John Pagel, MD, PhD, Discusses Dosing Regimens and Toxicity Associated With Zanubrutinib and Zandelisib

John Pagel, MD, PhD, from the Swedish Cancer Institute, spoke about the dosing regimen of zanubrutinib (Brukinsa) plus zandelisib as combination therapy for patients with B-cell malignancies treated on cohorts 10A and 10C of a phase 1 trial (NCT02914938). He also discusses significant adverse effects typically associated with PI3K inhibitors, which have not been seen thus far from these data.

Transcript:

In cohort 10A, there were very few patients enrolled who had a dose of zandelisib at 80 mg daily continually for 8 weeks before going to the [1 week on, 3 weeks off] approach. Zanubrutinib was also [given to patients] in cohort 10A at 160 mg orally twice daily. The follow-up was relatively short for assessing dose-limiting toxicities [DLTs], and that was amended in cohort 10C to allow for a longer follow-up for a DLT observation period of 56 days [using] even more tolerable doses of the combination. In cohort 10C, zandelisib was delivered at 60 mg daily, on days 1 through 7 of each 28-day cycle, again starting from cycle 1. There wasn’t continuous dosing daily for 2 months like there was in cohort 10A and the zanubrutinib is at a lower dose in cohort 10C, at 80 mg twice a day. The follow-up for assessing the dose-limiting toxicities is 56 days.

One of the major problems that we’ve had with PI3K inhibitors in the past has been their immune-mediated toxicities. It appears that with this novel strategy of combination therapy with an intermittent schedule of the PI3K inhibitor, zandelisib is well tolerated and does appear to strongly mitigate those immune-related toxicities. We are seeing low rates of transaminitis, colitis, and pneumonitis that suggest to us that this is an important regimen. This is also something that many patients who have relapsed disease can benefit from.

Compared with zandelisib as a monotherapy, there does not appear to be any increase in the incidence of adverse events that are commonly associated with PI3K inhibitors. We are not seeing transaminitis increases, colitis, rash, pneumonitis, or any infections of significance compared with the zanubrutinib monotherapy. The most common adverse event has been some neutropenia. Dose adjustments have suggested that [adverse events] are going to be much better tolerated as well from that standpoint.

Reference

Soumerai J, Jagadeesh D, Salman H, et al. Initial results of the combination of PI3Kδ inhibitor zandelisib (ME-401) and the BTK inhibitor zanubrutinib in patients (pts) with relapsed or refractory (R/R) B-cell malignancies. J Clin Oncol. 39 (supply15): 7553. doi: 10.1200/JCO.2021.39.15_suppl.7553