Constantine Tam, MD, professor of hematology at Monash University, sat down with Pharmacy Times® to discuss the efficacy of zanubrutinib in treating chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), particularly in relapsed/refractory (R/R) and treatment-naïve settings. The discussion is based on data presented at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition that took place December 7-10 in San Diego, California.
Long-term data, with follow-up exceeding six years, demonstrate high response rates and durable remission in patients with CLL and SLL treated with zanubrutinib, especially in treatment-naïve patients, according to Tam. The combination of zanubrutinib and obinutuzimab also demonstrated effectiveness and tolerable safety. While hypertension and atrial fibrillation are concerns with treatment, Tam highlights how utilizing proper cardiovascular monitoring can mitigate risks.
Pharmacy Times: How do these data further solidify the efficacy of zanubrutinib in treating CLL/SLL, particularly in relapsed/refractory settings?
Key Takeaways
1. Durability and Response: Zanubrutinib shows durable responses in CLL/SLL, with over 75% of treatment-naïve patients in remission six years after starting therapy.
2. Safety Considerations: Cardiovascular screening and management are crucial for mitigating risks like hypertension and atrial fibrillation associated with BTK inhibitors.
3. Emerging Combinations: Research into zanubrutinib with BCL2 inhibitors, such as sonrotoclax, promises improved efficacy and progression-free survival in ongoing studies.
Constantine Tam, MD: Zanubrutinib (Brukinsa; BeiGene) is now a widely prescribed Bruton tyrosine kinase inhibitor (BTKi) for the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Of course, it is a second-generation drug, so the history of the drug is not as long as, for example, ibrutinib (Imbruvica; AbbVie). In this respect, what we presented at ASH this year is the longest data available on zanubrutinib, and these are regular patients who were initially enrolled on the 2 phase 1 studies. The phase 1 study of zanubrutinib monotherapy, as well as the combination of zanubrutinib and obinutuzimab (Gazyva; Genetech, Roche). These 2 studies have now got a median follow up of 6 ½ years, with some patients having more than 8 years of follow up. As in many medications, long term follow up is important to make sure that the efficacy is preserved and that there are no unusual side effects. This is the trial that helps provides that data.
Pharmacy Times: What explains the particularly high response rate in patients who are treatment-naive?
Tam: The response rate for CLL and SLL is essentially close to 100%; that's not surprising. Most BTKis do work very well in patients who are treatment-naive or in the relapsed/refractory setting with CLL. The only patients who really don't respond are the ones who have Richter transformation. I think what's really pleasing though, is not just the overall response rate (ORR), but the complete remission rate (CRR), which, at least in the case of this very long term follow up, is 36% for patients with monotherapy, and 60% in combination with obinutuzimab. Currently, the drug is not used with obinutuzimab, so we can discount that CR rate, but within a CR rate of 36%, that's 1 in 3 patients being in complete remission, which is a very high rate, especially in the frontline setting for a BTKi, and we think the reason for that is because of the prolonged follow up. With BTKis, remissions are uncommon. After the first year or two of therapy, and then over prolonged therapy, as with other BTKis, we have seen an improvement in CR rates. We also must remember that this is an agent that has been compared in randomized fashion against ibrutinib, and that zanubrutinib is a more potent agent with better efficacy. So, I think it's a combination of a better drug as well as a prolonged follow up.
Pharmacy Times: Are there any safety considerations or monitoring strategies that health care providers should be aware of when prescribing zanubrutinib in this patient population?
Tam: My comment would not just apply to zanubrutinib, but also all BTKis, in that there is an increasing appreciation of the target vessel used these drugs. We do know that patients can get cumulative hypertension, and this is true of all the drugs that are available, including acalabrutinib (Calquence; AstraZeneca) and zanubrutinib. Some drugs have lower risk profiles than others, but essentially, hypertension is an adverse effect, as is atrial fibrillation. I think it really emphasizes the need for primary providers to do a comprehensive cardiovascular screening at baseline to make sure the patient is fit in terms of cardiovascular health. At least in my mind, what that means is that the patient is not showing symptoms of heart failure, and that the patient has either mild or well-controlled hypertension, no more than 2 drugs needed to control the hypertension, as well as the ongoing awareness in these patients that over time, hypertension is a cumulative signal. The primary health providers need to monitor the blood pressure and bring additional anti-hypertensive agents as needed.
Pharmacy Times: How significant is the durability of response to therapy with zanubrutinib? Did response durability differ significantly between those receiving zanubrutinib monotherapy and zanubrutinib + obinutuzimab?
Tam: The data point that is the strongest in our paper is in the treatment-naïve subgroup, because you are comparing apples to apples. For R/R patients, there's a variety of history, and the message is a bit more mixed. But when you look at the durability in the frontline setting, in both the monotherapy as well as combination therapy groups, you've got a greater than 75% probability of remaining in remission in the frontline at 6 years after starting treatment. That range is very similar, irrespective of whether it was obinutuzimab or whether it was zanubrutinib as a monotherapy. I think that that speaks to durability, that 6 years after starting that first course, patients will remain in remission and under control. The question is about the contribution of obinutuzimab to that durability, and I will say that in this non-randomized comparison, that if there is a benefit to obinutuzimab, it is only very minor, and we also saw that with other drugs; for example, in acalabrutinib, where the addition of obinutuzimab only very modestly increased the durability of the response over monotherapy.
The 66th ASH Annual Meeting and Exposition took place from Saturday, December 7 to Tuesday, December 10 in San Diego, California. You can read our coverage here.
Pharmacy Times: Are there any ongoing or planned studies to further explore zanubrutinib’s potential in different CLL/SLL patient populations or in combination with other therapies?
Tam: This is a long-term report, the initial report in a first-in-human phase 1 trial. Of course, since then, zanubrutinib has been compared in multiple phase 3 settings. In the ALPINE study, where zanubrutinib was compared against ibrutinib, the drug was safer and more effective. In the frontline setting for patients with triple-naive CLL in the SEQUOIA study, zanubrutinib has been compared against bendamustine-rituximab were, once again, there's an improved progression-free survival. So, zanubrutinib monotherapy, since this initial report, has been well compared with comparative agents, and has been established as a standard of care for both frontline and R/R settings. Regarding questions about combinations, there are now investigations analyzing zanubrutinib combined with a BCL2 inhibitor, most prominently sonrotoclax, which is a second-generation BTK inhibitor. We report on the very high efficacy outcome of this combination at ASH this year in the phase 1 setting. But, in fact, the phase 3 study has just about finished recruitment, and that's a comparator of zanubrutinib and sonrotoclax versus venetoclax (Venclexa; AbbVie, Roche) and obinutuzimab in a study called CELESTIAL.
