In the first article of a 2-part series, Sameer A. Parikh, MBBS, discusses the makeup and design of the phase 3 ALPINE study that showed the promise for the next-generation Bruton tyrosine kinase inhibitor zanubrutinib.
CASE SUMMARY
History and Presentation:
A 70-year-old White man with asymptomatic lymphocytosis identified 4 years previously
Comorbidities:
Medications:
Current Status:
Six Months Later:
Diagnostic Workup:
Due to progression of disease after BCL2 inhibitor, the decision was made to initiate therapy with a Bruton tyrosine kinase (BTK) inhibitor.
Targeted Oncology: What was the design of the phase 3 ALPINE study (NCT03734016) looking at the use zanubrutinib (Brukinsa) in patients with relapsed chronic lymphocytic leukemia (CLL)?
SAMEER A. PARIKH, MBBS: This study took all comers with relapsed CLL and they randomly assigned patients to either zanubrutinib or ibrutinib [Imbruvica].1 This was also a large study with a number of stratification factors, [such as age, geographic region of the patient, refractory and del(17p) or TP53 mutation status], but the primary end point was the overall response rate [ORR].1 This, however, is 1 of the criticisms of this study, because we know that BTK inhibitors [don't always get] complete responses, and all we care about is progression-free survival [PFS] or how long the duration of response is for the patient, but according to the FDA, the ORR was allowed to be a primary end point.
What were the makeup of patients on this study?
They enrolled more than 600 patients from all across the world, and the median age [for these patients] was about 68 years old with the majority being male, which is what we expect in CLL.1 Now, [patients with this disease] can have a TP53 mutation without a del(17p). In this trial, 9.2% of patients had a TP53 mutation in their disease without 17p(del) in the zanubrutinib arm, [compared with] 7.7% in the ibrutinib arm. Other baseline characteristics [of patients on this trial] were typical, like [73.1%] of the patients had an unmutated IGVH status, and [58.7% of patients in the zanubrutinib arm] had a median of 1 prior line of therapy. [For patients in both arms], chemotherapy was the most prescribed regimen in the first-line setting [at 83.8% in the zanubrutinib arm and 79.4% in the ibrutinib arm].1
What would you highlight from the efficacy data from this study?
I [don't talk much about] the ORR from the trial because we don't think about it as an important end point [in the BTK inhibitor drug class]. The best improvement with this therapy is surprisingly associated with a superior PFS with zanubrutinib [compared with ibrutinib at 24-months at 78.4% vs 65.9%, respectively (HR 0.65; 95% CI, 0.49-0.86, P = .002].1
One of the [other points] that has been a criticism for the study is how did ibrutinib underperform in this study? I don't know the answer to that question. I think there [will be more follow-up], so it'll be interesting to see how these curves split [over more time], but certainly one thing's for sure is that zanubrutinib is an effective BTK inhibitor. Similar data was seen in patients with del(17p), TP53, or both mutations. This high-risk group of patients in the relapsed setting at 24-months [of follow-up] had a PFS rate of 72.6% with zanubrutinib [compared with 54.6% in the ibrutinib arm (HR, 0.53; 95% CI, 0.31-0.88)].1
Reference:
Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023; 388:319-332. doi:10.1056/NEJMoa2211582
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