PFS in relapsed/refractory CLL/SLL: Zanubrutinib triumphs over ibrutinib

The second-generation BTK* inhibitor zanubrutinib was superior to the standard-of-care ibrutinib in improving progression-free survival (PFS) among patients with relapsed/refractory chronic lymphocytic leukaemia (R/R CLL) or small lymphocytic lymphoma (SLL), according to results of the phase III ALPINE trial presented at ASH 2022.

“Zanubrutinib not only improves the response rate, it also improves PFS compared to ibrutinib, including in our highest-risk patients,” said Professor Jennifer Brown from the Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, US. [https://ascopost.com/news/december-2022/zanubrutinib-found-superior-to-ibrutinib-for-cll-and-sll/, accessed 27 December 2022]

The multinational, open-label trial involved 652 adults (median age 67 years, 14 percent Asian) with R/R CLL/SLL with exposure to ≥1 prior treatment (excluding a prior BTK inhibitor; 8 percent had prior exposure to >3 lines of treatment). They were randomized 1:1 to receive zanubrutinib (160 mg BID) or ibrutinib (420 mg QD) until disease progression or unacceptable toxicity.

Forty-five percent of patients had bulky disease at baseline, 73 percent had unmutated immunoglobulin heavy-chain variable region (IGHV) status, and 23 percent had a chromosome 17p deletion, TP53 mutation, or both.

 

Improved outcomes with zanubrutinib

Investigator-assessed overall response rate was higher in the zanubrutinib than ibrutinib group (83.5 percent vs 74.2 percent). [ASH 2022, abstract LBA-6; N Engl J Med 2022;doi:10.1056/NEJMoa2211582]

There were more patients on zanubrutinib than ibrutinib with an investigator-assessed partial response with lymphocytosis or better (89.9 percent vs 82.5 percent). Duration of response was not reached in the zanubrutinib and 33.9 months in the ibrutinib group. Investigator-assessed event-free response was noted in 79.5 and 71.3 percent of the zanubrutinib and ibrutinib groups, respectively, at 24 months.

At a median 29.6 months, patients assigned to zanubrutinib had significantly improved PFS (as per investigator assessment) compared with those assigned to ibrutinib, with the former showing superior efficacy over the latter with regard to this outcome (hazard ratio [HR], 0.65, 95 percent confidence interval [CI], 0.49–0.86; p=0.002). Median PFS was not reached in the zanubrutinib group and 34.2 months in the ibrutinib group. Two-year PFS rates were 78.4 and 65.9 percent for zanubrutinib and ibrutinib, respectively.

The investigator-assessed PFS benefit with zanubrutinib was consistent in high-risk patients with a 17p deletion, a TP53 mutation, or both (HR, 0.53, 95 percent CI, 0.31–0.88), with 2-year PFS rates of 72.6 and 54.6 percent for zanubrutinib and ibrutinib, respectively. The results were also consistent regardless of age, previous lines of therapy, disease stage, and IGHV mutational status.

The benefits of zanubrutinib over ibrutinib were also noted in the independent review analysis, said the authors.

At 24 months, 79.9 and 65.0 percent of patients in the zanubrutinib and ibrutinib groups, respectively, were free from treatment failure.

There was a trend toward improved overall survival with zanubrutinib vs ibrutinib at data cut-off (median not reached in either group; HR, 0.76, 95 percent CI, 0.51–1.11), with follow-up ongoing to assess this outcome.

 

Safety assessment

Zanubrutinib and ibrutinib recipients received treatment for a median 28.4 and 24.3 months, respectively. At data cut-off, 72.8 and 58.5 percent of patients were still receiving zanubrutinib and ibrutinib respectively. Adverse events (AEs) were the most common reason for treatment discontinuation (16.2 and 22.8 percent, respectively), followed by disease progression (7.3 and 12.9 percent, respectively).

Grade ≥3 AEs occurred in 67.3 and 70.4 percent of zanubrutinib and ibrutinib recipients, respectively, the most common (≥15 percent in either group) of which were neutropenia (16.0 percent vs 13.9 percent) and hypertension (14.8 percent vs 11.1 percent). Serious AEs occurred in 42.0 percent vs 50.0 percent and led to dose reduction in 12.3 percent vs 17.0 percent, dose interruption in 50.0 percent vs 56.8 percent, treatment discontinuation in 15.4 percent vs 22.2 percent, and death in 10.2 percent vs 11.1 percent.

Fewer cardiac events occurred in zanubrutinib than ibrutinib recipients (21.3 percent vs 29.6 percent), with one and 14 patients in the respective groups discontinuing treatment due to cardiac issues. All six cardiac event-related deaths were in ibrutinib recipients. The incidence of atrial fibrillation or flutter was lower in the zanubrutinib than ibrutinib group (5.2 percent vs 13.3 percent), including grade ≥3 events (2.5 percent vs 4.0 percent).

Any-grade neutropenia occurred in 29.3 percent vs 24.4 percent. Any-grade infections occurred in 71.3 percent vs 73.1 percent, with 26.5 percent vs 28.1 percent grade ≥3. Seven and 10 zanubrutinib and ibrutinib recipients, respectively, developed opportunistic infections. About 15 percent in each group used colony-stimulating growth factors. Any-grade hypertension occurred in 23.5 and 22.8 percent, respectively, and grade 3 hypertension in 15.1 and 13.6 percent, respectively, with no incidents of grade 4 hypertension.

 

A new standard emerges

“The BTK inhibitor drug class has been transformative for CLL therapy, but the first-in-class drug ibrutinib has been somewhat hard to tolerate for many patients, with cardiac side effects being one of the biggest problems,” Brown said. “We found that zanubrutinib caused fewer AEs, and in particular, much less cardiac toxicity.”

“The efficacy of zanubrutinib was superior to that of ibrutinib in patients with R/R CLL/SLL, and no new safety signals were observed,” said Brown and co-authors.

“PFS is pretty much our gold standard for efficacy, so our data suggest that zanubrutinib should really become the standard of care in this setting,” Brown concluded.