Novel Agents and Approaches Continue to Advance Through CLL Pipeline

The expansion of targeted agents has shifted the treatment landscape of chronic lymphocytic leukemia (CLL), enabling physicians to focus on combinations and sequences most likely to elicit deep responses with the most curative potential, explained Mazyar Shadman, MD, MPH.

“Ongoing studies will [reveal] the treatment that will provide deep responses with no detectable disease,” said Shadman, an assistant member of Fred Hutchinson Cancer Research Center. “That will give us the opportunity to stop treatment or hold treatment with minimal side effects. As next generations of BTK inhibitors or PI3K inhibitors [come out, we may be able to] combine those drugs with a drug like venetoclax (Venclexta). The idea would be to offer treatment for a limited duration of time and then hopefully cure the patients. If not cure, let them have a disease-free life for as long as possible.”

One novel agent to recently enter the landscape is duvelisib (Copiktra), which was granted FDA approval in September 2018 for the treatment of patients with relapsed/refractory CLL/small lymphocytic lymphoma (CLL/SLL) or relapsed/refractory follicular lymphoma. The CLL/SLL indication is based on data from the phase III DUO trial, which showed a 60% reduction in the risk of disease progression or death compared with ofatumumab (Arzerra), with a median progression-free survival of 16.4 months versus 9.1 months, respectively (HR, 0.40).

OncLive^®: What advancements have we seen in CLL over the past couple years?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Shadman discussed the evolution of therapy in CLL and how physicians are working to balance these novel agents with additional modalities.Shadman: In the past few years, we have witnessed major advancements in the treatment of patients with CLL. The main reason for that has been the introduction of novel agents, such as pathway inhibitors like ibrutinib (Imbruvica) or idelalisib (Zydelig) and more recently a BCL-2 antagonist, venetoclax. While most patients have benefitted from these new agents, we have seen a major change in the treatment of high-risk patients, namely those with a 17p deletion and p53 mutation. In these patients, we no longer use chemotherapy.

With all the new advancements, we're still far from cure in these patients. Response rates are not as great as what we see in patients with standard-risk disease. The idea is to find the best sequence of these new drugs. In the meantime, we have access to some new technologies for treatment. One of the most promising [approaches] is chimeric antigen receptor (CAR) T-cell therapy. While it is not approved for CLL at this time, we're really hoping that in the next few years we'll have that available for our patients.

We also have a very long track record for a very [potent] and effective treatment for CLL, and that's allogeneic stem cell transplant (ASCT). Because of the high rate of mortality and morbidity from this process, we try to avoid using it unless we have to. The question is: with the novel agents and the new technologies, what is the right sequence of these 3 modalities in the treatment of patients with high-risk features?

What is the future of venetoclax in this landscape?

In my talk, I presented data regarding what we know about the novel agents, how good they are, what the side effects are, and what their future is. Additionally, what the right time is to refer a patient for a clinical trial using CAR T cells and what the right decision is after CAR T in terms of using ASCT. We still have a lot to learn, but in the absence of randomized clinical trials, we have to look at the available data and come up with recommendations.Venetoclax is of course one of the novel agents. Ibrutinib is a Bruton’s tyrosine kinase inhibitor that provides excellent responses in patients. What is lacking in patients who are treated with any of the B-cell receptor inhibitors is depth of response. In other words, we rarely see complete responses with minimal residual disease negativity. For an ongoing treatment, it may not be a real issue, but what we see in the clinic are patients who want the opportunity to stop treatment.

We believe that is only possible if you can provide a deep response. What's unique about venetoclax is the fact that it can, in fact, provide very deep responses. Not only do these patients have a very good response in terms of lymph node size reduction, we also see a good number of patients with minimal disease in the bone marrow or in the blood. With longer follow-up, we're hoping that patients who had a great response can stop treatment and get treatment holidays for a long time. That is the promising future of this drug. You don't see that with the B-cell receptor inhibitors.

As time goes on, where could some of these PI3K inhibitors fit into the paradigm?

There are many studies ongoing that will combine venetoclax with the B-cell receptor inhibitors, namely ibrutinib and next generations of these drugs. The idea is to combine the benefit of a drug that's very good in eradicating disease in the bone marrow with a B-cell receptor inhibitor, which is great in terms of lymph node response. With the combination, we're hoping to induce a better and deeper response. The future could be treating patients for a limited duration of time with an optimal combination [and then] we can hopefully [discontinue] forever. If not forever, then for a long time. Of course, we need to learn more about the toxicities and safety of these combinations.PI3K inhibitors are a very effective class of drugs for CLL. Idelalisib is already approved in combination with rituximab (Rituxan). Hopefully, we'll have next generations of these drugs like duvelisib, and hopefully umbralisib.

What is concerning about these drugs is not their efficacy. It's more an issue of safety and toxicity. We know from different studies that some of the toxicities of PI3K inhibitors are more prominent if you use them in the frontline setting. At this point, it is not recommended to use idelalisib in a treatment-naïve patient. That has to do with the intact immune system of a patient who has not received chemotherapy.

What are you hoping to learn from the trial that is comparing ibrutinib with acalabrutinib (Calquence)?

What types of CAR T-cell products are being explored in clinical trials?

Where would you like to see research focused in the coming years?

I would say they definitely have a role; if it’s not in the first-line setting, then it has a role in another setting. In a patient with high-risk disease, the key is to achieve mileage from any available agent. As we get better in making new PI3K inhibitors with fewer adverse events (AEs) and also make progress in managing em, the key will be finding the right partner in clinical trials. There are studies looking at PI3K inhibitors and other agents. We need many drugs from different families because patients have unique AEs from each drug. There is definitely room for a variety of novel agents for these diseases. Ibrutinib has been a real game changer for CLL and many other lymphoid tumors. I hope that the new BTK inhibitor has better efficacy, but what we are really hoping to see is less toxicity. Tolerability is a real issue that some of us have in the clinic. Having a cleaner BTK inhibitor that has less off-target effects would be ideal. That's what I expect from looking at the head-to-head studies comparing ibrutinib with some of the newer generations of drugs.We know a little bit about the CD19-targeted CAR T cells. If we get an approval, I believe it would be the CD19-targeted CAR T-cell agent. There are clinical trials in many centers that are targeting other antigens including CD20-targeted CAR T cells. CD19 seems to be more advanced. We are expecting to have registration studies open soon. Hopefully, that will be another option for our patients, especially our high-risk patients. Now, we have some of the novel treatment methods like CAR T-cell therapy, or ASCT if needed for those who still don't respond to what we have. That will be the future. Hopefully, we'll use treatments like ASCT less in the future and rely more on the combinations of the novel agents and some of the immunotherapy approaches for more high-risk patients.

Verastem oncology receives FDA approval of COPIKTRA™ (duvelisib) capsules. Published September 24, 2018. https://bit.ly/2NDQm80. Accessed September 26, 2018.