Zandelisib Elicits High Response Rates in Indolent Non-Hodgkin Lymphoma

The oral PI3Kδ inhibitor zandelisib (ME-401) produced an overall response rate (ORR) in Japanese patients with relapsed/refractory indolent B-cell non-Hodgkin lymphoma (iB-NHL) without small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL), and Waldenström macroglobulinemia (WM), according to data from the phase 2 MIRAGE trial (NCT04533581).¹

Among 61 enrolled patients, the ORR was 75.4% (95% CI, 62.7%-85.5%) with a complete response (CR) rate or 24.6% (95% CI, 14.5%-37.3%). At the time of data cutoff, the final duration of response (DOR) was not yet estimable.

“We continue to see a favorable profile of zandelisib with intermittent dosing that aims to balance efficacy and safety in Japanese patients who have been heavily pretreated,” Yoshifumi Torii, PhD, executive officer, vice president, and head of R&D Division at Kyowa Kirin, stated in a press release. “These results are consistent with the data of the similarly designed [phase 2] TIDAL study [NCT03768505] already announced in November 2021. We remain committed to maximizing the value of zandelisib in B-cell malignancies with our partner MEI Pharma and bringing hope to lymphoma patients around the world."

In the TIDAL trial, single-agent zandelisib demonstrated an ORR of 70.3% by an independent review committee assessment in patients with follicular lymphoma (FL) patients who received at least two prior systemic therapies (n = 91). Notably, 35.2% of those patients achieved a CR.

The multicenter, open-label, single-arm MIRAGE trial evaluated zandelisib monotherapy in Japanese patients at least 20 years of age with relapsed/refractory iB-NHL who received at least 2 prior systemic therapy. Patients were not permitted to have prior treatment with PI3K or BTK inhibitors, and they needed to have an ECOG performance status of 0 or 1.²

Patients with iB-NHL categorized as SLL, LPL, or Waldenström macroglobulinemia by WHO classification were not allowed to enroll. Other exclusion criteria included histologically confirmed FL Grade 3b transformation from FL to an aggressive lymphoma at least once, lymphomatous involvement of the central nervous system, uncontrolled clinically significant illness, or active or a history of interstitial lung disease.

Enrolled patients received 60 mg of oral zandelisib once per day during the first two 28-day cycles, followed by 60 mg of oral zandelisib once per day for the first 7 days of each subsequent 28-day cycle.

ORR up to approximately 2 years served as the trial’s primary end point. Secondary end points included DOR, progression-free survival, CR rate, time to treatment failure, ORR, and safety up to approximately 4 years.

The median age of enrolled patients was 70 years, and the median number of prior therapies was 3 (range, 2-9).

Regarding safety, at a median follow-up of 9.5 months (95% CI, 8.0-11.1), 14.8% of patients discontinued treatment due to any treatment-emergent adverse effect (AEs). Grade 3 AEs of special interest included increased aspartate aminotransferase and alanine transaminase (8.2%), rash (3.3%), diarrhea (1.6%), colitis (1.6%), and lung infection (1.6%).

In March 2020, the FDA granted a fast track designation to zandelisib for the treatment of adult patients with relapsed/refractory follicular lymphoma who have received at least 2 prior systemic therapies. In November 2021, the FDA granted an orphan drug designation to zandelisib for the treatment of patients with follicular lymphoma.

References

1. Kyowa Kirin and MEI Pharma announce topline data from the phase 2 MIRAGE study evaluating zandelisib in patients with indolent B-cell non-Hodgkin’s lymphoma in Japan. News release. Kyowa Kirin. November 18, 2022. Accessed November 21, 2022. http://bit.ly/3AxOQLc
2. Study of ME-401 in subjects with relapsed or refractory indolent B-cell non-Hodgkin's lymphoma (NHL). ClinicalTrials.gov. Updated December 27, 2021. Accessed November 21, 2022. https://clinicaltrials.gov/ct2/show/NCT04533581