Zandelisib on Intermittent Dosing Schedule is Safe in R/R B-Cell Malignancies

Zandelisib (ME-401) given to patients with relapsed/refractory B-cell malignancies at 60 mg once a day using an intermittent dosing schedule demonstrated a promising safety profile and showed a low frequency of grade 3 or worse adverse events (AEs), according to results of a phase 1 trial (NCT02914938) published in The Lancet Oncology.¹

Findings revealed that the objective response rates were 92.0% (95% CI, 61.5%-99.8%) in both the 60 mg arm and 120 mg groups, and 83.0% (95% CI, 35.9%-99.6%) in the 180 mg group, showing similarity across all 3 arms.

Additionally, the median duration of treatment exposure was 15.2 months in the intermittent dosing group and 10.4 months in the continuous dosing group. Patients who remained on therapy had a median exposure duration of 18.6 months for intermittent dosing and 35.9 months for continuous dosing.

“Since immune-related toxicities have substantially limited the adoption of PI3Kδ inhibitors in clinical practice, we hypothesize that zandelisib has the potential to overcome the safety challenges of the PI3Kδ inhibitor class,” wrote the study authors. “Intermittent dosing did not result in reduced efficacy, as patients with follicular lymphoma, chronic lymphocytic leukemia or small lymphocytic lymphoma, or marginal zone lymphoma had high overall response rates, both overall (82% with follicular lymphoma [FL], 100% with chronic lymphocytic leukemia [CLL] or small lymphocytic lymphoma [SLL], and 100% with marginal zone lymphoma [MZL]) and across different subgroups by treatment and by dosing schedule.”

In this open-label, first-in-patient, dose-escalation and dose-expansion, phase 1b trial, investigators aimed to evaluate the safety and antitumor activity of zandelisib given with continuous or intermittent dosing as either a monotherapy or in combination with rituximab (Rituxan), in patients with relapsed or refractory B-cell malignancies.²

Enrollment in the trial was open to patients aged 18 years or older with relapsed or refractory B-cell malignancies. Patients must have had an ECOG performance status of 0-2, adequate renal function, hepatic function, adequate hematological parameters, received at least 1 previous systemic therapy for their B-cell malignancy, and have disease progression requiring therapy.

A total of 97 patients were enrolled and eligible for assessment. There were 31 patients included in the dose-escalation cohorts and 66 in the expansion cohorts. Within the dose escalation cohorts of the trial, patients with FL, CLL, or SLL received zandelisib at 60 mg (n = 13), 120 mg (n = 12), or 180 mg (n = 6).

Due to similarly high response rates and safety profiles between tested dose levels, dose escalation ended at 180 mg and the maximum tolerated dose was not determined. Because of this, 60 mg was deemed both the minimum biologically effective dose and recommended phase 2 dose for further evaluation.

Zandelisib monotherapy was given to 56 patients enrolled in the study, and 41 were treated with zandelisib and rituximab. A total of 59 patients were given zandelisib as intermittent dosing therapy and 38 received continuous dosing. Of the 38 patients in the continuous schedule dosing group who were still on the study treatment as of Jan 2, 2018, 21 (55%) were switched to intermittent dosing after a median of 7 cycles (range, 6-9) and the other 17 patients discontinued therapy before intermittent dosing was implemented. These patients received only continuous dosing. Among the 97 evaluable patients enrolled, 58 (60%) discontinued therapy, with 39 (40%) patients remaining on treatment after the cutoff date of September 2020.

In all 97 patients, safety was enrolled, and grade 3/4 AEs were observed in 44% of those in the intermittent dosing group and 76% in the continuous dosing group. The most frequent grade 3 or higher AEs included neutrophil count decrease (14%), diarrhea (11%), pneumonia (7%), alanine aminotransferase increase (5%), and colitis (3%).

A total of 39% of patients in the continuous dosing group and 44% in the intermittent group had their treatment interrupted due to AEs. In the continuous and intermittent dosing groups, serious AEs were observed in 34% vs 22%, and serious treatment-related AEs (TRAEs) occurred in 21% vs 8%, respectively. The most frequently reported serious TRAEs were pneumonia in 3 patients and diarrhea in 2 patients in the continuous group. In the intermittent group, the most frequent serious TRAEs were colitis in 3 patients and pneumonitis in 2. Further, grade 3 or higher AEs of special interest between both groups were diarrhea or colitis (24% vs 8%), and lung infection (16% vs 2%).

At a median follow-up of 24.9 months (95% CI, 6.5-33.9) in the continuous dosing group and 15.7 months (95% CI, 10.4-17.9) in the intermittent dosing group, the cumulative incidence of grade 3 or worse AEs was 45% in the continuous dosing group vs 20% in the intermittent dosing group. Additionally, there was a decreased cumulative hazard rate in the intermittent dosing group after switching to intermittent dosing.

Six of the 38 patients (16%) in the continuous dosing group ended up discontinuing treatment due to AEs after a median of 6.7 months (range, 4.8-10.3). These AEs included rash (n = 2), arthritis (n = 1), cardiomyopathy (n = 1), drug intolerance (n = 1), and diarrhea (n = 1). Within the intermittent dosing group, 6 of 59 patients (10%) ended up discontinuing treatment due to AEs after a median of 3.2 months (range, 2.6–8.8), including diarrhea (n = 3), pneumonitis (n = 1), rash (n = 1), and fungal infection (n = 1). Only 1 grade 5 AE was observed in a patient in the intermittent dosing group who died from COVID-19. However, this was not deemed to be related to treatment and there were no treatment-related deaths reported.

With positive safety and efficacy profiles, these data warrant the continuation of the ongoing global phase 2 trial (NCT03768505) evaluating zandelisib monotherapy after failure of at least 2 previous therapies in patients with FL or MZL and the phase 3 trial (NCT04745832) of zandelisib plus rituximab versus chemoimmunotherapy in patients with indolent non-Hodgkin lymphoma after failure of previous immunochemotherapy.

References:

1. Pagel JM, Soumerai JD, Reddy N, et al. Zandelisib with continuous or intermittent dosing as monotherapy or in combination with rituximab in patients with relapsed or refractory B-cell malignancy: a multicentre, first-in-patient, dose-escalation and dose-expansion, phase 1b trial. Lancet Oncol. 2022;23(8):1021-1030. doi:10.1016/S1470-2045(22)00333-3

2. A study of ME-401 in subjects with CLL/SLL, FL, and B-cell non hodgkin's lymphoma. ClinicalTrials.gov Updated December 15, 2021. Accessed August 2, 2022. https://clinicaltrials.gov/ct2/show/NCT02914938