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Venetoclax + Obinutuzumab: Impact on CLL Management

Panelists: Ian W. Flinn, MD, PhD, Sarah Cannon Research Institute; Matthew S. Davids, MD, MMSc, Center for Chronic Lymphocytic Leukemia at Dana-Farber Cancer Institute; Brad Kahl, MD, Washington University School of Medicine; John Pagel, MD, PhD, Swedish Cancer Institute
Published: Wednesday, Jul 31, 2019



Transcript: 

Ian W. Flinn, MD, PhD: You brought up an important topic. Let’s get into it. It’s a good segue. There were the CLL14 data, the German CLL Study Group data that were presented at ASCO [the American Society of Clinical Oncology annual meeting]. It’s been published now. We’ve seen it at meetings such as here in Lugano. It’s examining that whole question of time-limited therapy. This was a study where patients with comorbidities or decreased renal function were randomized to receive obinutuzumab and chlorambucil versus venetoclax and obinutuzumab, and we saw really impressive deep MRD [minimal residual disease]-negative states in the patients who were randomized to the venetoclax arm. What’s your take on that data? I’m very impressed by it.

Matthew S. Davids, MD, MMSc: This is a very important study. Previously in our discussion, we’ve been talking about this dichotomy where we have to choose between time-limited chemotherapy-based approaches or novel agent-based approaches where we have to do continuous therapy. This regimen of venetoclax plus obinutuzumab is sort of the best of both worlds. It’s novel agent-only and it’s time-limited. All the patients were given 1 year total of therapy—6 months of the combination of VEN/OBIN [venetoclax/obinutuzumab], then 6 of venetoclax, and then all patients stopped therapy. Certainly, we saw very high response rates, around 85%, with about half of patients achieving complete remission. There were bone marrow MRD rates of around 57%, and peripheral blood even higher than that, and that was in an intent-to-treat analysis where a lot of samples were missed. Actually, the true rate of MRD was probably even higher than that.

This is an important study because it gives a new option for frontline therapy for our CLL [chronic lymphocytic leukemia] patients that’s time-limited and novel agent-based. Unfortunately, this study doesn’t compare to ibrutinib, so that remains the open question of which strategy is better. Now, we have IV [intravenous] also, so there are still a lot of unanswered questions. CLL14 is certainly a very nice first step toward developing novel agent-based, time-limited therapy. The key is whether this is going to be a durable enough response. If you do a year of time-limited therapy and 6 months later, everyone is progressing, that’s not going to be feasible.

The follow-up remains relatively short on CLL14. It’s a 28-month median follow-up time right now. What has been impressive so far is that at the median time, about 88% of patients are still progression-free, and that’s a year or more after stopping therapy. There does seem to be some durability of this time-limited therapy, particularly for those patients who don’t have deletion 17p or TP53 mutation. Unfortunately, we have started to see some progression events for those high-risk patients already, which is a little bit worrisome. One year of time-limited therapy with [venetoclax/obinutuzumab] is probably not going to be sufficient for those patients.

Ian W. Flinn, MD, PhD: There was a lot of discussion in the meeting about that specific subgroup. Now thankfully, it’s only about 5% to 10% of patients in the frontline setting, but more follow-up is going to be needed. John, does this change your discussion with patients? Are you having that discussion, saying, “You can get venetoclax.” Brad was talking about the advantages of time-limited therapy,  chemotherapy. The good thing is, you’re off. You don’t have to be on this forever. This is a more targeted approach to time-limited therapy to begin with. Has this changed how you’re talking with your patients in frontline choices?

John Pagel, MD, PhD: It certainly does. I think in the right patient, the idea of being able to stop treatment is very important. We need that with ibrutinib/venetoclax, as well. We have a little bit of data about that emerging. In this setting, I think a year of therapy in many patients who don’t have high-risk features is very reasonable. The other important thing is, it gives us another option in the front line. Not everybody is an appropriate candidate for a BTK [Bruton tyrosine kinase] inhibitor. There are people with underlying structural heart disease where you might be a little more concerned about atrial fibrillation, or people who are on anticoagulants. In particular, there are a large number of people who are on warfarin, as an example, and we shouldn’t be giving BTK inhibitors to those patients. It gives us an option, especially in an older patient population where they have a lot of comorbidities. It does change the conversation. I think it’s an important conversation to have with a patient around time-limited therapy, but also in trying to figure out what the right agent is based on their comorbidities.

Ian W. Flinn, MD, PhD: Brad, how do you think about sequencing these? The good news is, we’ve got many different options now. The bad news is, we’ve got many different options, and it’s hard to know what the right order is, right?

Brad Kahl, MD: Yes. It’s a good problem to have—all these good options. It’s amazing how fast the field has emerged. Earlier, I mentioned this conversation that I have with patients about FCR [fludarabine/cyclophosphamide/rituximab] versus ibrutinib or BR [bendamustine/rituximab] versus ibrutinib. Honestly, that conversation completely changed as of about a month ago when we got the FDA approval of venetoclax/obinutuzumab. Now, you have this third option, which is very attractive—targeted therapy, no chemotherapy, time-limited. I just saw a 52-year-old woman in clinic 2 weeks ago. She’s had CLL for a few years. Her disease is getting to be very advanced. She’s getting very close to the time where she needs treatment, and I was able to talk to her about this brand new option of venetoclax/obinutuzumab.

For me, it’s an extremely attractive option, and I see that being, until more data emerge, my go-to regimen, except in, perhaps, these very high-risk patients for whom I’m uncomfortable giving 1 year of therapy and then stopping, like a 17p-deleted patient, for example. It’s important for people to remember we’re talking about progression-free survival differences by and large between all these regimens, and it’s very unusual for any of these things to have an overall survival difference. Imagine that you give venetoclax/obinutuzumab and achieve a 3- or 4-year remission. That’s 2 or 3 years that your patient was able to be off all therapy. When their disease starts to recur, you often do not have to start treatment right away, and when you do need to go to second-line treatment, you could come in with ibrutinib at that point. Even if venetoclax/obinutuzumab ends up being a little inferior to ibrutinib as a frontline option, that isn’t necessarily a reason not to use it, if we’re just talking about small progression-free survival differences. I’m a big believer in giving patients a break from therapy whenever possible, and that’s one of the reasons I really like this new option.

Ian W. Flinn, MD, PhD: Yes, I think it is an important option. You briefly touched on the 3-drug regimens, but there’s a lot more to learn about those and whether we can get patients into such a deep remission that it prolongs progression-free and overall survival along the line. There have always been concerns since the early days of the fludarabine studies about using all your eggs in 1 setting, or whether you should try to sequence them. I don’t think we have data today to know that, but it’s an age-old question.

Transcript Edited for Clarity
 

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Transcript: 

Ian W. Flinn, MD, PhD: You brought up an important topic. Let’s get into it. It’s a good segue. There were the CLL14 data, the German CLL Study Group data that were presented at ASCO [the American Society of Clinical Oncology annual meeting]. It’s been published now. We’ve seen it at meetings such as here in Lugano. It’s examining that whole question of time-limited therapy. This was a study where patients with comorbidities or decreased renal function were randomized to receive obinutuzumab and chlorambucil versus venetoclax and obinutuzumab, and we saw really impressive deep MRD [minimal residual disease]-negative states in the patients who were randomized to the venetoclax arm. What’s your take on that data? I’m very impressed by it.

Matthew S. Davids, MD, MMSc: This is a very important study. Previously in our discussion, we’ve been talking about this dichotomy where we have to choose between time-limited chemotherapy-based approaches or novel agent-based approaches where we have to do continuous therapy. This regimen of venetoclax plus obinutuzumab is sort of the best of both worlds. It’s novel agent-only and it’s time-limited. All the patients were given 1 year total of therapy—6 months of the combination of VEN/OBIN [venetoclax/obinutuzumab], then 6 of venetoclax, and then all patients stopped therapy. Certainly, we saw very high response rates, around 85%, with about half of patients achieving complete remission. There were bone marrow MRD rates of around 57%, and peripheral blood even higher than that, and that was in an intent-to-treat analysis where a lot of samples were missed. Actually, the true rate of MRD was probably even higher than that.

This is an important study because it gives a new option for frontline therapy for our CLL [chronic lymphocytic leukemia] patients that’s time-limited and novel agent-based. Unfortunately, this study doesn’t compare to ibrutinib, so that remains the open question of which strategy is better. Now, we have IV [intravenous] also, so there are still a lot of unanswered questions. CLL14 is certainly a very nice first step toward developing novel agent-based, time-limited therapy. The key is whether this is going to be a durable enough response. If you do a year of time-limited therapy and 6 months later, everyone is progressing, that’s not going to be feasible.

The follow-up remains relatively short on CLL14. It’s a 28-month median follow-up time right now. What has been impressive so far is that at the median time, about 88% of patients are still progression-free, and that’s a year or more after stopping therapy. There does seem to be some durability of this time-limited therapy, particularly for those patients who don’t have deletion 17p or TP53 mutation. Unfortunately, we have started to see some progression events for those high-risk patients already, which is a little bit worrisome. One year of time-limited therapy with [venetoclax/obinutuzumab] is probably not going to be sufficient for those patients.

Ian W. Flinn, MD, PhD: There was a lot of discussion in the meeting about that specific subgroup. Now thankfully, it’s only about 5% to 10% of patients in the frontline setting, but more follow-up is going to be needed. John, does this change your discussion with patients? Are you having that discussion, saying, “You can get venetoclax.” Brad was talking about the advantages of time-limited therapy,  chemotherapy. The good thing is, you’re off. You don’t have to be on this forever. This is a more targeted approach to time-limited therapy to begin with. Has this changed how you’re talking with your patients in frontline choices?

John Pagel, MD, PhD: It certainly does. I think in the right patient, the idea of being able to stop treatment is very important. We need that with ibrutinib/venetoclax, as well. We have a little bit of data about that emerging. In this setting, I think a year of therapy in many patients who don’t have high-risk features is very reasonable. The other important thing is, it gives us another option in the front line. Not everybody is an appropriate candidate for a BTK [Bruton tyrosine kinase] inhibitor. There are people with underlying structural heart disease where you might be a little more concerned about atrial fibrillation, or people who are on anticoagulants. In particular, there are a large number of people who are on warfarin, as an example, and we shouldn’t be giving BTK inhibitors to those patients. It gives us an option, especially in an older patient population where they have a lot of comorbidities. It does change the conversation. I think it’s an important conversation to have with a patient around time-limited therapy, but also in trying to figure out what the right agent is based on their comorbidities.

Ian W. Flinn, MD, PhD: Brad, how do you think about sequencing these? The good news is, we’ve got many different options now. The bad news is, we’ve got many different options, and it’s hard to know what the right order is, right?

Brad Kahl, MD: Yes. It’s a good problem to have—all these good options. It’s amazing how fast the field has emerged. Earlier, I mentioned this conversation that I have with patients about FCR [fludarabine/cyclophosphamide/rituximab] versus ibrutinib or BR [bendamustine/rituximab] versus ibrutinib. Honestly, that conversation completely changed as of about a month ago when we got the FDA approval of venetoclax/obinutuzumab. Now, you have this third option, which is very attractive—targeted therapy, no chemotherapy, time-limited. I just saw a 52-year-old woman in clinic 2 weeks ago. She’s had CLL for a few years. Her disease is getting to be very advanced. She’s getting very close to the time where she needs treatment, and I was able to talk to her about this brand new option of venetoclax/obinutuzumab.

For me, it’s an extremely attractive option, and I see that being, until more data emerge, my go-to regimen, except in, perhaps, these very high-risk patients for whom I’m uncomfortable giving 1 year of therapy and then stopping, like a 17p-deleted patient, for example. It’s important for people to remember we’re talking about progression-free survival differences by and large between all these regimens, and it’s very unusual for any of these things to have an overall survival difference. Imagine that you give venetoclax/obinutuzumab and achieve a 3- or 4-year remission. That’s 2 or 3 years that your patient was able to be off all therapy. When their disease starts to recur, you often do not have to start treatment right away, and when you do need to go to second-line treatment, you could come in with ibrutinib at that point. Even if venetoclax/obinutuzumab ends up being a little inferior to ibrutinib as a frontline option, that isn’t necessarily a reason not to use it, if we’re just talking about small progression-free survival differences. I’m a big believer in giving patients a break from therapy whenever possible, and that’s one of the reasons I really like this new option.

Ian W. Flinn, MD, PhD: Yes, I think it is an important option. You briefly touched on the 3-drug regimens, but there’s a lot more to learn about those and whether we can get patients into such a deep remission that it prolongs progression-free and overall survival along the line. There have always been concerns since the early days of the fludarabine studies about using all your eggs in 1 setting, or whether you should try to sequence them. I don’t think we have data today to know that, but it’s an age-old question.

Transcript Edited for Clarity
 
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