FDA Discourages Marketing Authorization for Zandelisib in Patients With FL or MZL

The FDA discouraged marketing authorization for zandelisib based data from the phase 2 TIDAL study which examined the PI3K inhibitor in subjects with relapsed/refractory follicular lymphoma or marginal zone lymphoma.

The FDA discouraged marketing authorization for zandelisib (ME-401), a phosphatidylinositol-3-kinase (PI3K) inhibitor drug candidate by way of the accelerated approval pathway under 21 CFR Part 314.500, for patients with relapsed/refractory follicular lymphoma (FL) or marginal zone lymphoma (MZL) according to a press release from MEI Pharma, Inc.1

The recommendation is based on data generated by the single arm phase 2 TIDAL study (NCT03768505) which examined zandelisib in subjects with relapsed/refractory FL or MZL after failure of at least 2 prior lines of systemic therapy.2

"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 ODAC 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," said Daniel P. Gold, PhD, president and chief executive officer of MEI Pharma in the press release.

In November 2021, MEI Pharma announced data from the multicenter, open-label, single arm TIDAL study which enrolled a total of 121 patients into the relapsed/refractory FL cohort who had received at least two prior systemic therapies. The median age of patients with FL was 64 years old and patients enrolled in both the FL primary efficacy and total patient populations received a median of 3 prior lines of treatment (range, 2-8).

Eligibility for TIDAL was open to patients aged 18 and older with confirmed FL or MZL. Other requirements included to have at least 1 measurable nodal lesion, have adequate hematological, renal, and hepatic parameters at screening, and a left ventricle ejection fraction of ≥ 45%.

Patients were administered zandelisib at 60mg orally, once a day on an intermittent schedule. The primary end point of the study is objective response rate (ORR). Secondary end points include duration of response (DOR), complete response (CR), progression-free survival, overall survival (OS), and the overall incidences of treatment-emergent adverse events (TEAEs).

Findings showed zandelisib to demonstrate a 70.3% ORR as determined by Independent Review Committee assessment in the primary efficacy population (n = 91). A total of 35.2% of patients achieved a CR and at the time of the data cutoff, the data were insufficiently mature to accurately estimate duration of response (DOR).

In line with previously reported data, zandelisib was generally well tolerated. At a median duration follow-up of 9.4 months (range, 0.8-24) in the total study population (n = 121), interim data showed a discontinuation rate due to any zandelisib adverse event of 9.9%. Ongoing studies of TIDAL would evaluate patients with MZL as well as a continued follow up in the FL cohort.

In the meeting, the FDA informed the company that a randomized trial is needed to adequately assess the efficacy and safety of PI3K inhibitor drug candidates, including zandelisib. The FDA also emphasized that they should continue efforts as planned with the ongoing, randomized phase 3 COASTAL study (NCT04745832) which looks to compare zandelisib in combination with rituximab (Rituxan), in comparison to standard immunochemotherapy for patients with relapsed/refractory FL or MZL.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. Today’s announcement in no way diminishes our conviction to the development of zandelisib and the promise of its emerging clinical profile,” said Gold.

The open label, two-arm COSTAL study in subjects with relapsed or refractory FL and MZL aims to enroll approximately 534 subjects who have relapsed after at least 1 line of previous systemic immunochemotherapy.

Inclusion in the trial is open to individuals aged 18 years and older with a histologically confirmed diagnosis FL or MZL. Additionally, subjects with relapsed or refractory disease who received ≥1 prior lines of therapy, at least one bi-dimensionally measurable lesion >1.5 cm, adequate hematologic parameters at screening, adequate renal and hepatic function, and adequate cardiac function based on ECG and LVEF assessments were eligible for enrollment.

In one of the experimental arms, patients will be administered rituximab plus zandelisib for 6 cycles followed by zandelisib for 20 cycles while in the other, they will be given rituximab plus chemotherapy for 6 cycles.

The primary end point of the trial is progression-free survival defined as the time from randomization until the date of disease progression, or death from any cause with secondary end points include ORR, OS, and complete response rate number of TEAEs.

“[W]e 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. 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,” stated Gold.

  1. MEI Pharma and Kyowa Kirin provide regulatory update on zandelisib following meeting with the FDA. News Release. Mei Pharma; March 24, 2022. Accessed March 25, 2022. https://bit.ly/3tEdre9
  2. Zandelisib (ME-401) in Subjects With Follicular Lymphoma or Marginal Zone Lymphoma After Failure of Two or More Prior Therapies (TIDAL). Clinicaltrials.gov. Accessed March 25, 2022.https://clinicaltrials.gov/ct2/show/NCT03768505
  3. Phase 3 Study of Zandelisib (ME-401) in Combination With Rituximab in Patients With iNHL - (COASTAL). Clinicaltrials.gov. Accessed March 25, 2022. https://clinicaltrials.gov/ct2/show/NCT04745832