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Selected coverage of chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL) from the 65th American Society of Hematology Annual Meeting and Exposition, December 9-12, 2023, San Diego, California.
At 39 months, patients taking zanubrutinib after 1 prior treatment for chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia retained a 32% edge in progression-free survival (PFS) over those taking ibrutinib, according to extended results of a phase 3 trial unveiled December 9, 2023.
The findings were presented during the 65th American Society of Hematology (ASH) Annual Meeting and Exposition, taking place in San Diego, California.1
Zanubrutinib, a second-generation Bruton tyrosine kinase (BTK) inhibitor, sustained its advantage over ibrutinib in the latest findings, which came a year after final results from the ALPINE trial (NCT03734016) were presented at ASH in New Orleans.2 Those data, published in the New England Journal of Medicine, showed zanubrutinib offered a 35% PFS advantage over ibrutinib after an average of 29.6 months.3
Sold as Brukinsa, zanubrutinib is made by BeiGene and approved for treatment of CLL and SLL based on results of the ALPINE and SEQUOIA (NCT03336333) trials. It is also approved to treat certain patients with mantle cell lymphoma, marginal zone lymphoma, and Waldenström macroglobulinemia.
If there was a lingering question from ALPINE, it was whether that edge for zanubrutinib would last beyond 2 years, lead investigator Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute, told Evidence-Based Oncology in an interview. The head-to-head ALPINE trial has been compared with the ELEVATE-RR trial (NCT02477696), which evaluated ibrutinib against acalabrutinib over 36 months, she said.4
The extended ALPINE data showed that benefits were also sustained for the highest-risk patients, those with 17p deletion and TP53 mutation, where zanubrutinib holds an even greater advantage over ibrutinib.1
“I think people have been very eager to see whether the benefit of zanubrutinib holds up at this year’s follow-up, which is 39 months. And as you can see from the abstract, it does,” Brown said in the interview.
In addition, the data at 39 months show a trend toward an overall survival advantage for zanubrutinib over ibrutinib, but the results did not reach significance.
Improved Mechanism of Action
Brown explained that compared with ibrutinib and acalabrutinib, zanubrutinib has higher concentration ratios and thus offers more complete inhibition of BTK; also, unlike the others, it has no active metabolite on kinases beyond BTK, so it produces fewer off-target effects.
ALPINE was designed to evaluate zanubrutinib’s efficacy and safety head-to-head against ibrutinib, the first-generation BTK inhibitor that reached the market in 2014 for patients who had received at least 1 prior therapy for CLL. The study compared 327 patients taking zanubrutinib with 325 taking ibrutinib; results published in last year showed an HR for PFS of 0.65 (95% CI, 0.49 to 0.86; P = .002).3
Those data showed that among patients with a 17p deletion, a TP53 mutation, or both, the zanubrutinib group had longer PFS than those taking ibrutinib (HR, 0.53; 95% CI, 0.31 to 0.88).
New Data Show Advantage Is Sustained
At 39 months, 194 patients from the zanubrutinib group (59%) are still undergoing treatment, compared with 152 patients in the ibrutinib group (47%). There have been 51 patients with disease progression in the zanubrutinib group, compared with 62 in the ibrutinib group.
Data at the 39-month mark are as follows1:
Brown discussed the findings for the highest-risk patients and explained why they demonstrate the drug’s efficacy.
“These are the patients who are particularly poorly served historically by chemotherapy, and so the development of the BTK inhibitors was particularly revolutionary for them. That’s a group that we’re always particularly interested in looking at the outcomes for,” she explained.
“We actually see an even bigger difference benefiting zanubrutinib compared to ibrutinib than we do in the overall population,” Brown continued. “And at this time point, we have 59% of patients still progression-free on zanubrutinib, compared to 41%, with ibrutinib. So that’s an 18% improvement in the progression-free survival at 39 months for this very high-risk subgroup.
“I think the fact that we see an even bigger difference in this subgroup compared to the total population underscores the fact that it’s likely a real efficacy difference that we’re seeing driving the results of the trial, because this is the group where difference in efficacy should be most pronounced,” Brown said. “The fact that we’re seeing it there in particular, even more so than the overall population, I think is very convincing.”
Safety Results, Potential Health Savings
Beyond the efficacy findings, the extended follow-up also showed superior safety findings for zanubrutinib. A key advantage of second-generation BTK inhibitors over ibrutinib is a reduction in cardiac effects; at 39 months, the differences in ALPINE were significant1:
Given that patients with CLL may take a BTK inhibitor for several years, what are the implications of these cardiac results for the health system?
Based on ALPINE, Brown said: “We did look into the rates of hospitalization at this follow-up for zanubrutinib vs ibrutinib, and it’s actually a 10% lower rate [for zanubrutinib]. So 46% of patients on zanubrutinib were hospitalized for some reason over the course of the trial vs 56% for ibrutinib. That’s a pretty significant difference,” she said. “So it looks like it’s translating into benefits for the health care system as well.”
Similarly, Brown was asked if the cardiac safety differences become more important over time. She said they become significant when one looks at atrial fibrillation and arrhythmia rates “because we know those are continually increasing and the cumulative incidence just goes up.”
Quality of Life Over Time
Cardiac events are not the only adverse events (AEs) patients taking BTK inhibitors may experience. Brown was asked if there are other AEs that should be considered if the time horizon for taking the medication will be more than 3 years, as payers are wary if patients may stop taking a drug due to side effects. Brown said zanubrutinib has an advantage here, too.
“There are a number of side effects which are typically much more common with ibrutinib than zanubrutinib,” she said, listing rashes, joint aches, and diarrhea. “Fatigue related to the drug is something we also see with ibrutinib.”
“People can tolerate it for 6 months or even a year, but then you’re getting to 3 and 4 years, it’s forever,” she said. Although these symptoms may be considered grade 1 or 2 clinical trial criteria vs grade 3 or 4, they become more significant to patients if they continue over a long period of time.
“I think this is why especially with the ibrutinib trials, we tend to see patients going off [the drug] as you get to 3, 4, 5, 6 years. I think that’s going to be much less true with zanubrutinib,” Brown said. “My patients have told me they don’t even know they’re taking anything. Now that’s usually fairly soon after they start, but it still tends to stay similar.”
References
1. Brown JR, Eichhorst B, Lamanna N, et al. Extended follow-up of ALPINE randomized phase 3 study confirms sustained superior progression-free survival of zanubrutinib versus ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL). Presented at: 65th American Society of Hematology Annual Meeting and Exposition; December 9-12, 2023; San Diego, CA. Paper No. 0202. doi:10.1182/blood-2023-174289
2. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib demonstrates superior progression-free survival (PFS) compared with ibrutinib treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL): results from final analysis of ALPINE randomized phase 3 study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract LBA-6. doi:10.1182/blood-2022-171538
3. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319-331. doi:10.1056/NEJMoa2211582
4. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210
Jennifer R. Brown, MD, PhD, director of the Chronic Lymphocytic Leukemia (CLL) Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute, discussed with Evidence-Based Oncology (EBO) the updated findings from the phase 3 ALPINE trial (NCT03734016) of zanubrutinib vs ibrutinib in CLL. Results from 39 months of follow-up were presented at the 65th American Society of Hematology Annual Meeting and Exposition in San Diego, California.
EBO: ALPINE results at 39 months show responses to zanubrutinib in CLL are sustained and deepened over time for most. How typical is it for patients with CLL or any hematological cancer to respond to a treatment this way?
Brown: When we first developed BTK [Bruton tyrosine kinase] inhibitors, I think we weren’t necessarily expecting this type of response, but this is actually what we see with BTK-targeted inhibition. It’s relatively slow in inducing response compared to something like chemotherapy, if the disease is sensitive to chemotherapy, but it continues to sustain and deepen the response over time and even over many years. So this is actually typical of what we see with BTK inhibitors with CLL. In fact, we see deepening responses even in the control arm with ibrutinib, as we do with zanubrutinib—it’s just that the response rate is higher and the CR [complete response] rate is higher with the zanubrutinib than the ibrutinib.
EBO: Can you discuss the difference in responses among patients with 17p deletion with TP53 mutation?
Brown: That’s our highest-risk subgroup of disease in CLL—patients who have p53 aberrant C, which is most commonly seen through deletion of the short arm of chromosome 17, but can also be seen through mutation. And most patients who have 17p deletion also have mutation of the other allele. These are the patients who are particularly poorly served historically by chemotherapy, so the development of the BTK inhibitors was particularly revolutionary for them. That’s a group that we’re always particularly interested in looking at the outcomes for, and that was a predefined subset in ALPINE.
In that group, we actually see an even bigger difference benefiting zanubrutinib compared to ibrutinib than we do in the overall population. And at this time point, we have 59% of patients still progression free on zanubrutinib compared to 41% with ibrutinib. So that’s an 18% improvement in the progression-free survival at 39 months for this very-high-risk subgroup. I think the fact that we see an even bigger difference in this subgroup compared to the total population underscores the fact that it’s likely a real efficacy difference that we’re seeing driving the results of the trial, because this is the group where difference in efficacy should be most pronounced and most important. So the fact that we’re seeing it there, in particular, even more so than in the overall population, I think, is very convincing.
EBO: If patients might be taking a BTK inhibitor for 3 years or even longer, do the differences in cardio safety results become even more important?
Brown: Absolutely, I think especially in terms of the atrial fibrillation and arrhythmia rates, because we know those are continually increasing and the cumulative incidence just goes up. So that will just continue to be different over time. For the issue of ventricular arrhythmias, we didn’t actually have any new events on either arm between the 2- and the 3-year follow-up. We don’t really know what the timing of that is—that may tend to be a little bit earlier—although we did have several events in the latter part of the 2-year follow-up, and we need to continue to follow that to try and better understand that the timing of that. But, presumably, the time on the drugs is ongoing risk of cardiac events.
Reference
Brown JR, Eichhorst B, Lamanna N, et al. Extended follow-up of ALPINE randomized phase 3 study confirms sustained superior progression-free survival of zanubrutinib versus ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL). Presented at: 65th American Society of Hematology Annual Meeting and Exposition; December 9-12, 2023; San Diego, CA. Paper No. 0202. doi:10.1182/blood-2023-174289
Patients with chronic lymphocytic leukemia (CLL) taking a next-generation combination of a Bruton tyrosine kinase (BTK) inhibitor and a therapy to target the BCL2 protein had 100% progression-free survival (PFS) after 9.7 months, signaling what could be a treatment shift for this population, according to results reported December 9, 2023, at the 65th American Society of Hematology Annual Meeting and Exposition in San Diego, California.1
Lead investigator Constantine Tam, MD, PhD, of St. Vincent’s Hospital, Melbourne, Australia, reported on results involving zanubrutinib, the second-generation BTK inhibitor sold as Brukinsa, and sonrotoclax, the investigational BCL2 inhibitor now being studied in several blood disorders. Both are made by BeiGene.
Advancing treatment options for patients with CLL or small lymphocytic lymphoma (SLL) is not about just finding new therapies for patients who relapse, but also keeping patients on therapy in the first place—and that may mean creating better, less toxic versions of what works.
Combing the BTK inhibitor ibrutinib with venetoclax, the BCL2 inhibitor, has been effective in clinical trials for patients with treatment naive CLL, but toxicity rates are high. A 2019 phase 2 study published in the New England Journal of Medicine showed high remission rates2; however, 60% of the patients had grade 3 adverse events (AEs). In the 2022 CAPTIVATE trial, the grade 3 AEs for patients receiving a fixed-duration regimen of ibrutinib and venetoclax were lower, but investigators reported that rates of diarrhea and neutropenia were “somewhat higher than expected with ibrutinib alone.”3
Since then, the second-generation BTK inhibitor zanubrutinib has been approved for treatment of CLL, having demonstrated superior efficacy to ibrutinib in the head-to-head ALPINE trial (NCT03734016) with fewer cardiac effects. Now a next-generation BCL2 inhibitor, sonrotoclax, is being studied with zanubrutinib in CLL, with preliminary results.
The ALPINE results make zanubrutinib “the natural partner to be chosen to be paired with the second-generation BCL2 inhibitor,” Tam said.
Sonrotoclax is described as a BH3 mimetic with greater than 10-fold potency compared with venetoclax, with higher selectivity. Tam said it also has a shorter half-life than venetoclax, which makes it easier to develop a rapid dose escalation schedule.
The phase 1/2 BGB-11417-101 trial (NCT04277637) involves patients with treatment-naive CLL or small lymphocytic lymphoma; it is evaluating sonrotoclax as a monotherapy and in various combinations to determine efficacy and appropriate dosing for further study.
Based on the positive phase 1/2 results, BeiGene officials have said the 320-mg dose of sonrotoclax will be evaluated in a global phase 3 trial (NCT06073821).
Tam reported on the study arm involving 107 patients who were treated with the combination of sonrotoclax and zanubrutinib. In this arm, patients were treated with zanubrutinib monotherapy for 8 to 12 weeks before receiving sonrotoclax dosing; sonrotoclax was dosed orally, 30 minutes after a low-fat meal. A ramp-up schedule was used to reach a target dose.
In this arm, 51 patients received 160 mg and 56 received 320 mg of sonrotoclax, plus zanubrutinib. Slightly more than a third of the group were 65 years or older (39% of the 160-mg group, 34% of the 320-mg group). Roughly a quarter had high-risk clinical features, namely 17p deletion and/or TP53 mutation status (24% of the 160-mg group, 27% of the 320-mg group).
Results were as follows:
Selected AEs were as follows:
Investigators measured minimal residual disease (MRD), which showed a deepening response over time. By week 48, 100% of patients in the 320-mg group and 75% of patients in the 160-mg group had achieved undetectable MRD levels.
References
1. Tam CS, Anderson MA, Lasica M, et al. Combination treatment with sonrotoclax (BGB-11417), a second-generation BCL2 inhibitor, and zanubrutinib, a Bruton tyrosine kinase Inhibitor, is well tolerated and achieves deep responses in patients with treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma: data from an ongoing phase 1/2 study. Presented at: 65th American Society of Hematology Annual Meeting and Exposition; December 9-12, 2023; San Diego, CA. Paper No. 0327. https://doi.org/10.1182/blood-2023-179541
2. Jain N, Keating M, Thompson P, et al. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med. 2019;380(22):2095-2103. doi:10.1056/NEJMoa1900574
3. Tam CS, Allan JN, Siddiqi T, et al. Fixed-duration ibrutinib plus venetoclax for first-line treatment of CLL: primary analysis of the CAPTIVATE FD cohort. Blood. 2022;139(22):3278-3289. doi:10.1182/blood.2021014488
4. Caffrey M. FDA gives zanubrutinib approval for first-line, R/R CLL, SLL. The American Journal of Managed Care. January 19, 2023. Accessed December 13, 2023. https://www.ajmc.com/view/fda-gives-zanubrutinib-approval-for-first-line-r-r-cll-sll