logistics and are designed to ensure transport and arrival to all treatment centers in under 72 hours anywhere in the world. This feature will allow clinical centers to have at least 14 days to schedule and the flexibility to reschedule the patient's treatment if needed. With a robust manufacturing and supply chain established, our near-term goal is to continue to closely collaborate with the FDA and EMA to bring iopofosine to WM patients in both the United States and Europe as rapidly as possible. To that end, we plan to complete our NDA filing and submit to the FDA for approval in the second half of this year. And in parallel, leverage our prime designation work with the EMA or EMA to bring iopofosine to Europe as soon as possible. Based on iopofosine WM Fast Track and Orphan Drug designations, we have engaged the FDA in regular discussions that have provided clear and helpful guidance on information and requirements necessary for the submission. We have been very pleased with the nature of these discussions and the ongoing collaboration with the agency and are working diligently to ensure our submission for iopofosine addresses all agencies requested elements. Assuming the priority review associated with the Fast Track designation is accepted, we would expect an approximate 6-month review period date of submission for our NDA. With that, I will now turn the call over to Dr. Shustov. Andrei?

Thank you, Jarrod. As my colleagues already stated, we are very excited with top-line results from our CLOVER-WaM study. The efficacy and safety profile of iopofosine i-131 in a heavily pretreated elderly patient population with highly refractory disease are impressive and possibly treatment paradigm shifting. Beyond 2 lines of therapy, treatment options and their clinical benefits are limited. In addition, current treatment approaches commit most WM patients to long-term or continuous therapy to maintain disease control without meaningful disease-modifying effect and perpetual toxicity with no or very limited treatment-free intervals. We believe that iopofosine's limited duration therapy, favorable toxicity profile, meaningful durability of response and prolonged freedom from therapy, may provide a novel treatment option to patients in high need. As Shane mentioned earlier, over half of all prevalent WM patients are managed in a community setting. Therefore, to appreciate the community physicians perspective, and reaction to CLOVER-WaM results. It is my great pleasure to introduce Dr. Yair Levy from Texas Oncology Networks, one of the largest community cancer care organizations in the U.S. Dr. Levy possesses a unique background with experience in both the community and academic setting. He's a hematologic oncologists with over 15 years of community oncology experience. He is also an Associate Professor of Medicine, at Texas A&M HSC College of Medicine and Director of Hematologic Malignancies research at Baylor University Medical Center in Dallas, Texas, and he is an author in over 50 publications in the field of hematologic malignancies. He obtained his medical degree from University of Wisconsin and completed from University of Wisconsin and completed oncology fellowship at John Hopkins University. Dr. Levy practices at Texas Oncology network with his primary office in Dallas, Texas. Texas Oncology encompasses over 280 locations in the state with approximately 1,200 WM patients currently under care. Dr. Levy?

Thank you, Andrei, and thanks for the team for inviting me to participate in this call. Let me start with a review of the study design and patient enrollment criteria before moving to a review of the top-line results. So the CLOVER-WaM pivotal trial is a global open-label, single-arm study examining iopofosine iodine-131 in relapse and refractory Waldenstrom's macroglobulinemia patients, who require therapy due to symptomatic disease progression. Patients enrolled in the trial had to have histologically and serologically confirmed Waldenstrom's macroglobulinemia. An ECOG performance status of 0, 1 or 2 and have received at least 2 prior lines of a standard of care therapy, including our Bruton tyrosine kinase inhibitor. Note that the study also included Waldenstrom's patients with central nervous system involvement also known as Bing Neel syndrome. Given the ability of iopofosine iodine-131 to cross the blood-brain barrier. Additionally, included were patients with lymphoplasmacytic lymphoma, establishing CLOVER-WaM as the first study to address these high-need populations. Patients were dosed in 2 cycles. The first cycle occurring on days 1 and day 15 and the second cycles on day 57 and day 71 from the study entry, respectively. The primary endpoint of the trial was a major response rate, which is defined as a partial response or better. A partial response is defined as a 50% or more reduction in the disease biological marker, which is IgM. Key secondary endpoints included a duration of response, progression-free survival and treatment-free survival. So the study protocol target is 50 patients in the modified intent-to-treat population and top-line data was reported on 41 evaluable patients meeting protocol criteria for efficacy assessment at the data cutoff date of January 3, 2024 and having sufficient follow-up after the last administered dose to enable the development of therapeutic effect. Median age was 71 years old with the oldest enrolled patient 88 years old. And patients in the trial received a median of 4 prior lines of therapy. So this is now fifth-line therapy with a range of from 2 to 14 prior lines, nearly 90% of the evaluable patients who are refractory to either rituximab or a Bruton tyrosine kinase inhibitor. 27% were dual class refractory to both a CD20 monoclonal antibody as well as a Bruton tyrosine kinase inhibitor. 80% of patients were previously treated with a Bruton tyrosine kinase inhibitor of whom 50% were refractory to the BTKi. 91% of patients were exposed to rituximab of whom 40% were refractory. This represents the most refractory Waldenstrom's macroglobulinemia patient population reported in clinical trials. Let me also note that nearly half of the patients in the CLOVER-WaM study were considered either moderate or high risk based on IPSS Waldenstrom's macroglobulinemia score, which is a recognized negative prognostic factor for both progression-free and overall survival in Waldenstrom's macroglobulinemia. Furthermore, nearly 30% of study patients were found to have a wild-type MYD88 gene, which is a known genomic factor conferring less response to Bruton tyrosine kinase inhibitor therapy. So the study achieved its primary endpoint with a major response rate of 61%, with that 95% confidence interval ranging from 44% to 75%. The overall response rate was 75.6% and disease control rate was 100%. It's important to point out that attainment of complete remission, complete response in 8% of patients is impressive and is rarely reported in relapsed and refractory Waldenstrom's macroglobulinemia with any patients. So the review of individual responses is very instructive and provides further details of iopofosine iodine-131 potent activity in this patient population. First, the attainment of a complete remission in 3 patients is very impressive and rarely if ever reported in trials of patients with relapsed or refractory Waldenstrom's macroglobulinemia. You'll note that 3 additional patients achieved a very good partial remission or near complete remission. And with additional follow-up time might improve their responses from a VGPR to a CR, therefore increasing the CR rate. Every individual bar is facing down on this waterfall plot indicating tumor volume reduction and disease control rate of a 100% in this patient population. Based on the biology of Waldenstrom's macroglobulinemia, iopofosine iodine-131 mechanism of action and the current CLOVER-WaM efficacy results. We expect to see further improvement in the major response rate as well as the depth of these responses. To elaborate, among the first 25 consecutively enrolled patients in the study the major response rates at 3 and 6 months were 28% and 72%, respectively. This is a 2.6x increase in these response rates with additional follow-up after completion of therapy. The corresponding overall response rate at 3 and 6 months were 64% and 88% respectively, a 37% relative increase with additional follow-up, but not additional treatment. So the Kaplan-Meier analysis utilized 30 evaluable patients with responses and responses were durable with a median duration of response not yet reached at a median follow-up of 8 months with maximum ongoing responses continuing beyond 30 months. The confidence interval predicts for a median duration of response of no less than 11.4 months in these multi-class refractory patients -- so iopofosine iodine-131 was well tolerated with a safety profile consistent with previously reported data. As anticipated, in heavily pretreated elderly population, the most common treatment-related adverse events of grade 3 or higher that occurred in more than 10% of patients were hematologic in nature and included thrombocytopenia in 55% and neutropenia in 37% and anemia in 26%. These cytopenias were predictable, manageable and all of the patients recovered from treatment emergent cytopenias. Importantly, there were no treatment discontinuations due to drug-related AEs. There were no treatment-related deaths, and there were no clinically significant or life-threatening bleeding events. So in summary, iopofosine iodine-131 demonstrated an impressive and potent activity in a highly refractory heavily pretreated patient population and possesses an ability to become a paradigm-shifting treatment options for these patients with a high unmet need for novel therapies. Notably, the duration of response currently demonstrated in the CLOVER-WaM study is approximately double of what we would have expected in patients with a similar profile. Based on available data, the responses are likely to improve over time in terms of the rate and depth of responses. The attainment and maintenance of complete remissions or complete responses after completion of therapy in this patient population is unprecedented and speaks towards a disease-modifying quality of iopofosine. Additionally, the safety profile was quite impressive for both the age of the patients enrolled and the amount of prior therapies that they have also received. I would have expected more adverse events and more grade 3 plus cytopenias. If I were giving these patients any of the non-approved salvage therapies that are currently available in this disease stated to them. And I'll conclude with this. From the perspective of community oncology physicians, I would particularly emphasize the key advantages of iopofosine for Waldenstrom's macroglobulinemia patients, for which the overwhelming majority of them are elderly. So based on the experience of our practice, iopofosine is easy to handle and administer. The extended half-life allows for scheduling flexibility and extra accommodations for patients and physicians needs in terms of scheduling, even patients who live many miles away from treatment centers and who are at risk for travel delays and cancellations are not at risk of missing doses. Our patients particularly appreciated the limited and fixed duration of therapy, resulting in a positive impact of quality of life. Patients and physicians truly appreciate having effective treatment options with a novel and unique mechanism of action. And there's truly a paradigm shift from just "keeping disease stable or under control with continuous therapy to disease-modifying agents that have limited duration of therapy and a long time off of therapy without disease progressing." There's also an additional benefit of not having required dosimetry. There's no need for specific inpatient isolation compared to earlier generations of radio therapeutics. Having said all that, it's now my pleasure to return the call to Jim Caruso.

Thank you, Dr. Levy. Let's now transition to the Q&A portion of today's program. Operator?

Thank you. [Operator Instructions] Our first question comes from Jonathan Aschoff from ROTH MKM.

And what are the drugs used in the continuous drug regimen for these refractory patients? And would you just necessarily switch them right over from that continuous therapy to 131? Or would you need some specific reason to do that?

Thank you for your question, much appreciate it. We'll turn that -- we'll transition over to Dr. Levy to manage that.

No, absolutely. So in terms of a continuous treatment paradigm, the one that is most frequently used and used per the FDA label is in the class of drugs called Bruton tyrosine kinase inhibitors for which there are currently 2 drugs approved. The first one was a drug called ibrutinib or Imbruvica that was approved either as a monotherapy or in combination with the CD20 monoclonal antibody. And these drugs are typically given -- and the second one, of course, is zanubrutinib or Brukinsa. And these drugs are typically given until progression or intolerance. So as long as we're seeing that they're receiving clinical therapeutic benefit from getting the drug and they're tolerating the drug, these drugs are continued. Now in terms of another drug that can be used in a continuous modality, the other one that we sometimes use as a drug called venetoclax, but that is an off-label use of a drug and certainly is not seen being used very much in the management of this disease. And while you certainly could stop the therapy and switch over to iopofosine. Most physicians, as long as somebody is responding and tolerating a Bruton tyrosine kinase inhibitor would actually keep that therapy going?

Regarding liquid tumor patients outside of WM, do you believe that the existing data, particularly outside of this data set, support iopofosine use in other cancers? And if yes, which liquid tumors?

Well, so I mean, again, certainly, there is a lot of preclinical and also some clinical rationale for the use in other disease. And this is certainly a very intriguing platform in terms of therapeutic delivery. But I think that most of the data that we have is in Waldenstrom. So I can certainly say that I'd be very encouraged about particular platform and delivery model for use in other cancers as well. But I think the most robust data that we have currently is in Waldenstroms. This is a very nice proof of concept for this delivery vehicle.

Why don't we have -- Andrei, would you like to provide some further clarity about our thoughts relative to our existing data sets beyond WM and perhaps some future perspective on the potential clinical development of the asset.

Sure. Jim, as stated just a minute ago, our most advanced data naturally is in Waldenstrom’s macroglobulinemia with recently released results. Having said that, as we previously reported, CLOVER-WaM study has emerged from a broader basket trial or Phase IIa study that enrolled patients with numerous lymphoid malignancies and plasma cell malignancies, including multiple myeloma and variety of non-Hodgkin lymphomas. We have previously reported our activity in highly refractory multiple myeloma, including post-BCMA therapy, very impressive as well as results in non-Hodgkin lymphoma, including those with central nervous system involvement. So if you think about the broad if not uniform distribution of the target for our platform, Lipid Rafts. We can virtually target any tumor because it's a very basic mechanism for tumor survival and then pair this with a specific payload. So our programs that are currently running those, again, in additional varieties of non-Hodgkin lymphomas, multiple myeloma, and it certainly makes sense to target diseases related to WM or indolent lymphomas such as, say, marginal zone, mantle zone and potentially others. So we have really high interest in advancing and expanding iopofosine use in hematologic malignancies, and we'll be proceeding in that direction.

And my last question is more for management. What price do you think the U.S. market would support for this drug? Are you seeking an EU partner? And have you received the $44 million?

It sounds like there was -- the last question included 3 separate questions, Jonathan, very clever. Why don't we have Shane address your question relative to general thoughts relative to the pricing piece.

Yes. Very good every important question. I think as we're continuing to evaluate the market opportunities, certainly, looking at the capabilities that iopofosine provides and understanding the dynamics of the market from a value perspective, especially related to other products and continuous therapies total cost of therapies with some of these continuous products could be as high as $1 million. Obviously, we believe with iopofosine's profile, we have the opportunity here for orphan drug pricing. But we're going to continue to do the research on our end to ensure that we're providing the right price, the right value based on the novel mechanism of action and the ability to address unmet need in this high and mid market.

All right. And then we'll have Jarrod address our ex U.S. co-promotion thinking.

Yes. We're giving us all a chance to answer your question. So yes, we are engaged in a number of dialogues for, as Jim alluded to, ex U.S. co-promotion collaboration -- as it currently sits and as you -- as Shane just alluded to, obviously, in the U.S., we're looking to promote this on our own. But Ex U.S. we are in a deeper discussions with various partners for different territorial control.

And then relative to the tranche A $44 million, the conversions are ongoing, and we fully expect to secure the entire $44 million no later than Tuesday of next week. They are ongoing. Obviously, I will make this comment, regardless of the external constituent, the data has been viewed very, very positively.

Our next question comes from Jeff Jones from Oppenheimer.

A couple of them not surprisingly. I guess first off to Dr. Levy, can you speak to some of the logistics of implementing a product like this in your practice of targeted radiopharmaceuticals using i-131 things like the license disposal shielding the level of complexity of implementing that in practice in some of the key barriers?

No, absolutely. So I think that's a wonderful question, especially given the previous history of Zevalin and Bexxar in the hematologic treatment realm. For radio therapeutics. But I should say that there are several, obviously, key differences. So those 2 products that I previously mentioned were ones that were approved in indolent non-Hodgkin's lymphomas and did not you get much uptake from the market despite reasonable efficacy. And one of the main reasons is we did have other therapeutic alternatives, if that medical oncologists were able to use. And here in -- especially in these patients that we treated with Waldenstroms on the study, there were no other readily available therapeutic options and certainly not ones with anywhere near the efficacy that we have seen so far in this study. Now in terms of logistics, so this drug does require either a nuclear medicine or radiation oncology for administration, but there are currently, a lot of products on the market that utilize this radioactive payload. So this is not a payload that physicians are uncomfortable with. Furthermore, just about every medical oncologist, in the United States has a working relationship with radiation oncology is oftentimes dual treatment modalities are required in the treatment of various malignancies. So I can tell you that in our own experience, the logistics have not been difficult at all and actually quite favored by patients. And we had this trial open here in Dallas and Texas Oncology is obviously a very large network of physicians that encompass the whole great state of Texas. And as you know, Texas is a pretty big state with 2 time zones. So we were able to even get the patients from as far as El Paso to come and they stayed locally, while they were receiving their treatment, and then we're actually able to go back to their referring physicians. So obviously, with commercial approval of the product, this can be given by almost every nuclear medicine or radiation oncologists in the country and certainly would not require somebody traveling such a distance, but even if that was required, it was still logistically very easy and feasible to do. And I think the other really neat aspect of this therapeutic is not just the fixed duration of therapy, which obviously patients and payers both favor. Patients favor it because of time off therapy and time off therapy allows you to get back to what we call a more normal existence. And obviously, payers like fixed duration of therapy because it limits their exposure to additional cost of therapeutics and cost of therapeutics usually tend to be lower for fixed duration of therapy as opposed to indefinite therapy. But the side effect profile in our experience was also quite good with patients having predictable and delayed cytopenias, meaning lower blood counts. But if you take a look also at physician comfort with adverse reactions as well as patient comfort with adverse reactions. Physicians are very comfortable managing cytopenias. And patients usually do not feel bad with cytopenias. It just sometimes requires transfusional support and/or what's called growth factor support, so medicines to help make the accounts come back faster. And if their white count comes low, we also sometimes will place them on some antibiotics to try to prevent infections as well. But logistically, this has been a very easy therapeutic to give.

Really appreciate that detail. Could you speak a little more to the issue of BTKi tolerability and what might impact sort of patient decision-making between the transition from a BTKi to iopofosine?

Absolutely. So I mean -- so first of all, we should say that not every patient will do well with Bruton tyrosine kinase inhibition. They've certainly been a godsend in this disease because, again, it's an effective, well-tolerated therapy for most, but not for all. And the issue is what do you do when somebody progresses because it's clearly not curative therapy. So it's not only that we'll have people switch from a Bruton tyrosine kinase inhibitor because of progression, but sometimes it will also switch for intolerance. Remember, these are drugs that you're taking indefinitely for a prolonged period of time. and despite the fact that these drugs are so much better tolerated than traditional cytotoxic chemotherapy, there are sometimes these nagging adverse reactions that can occur with the drug both in the short and the long term.