Eliminating Chemotherapy in the Treatment of CLL

The efficacy of Imbruvica (ibrutinib) and Zydelig (idelalisib) in chronic lymphocytic leukemia (CLL) suggests the drugs could potentially replace chemoimmunotherapy completely for some patients, according to Steven Coutre, MD, a professor of Medicine (Hematology) at Stanford University Medical Center.

Phase 3 studies have shown higher overall response rates with Zydelig plus Rituxan (rituximab; 77%) versus what has been traditionally seen with Rituxan plus chemotherapy for patients with previously treated CLL (54%). Additionally, Imbruvica as a single-agent has shown response rates (58.3%) that are similar to the combination of Rituxan and chemotherapy in previously treated CLL. These observations have led researchers to believe that chemotherapy can be omitted altogether, making room for less toxic, orally administered novel agents.

Currently, Imbruvica is indicated for treatment of patients with CLL receiving one prior therapy and for patients with a 17p deletion. Zydelig is approved for use in combination with Rituxan in patients with relapsed CLL who are good candidates for single-agent Rituxan due to comorbidities.

Coutre, who has conducted research with Imbruvica and Zydelig, recently presented results from an Imbruvica trial at the 2015 AACR Annual Meeting. The study demonstrated durable responses, including complete responses, with long-term use of the drug.

To gain further insight into the impact of Imbruvica and Zydelig, as well as other emerging therapies and treatment strategies in CLL, CURE sat down with Coutre at the AACR meeting, which took place from April 18 to 22 in Philadelphia.

CURE: Imbruvica has been approved for CLL since early 2014. What is its impact on clinical practice so far and how do you see its use evolving?

Coutre: The drug has had a significant impact already. It is a very well tolerated therapy, so that gives you an option for patients who might not tolerate standard chemoimmunotherapy. Also, for patients who no longer respond to standard therapy, it is a great alternative. It also meets an unmet need in CLL, specifically those patients who have the 17p deletion. In fact, it has a specific approval as initial therapy for those patients.

Can you discuss the development of Imbruvica resistance and, specifically, a recent study from Ohio State University researchers published in JAMA Oncology on Imbruvica resistance mechanisms?

The study published from The Ohio State University really details their experience with a large number of patients, including patients from our study. It really tells us two things. First, we see patients who progress because of a transformation, such as Richter’s transformation, which, fortunately, is a minority of individuals. It may simply reflect the advanced nature of the patients’ disease in these trials. Secondly, it tells us that the reason the majority of patients who progress for other reasons is likely due to mutation—a mutation that leads to specific resistance to Imbruvica.

You have also been involved in research with another CLL drug, Zydelig. What are the latest developments with this agent?

Zydelig is another FDA-approved drug. It is also an oral therapeutic, but it is a different target. It is a PI3K-delta inhibitor, so it is really the first-in-class of those drugs. Zydelig is also a very effective agent for relapsed/refractory disease. It was approved in CLL in combination with Rituxan, including patients who were not fit for standard chemoimmunotherapy. From an efficacy standpoint, it is also a terrific drug, as is Imbruvica.

The side-effect profile is a bit different. You can see early transaminitis, which is generally reversible, and it usually does not limit subsequent use of the drug. However, later side effects include a diarrheal illness, likely colitis, and perhaps an inflammatory insult to the colon. That has led to problems with being able to continuously dose the drug. I think we will need to see further studies that really tell us how best to use this particular drug. Regarding the 2015 AACR Annual Meeting, I’m not aware that there are any new findings being presented on Zydelig.

What impact has Zydelig had on patient treatment since its approval for CLL in 2014? Have there been any findings in terms of acquired resistance mechanisms with the drug?

Zydelig's impact has been less than Imbruvica, primarily because of the side-effect issues, not from an efficacy standpoint. I think physicians have much more of a limited experience with it to date.

As I mentioned, I think we are going to have to learn how best to dose this drug, because continuous dosing is problematic from a side effects standpoint. There is a manuscript that was recently published in Leukemia & Lymphoma regarding side-effect management, specifically the management of diarrhea. That should be a good resource for physicians. In terms of resistance, we know essentially nothing with resistance mechanisms with Zydelig to date.

What other significant research in CLL is being presented at the 2015 AACR Annual Meeting beyond Imbruvica and Zydelig?

There is a tremendous amount of new data being presented at this meeting. Of course, there are some preclinical studies with different types of compounds and different targets. However, there is nothing that has really risen to the level of 'this is the next best thing.' We’re not seeing a lot at the clinic, at least at this meeting.

As the role of targeted therapies continues to grow, what do you see as the future role of chemotherapy in treating CLL?

The role of chemotherapy, or chemoimmunotherapy, in CLL is going to be very interesting. A lot of patients are really not interested in that at all, and I predict that will only accelerate because of the efficacy and tolerability of these novel agents. Currently, we are conducting randomized trials in the frontline setting compared to our standard therapies. Once those results come out, and if they are positive with respect to the novel agents, that will only accelerate the trend toward no chemoimmunotherapy.

It would be a remarkable accomplishment if you can have the average CLL patient who, needs their initial therapy and is in their mid-70s, starts a therapy that is oral and well tolerated. Even if it does not eliminate their disease, it could manage it for the rest of their natural life. I think that is a tremendous accomplishment.

Can you discuss the progress of integrating novel CLL agents into the frontline setting?

In the frontline setting there is Gazyva (obinutuzumab), an anti-CD20 antibody that does have an indication in combination with chlorambucil. There will be studies, and our studies, that are looking at Gazyva in combination with some of these newer oral agents. For example, there is another investigational drug called ABT-199, which is an oral Bcl-2 inhibitor. That is being used in combination with Gazyva in the frontline setting.

We have a variety of trials using Imbruvica, or Imbruvica plus anti-CD20 antibodies in frontline studies, as well as Zydelig in frontline studies. Arzerra (ofatumumab) has been around for quite awhile in the United States as a drug for relapse patients. I do not think it is going to gain much traction in the frontline setting because of these other choices and the results that we have to date. It will be interesting to see if there is value added to the new oral agents with any of the anti-CD20 antibodies, or if we will do fine without them.

Is there anything else about managing CLL that community oncologists should be aware of?

With respect to the future of CLL, we have these types of drugs—and we’ll see more—so I think there is reason to be optimistic for the future. Other very novel therapies, such as the checkpoint inhibitors that are all the rage for solid tumors, will be investigated, possibly in combination with these approved drugs.

Also, chimeric antigen receptor (CAR) T-cell therapy in CLL should be examined. Remember, the first splash that therapy made in recent years was for refractory CLL. Now, the focus is on acute lymphoblastic leukemia, perhaps large-cell lymphoma, but efforts are still ongoing with CLL. I think in the next 2 years, we will start to get answers as to whether that can be a curative therapy for CLL.