Breaking Down the Expanded Approval of a CLL Treatment

In this podcast, Andree Amelsberg, vice president of US Medical Affairs Oncology and Hematology at Janssen, and Danelle James, Imbruvica clinical science lead at Pharmacyclics LLC, an AbbVie company, discuss the recent expanded approval of Imbruvica (ibrutinib) plus rituximab for the treatment of CLL, and provide various real-world applications of this approval in clinical practice.

Podcast transcript:

Julie Gould:  Welcome back to Pop Health Perspectives, a conversation with the Population Health Learning Network where we combine expert commentary and exclusive insight into key issues in population health management and more.

Today we're joined by Andree Amelsberg, vice president of US Medical Affairs Oncology and Hematology at Janssen, and Danelle James, Imbruvica Clinical Science Lead at Pharmacyclics LLC, an AbbVie company. They discuss the recent approval of ibrutinib plus rituximab for the treatment of CLL and highlight why this approval is so important.

Andree Amelsberg:  My name is Andree Amelsberg. I'm the Head of US Medical Affairs for Oncology and Hematology at Janssen Oncology. I've been in that company for four years, and I think it's exciting on what we stand for, patients with solid tumors and hematologic diseases.

I've been in the industry in the clinical research or medical affairs almost exclusively in oncology for the last 20 years. It's a great opportunity to speak to you today.

Danelle James:  Hi, my name is Danelle James. I'm a hematologist and medical oncologist. I've been working at Pharmacyclics, an AbbVie company, now for almost 10 years. I've worked very closely on this program that we're speaking about Imbruvica.

Prior to that, I was in academia. I was at UCSD, University of California San Diego, for about 10 years and was on the faculty there with a clinical and translational research focused in chronic lymphocytic leukemia and non-Hodgkin's lymphoma.

Julie:  Can you briefly discuss the recent approval of Imbruvica plus rituximab for frontline CLL?

Danelle:  Our recent approval is quite exciting. It actually was a thought collaborative effort. The study results and the approval are based on the landmark Phase III study called E1912, which was a cooperative group study throughout the United States, conducted and led by the ECOG-ACRIN Cancer Research Group that's sponsored by the National Cancer Institute and the National Institute of Health.

In addition, a huge collaboration in terms of a study conduct, it was also reviewed under the FDA's Real-Time Oncology Review, which allows for a more rapid review of data and hopefully leading to early approvals of drugs as appropriate.

It was part of the FDA's recently established Project Orbis, which allows for multiple health authorities around the world to review the data with the FDA, hoping to facilitate speedier approvals globally.

This approval is, I believe, our 11th approval for Imbruvica from the US FDA. It's a really exciting addition to our USPI, marking the sixth study in CLL and the fifth randomized study within our prescribing information.

Andree:  What is so interesting about it is that the ECOG-ACRIN group evaluated a younger patient population, age 70 or younger, and that the comparator arm, the standard of care arm, was a very well-established treatment option. It's called FCR, fludarabine, cyclophosphamide, and rituximab. The rituximab is a CD20 antibody that also was maintained in the comparator arm.

The thing is also it was a great effort to start this study. It really contributes to the overall data logged to the data that we have for Imbruvica. It's really exciting to see those data.

Julie:  What existing data led the research investigators to examine this drug combination? Can you summarize the major study findings?

Danelle:  Being in clinical practice prior to joining AbbVie, the most aggressive, most potent standard of care was fludarabine, cyclophosphamide, and rituximab, as Andree mentioned. It's so potent and so aggressive that it's actually not very well-tolerated by older individuals.

However, for those that were younger and had good performance status and could tolerate it, it was the most aggressive thing we could give for a patient's CLL. When the ibrutinib started evolving very early on, ECOG and the collaborators within the NCI recognized that ibrutinib had the potential to at least be as good as FCR. What we find in the study is that it's actually superior to FCR.

When I say ibrutinib, the study specifically evaluated ibrutinib in combination with rituximab, an antibody against CD20. The results were pretty outstanding, with a 66% reduction in the risk of progression or death favoring the ibrutinib-rituximab arm over FCR, led to early reporting out of the results. Really, what the investigators considered to be practice-changing results.

In addition to the progression-free survival data, the safety data also looked very promising. This combination, with issues with FCR chemotherapy being prolonged blood count reduction and sometimes infections and fever, on par with that, the ibrutinib-rituximab regimen was fairly well-tolerated and was able to avoid some of those chemotherapy-like toxicities, which is an important advance.

Interesting, we know that even that most potent chemotherapy doesn't work very well in some of the highest-risk patients. This study specifically excluded patients with deletion 17p, which really have been found to not have any kind of durable remissions to even the most aggressive chemotherapy.

These patients tend to have TP53 mutations, which confers resistance to chemotherapy. Interestingly, Imbruvica has approval for deletion 17p patients and actually was our first breakthrough therapy designation in chronic lymphocytic leukemia. The investigators actually didn't even include those patients in the study.

There are, however, a number of other high-risk populations in CLL. Within the E1912 study, about 59% of those patients had some of those high-risk characteristics. Not only did Imbruvica and rituximab improve the progression-free survival in all patients, but it did so in the patients with the highest-risk disease, really allowing for one treatment that can be given regardless of risk.

The progression-free survival results were quite astonishing. Most people were thinking that FCR was as good as it could get in terms of efficacy in CLL, but it's been recognized that based on the results of this study that there is something far superior in terms of reducing the risk of progression.

In addition, the FDA included longer-term data in the US Prescribing Information, with a median follow-up of about 49 months. The overall survival of patients was not reached.

There were 3% of the patients on the Imbruvica plus rituximab arm that died over that up to five-year follow-up compared to 7%, more than twice as many, in the FCR treatment arm. Put together, these results were pretty outstanding and really supported this important approval for Imbruvica.

Andree:  Danelle, that was a great summary. You mentioned that before the hazard ratio was 0.34, which is a 66% improvement in either progression-free survival or death. That's an amazing number and probably contribute to the fact that at the first interim analysis, the study was already positive.

Considering that is against a very effective regimen is really a great achievement of the ECOG-ACRIN investigator. As you mentioned before, the rate of neutropenia and infectious complications was lower, while there was not a change in the safety profile for Imbruvica in this combination of ibrutinib with rituximab. That's another important factor to consider.

Danelle:  Just to follow up on that, why did the researchers do this study? What we've seen groups like ECOG-ACRIN is they really want to do things that are going to be clinically meaningful for patients. This comparison of Imbruvica-rituximab versus FCR was the most clinically meaningful comparison that they could make.

Indeed, it has changed the standard practice in CLL. These researchers really are aiming to improve the care of patients and what's going to be important for their providers. It was really a fortunate and great relationship to work with them to bring this data to the FDA.

Andree:  I agree. That's fantastic. What I thought was interesting -- you mentioned that before -- the RTOR process that really helped us with bringing this study through the FDA and discuss it with the FDA as well as the Project Orbis that was another submission framework. To have this close collaboration with the FDA along the way was really beneficial to patients.

Julie:  Of these findings, were any of those particularly surprising that weren't expected?

Danelle:  From my point of view, working in Southern California at UCSD, really focused in improving outcomes in CLL patients, we always thought there would be something better than chemotherapy, but we were strapped to be able to find it, which is one of the impetus for me coming to industry to work on ibrutinib.

Just the sheer magnitude of the benefit and how early it was observed in terms of reducing the risk of progression or death in the patients on study. I don't think anybody was expecting to see that so early and so robustly.

That's my biggest surprise, the progression-free survival, including how they've detailed the overall survival, were really just supportive of having a new gold standard of care, which is very important to set a new bar for CLL patients.

Andree:  I agree. That was, for me, the most exciting outcome of this study. When I heard that it was highly positive and then the collaboration with the investigators at ECOG-ACRIN. To show such a profound Improvement in progression-free survival was really, to some extent, unexpected.

Danelle already talked about the risk profile of those patients. To see this consistently in patients with the higher-risk profile versus the lower-risk profile was definitely an improvement and was exciting. We already talked about the death event after a prolonged period of time. The number of Imbruvica patients was lower than the number of FCR patients who died.

Taking it all together and taking it together with the overall profile that we have with Imbruvica as an established treatment option for first-line CLL patients, either as a single agent, in combination with rituximab, which is what we are talking about right now, as well as in combination with another CD20 antibody.

All of that gives us confidence that we're doing the right thing for patients and that we are on the forefront of pushing the boundaries for the treatment of first-line CLL patients forward.

Julie:  What are the real-world applications for this approval in clinical practice?

Andree:  If we take together the evidence that we have generated with ibrutinib, this increases the treatment options for patients with upfront treatment with CLL. The treatment of Imbruvica and rituximab, it's a real option for patients. That is the real-world application that we are seeing. Danelle, what do you think?

Danelle:  In terms of the real-world applications and the meaning for general clinical practice, it's most evidenced by the National Cancer Network, the NCCN's guidelines.

Based on the results of this study, what used to be considered the recommended treatment for younger patients, a category 1 treatment for younger patients, fludarabine, cyclophosphamide, and rituximab, has now been completely rewritten. Imbruvica is the only NCCN category 1 recommended therapy now in frontline CLL.

The chemotherapy options have now been moved down and are no longer in that category 1 place. Category 1 is a condition that you only get when you have the highest level of evidence in a well-conducted Phase 3 study and showing at least progression-free survival, but also benefits in other important efficacy outcomes.

Now when prescribers look at the guidelines, they're able to easily parse out that Imbruvica, in some fashion, is category 1 recommended and is the only category 1 recommended first-line therapy for chronic lymphocytic leukemia patients without deletion 17p.

This is important because now providers don't necessarily have to try to figure out what's the best therapy, one out of multiple chemotherapy options.

In the Imbruvica program, where we have six randomized studies that have read out, five of them being in our USPI, we've gone up against every single standard of care, with this one being the most meaningful because, as we've talked about, it was the gold standard therapy, FCR, in frontline CLL.

The NCCN guidelines have really simplified it for providers and will hopefully allow for many patients to get alternative option from chemotherapy, one that can be effective in patients with the highest-risk disease.

Julie:  Probably my favorite question here. We talked a lot about the clinical side of things. What are you most excited about in regards to this approval?

Andree:  During this podcast, we talked about it in brief, the patients and increasing options for patients. That is what drives me. That is what drives all of us. It's to make options available for patients and to make options available that are reasonably well-tolerated, that have a defined safety profile, and have an increased efficacy profile.

With Imbruvica, we have shown, multiple times, that this is a drug that can be used in front-line CLL, in other CLL settings as well. That's what is important to me and that is important to us, to make options available for patients.

When we have CLL patients that we can see what a drug like Imbruvica can do to those patients in prolonging time to progression or death in this case, as the definition of progression-free survival, that is really meaningful. That is something that we all strive for.

Over the last decades, we have seen substantial improvements in how we are treating cancer patients, in general. To see that in a disease setting like CLL, it's clearly very, very exciting.

Danelle:  What makes me excited is what it means for the patients and the community in terms of having an alternative option to chemotherapy with Imbruvica-based therapy. That holds a lot of promise not only for these CLL patients and their providers, but it also gives a lot of hope in terms of other non-Hodgkin's lymphomas and B-cell malignancies that are currently being treated with chemotherapy that are not achieving cures.

The paradigm of being able to supplant a very aggressive chemotherapy regime with a non-chemotherapeutic approach and demonstrating it can do it so superbly in this E1912 study gives us a lot of hope outside of CLL in other blood cancers that are still being managed with chemotherapy.

Julie:  Is there anything else that you would like to add in addition?

Andree:  Yeah. We've covered most. It is about the patient. It is about treatment options. We are very excited about the options that we have for our patients. With Imbruvica, we have seen the drug is around for some time and has been explored in many different settings.

We have seen that there is long-term follow-up data and that we can use it in different settings and with different combinations, as we discussed today. That is really something that we are excited about. We mentioned a little before.

If you think about it, the 11th approval for Imbruvica and the fifth approval in the frontline setting, these are clearly exciting data and results and times for patients and providers.

Danelle:  I'm just really proud to be involved in this program. Imbruvica has one of the largest, if not the largest, development programs for a single molecule in all of hematology. Certainly, it is the largest breadth and depth of evidence we've ever seen in chronic lymphocytic leukemia.

Not only has it been amazing to work on this molecule and bring it forward in a place where there was never a BTK inhibitor being investigated or even thought to work over a decade ago, it's been a great collaboration, not only between AbbVie, Pharmacyclics, Janssen, but also with the US Intergroups, the FDA.

If you look back historically, Imbruvica was the first to receive breakthrough therapy designation in oncology. That allowed us to get very good guidance from the FDA. Really working together, we're able to do things very quickly and in a very meaningful way for patients.

Andree:  That's important. The collaboration with the FDA or regulators around the world, essentially. Doing something good for patients, that's the important element.