The more selective BTK inhibitor zanubrutinib offers better tolerability and possibly better efficacy than ibrutinib for patients with Waldenström macroglobulinemia, an Australian study has shown.

Presented at the ASCO 2020 virtual meeting by Professor Con Tam of the Peter MacCallum Cancer Centre in Melbourne, the results of the ASPEN Phase III study showed zanubrutinib was less cardiotoxic than ibrutinib and had a trend to better outcomes in terms of  complete response (CR) and very good partial response (VGPR) rates.

The trial was done to investigate the hypothesis that zanubrutinib  would have more efficacy and fewer side effects because it is a potent next-generation BTK inhibitor designed to maximize BTK occupancy and with more selectivity than ibrutinib to minimize off-target inhibition.

In the study, 201 patients with Waldenström macroglobulinemia and a MYD88 mutation were randomized to either twice-daily zanubrutinib 160 mg (n=102) or once-daily ibrutinib 420 mg (n=99).

After a median follow up of 19.4 months, there were few CR, and the combined CR and VGPR rates were  19.2% for ibrutinib and 28.4%, which did not meet statistically significant (p-value  0.0921).

However Professor Tam noted that in subsequent follow up after a further five months the investigator-rated responses were significantly better for zanubrutinib, with a VGPR rate   up to 30.4% on the zanubrutinib arm vs 18.2% for ibrutinib (p value 0.0302).

For progression-free survival  at 12 months, the rates were 89.7% for zanubrutinib and 87.2% for ibrutinib.  IgM reduction was also faster and deeper for patients receiving zanubrutinib as compared to ibrutinib with a p-value of 0.037.

In terms of adverse events, atrial fibrillation and flutter rates were seven-fold lower for zanubrutinib (2% vs 15.3% for ibrutinib), with a highly significant p-value. Patients treated with zanubrutinib also had lower rates of major haemorrhage (5.9% vs 9.2%) diarrhoea (20.8% vs 31.6%) and  hypertension (10.9% vs 17.3%) compared with ibrutinib. There was an increased range of neutropenia and associated events for patients treated with zanubrutinib but this did not translate into greater rates of severe or total infections, which were equivalent for both drugs.

“True to our study hypothesis, zanubrutinib, being a more targeted drug, may be associated with fewer side effects and better tolerability,” said Professor Tam.

“In general, zanubrutinib was better tolerated, with fewer adverse events leading to death, treatment discontinuation, or treatment interruption.”

Commenting on the findings in a ASCO 2020 discussion session, Dr Krish Patel, Director of the Lymphoma Program at the Swedish Cancer Institute (SCI) in Seattle,  said the ASPEN study showed that the degree of selectivity of BTK inhibitors has an impact on specific adverse events.

“Beyond the potential impact on long-term mortality for our patients, the financial impact of hypertension, atrial fibrillation, and other cardiac events to society is substantial. Given that most patients with lymphoid malignancies treated with BTK inhibitors are older than age 60, the consequences of these differing toxicity profiles may have important health economic events,” he said