FDA Withdraws Approvals for Umbralisib in Marginal Zone and Follicular Lymphoma

The FDA has withdrawn its approval for the umbralisib, which had previously been approved for marginal zone lymphoma and follicular lymphoma.

The FDA has withdrawn its approval for the oral inhibitor of PI3K-δ and CK1-ε, umbralisib (Ukoniq), which had previously been approved for marginal zone lymphoma (MZL) and follicular lymphoma (FL).1

Umbralisib previously received accelerated approval in February 2021 as treatment for adults with MZL following at least one prior anti-CD20-based regimen and adults with relapsed or refractory FL who had received at least 3 prior lines of systemic therapy.2

However, safety concerns emerged in February 2022 after findings from the phase 3 UNITY-CLL trial (NCT026112311) suggested that umbralisib may be associated with an increased risk of death in patients.3

Now the FDA has announced that health care professionals should immediately stop prescribing umbralisib and instead, change to giving patients alternative treatments. As for patients, it is recommended to return the unused drug to a take-back location such as a pharmacy or safely dispose of it.

"Updated findings from the UNITY-CLL clinical trial continued to show a possible increased risk of death in patients receiving Ukoniq. As a result, we determined the risks of treatment with Ukoniq outweigh its benefits," the FDA wrote in the press release.

For patients deriving benefit, the company plans to make umbralisib available in limited circumstances under expanded access.

In April 2022, the drugs manufacturer, TG Therapeutics, also pulled umbralisib from the market and voluntarily withdrew a biologics license application and supplemental new drug application seeking approval for umbralisib plus ublituximab (TG-1101) in adults with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) in April 2022.4

The decision to withdraw is based off of UNITY-CLL, in which investigators evaluated umbralisib/ublituximab (U2) vs obinutuzumab (Gazyva)/chlorambucil in patients with treatment-naïve or relapsed/refractory CLL.5

Within the trial, 421 patients were enrolled in the primary analysis. Participants were randomly assigned to 1 of 4 arms consisting of either ublituximab monotherapy, umbralisib monotherapy, U2, or obinutuzumab/chlorambucil.

Based on the contribution of U2 in the combination arm for the prespecified interim analysis, investigators permitted the termination of the single-agent arms.

Findings revealed that U2 significantly improved progression-free survival (PFS) when compared with the control regimen in those with CLL (31.9 vs 17.9 months, respectively; HR, 0.546; 95% CI, 0.413-0.720; P < .0001). However, a potential increased risk for death was also examined by the investigators within patients who received the U2 regimen.

In February, it was determined by the FDA that those receiving the combination were also experiencing more serious adverse effects (AEs) than those in the control arm. Although the study looked at patients specifically with CLL, the concern of those findings in regard to patients prescribed U2 for MZL or FL was high enough to be flagged for safety concerns.1

  1. FDA approval of lymphoma medicine Ukoniq (umbralisib) is withdrawn due to safety concerns. News release. FDA. June 1, 2022. Accessed June 2, 2022. https://bit.ly/3NdNE3P
  2. FDA grants accelerated approval to umbralisib for marginal zone lymphoma and follicular lymphoma. News release. FDA. February 5, 2021. Accessed June 2, 2022. https://bit.ly/3NgZday
  3. FDA investigating possible increased risk of death with lymphoma medicine Ukoniq (umbralisib). News release. FDA. February 3, 2022. Accessed June 2, 2022. https://bit.ly/3alt9U0
  4. TG Therapeutics announces voluntary withdrawal of the BLA/sNDA for U2 to treat patients with CLL and SLL. News release. TG Therapeutics, Inc.; April 15, 2022. Accessed June 2, 2022. https://bit.ly/3ze1QFC