FDA’s ODAC Casts Unanimous Vote for Randomized Data to Support PI3K Inhibitor Approvals in Hematologic Malignancies


A unanimous vote cast by the FDA’s Oncologic Drugs Advisory Panel highlighted a need for randomized clinical trial data to support FDA approvals of PI3K inhibitors for patients with hematologic malignancies.

The FDA's Oncologic Drugs Advisory Committee (ODAC) met on April 21, 2022 and voted 16-0 with a single abstention to recommend that future approvals of PI3K inhibitors for patients with hematologic cancers be supported by randomized clinical data.1,2

“The bottom line is, if we aren’t improving length of life with any therapy but exposing patients to toxicity and therefore decreasing their quality of life, are we truly helping our patients? I don’t believe so,” Christopher Lieu, MD, associate director for clinical research and co-director of gastrointestinal medical oncology at the University of Colorado Cancer Center, said in a press release.3

Several PI3K inhibitors have received FDA approval in the hematologic space based on single arm findings, including idelalisib (Zydelig), which was approved in July 2014 in chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), and follicular lymphoma; copanlisib (Aliqopa), which was approved in September 2017 for previously treated relapsed follicular lymphoma; duvelisib (Copiktra), which was approved in September 2018 for previously treated CLL and SLL; and umbralisib (Ukoniq), which was approved for marginal zone lymphoma (MZL) and follicular lymphoma in February 2021 following 1 previous anto-CD20 therapy and 3 systemic therapies, respectively.

However, 2 of these drugs have since been removed from the market. Duvelisib was withdrawn from its relapsed/refractory follicular lymphoma indication in December 2021 after a drug and holding discussion with the FDA. Although development was set to continue for patients with T-cell lymphoma, the regulatory organization cited that the cost, logistics and timing for the post-marketing requirements were no longer warranted. An application for umbralisib and ublituximab was also withdrawn for CLL and SLL in April 2022. Additionally, in light of this decision, umbralisib was withdrawn from sale in its approved indications for MZL and follicular lymphoma. The decision was based on an increasing imbalance in overall survival (OS) between study arms in the phase 3 UNITY-CLL trial (NCT02612311).

Despite yielding promising responses and improved progression-free survival in patients with hematologic cancers, the ODAC panel cited that randomized data in this class of drug highlighted a high rate of fatal adverse effects (AEs) and other serious AEs compared with single-arm research. In particular, the regulatory organization stated that single-arm studies have limitations that could provide challenges in balancing efficacy and AEs.

Specifically, patients with CLL and indolent non-Hodgkin lymphoma appear to experience a worse OS following treatment with a PI3K inhibitor compared with patients in the control arm. The class of drug has also raised safety concerns, with gamma- and delta-isoform–specific inhibitors, which yield AEs such as colitis, pneumonia, and rashes leading to some fatal infections. Other concerns include the issue as to whether dosage levels have been properly assessed to combat toxicities and maintain efficacy—a problem that could be addressed with randomized clinical research.

“While we definitely want to expedite drug development and make sure there are new therapies available to patients as soon as possible, it’s imperative, in our view, that we ensure those products are safe and effective,” Nicole Gormley, MD, acting division director of hematology products for the FDA, concluded.


  1. Meeting of the oncologic drugs advisory committee (ODAC) day 1. FDA. Accessed April 22, 2022. https://bit.ly/3rIDHCw
  2. PI3K inhibitors in hematologic malignancies ODAC briefing document. FDA. Accessed April 22, 2022. https://bit.ly/36CFphH
  3. FDA advisory panel calls for randomized data for PI3K inhibitor approvals for blood cancers. News release. OBR Oncology. April 22, 2022. Accessed April 22, 2022. https://bit.ly/3EEBqxz
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