Alisertib

Overview

Alisertib (MLN8237) is an orally bioavailable, selective inhibitor of Aurora A kinase (AURKA) originally developed by Millennium/Takeda and in-licensed by Puma Biotechnology in 2022 for further development in breast cancer and small cell lung cancer (SCLC). It has undergone multiple phase 1–2 studies across hematologic malignancies and solid tumors, with ongoing biomarker-directed evaluation in SCLC (e.g., NCT06095505). (aacrjournals.org)

Mechanism of action

• Target: Aurora A serine/threonine kinase, a regulator of centrosome maturation, spindle assembly, and mitotic entry. Alisertib is a slow, tight-binding ATP-competitive AURKA inhibitor with high functional selectivity over Aurora B at clinically relevant exposures. Inhibition leads to mitotic defects, G2/M arrest, and downstream apoptosis/senescence. (aacrjournals.org)
• Preclinical activity: Broad antiproliferative effects in vitro; tumor growth inhibition/regressions in xenograft models, including lymphoma; pharmacodynamic assays demonstrate AURKA pathway inhibition in vivo. (pubmed.ncbi.nlm.nih.gov)

Efficacy

Hematologic malignancies - Relapsed/refractory aggressive B- and T-cell non-Hodgkin lymphomas (phase 2, single-agent alisertib 50 mg BID days 1–7 q21d; n=48): overall response rate (ORR) 27% (10% CR, 17% PR) across histologies. (pmc.ncbi.nlm.nih.gov)
- Peripheral T‑cell lymphoma and transformed mycosis fungoides (SWOG S1108, phase 2; n=37 treated): ORR 24% overall; within PTCL subtypes, ORR 30% (7% CR, 23% PR); median PFS 3.0 months, median OS 8.0 months. (pmc.ncbi.nlm.nih.gov)

Small cell lung cancer - Randomized, double-blind phase 2 (second-line): paclitaxel ± alisertib (n=178). Median PFS 3.32 vs 2.17 months; HR 0.77 (95% CI 0.56–1.07; p=0.113 ITT). A protocol-corrected analysis showed HR 0.71 (95% CI 0.51–0.99; p=0.038). Exploratory biomarkers suggested improved outcomes with c‑MYC expression and with mutations in RB pathway/cell-cycle regulators. (mdanderson.elsevierpure.com)
- Ongoing phase 2 monotherapy study after chemo‑immunotherapy (PUMA‑ALI‑4201; biomarker-driven; enrolling as of 2025). (dana-farber.org)

Ovarian/breast cancer - Recurrent ovarian cancer (randomized phase 2): alisertib + weekly paclitaxel vs weekly paclitaxel. Median PFS 6.7 vs 4.7 months (HR 0.75; prespecified 2‑sided α=0.20 threshold met); higher toxicity with the combination. (jamanetwork.com)

Pediatric neuroblastoma - Relapsed/refractory neuroblastoma (phase 2): alisertib + irinotecan + temozolomide. In evaluable patients, ORR ~20–21%; 1‑year PFS ~34%; activity appeared greater in MYCN‑nonamplified tumors. (pubmed.ncbi.nlm.nih.gov)

Safety

Across studies, the most common adverse events are hematologic: - Lymphoma (single agent): grade 3–4 neutropenia 63%, leukopenia 54%, anemia 35%, thrombocytopenia 33%; stomatitis 15%; febrile neutropenia 13%. (pubmed.ncbi.nlm.nih.gov) - PTCL (single agent): safety consistent with hematologic toxicity; median of 4 cycles administered (range 1–17). (pmc.ncbi.nlm.nih.gov) - SCLC (with paclitaxel): grade ≥3 drug‑related AEs in 67% with alisertib/paclitaxel vs 22% with placebo/paclitaxel; four treatment‑related deaths reported in the alisertib arm. (mdanderson.elsevierpure.com) - Ovarian cancer (with weekly paclitaxel): increased grade ≥3 neutropenia (77% vs 10%), stomatitis (25% vs 0%), and anemia (14% vs 3%) compared with paclitaxel alone. (jamanetwork.com)

Further reading

• Characterization and selectivity of alisertib (preclinical): Clinical Cancer Research 2011. (aacrjournals.org)
• Aggressive NHL (single-agent phase 2): Journal of Clinical Oncology 2013; full text (PMC). (pmc.ncbi.nlm.nih.gov)
• PTCL/transformed MF (SWOG S1108, phase 2): Journal of Clinical Oncology 2015; full text (PMC). (pmc.ncbi.nlm.nih.gov)
• SCLC second-line (randomized phase 2): Journal of Thoracic Oncology 2020. (mdanderson.elsevierpure.com)
• Recurrent ovarian cancer (phase 1/2 randomized): JAMA Oncology 2018. (jamanetwork.com)
• Neuroblastoma (phase 2 combination): Clinical Cancer Research 2018. (aacrjournals.org)
• Puma Biotechnology licensing announcement for alisertib (development context). (pumabiotechnology.com)

Notes: As of October 2025, no phase 3 trials demonstrating definitive survival benefit were identified; development appears focused on biomarker-enriched populations and combinations, with active trials ongoing. (dana-farber.org)

Last updated: Oct 2025