Introduction
Alisertib, also known as MLN8237, is a selective, small-molecule inhibitor of aurora kinase A, a critical enzyme involved in cell division. Developed by Puma Biotechnology, alisertib has been under extensive clinical evaluation for various types of cancers, including small cell lung cancer (SCLC) and breast cancer. Here, we delve into the current development status and market projections for this promising drug candidate.
Clinical Development Overview
Small Cell Lung Cancer (SCLC)
Alisertib has shown significant promise in the treatment of extensive-stage small cell lung cancer (ES-SCLC). The FDA granted alisertib an orphan drug designation for this indication, highlighting the urgent need for new treatments in this area[1].
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PUMA-ALI-4201 Trial: This phase 2 trial is designed to evaluate alisertib as a monotherapy in patients with ES-SCLC whose disease has progressed following first-line platinum-based chemotherapy and immunotherapy. Patients will receive alisertib at 50 mg twice daily on days 1 to 7 of every 21-day cycle. The primary endpoint is the objective response rate (ORR), with secondary endpoints including duration of response, disease control rate, progression-free survival (PFS), and overall survival[1][5].
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Previous Data: In a previous phase 2 trial, alisertib demonstrated an ORR of 21% in patients with SCLC, with all responses being partial. The most common grade 3/4 treatment-related adverse effects included neutropenia, leukopenia, and anemia[1][4].
Breast Cancer
Alisertib is also being developed for the treatment of various types of breast cancer, including metastatic estrogen receptor-positive (ER-positive) HER2-negative breast cancer and triple-negative breast cancer.
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TBCRC-041 Trial: This randomized phase 2 trial evaluated alisertib alone versus alisertib plus fulvestrant in patients with endocrine and CDK4/6 inhibitor-resistant metastatic breast cancer. The trial showed response rates of 17.8% and 20.0% for the alisertib alone and combination arms, respectively, with median PFS of 5.6 and 5.1 months[2][4].
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Future Trials: Puma Biotechnology plans to initiate additional phase 2 trials, including ALISCA-Breast1, which will evaluate alisertib in combination with endocrine treatment in chemotherapy-naïve HER2-negative, hormone receptor-positive metastatic breast cancer[5].
Safety and Efficacy Profile
Safety
Alisertib's safety profile has been consistent across various clinical trials. The most common grade 3/4 treatment-related adverse effects include neutropenia, leukopenia, anemia, and thrombocytopenia. These adverse effects are typical for a drug targeting the cell cycle[1][3][4].
Efficacy
- SCLC: Alisertib has demonstrated a response rate of 21% in patients with ES-SCLC, with a median PFS of 7.9 months in certain cohorts[1][4].
- Breast Cancer: In hormone receptor-positive, HER2-negative metastatic breast cancer, alisertib has shown response rates ranging from 17.8% to 25%, with median PFS ranging from 5.1 to 10.2 months when combined with other therapies[2][4].
Market Projections
Unmet Need
The market for SCLC and certain types of breast cancer remains underserved, with limited treatment options available, especially for patients who have progressed on first-line therapies. Alisertib addresses this unmet need by offering a novel mechanism of action that targets aurora kinase A, a key enzyme in tumor cell proliferation.
Competitive Landscape
The landscape for SCLC and breast cancer treatments is evolving, with several new agents being developed. However, alisertib's unique mechanism and promising clinical data position it as a potential game-changer. For instance, in SCLC, alisertib's ability to improve PFS and ORR in patients with chemotherapy-resistant disease makes it an attractive option[1][4].
Regulatory Pathway
Puma Biotechnology is actively engaging with the FDA to discuss the registration pathway for alisertib in both SCLC and breast cancer. The orphan drug designation for ES-SCLC and the ongoing clinical trials are critical steps towards potential regulatory approvals[1][5].
Expert Insights
Alan H. Auerbach, CEO, President, and Founder of Puma Biotechnology, emphasized the urgent need for new treatments in SCLC and the company's commitment to developing alisertib for this indication: "There is an urgent need for new treatments for patients with SCLC, and we look forward to the initiation of our phase 2 [PUMA-ALI-4201] trial of alisertib in SCLC."[1]
Tufia Haddad, MD, from the Mayo Clinic Comprehensive Cancer Center, highlighted the potential of aurora kinase A inhibitors in endocrine and CDK4/6 inhibitor-resistant metastatic breast cancer: "Further understanding of which patients may derive the greatest benefit to alisertib in the evolving landscape of endocrine- and CDK4/6i-resistant metastatic breast cancer may help us to focus on biomarker-defined populations that can be studied in future clinical trials of alisertib."[2]
Key Takeaways
- Clinical Trials: Alisertib is currently being evaluated in phase 2 trials for ES-SCLC and various types of breast cancer.
- Safety and Efficacy: The drug has shown a manageable safety profile and promising efficacy in clinical trials.
- Market Need: Alisertib addresses a significant unmet need in the treatment of SCLC and certain breast cancers.
- Regulatory Pathway: Puma Biotechnology is actively working with the FDA to advance the regulatory approval process.
- Expert Insights: Industry experts highlight the potential of alisertib in targeting specific patient populations with biomarker-defined characteristics.
FAQs
What is alisertib and how does it work?
Alisertib is a selective, small-molecule inhibitor of aurora kinase A, an enzyme crucial for cell division. By inhibiting this enzyme, alisertib disrupts mitosis, leading to apoptosis of rapidly proliferating tumor cells.
Which cancers is alisertib being developed for?
Alisertib is primarily being developed for the treatment of extensive-stage small cell lung cancer (ES-SCLC) and various types of breast cancer, including metastatic ER-positive HER2-negative and triple-negative breast cancer.
What are the key clinical trials for alisertib?
Key trials include the PUMA-ALI-4201 phase 2 trial for ES-SCLC and the TBCRC-041 trial for endocrine and CDK4/6 inhibitor-resistant metastatic breast cancer.
What is the safety profile of alisertib?
The most common grade 3/4 treatment-related adverse effects of alisertib include neutropenia, leukopenia, anemia, and thrombocytopenia.
What are the regulatory milestones for alisertib?
Puma Biotechnology has received an orphan drug designation for alisertib in ES-SCLC and is engaged in discussions with the FDA to define the registration pathway for both SCLC and breast cancer indications.
How does alisertib compare to other treatments in its class?
Alisertib's unique mechanism of action targeting aurora kinase A positions it as a potential alternative to existing treatments, especially in patients who have progressed on first-line therapies.
Sources
- FDA Awards Orphan Drug Designation to Alisertib in ES-SCLC. Onclive.
- Puma Biotechnology Announces Presentation of Findings from a Phase II Study of Alisertib in Endocrine-Resistant Metastatic Breast Cancer. Puma Biotechnology Investor Relations.
- Randomized Phase III Study of Alisertib or Investigator's Choice in Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma. PubMed.
- Puma Biotechnology 2022 Annual Report. Puma Biotechnology.
- Puma Biotechnology Corporate Presentation. Puma Biotechnology.