FDA Requires Randomized Data to Support PI3K Inhibitor Approvals

The Oncologic Drugs Advisory Committee (ODAC) convened a meeting on April 21, 2022, to review the data used to support phosphatidylinositol 3-kinase (PI3K – a class of medical drugs that are used mainly to treat advanced cancers) inhibitor approvals in hematologic malignancies. ODAC unanimously voted (16-0 with one abstention) that future approvals of PI3K inhibitors are to be supported by randomized controlled trials (RCTs) in which subjects are randomized to an active arm with the PI3K inhibitor or a comparator arm consisting of standard of care therapy, for example. Single-arm trials, where there is no direct comparator arm, will no longer be accepted as pivotal registration trials for PI3k inhibitors in hematologic malignancies.

This vote may bring frustration and trepidation to some sponsors and investors as this will dramatically increase spend and lengthen recruitment and enrollment timelines, as well as raise the bar for their PI3K inhibitor to demonstrate substantial evidence of effectiveness and safety when directly compared to a control arm. However, this decision gets at the core of our shared mission to impact human health by providing meaningful safe effective therapies to patients in need.

Overview of PI3K Inhibitor Approvals in Hematologic Malignancies

PI3K inhibitors have been approved under both traditional approval and accelerated approval pathways. Those approved under the accelerated approval pathway had to conduct post-approval confirmatory trials to confirm efficacy and safety. PI3K inhibitors have been approved in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), follicular lymphoma (FL), and marginal zone lymphoma (MZL) and are being developed in patients with B-cell and T-cell non-Hodgkin lymphoma (NHL). The initial approval pathway and endpoints, along with post-approval trials and outcomes, are outlined in Table 1.

Table 1: Status of FDA-Approved PI3K Inhibitors for Hematologic Malignancies

Source: U.S. Food and Drug Administration, ODAC Briefing Document, April 21, 2022, P. 12-13.

Core Issues Raised and Discussed at the FDA ODAC Meeting

The FDA has identified key issues with the development of PI3K inhibitors concerning endpoints, safety profile of PI3K inhibitors, inadequate dose optimization, and trial design. It was evident the FDA has the patient’s welfare at the center of the argument when Nicole Gormley, MD, Acting Division Director of Hematology products for the FDA stated: “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.” Three core issues discussed during the ODAC meeting were the endpoint of Overall Survival (OS), the toxicity profile of PI3K inhibitors, and dosing evaluation.

Overall Survival as both an efficacy and safety endpoint:

• OS is viewed as the “gold standard” endpoint in oncology trials, however, it is often not used as the primary endpoint to support initial approval due to duration needed to demonstrate a substantial effect. Thus, alternative endpoints such as progression-free survival (PFS) and overall response rate (ORR) are used as an intermediate endpoint to support approval, such is the case for the approved PI3K inhibitors (Table 1). In the case of approved PI3K inhibitors, although OS was not used as the primary efficacy endpoint to support approval, FDA requires the submission of survival data for drugs approved used PFS endpoints, since OS is both an efficacy and safety endpoint

Toxicity Profile of PI3K:

• Despite the improvements in ORR and/or improvements in PFS, PI3K inhibitors have also demonstrated substantial toxicity, which impacts the benefit: risk ratio to be considered for patients. Noteworthy toxicities include fatal or serious infections, neutropenia, and immune-related toxicities. Further, the distinct mechanisms of action of PI3K inhibitors result in a differentiated safety profile, depending on the isoform targeted (Phillips et al., 2021). Six randomized trials evaluating a PI3K inhibitor have demonstrated a higher rate of death or concerning OS results, which suggests potential harm to patients (Source: FDA Briefing Document)
• The observation of a potential detriment in OS across this many randomized trials is unprecedented in oncology. Because OS can only be meaningfully evaluated in randomized trials, these worrisome findings challenge the paradigm of basing accelerated approvals of PI3K inhibitors on single-arm trials and likely resulted in the 16-0 vote

Dosing:

• Consistent with the aims of FDA’s Project Optimus in which the initiative is to reform the dose optimization and dose selection paradigm in oncology drug development, the ODAC committee raised concerns with dose selection in PI3K inhibitor clinical trials. Early on in development trials, developers should evaluate doses to assess which doses can confirm the maximum efficacy while demonstrating the least amount of toxicity
• This dose optimization is especially important for PI3K inhibitors, which have a narrow dose range between effective and toxic doses. FDA stated in the FDA Briefing Document “For the PI3K inhibitor class of drugs, dose optimization was generally not achieved, in part because the focus was determining the maximum tolerated dose (MTD).” This approach assumes that maximum efficacy will be achieved at the MTD. The shortcoming of this approach is that lower doses, which may offer significant efficacy with reduced toxicity, are generally not explored extensively

Impacts to Future PI3K Inhibitor Development

While it is important that potentially lifesaving therapies make it into the hands of patients, it is also critical that those same therapies are both safe and effective. The exhibited toxicity of the PI3K inhibitors draws into question not only the benefit: risk ratio of those therapies, appropriate trial design, primary endpoints, and dose optimization.

Historically, PI3K Inhibitor drugs were approved based on single arm studies and intermediate primary end points (PFS, ORR). Due to the concerning toxicities of FDA approved PI3K Inhibitor class drugs, it is FDA’s view that randomized, controlled trials with a primary end point of OS may better support both safety and efficacy of these therapies. Additionally, optimizing dose range may greatly reduce toxicity concerns in the relevant patient population.

The ODAC decision will undoubtably cause frustration for investors and sponsors alike due to the increase spend, extension of timelines and recruitment, as well as increase data-based evidence requirements to support both safety and effectiveness of potential PI3K Inhibitor therapies. It will become incredibly important that sponsors consider FDA’s view on PI3K Inhibitor class drugs indicated to treat Hematologic Malignancies while designing their proposed clinical studies, selection of primary endpoints, and determining evidence-based dose selection. Determining benefit of risk ratio of PI3K inhibitors can only be done within the setting of randomized, controlled trials in which OS is both the efficacy and safety endpoint.

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If you have any questions about this regulatory update and want to further the discussion, please be in contact with the authors:

• Niki Gallo, Associate Principal Consultant, Regulatory Affairs, Halloran Consulting Group
• Genna Jenkins, Project Associate, Regulatory Affairs, Halloran Consulting Group

Our regulatory team will also be releasing insights on FDA’s Project Optimus (as referenced in this blog post) in the near future. Please check here for an update.

References:

Phillips TJ, Michot JM, Ribrag V. Can next-generation PI3K inhibitors unlock the full potential of the class in patients with B-cell lymphoma? Clin Lymphoma Myeloma Leuk 2021; 21(1): 8-20 e3.

U.S. Food and Drug Administration, Oncological Drugs Advisory Committee Meeting (ODAC) Briefing Document. (April 21, 2022). Phosphatidylinositol 3-Kinase (PI3K) Inhibitors in Hematologic Malignancies, pgs. 12-13. https://www.fda.gov/media/157762/download