FDA Discourages Pursuit of Marketing Authorization for Zandelisib in MZL, Follicular Lymphoma


The FDA has discouraged the pursuit of a marketing authorization of the PI3K inhibitor zandelisib in patients with follicular lymphoma or marginal zone lymphoma, citing the need for randomized trial data.



The FDA has discouraged the pursuit of a marketing authorization of the PI3K inhibitor zandelisib (ME-401) in patients with follicular lymphoma or marginal zone lymphoma (MZL) via the accelerated approval pathway under 21 CFR Part 314.500, subpart H.1

The regulatory agency stated that a randomized trial is needed to effectively evaluate the safety and efficacy of PI3K inhibitor candidates, including zandelisib. As such, a filing based on the phase 2 TIDAL trial (NCT03768505), which examined zandelisib in patients with relapsed or refractory follicular lymphoma or MZL after at least 2 prior lines of systemic treatment, is discouraged.

The agency emphasized that efforts to launch the phase 3 COASTAL trial (NCT04645832) should continue as planned. The FDA also stated that although the intermittent dosing schedule of 60 mg with zandelisib appears reasonable, continued dose exploration is recommended to further support the current dose and regimen.

MEI Pharma, Inc. and Kyowa Kirin Co, Ltd., shared that in accordance with the regulatory agency’s recommendation, they will not submit the application based on TIDAL.

“The FDA’s current position on the assessment of benefit and risk of PI3K inhibitors solely based on single-arm studies appears to have evolved, as evidenced by the position the FDA communicated at the recent meeting on zandelisib, and the upcoming Oncologic Drug Advisory Committee meeting scheduled for April 21, 2022 to discuss whether randomized data should be required for the class of PI3K inhibitors to demonstrate appropriate evidence of efficacy and safety,” Daniel P. Gold, PhD, president and chief executive officer of MEI Pharma, stated in a press release.

The global, phase 2 TIDAL trial is examining single-agent zandelisib across 2 cohorts: those with relapsed or refractory follicular lymphoma and those with relapsed or refractory MZL. To be eligible for participation, patients needed to have experienced progressive disease on at least 2 previous systemic therapies, including chemotherapy and an anti-CD20 antibody.2

The primary end point of the trial is ORR, and a key secondary end point is duration of response (DOR) in the primary efficacy population of patients with follicular lymphoma.

A total of 121 patients were enrolled to the follicular lymphoma cohort, 91 of which comprised the primary efficacy population. The median age of these patients was 64 years, and the median of prior lines of therapy received was 3 (range, 2-8).

Study participants were given zandelisib once daily for two 28-day treatment cycles as response induction therapy followed by once-daily dosing for the first 7 days of each subsequent 28-day cycle.

Data presented during the 2021 ASH Annual Meeting showed that at a minimum follow-up of 6 months, zandelisib produced an objective response rate of 70.3% (95% CI, 59.8%-79.5%) per independent review committee assessment in the primary efficacy population, which included a complete response rate of 35.2% (95% CI, 25.4%-45.9%). At a median follow-up of 8.4 months, which was immature, the median DOR had not yet been reached.

The agent was found to be generally well tolerated. Adverse effects of special interest that were grade 3 or higher in severity included alanine aminotransferase or aspartate aminotransferase increased (1.7%), colitis (1.7%), diarrhea (5%), mucositis (2.5%), pneumonitis (0.8%), and rash (3.3%).

“Clearly, the outcome of our recent FDA meeting is a disappointing development. Nonetheless, we will continue to focus on the ongoing phase 3 COASTAL study as we consider options that provide the most expeditious approval pathway utilizing randomized data, and which we believe will demonstrate the potential of zandelisib to help patients,” Gold added.

The open-label, controlled, multicenter, phase 3 COASTAL trial (NCT04745832) will evaluate zandelisib in combination with rituximab (Rituxan) vs standard treatment with chemoimmunotherapy in patients with relapsed or refractory indolent non-Hodgkin lymphoma (NHL).3

To be eligible for enrollment, patients need to have a histologically confirmed diagnosis of CD20-positive NHL with histological subtype limited to grade 1, 2, or 3a follicular lymphoma and splenic, nodal, or extra-nodal MZL.

Patients must have relapsed or refractory disease and have received at least 1 prior line of therapy, which must have included an anti-CD20 antibody plus chemotherapy or lenalidomide (Revlimid). They also need to have at least 1 bi-dimensionally measurable lesion, an ECOG performance status of 0 or 1, and acceptable hematologic, renal, and hepatic function.

If patients had a histologically confirmed diagnosis of follicular grade 3b or transformed disease, received rituximab plus bendamustine and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as prior lines of treatment, or only received single-agent anti-CD20 monoclonal antibody therapy as a prior line of treatment, they will be excluded.

Other exclusion criteria include having received prior PI3K inhibitors, ongoing or a history of drug-induced pneumonitis, known lymphomatous involvement of the central nervous system, or being seropositive for an active infection with hepatitis B virus, or hepatitis C virus, human immunodeficiency virus.

The trial is planned to enroll 534 patients who will be randomized 1:1 to receive zandelisib plus rituximab for 6 cycles then zandelisib alone for 20 cycles or rituximab plus bendamustine or R-CHOP for 6 cycles.

The primary objective of the trial is to show that the combination of zandelisib and rituximab is superior to that of standard chemoimmunotherapy with regard to improving progression-free survival per independent response review committee (IRRC) assessment in previously treated patients with follicular lymphoma and MZL.

Key secondary objectives include overall response rate per IRRC assessment, overall survival, patient-reported outcomes, as well as safety and tolerability.

“In partnership with Kyowa Kirin, we remain committed to the ultimate potential of zandelisib to address important medical needs as a single agent or in combination with other therapies providing physicians, and their patients, important new treatment options,” Gold concluded. “We plan on completing evaluation of the phase 2 TIDAL study, and look forward to sharing final data later this year to further advance an understanding of zandelisib’s clinical utility.”


  1. MEI Pharma and Kyowa Kirin provide regulatory update on zandelisib following meeting with the FDA. News release. MEI Pharma, Inc. and Kyowa Kirin Co, Ltd; March 24, 2022. Accessed March 25, 2022.
  2. MEI Pharma and Kyowa Kirin announce data from the ongoing global phase 2 TIDAL study evaluating zandelisib as a single agent in patients with relapsed or refractory follicular lymphoma. News release. Mei Pharma. November 30, 2021. Accessed March 25, 2022.
  3. Jurczak W, Zinzani PL, Cunningham D, et al. Coastal: a phase 3 study of the PI3Kδ inhibitor zandelisib with rituximab (R) vs immunochemotherapy in patients with relapsed indolent non-Hodgkin’s lymphoma (iNHL). J Clin Oncol. 2021;39(suppl 15):TPS7573. doi:10.1200/JCO.2021.39.15_suppl.TPS7573
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