Zanubrutinib Pulls Away From Ibrutinib in Update, Shows Durable Responses in Waldenstrom Patients Lacking Key Mutation

Zanubrutinib, the BTK inhibitor approved by FDA to treat mantle cell lymphoma, showed an advantage over its competitor in new data and produced meaningful and durable responses in certain patients with Waldenstrom macroglobulinaemia (WM), even though they lacked a key mutation that has signaled successful treatment, according to updated results of the ASPEN trial.¹

Results were presented during American Society of Clinical Oncology 2020 annual meeting, which offered presentations online Friday.

In this rare form of lymphoma, MYD88 mutations are present in 95% of the patients, and Bruton tyrosine kinase (BTK) inhibitors have been effective in treating WM patients who have this mutation. Prior research shows poorer response rates and shorter progression-free survival (PFS) among those who lack the mutations. Complicating matters is the fact that diagnosing mutations in WM can be tricky.

Results from ASPEN released in December 2019, and updated at ASCO,² compared zanubrutinib to ibrutinib in WM patients with the MYD88 mutation. Early reactions were mixed. Some analysts noted that the ASPEN trial missed the goal of doubling ibrutinib’s rate of complete or very good partial responses, but others pointed to the fact that data showed zanubrutinib numerically outperformed ibrutinib, with 28.9% of relapsed or refractory patients achieving this mark, compared with 19.8% for ibrutinib. Results for all patients, including those starting treatment, were comparable—28.4% vs 19.2%.

In an interview with The American Journal of Managed Care®, lead investigator Constantine Tam, MBBS, MD, a clinical hematologist and professor at the Peter MacCallum Cancer Centre in Victoria, Australia, noted there were “some inbalances” in the randomization; more patients in the zanubrutinib arm were over age 75 and more were anemic.

Updated Data at ASCO

ASPEN did more follow-up in January, accruing another 5 months of data. “This is important,” Tam said. “The longer you take the drug, the better your responses become.” So, while the study technically did not meet its end point, Tam said the lines separating zanubrutinib and ibrutinib have diverged since the first results were announced. Data posted Friday showed the following:³

• Complete response (CR) plus very good partial response (VGPR) as assessed by investigator for zanubrutinib was 30.4% compared to 18.2% for ibrutinib (exploratory analysis; 2-sided descriptive P = .0302)
• Adverse events (AEs): Compared with ibrutinib, zanubrutinib had less atrial fibrillation/flutter of any grade (3.0% vs 18.4%), bleeding of any grade (50.5% vs. 60.2%), major hemorrhage (5.9% vs 10.2%), diarrhea (21.8% vs. 32.7%), and hypertension (12.9% vs 20.4%). Patients taking zanubrutinib did have more neutropenia (31.7% vs. 15.3%)
• Rates of grade ≥ 3 neutropenia were higher in the zanubrutinib arm (22.8% vs. 8.2% for ibrutinib); however, rates of infection were comparable among patients in both arms (all grade: 69.3% vs 71.4%; grade ≥ 3: 18.8% vs 23.5%)
• No additional patients stopped treatment due to AEs in the zanubrutinib arm, compared with 5 patients in the ibrutinib arm (4% vs 14.3%). Neither arm had additional patients with an AE leading to death (1.0% vs 4.1%).

Data From Patients Without Key Mutation

The early data did not include patients without MYD88 mutations. At enrollment in ASPEN, patients were assigned to cohorts based on mutation status. Today’s updated results cover 28 patients, including 26 who were WM with MYD88 wild type, enrolled in the cohort for patients lacking the mutation. Their median age was 72 years; 5 were not previously treated and 23 were relapsed/refractory. With a median follow-up of 17.9 months, results were the following:

• 2 patients stopped treatment due to adverse events
• 6 patients experienced disease progression
• the overall response rate (ORR) was 80.8%
• the ORR featured a major response rate of 50.0%, including a very good partial response rate of 26.9%
• PFS event-free rate at 12 months was 72.4%

Common AEs were diarrhea, anemia, contusion, pyrexia, and upper respiratory tract infection.

Importance of Safety Data

The early ASPEN results showed that zanubrutinib produced fewer serious adverse events (AEs) and fewer AEs that led to discontinuation. Patients taking zanubritinib were also far less likely to experience atrial fibrillation (2.0% vs 15.3%), hypertension (10.9% vs 17.3%) or major bleeding (5.9% vs 9.2%). Those taking zanubrutinib did experience more neutropenia (29.7% vs 13.3%).

But overall, do the results point to zanubrutinib for certain groups of patients with WM?

“At the moment, there’s not a whole lot of data about which patients get these other vascular side effects,” Tam said. ASPEN did not set out to study examine which drug was better for patients who have hypertension or related risk factors, and Tam noted the event rates were fairly low.

However, he said, one may come away from the study and say, “Well, those patients who potentially have a history of hypertension or have a history of atrial fibrillation—or have an abnormal ECG or abnormal echocardiogram—maybe they’re the ones who would be better of on [zanubrutinib] compared to ibrutinib.”

When asked if this second-generation BTK inhibitor would produce fewer cardiac effects, Tam said, “We think it’s how clean the targeting is.” The updated data being presented at ASCO show even greater differences between the 2 drugs in toxicity and atrial fibrillation, he said.

“It is nice to have a drug that is fairly clean,” Tam said. Zanubrutinib does have to be taken twice a day, but there is no fasting requirement . “From a side effect profile, it’s worth it,” he said.

Zanubrutinib, sold in the United States as Brukinsa by BeiGene, last year received the first FDA approval from data gathered mostly in China.

References

1. Garcia-Sanz R, Dimopoulos MA, Lee HP, et al. Updated results of the ASPEN trial from a cohort of patients with MYD88 wild-type (MYD88^WT) Waldenström macroglobulinemia (WM). J Clin Oncol 2020; 38 (suppl; abstr e20056) doi: 10.1200/JCO.2020.38.15_suppl.e20056.
2. Tam CSL, Opat S, D’Sa S, et al. ASPEN: Results of a phase III randomized trial of zanubrutinib versus ibrutinib for patients with Waldenström macroglobulinemia (WM). 2020; J Clin Oncol 38 (supp;abstr 8007). doi: 10.1200/JCO.2020.38.15_suppl.8007
3. BeiGene presents updated head-to-head results from phase 3 trial of zanubrutinib vs. ibrutinib in patients with Waldenström’s Macroglobulinemia at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program [press release]. Cambridge, MA, and Beijing, China: BeiGene; May 29, 2020. ir.beigene.com/news-releases/news-release-details/beigene-presents-updated-head-head-results-phase-3-trial?loc=US