Jennifer R. Brown, MD, PhD, presents data from the extended follow-up of the ALPINE study investigating zanubrutinib in relapsed/refractory CLL.

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)

ALPINE, a randomized, multinational phase 3 study (NCT03734016) in patients with R/R CLL/SLL, established the statistical and clinically meaningful superiority of zanubrutinib over ibrutinib on progression-free survival (PFS) and overall response rate (ORR) and confirmed the favorable safety/tolerability profile of zanubrutinib (Brown et al. NEJM; 2022).

Now, with 3 years of overall study follow-up, we report the results of an extended follow-up analysis.

As previously published, patients with R/R CLL/SLL who had received ≥1 prior therapy and had measurable disease were randomized 1:1 to receive zanubrutinib or ibrutinib. Efficacy assessments, including PFS and ORR, were evaluated by the investigator based on 2008 iwCLL criteria; sensitivity analyses to confirm PFS results were also conducted. Updated safety analyses were performed. All reported P-values are descriptive.

Overall, 652 patients were randomized to receive zanubrutinib (n=327) or ibrutinib (n=325).

As of 15 May 2023, 63.3% (n=207/327) of patients remain on zanubrutinib and 52.3% (n=170/325) remain on ibrutinib.

At a median study follow-up of 36.3 months, benefit of zanubrutinib over ibrutinib was sustained (HR: 0.67 [95% CI, 0.52-0.86]; 2-sided P=.002; Fig 1).

At 36 months, the PFS rates were 65.8% with zanubrutinib and 54.3% with ibrutinib. Benefits in PFS with zanubrutinib were also observed across major subgroups, including in patients with del(17p)/ TP53 mutations (HR: 0.52 [95% CI, 0.32-0.83] 2-sided P=.005) where 36-month PFS rates were 60.1% and 43.6%, respectively. Additionally, the zanubrutinib PFS benefit was confirmed in a sensitivity analysis that included only progression and death events that occurred on active treatment (HR: 0.69 [95% CI, 0.49-0.97]; 2-sided P=.031).

ORR remained higher with zanubrutinib compared with ibrutinib (85.0% vs 74.8%; 2-sided P=.001). Responses deepened in both arms with CR/CRi rates of 10.1% (zanubrutinib) and 7.4% (ibrutinib); therate of PR-L or better was 90.2% vs 82.8%, respectively. Fifty-nine (18.0%) patients treated with zanubrutinib and 71 (21.8%) treated with ibrutinib had died (OS HR: 0.76 [95% CI, 0.54-1.08]); 36-month OS rates were 82.6% (zanubrutinib) and 79.7% (ibrutinib).

In this extended follow-up, median treatment duration was 34.7 months (zanubrutinib) and 31.5 months (ibrutinib). Across both arms, the most common reasons for treatment discontinuation were AEs (20.2%, zanubrutinib; 24.9%, ibrutinib) and progressive disease (12.2%, zanubrutinib; 16.3%, ibrutinib). Dose interruption and dose reduction due to AEs were 59.6% vs 61.1% and 14.2% vs 17.6% with zanubrutinib vs ibrutinib, respectively.

The most common AEs of any grade with zanubrutinib and ibrutinib were COVID-19 (37.3% vs 25.6%), diarrhea (17.9% vs 25.6%), and upper respiratory tract infection (25.9% vs 17.3%). Rates of any grade ≥3 AEs and serious AEs were 72.2% vs 75.6% and 49.7% vs 57.4% with zanubrutinib vs ibrutinib, respectively.

Most commonly reported grade ≥3 AEs were neutropenia (17.3% vs 16.4%) and hypertension (15.1% vs 12.0%). Rates of serious infections were 30.6% in each treatment arm. Discontinuation rates due to cardiac disorders were lower with zanubrutinib (0.6% [n=2]) vs ibrutinib (4.6% [n=15]).

Overall cardiac events remain lower with zanubrutinib, including atrial fibrillation/flutter (6.2% vs 16.0%; 2-sided P<.0001). Across this study, no grade 5 AEs due to cardiac disorders were observed with zanubrutinib but were reported in 6 patients (1.9%) with ibrutinib.

ALPINE was the first study to demonstrate PFS superiority in a head-to-head comparison of BTK inhibitors. At a median follow-up of 3 years, the study showed sustained PFS benefits of zanubrutinib over ibrutinib. The durable PFS benefits with zanubrutinib were observed across major subgroups, including multiple sensitivity analyses.

The overall safety/tolerability profiles were consistent with previous reports for both treatments.

The cardiac safety profile remained favorable for zanubrutinib compared with ibrutinib, with no new safety signals emerging with longer follow-up.

With over 3 years of treatment, zanubrutinib continues to be a more efficacious and better tolerated treatment than ibrutinib for patients with R/R CLL/SLL.

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 ASH Annual Meeting and Exposition, December 9-12, 2023. San Diego, California.

Videos

Jennifer R. Brown, MD, PhD, presents data from the extended follow-up of the ALPINE study investigating zanubrutinib in relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma.

Jennifer R. Brown, MD, PhD, director, CLL Center, Dana-Farber Cancer Institute, associate professor of Medicine, Harvard Medical School, discusses the recent progress seen in the treatment landscape of chronic lymphocytic leukemia (CLL), and what still needs to be accomplished going forward.

The real progress has come with multiple new drug approvals in the last few years, says Brown, which has provided several new treatment options that oncologists have never had in the relapsed/refractory setting of CLL.

One such drug is the BTK inhibitor ibrutinib (Imbruvica), which is approved in any line of therapy for patients. Another agent is idelalisib (Zydelig), a PI3k inhibitor, which has been approved in combination with rituximab (Rituxan) for relapsed patients with comorbidities. Moreover, in April 2016, venetoclax (Venclexta) was approved as a treatment for relapsed patients with 17p deletion.

According to Brown, this influx of new drugs for patients with CLL can be described as a sort of “embarrassment of riches.” However, at the same time, she says, there is still much to be learned about how to optimize the use of these drugs in this setting.

The current model calls for sequential single agents, though oncologists know that patients who relapse on ibrutinib, for example, can be quite hard to salvage. Brown says she and others in her field are unsure if such patients will have extended responses to subsequent agents.

Brown is mainly interested in combination therapies that could potentially achieve deeper remissions and allow patients to have longer breaks from therapy.

Jennifer R. Brown, MD, PhD, Director, CLL Center, Dana-Farber Cancer Institute, associate professor of Medicine, Harvard Medical School, discusses the recent progress seen in the treatment landscape of chronic lymphocytic leukemia (CLL), and what still needs to be accomplished going forward.

Jennifer R. Brown, MD, PhD

Articles

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)

Dr. Brown on Recent Progress in the Treatment Landscape of CLL