August 2015, Vol 4, No 4

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Challenges in Treating Multiple Myeloma and the Impact of New Oral Oncolytics

Interview with the Innovators

An Interview with Dixie-Lee Esseltine, MD, and George Mulligan, PhD, of Takeda Pharmaceuticals

Multiple myeloma (MM) is a difficult cancer to treat as it is heterogeneous in nature. Each line of therapy pre­sents many choices for physicians and their patients, making it challenging to know which treatment is best for that particular patient. However, having “too many” choices may ultimately be a good problem to have, and research is under way to provide answers for those in this community in need of direction. The current era in MM might be seen as the beginning of a “golden age” of sorts for those in MM research and drug development, with new options for patients on the horizon. In this interview, we focus on the challenges within the different lines of therapy for patients with MM and an investigational oral oncolytic from Takeda Pharmaceuticals, ixazomib, which is the first oral proteasome inhibitor to enter phase 3 clinical trials. Earlier this year, Takeda announced that, in the first interim analysis of the phase 3 study of oral ixazomib in patients with relapsed or refractory MM, it met the primary end point of improvement in progression-free survival. At the recent American Society of Clinical Oncology Annual Meeting, the publishers of Personalized Medicine in Oncology (PMO) had the pleasure of meeting with 2 experts in the field, Drs Dixie-Lee Esseltine and George Mulligan of Takeda Pharmaceuticals, to discuss the landscape of care for patients with MM, including challenges at all stages and what the future of care might hold. What follows is our insightful exchange.
PMO Thank you very much for meeting with us today. To begin, can you describe the challenges in the current standard of care for patients with multiple myeloma in the frontline therapy setting? Dr Esseltine One of the biggest challenges for any line of treatment is that there is no one treatment that’s curative. In fact, we’re probably only getting close to extending survival in a fraction of patients. There are still a large number of patients for whom the available treatments are not curative, but the frontline setting is where we have the best chance to characterize the myeloma. Another challenge is the effective dissemination of knowledge from the academic centers into the community centers, where many patients are still treated. It’s this kind of communication, collaboration, and openness with data that I think we’re just on the brink of executing effectively. Dr Mulligan There’s a great deal of innovative research that is leading the way toward combining our standard-of-care drugs that currently exist with new approaches that will better take into consideration the patients’ biology and then begin to develop therapies that are appropriately tailored to that population. The CoMMpass registry study, which is led by the Multiple Myeloma Research Foundation [MMRF] in conjunction with a pharma-academic-patient advocacy alliance, is one of the innovative studies leading the way in that space. This study is clearly focused on the cure, but it has also made progress in the last few years to bring people together and present the science that uncovers the biology that is critical in the disease. PMO In your opinion, what are some of the therapeutic challenges encountered in the relapse setting? Dr Esseltine Currently, we have more medicines to choose from, especially in the relapse setting, and more clinical trials available to patients, so our challenge is to determine the best fit for each patient. The disease is heterogeneous, so even though you have relapsed or refractory disease, you’re very different from somebody else in that same general category. We still have to categorize the tumor, consider comorbidities and side-effect profiles, and determine the patient’s goals for their treatment before selecting the treatment course. We have to remember that this disease is still not curable. I do think that we have more options for long-term benefit in the relapse setting, but we definitely need newer medicines as well. Dr Mulligan In the relapse setting in particular, there are so many options. One of the major challenges is to get people into studies, preferably studies that have relevant research around the patient’s biology, which will begin to sort out and compare the various treatment options. Because there are currently so many options, there may not be as many patients enrolling in studies as we would like in order to answer these questions expeditiously. But it’s still critical to answer them with the right study end points. PMO Can you speak to considerations or challenges presented in the maintenance setting? Dr Esseltine Maintenance presents unique challenges in that we’re only recently appreciating its value in multiple myeloma. We’ve got a lot of work to do in this setting; determine where therapy is best suited for individual patients, what is the most appropriate drug, as well as the most appropriate duration. Dr Mulligan The maintenance setting offers opportunities for important research. Dr Esseltine highlighted the important question of duration of therapy. In that setting, one of the key aspects is understanding how much disease burden there is and whether patients are benefiting from that longer?term therapy. Is the disease being held at a very low level? Is it undetectable? There are several related clinical questions; how long to treat the patient, or if disease appears to be emerging, do you change the course of therapy at that subclinical detection of the disease? These issues need to be addressed through clinical studies. There are also technical aspects to consider related to minimal residual disease. There’s a case for flow cytometry being a key measurement to detect residual cells and find tumor burden. In the past few years, there have been other options, including next-generation sequencing–based detection of tumor that appears extremely sensitive and quite specific, and may, over time, compete with or supersede flow cytometry. Dr Esseltine I think the FDA in particular is really interested in looking at this issue more closely. Whether it will be a regulatory end point in the next few years is yet to be seen, but I’m hoping we’re moving in that direction. For us, we’re excited because we have incorporated all of this into our trials. Our challenge as a company is to develop new medicines in anticipation of what’s going to be proven and validated in 5 or 7 years when your trial comes to fruition. We’re also excited that we have the ability to formulate more medicines that are oral, even subQ, which are more convenient for patients. That’s an important factor in maintenance. There are a number of things to think about when you start committing a patient to long term therapy. What are the long-term side effects and consequences? For the first time ever we’re thinking about having prolonged treatment with a proteasome inhibitor, and that has really never been done. PMO Please provide a brief overview of ixazomib, the dosing schedule, the clinical trials that are ongoing, and the indications that are being studied. Dr Esseltine Ixazomib is a proteasome inhibitor. It is a dipeptide boronate, but it has a different structure from Velcade. It also differs from Velcade in its dissociation rate. It binds the beta 5 constituent of the proteasome, and that’s what really knocks out the proteasome activity. This occurs quickly, providing a fast dissociation from the beta 5 and into the tissues where it’s really needed. I’d also like to speak about our late-stage, phase 3 trials program. These patients are on the trial whether they’re on treatment or not, they’re in long-term follow-up. We have our largest phase 3, the TOURMALINE MM1, with about 722 patients with relapsed and refractory multiple myeloma who are treated with ixazomib plus lenalidomide and dexamethasone versus a placebo plus lenalidomide and dexamethasone. This was a double-blind randomized study, with the primary end point being progression-free survival. It’s under review right now because in February we announced that it met our primary end point. We’ll be submitting that package to the health authorities globally. The second trial uses a similar treatment, ixazomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone, but in frontline, newly diagnosed patients. There is somewhat of an abbreviated duration of treatment; patients aren’t treated entirely to progression. That trial will conclude enrollment in the next couple of years. Then we’re also looking at the maintenance setting in 2 trials with ixazomib against placebo; both are randomized, double-blind studies. MM3 is the posttransplant study. MM4 includes elderly patients receiving any kind of induction therapy, and then that’s followed by a randomization to placebo or ixazomib. Then, of course, it would be natural that we go into amyloidosis, and we have a phase 3 trial in amyloidosis where we’re looking at the relapse setting in very advanced patients. We’re looking at ixazomib as a single agent with dexamethasone versus a physician’s choice of about 5 different regimens. Of course, there’s nothing approved, so these are regimens that are not available worldwide. We are also looking at other possible indications; we’re looking at lymphoma and subsets of solid tumors. PMO Where do you see ixazomib fitting into the treatment regimen for patients upon approval and beyond? Dr Esseltine It’s going to fit wherever the proteasome inhibitors fit. We’re fortunate to have a number of new drugs from our company and other companies that we hope are really going to make a difference in the choices that we have. But I expect ixazomib to be part of the backbone of treatment with the IMiDs [immunomodulatory drugs], so that’s how we’re initially studying it. Dr Mulligan That’s part of our clinical program. Then we’re also trying to sort out the role in the lymphoma space, where clearly in mantle-cell lymphoma in particular, proteasome inhibition is part of the core therapy. Dr Esseltine There may be characteristics of the drug that fit certain settings better than others, because it is oral, and depending on the side-effect profile could be used more chronically. But we’ll have to see if the data support that. PMO What do you anticipate being the top differentiating factor of ixazomib in comparison with current oral oncolytic therapies on the market? Dr Esseltine Of course, the data will have to emerge, but our aspiration is that this oral medicine will be well tolerated to allow patients to take it chronically for prolonged periods of time, changing the paradigm by allowing patients to have good quality of life. Dr Mulligan It’s also worth mentioning that proteasome inhibitors generally have shown great combinability with other drugs. We would expect that to be the case for ixazomib going forward. Dr Esseltine That’s a really good point, because ixazomib will definitely be used in combination if it is approved. Dr Mulligan That’s going to improve the outcomes for patients, a combination therapy that they can stay on with a reasonable quality of life to get the maximum benefit. Dr Esseltine Yes, you may get better compliance, and that’s critical. PMO What challenges do you see for patients as more and more oral oncolytics are developed? Dr Esseltine It’s challenging for patients to understand the nature of their disease and determine their aspirations of what might be the best treatment for them to get the best long?term results. I believe it is challenging for patients when faced with a number of different therapies that appear similar in nature given the fact they’re all oral. They’ll need an understanding from their doctors of the factors that should go into the treatment decision. The MMRF started the CoMMpass study, through which patients have come to better understand their disease and available treatment options that are specific for their type of disease. Dr Mulligan When we think about the challenges and observe the ways in which the field is evolving, there may be changes coming. Maybe we will get away from oral versus IV or combining based on overlapping toxicities and develop a new paradigm where we’re trying to combine active agents and also trying to understand the biology of the patient and that of the tumor. We can begin to think about inhibiting and selecting combinations rationally, going after the top survival or proliferation pathways in these tumors. Then maybe combining that with an agent that inhibits the top resistance mechanism that we’ve learned about by studying our patients, I think that may be the future of choosing combinations rather than the orals combined with orals or IV or toxicities. That information will ultimately lead to the best outcomes for individual patients. PMO What types of resources does Takeda offer to assist patients? Dr Esseltine The aspiration of Takeda is to cure cancer. It defines what we do at every level within the company. And certainly a pillar within that goal is to emphasize the role of the patient. We have a very active, strong patient advocacy group, and we have a commitment to external partnerships with advocacy groups and cooperative groups for further study. We have other research collaborations as well. We obtain external input from all stakeholders to make our research more meaningful and relevant as we go forward. It’s a commitment, a passion, a focus, and it is revered at the highest levels within Takeda. Dr Mulligan That commitment and those resources include being a partner in changing the outcome of this disease and ultimately getting to a cure, because we know that’s going to require partnerships with academia and pharma. We alluded earlier to the CoMMpass study, which brought together all of those players to improve outcomes. We’ll do patient-centric research throughout our clinical development program, whether it be the induction setting in the frontline, relapsed disease, or maintenance setting. Those are key opportunities to understand our patients. By way of example, the maintenance setting provides an opportunity to understand individual patients who may or may not be sensitive to the single agent that they’re taking. Some of the biomarker research that’s ongoing is sometimes confounded by patients getting triplets or doublets of particular agents. It would be important to understand in maintenance whether some of the biomarkers that may associate with those particular agents are relevant, especially if someone is going to stay on 1 drug for many months. We’re including those kinds of questions in our studies and cooperative work in global research. Dr Esseltine Yes, to your point, we have put resources toward studying those issues in some of the exploratory end points, and that’s a source of pride for us. We’re trying to develop a medicine that’s going to help patients, but we’re also contributing to the field. PMO Can you discuss the importance of learning from the contributions of others in cancer research? Dr Mulligan There is so much commonality across so many different tumor types, so many interlinking pathways between various solid tumors. Researchers are uncovering more and more links to similar pathways that span hematologic and solid tumors. Myeloma has already been in the lead with some of the first full genome sequencing that was published 4 years ago. Those pathways included some interesting B-cell biology, aberrations in p53, and other pathways. The MAP-kinase pathway is critically important in multiple myeloma, and we learned about it first in solid tumors. When you think about it, sometimes it’s a solid tumor pathway. Those interlocking pathways actually are potential opportunities to better understand this disease and cancer generally. PMO What types of patient management challenges do you see for healthcare practitioners as more and more oral oncolytics are developed? Dr Esseltine We have more and more oral medicines, so eventually we won’t consider the route of administration as much as we consider the effectiveness of that medicine to provide prolonged progression-free survival and how much of a burden it puts on patients in terms of serious side effects. The biggest challenge is always going to be choosing the right drugs for that patient’s tumor and individual circumstance. Dr Mulligan There will be a real emphasis on sharing information, learning from the many trials that are out there, and understanding the balance of information that’s emerging across similar trials. People have to sort out the efficacy, the toxicity, the comparability across these agents, in order to make an informed choice. That’s going to be a major complexity. It’s going to be important to have well-designed studies that can give those who are treating patients each day the most meaningful information, whether it be the depth of response or the toxicity profiles, that enables them to make a plan with their patients. Dr Esseltine The long-term follow-up is important, because right now we’re struggling to find short-term end points that predict long-term benefit. Right now, we’re in a position of committing patients in our studies to long-term follow-up, whereby we follow them over the course of 5 years as closely as we do in the early years. Dr Mulligan We have to understand the key subgroups, including the biologically driven subgroups as well as high-risk groups such as the frail and elderly. These are populations that may have different outcomes in these studies. We’re going to have to identify enough of those groups to conduct meaningful subanalyses. This research really helps clinicians and patients to make informed decisions. Dr Esseltine We’re going to find new subgroups. We probably won’t see blockbuster drugs for cancers with high incidence rates but rather drugs for cancers that are broken down into small subsets of patients that we really know a lot about and can more precisely treat. Dr Mulligan That’s both a challenge and an opportunity. A challenge for the doctor day?to?day, but an opportunity for the community to begin to study those and take from other cancers and learn for that particular patient. PMO What is the position of payers and/or practice managers as more oncolytics come into the market? Dr Esseltine They’re looking for value, and in this circumstance, value is defined by survival and progression-free survival. Payers will have to decide on the appropriate level of evidence, how good it is, and how it supports one drug versus another. Or is it just going to be decided based on the costs? Are you just going to get the cheapest one? I don’t think so. They’ll have to make evidence-based decisions, and we have to provide the data if we truly believe we’re the best treatment for the patients. Dr Mulligan The value piece and the length of the studies speak to a better understanding of the high-risk subgroups who typically have such poor outcomes. We can now begin to understand how they are doing, specifically, and whether they are an indicator of the value that can come from a therapy. PMO How will the launch of ixazomib impact Takeda’s approach to multiple myeloma care and other cancer types? Dr Esseltine It’s been great for us to work from the solid foundation we have built in our understanding of this disease over the past 15 or 20 years. With the launch of ixazomib, we’ll be stimulated and inspired again to continue the advances. We’ve made some progress in this disease so far, and some of it has been beneficial to patients. We see ourselves continuing and maybe even doing more than what we’ve been able to do. We know so much more now. We have tremendous experience. We have tremendous research within our own shop, and we also have tremendous collaborations. The world is much more open. There’s more sharing of data. All of this is just going to push us forward perhaps faster, and it’s something I look forward to being a part of, because I think we’re going to see a lot of changes, a lot of positive changes for patients. Dr Mulligan We’re going to build upon the success that we’re approaching right now. We’re a patient-centered company. We’re driven by the science. We’ll keep the patient at the center of our clinical research, our lab research, our patient advocacy. That will lead to additional scientific opportunities to better understand the variety of cancers that might benefit from this sort of an agent, either alone or in combination, with an approach that’s histology based or biomarker based. These are all ways that I think the success of any one drug feeds into a cycle of research that should deliver value beyond the group that we first approach. We can do that in a rational way. We’re certainly inspired by the concept of taking a new drug and suddenly finding out where else it applies. It’s exponentially changing the ways we develop cancer medicines. It’s an incredible time to be involved in this kind of science to improve the lives of patients. Dr Esseltine We have a global scope with the company being represented in close to 90 countries. We can reach more people with that capability, but there are still underserved populations. Those are other things we can work on just to refine the whole aspect of access to care as well. We’ve got a lot of work to do, and we’re ready to take it on.
Dr Esseltine is Vice President of Oncology Clinical Research, at Takeda Cambridge US. Dr Mulligan is Senior Director of Translational Medicine at Takeda Pharmaceuticals.
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