In this video, a panel of experts from The University of Texas MD Anderson Cancer Center, Houston, discuss 4-year follow-up data from a phase 2 trial exploring combined ibrutinib and venetoclax for the first-line treatment of patients with chronic lymphocytic leukemia (CLL).

The discussion is moderated by Jan Burger, MD, PhD, who is joined by Nitin Jain, MD, and Alessandra Ferrajoli, MD. The results of this analysis were presented at the 2022 American Society of Hematology (ASH) Meeting.

Transcript:

Jan Burger: Welcome to Oncology Learning Network. My name is Jan Burger and I'm a professor of medicine in the department of leukemia at the University of Texas MD Anderson Cancer Center in Houston.  I will be moderating today's discussion on combination treatment with ibrutinib and venetoclax for CLL patients in the frontline disease setting. I am joined today by a distinguished panel of experts who have worked closely on the phase 2 trial exploring this combination. Dr. Nitin Jain recently presented 4 year follow-up data from this trial at the 2022 ASH annual meeting, and he is joined by Dr. Alessandra Ferrajoli, who has placed patients on this trial and is very familiar with the data as well. If we can take a moment now for each of you to introduce yourselves and tell us a little bit about your roles related to this study, and we'll start with Dr. Ferrajoli.

Alessandra Ferrajoli: Thank you, Dr. Burger. I'm Alessandra Ferrajoli. I'm a professor in the same department at the department of leukemia at the University of Texas MD Anderson Cancer Center. I have many years of experience in treatment of patients with CLL, and clinical investigation and clinical trials in patient with the CLL. I'm very excited about the results of this study. This is a study that was designed in our department. We all collaborated through not only the initial design of the study, but also further modification and development that we reviewed and used to optimize the result. I think this is particularly important to send the message out. This is not the only study in CLL of this combination, but it has some unique features in terms of its design. And I will now give over to Dr. Jain.

Jan Burger: Dr. Jain, could you please introduce yourself, and then could you please tell us a little bit about this study background and the rationale for doing this study?

Nitin Jain: Absolutely delighted to be here. And hello to everyone. Myself, I’m Nitin Jain. I'm associate professor in the department of leukemia at MD Anderson Cancer Center in Houston. I work closely with Dr. Ferrajoli and Dr. Burger in the leukemia department here. This study specifically we are talking about here is a combination of two drugs, ibrutinib plus venetoclax for patients with CLL. We designed this study back in 2013, 2014 timeframe, when the data was emerging about single agent activity of ibrutinib and venetoclax, and pre-clinical data emerging of synergy between these 2 drugs.

Therefore, at that time, we elected to combine these 2 oral drugs together as part of this clinical trial. This is an investigator-initiated clinical trial run at MD Anderson. We enrolled a total of 200 patients over a course of about 3 years, of which 120 were frontline patients and then 80 patients were relapsed/refractory CLL. At this ASH meeting just a few weeks ago, what we did was presented an updated follow-up data of these patients, 120 frontline patients, with a median follow-up of just over four years.

Jan Burger: Thank you so much Dr. Jain. Maybe we can discuss one point and I'll give that question to Dr. Ferrajoli. With the longer term follow-up data, can you tell us if this becomes available outside of clinical studies, what particular patients you think this combination treatment is well suited for?

Alessandra Ferrajoli: I would say that this combination treatment would be suited for the patient that you are approaching with a curative intent. By that I mean not patients where you are trying to palliate the disease, not patients that have a high level of comorbidities, not patients that have a compromised performance status. The interesting point of this trial are the fact that there is a finite duration of treatment for the patient that meets the milestone. The duration of treatment can be extended for the patient that we identify as requiring a little bit of further therapy to reach the negativity for minimal measurable residual disease in the bone marrow. I would say this is a treatment for a patient that you are approaching with a full treatment intent, for a patient with a maintained organ function.

They can be older. We really have seen very good tolerance even in older patients, but they do require close monitoring.They need to be close to our center, especially during the 5-week ramp-up of the venetoclax where we do the monitoring for the tumor lysis syndrome. Those patient needs to be followed up with very attentively in terms of any changes in those, or any need for support with growth factors. And of course they need to be very reliable in terms of communication and involvement in their own treatment. I do not see this being something that you will use in a very remote location, for example, or something that you would use for a patient that has difficulties in coming for visits at your center.

Jan Burger: Thank you so much. Dr. Jain, you mentioned that you presented the 4-year follow-up at the ASH meeting. Could you maybe highlight what the main message was, and could you put some emphasis on the high-risk patients?

Nitin Jain: Sure. Just to kind of briefly recap the study design. So what we did was that all patients starts with ibrutinib. And after 3 cycles of ibrutinib, so about 3 months, we start the ramp-up with venetoclax. Al patients then are planned to get 2 years, about 2 years of combination of both ibrutinib plus venetoclax. And at that time if the patient is bone marrow MRD-negative, at 10 to -4 sensitivity, then they basically stop with the drugs. If they were bone marrow MRD-positive, then they can continue the doublet of ibrutinib and venetoclax for the third year of the therapy. Everyone basically got 2 years of therapy, 2 years of combination therapy, and some patients received the third year of combination therapy.

When we looked at these 120 patients, we had seen bone marrow assessments on these patients during the study. So on an intent-to-treat analysis, as a best response, 72% of these 120 patients achieved bone marrow undetectable MRD at any time during the therapy course. And then, when we looked at the progression-free survival at 4 or 4 and a half-year mark of follow-up, the progression-free survival (PFS) was 94%. And then we looked at what predicts for progression. So we looked at the usual suspects, to say a 17p, p53 mutation [] gene. And at least in this analysis, and I think likely because we had very few progression events, none of these high risk-genomic factors... And more importantly, we had 27 patients with deletion 17p or p53 mutation or both in the study and their PFS was still upwards of around 90%, similar to non-p53 cohort. So the p53 mutated patients, with a caveat of small number of patients, are doing well in the study so far.

Jan Burger: Thank you so much. And another discussion point maybe for Dr. Ferrajoli. With this combination treatment possibly getting approved in the US—it's not approved yet, but it may become approved in the near future. Where do you see the challenges to implement that into a clinical practice, and how much do you think this is going to take over single-agent treatment with the BTK inhibitors or single-agent venetoclax, or venetoclax in combination with the CD20 antibodies?

Alessandra Ferrajoli: I see a couple of challenges. First of all, probably, there is going to be quite a bit of an uptake of the study, because this is not the only study that showed that this combination is a very effective combination and gives good long-term results. We know that there are other studies such as the CAPTIVATE study and other single-institution study that support this finding. And there is a true desire from both the oncologists and the patients in particular to receive defined treatment duration in CLL. I think the 2 challenges that I mentioned will be—one will be the cost. There is going to be the need for very detailed cost analysis that will likely show that a higher cost upfront by administering the combination for a certain amount of time is going to be, in the long--term, cheaper than using monotherapy for an extended period of time.

The second challenge will be that the compliance is really depending on the patient, whereas with intravenous agents such, for example, with the combination of venetoclax and obinutuzumab, the patient, yes, has to be very compliant with the venetoclax, but the obinutuzumab is administered by the physicians, so it's kind of under very good control and monitoring. And if the dose is missed, that dose, it's going to be noted that it's missed. Instead, this is kind of a new generation, a new way of treating oncological patients where there is going to be a lot of education that needs to take place on the use of combination therapies that are both oral, the importance of adherence to the schedule, the importance of good adherence, and also the management of side effects for patients that are on a treatment that is administered at home on a continuous base. Those are the 2 components that I think will have most of the challenges, will be the upfront cost that will need to be analyzed and explained. I suspect it's going to be favorable. And the second is the optimalization of the patient management, with 2 oral agents given concomitantly.

Jan Burger: Thank you both so much. If you both don't have any other aspects to highlight related to this, then I would close by saying thank you for taking the time. Thanks to our listeners for listening to this, and thank you to our Oncology Learning Network for organizing this discussion.

Source:

Jain N, Keating MJ, Thompson PA, et al. Combined Ibrutinib and Venetoclax for First-Line Treatment of Patients with Chronic Lymphocytic Leukemia (CLL): 4-Year Follow-up Data. Presented at the ASH Annual Meeting & Exposition; December 10-13, 2022; New Orleans, LA, and virtual. Abstract 95.