3 FEATURE Indication Withdrawals of Small Molecule Inhibitors from the Accelerated Approval Program

Jiyeon Joy Park, PharmD, BCOP

Pharmacy Clinical Coordinator

PGY1 Pharmacy Residency Program Director

Englewood Health

David Awad, PharmD, BCOP

Clinical Pharmacy Specialist, Hematology/Oncology

Robert Wood Johnson University Hospital

Introduction

The United States Food and Drug Administration’s (FDA) Accel­erated Approval Program, which expedites approval of drugs and biologics that treat serious conditions such as cancer, has drawn criticism for allowing products to reach the market only to see their failure to confirm clinical benefit months to years later.1,2 Recent withdrawals of indications under the accelerated approval program include those of small molecule inhibitors.3

The Program, which began in 1992, allows for faster initial approval of drugs and biologics that treat serious conditions such as cancer. The Program approves products based on a surrogate endpoint, which helps shorten the approval process. Once the drug or biologic is approved through the Program, the manufacturer must conduct a subsequent confirmatory trial to obtain traditional approval of the drug.4 If the confirmatory trial does not verify clinical benefit, the manufacturer may volun­tarily withdraw the product, or the FDA may withdraw it after a public hearing.5 Although the Program has been running for more than three decades, the majority of oncology indication withdrawals have occurred in the last 3 years. In 2021, many of the immune checkpoint inhibitor indications were withdrawn. Recently, small molecule inhibitors such as ibrutinib, umbralisib, idelalisib, duvelisib, and panobinos­tat have accounted for the majority of the indication withdrawals.3

In response to criticism, the FDA issued guidance in March 2023 that recommends manufacturers conduct randomized con­trolled trials rather than single-arm trials to support accelerated approval. The guidance also recommends that manufacturers per­form blinded independent central review of the response assess­ment to minimize bias and variance in the assessment of tumor response.6,7 This article seeks to summarize the recent indication withdrawals of small molecule inhibitors and how pharmacists and healthcare professionals can help manage patients who may be affected by these withdrawals. Table 1 provides a list of recently withdrawn indications of small molecule inhibitors.

"With the FDA’s recent guidance provided to manufacturers to improve the transparency of accelerated approvals, costly withdrawals of drugs and biologics may be prevented in the future."

Withdrawal of Ibrutinib for Relapsed or Refractory Mantle Cell Lymphoma

In 2013, the FDA granted accelerated approval to ibrutinib for pa­tients with mantle cell lymphoma (MCL) who have received at least one prior therapy. The accelerated approval was based on a non-ran­domized, open-label phase 2 study (NCT01236391) in patients with relapsed/refractory (R/R) MCL who received ibrutinib.8 The study reported an overall response rate (ORR) of 68% (47% partial response [PR] and 21% complete response [CR]) with an estimated median follow-up of 15.3 months.8 The phase 3 confirmatory trial (SHINE study, NCT01776840) analyzed previously untreated stage II to IV MCL patients receiving either ibrutinib in combination with bendamustine and rituximab (BR) or placebo in combination with BR.9 Although the median progression-free survival (PFS) was longer in the ibrutinib group vs the placebo group (80.6 vs 52.9 months; HR 0.75; 95% CI 0.59-0.96; p=0.01), the overall survival (OS) at 7 years was similar between the two groups (55.0% vs 56.8%; HR 1.07; 95% CI 0.81-1.40). The ibrutinib group also had a higher rate of grade 3 or 4 adverse events (81.5 vs 77.3%) and a higher rate of death from adverse effects (10.7 vs 6.1%) compared to the placebo group.9 As a re­sult of the SHINE study, on April 6, 2023, AbbVie and Janssen, the manufacturers of ibrutinib, announced a voluntary withdraw of ibrutinib for R/R MCL. Ibrutinib was of­ficially withdrawn on May 18, 2023 for this indication.10,11

Alternative Bruton’s tyrosine kinase (BTK) inhibitors such as acalabrutinib and zanubrutinib are available as second-line treatment options for MCL, and pirtobru­tinib is available as a third-line option.12–14 Acalabrutinib and zanubrutinib are known to be more selective than ibrutinib for BTK with less off-target effects.15,16 In patients with brain metastases, although rare in MCL, data concerning the efficacy of BTK inhibitors other than ibrutinib are scarce.17,18 The withdrawal of ibrutinib for the MCL indication may pose challenges in treating MCL with central nervous system involvement. Clinicians should determine whether to continue treating these patients with ibrutinib off-label, which may or may not be covered under insurance policies. Of note, the National Comprehensive Cancer Network (NCCN) guidelines still have a category 2A recommendation for ibrutinib for R/R MCL as of June 2, 2023, although it is no longer listed under preferred regi­mens.19 The guideline recommendation may help mitigate insurance issues. Clinicians should also note that acalabrutinib, zanubrutinib, and pirtobrutinib were all approved under the accelerated approval process, with confirmatory trials projected for completion in 2024, 2027, and 2026 respectively.21 Clinicians should select appropriate