Amid Setbacks, Efforts to Target Aurora Kinases Persist

Roger Cohen, MD

Although researchers have known for more than a decade that aurora kinases play a role in the growth of cancers, the development of targeted agents aimed at these enzymes has proceeded slowly, and the future may lie in combination therapies.

Roger Cohen, MD, professor of Medicine at the Perelman School of Medicine, University of Pennsylvania in Jenkintown, spoke about advances in the development of aurora kinase inhibitors and remaining challenges at the Targeted Therapies congress.

Researchers have known since 1998 that aurora kinases—first identified in fruit flies in 1995—were linked to cancer in humans. Today, although aurora kinase inhibitors are an active area of research and pivotal phase III trials are under way, challenges remain.

Aurora kinases are essential for cell division, and are particularly important to mitosis. Three aurora kinases have been identified in humans: A, B, and C. These three members of the aurora kinase family are essential to spindle assembly, centrosome maturation, chromosomal segregation, and cytokinesis. Overexpression or amplification of the aurora kinases has been linked to oncogenic transformation and chromosomal instability in cancer cells.

In most normal tissues, expression of aurora A is low, Cohen said. The aurora A kinase gene has been found to be amplified in many tumor types, including breast, gastric, colorectal, bladder, pancreatic, and ovarian cancers. Aberrant aurora B expression, he said, has been found in a variety of cancers, including acute myeloid leukemia (AML).

Currently, the majority of aurora kinase inhibitors in development target aurora A, which seems to be more important than B. “Based on circumstantial evidence, [aurora A] is behaving as an oncogene. Aurora B inhibitors have mostly disappeared from development,” generally because they did not have a therapeutic effect but resulted in neutropenia, Cohen said.

Aurora A kinase inhibitors act by disrupting centrosome function, spindle assembly, and chromosome alignment, with the expected effects of mitotic delay, cell cycle arrest, apoptosis, growth inhibition (in xenografts), cell death, and tumor cell senescence.

Inhibitors Are in Development

Several aurora kinase inhibitors are in early-stage development, including AMG-900 (a pan-aurora inhibitor), AT9283 (an aurora A and B inhibitor), and GSK107916 (an aurora B and C inhibitor).

Alisertib (MLN8237), a selective, ATP-competitive oral reversible aurora A kinase inhibitor, is furthest along in development. In a large, phase I/II trial in 226 patients, at a dosage of 50 mg twice a day for seven days in 21-day cycles, there was little off-target toxicity.¹ Neutropenia was the most common adverse event, Cohen said.

In the phase II part of the trial, alisertib was evaluated in five tumor types: head and neck cancer, breast cancer, gastroesophageal adenocarcinoma, small cell lung cancer, and non-small cell lung cancer (NSCLC). As of March 2012, there was an approximately 10% response rate for the entire cohort, Cohen said, although the NSCLC cohort was ended early due to lack of a partial response. The other four cohorts achieved a partial response in two or more patients, and were expanded to include an additional 25 patients.

Preliminary data from the trial were presented at the 2012 American Society of Clinical Oncology (ASCO) annual meeting.¹ The most frequent drug-related adverse events grade 3 or higher reported at ASCO were neutropenia (37% of the safety population of 196), leukopenia (12%), fatigue, anemia, stomatitis, and thrombocytopenia (each 6%). The study is ongoing, as the results suggest that alisertib has activity in a range of solid tumors.

Alisertib also is being studied in hematologic malignancies. In an ongoing phase III, open-label, multicenter trial, patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) will be randomized to alisertib or investigator’s choice (pralatrexate, gemcitabine, or romidepsin) (Figure).² The primary endpoints are the overall response rate and progression-free survival. Secondary endpoints include complete response and unconfirmed complete response, overall survival, time to progression, and quality-of-life assessments. The trial is expected to be completed in 2017.

MLN8237 (alisertib): Ongoing Pivotal Trial

Phase III study in relapsed or refractory PTCL

• Phase III, randomized, two-arm, open-label, multicenter, international trial of alisertib (MLN8237) or investigator’s choice (selected single agent) in patients with relapsed or refractory peripheral T-cell lymphoma
• Endpoints: Primary: ORR, PFS Secondary: CR+CRu rate, OS, safety, TTP, DOR, TTR, time to subsequent antineoplastic therapy, plasma concentration time data, quality-of-life assessments

CR+CRu indicates complete response plus complete response unconfirmed; DOR, duration of response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PTCL, peripheral T-cell lymphoma; TTP, time to progression; TTR, time to response.

Source: Cohen R. Targeting aurora kinases—update and challenges. Presented at: 10th International Congress on Targeted Therapies in Cancer; August 17-18, 2012;Washington, DC.

Combinations Are Likely Needed

Despite these advances, “targeting aurora A kinases is not a home run,” Cohen said, adding, “not even close.” One of the challenges is that most solid human tumors probably don’t divide fast enough for a mitotic inhibitor to be effective due to mitotic inhibition alone. To that end, several combination approaches are under study, including combining alisertib with chemotherapy and the combination of aurora A kinase inhibitors with EGFR-targeting agents, Cohen said.

One phase I study that has just begun will evaluate alisertib in combination with radiotherapy and cetux-imab in patients with previously untreated locoregionally advanced head and neck squamous cell carcinoma.³ “We hypothesize that [alisertib] will be synergistic” with the other therapies, improving the efficacy of standard cetuximab-based radiotherapy, Cohen said.

There is also a need for the identification of biomarkers for clinical benefit from aurora kinase inhibitors. Although several potential biomarkers have been investigated, Cohen said, none have yet been shown to have predictive value.

References

• Lee P, Alvarez RH, Melichar B, et al. Phase I/II study of the investigational aurora A kinase (AAK) inhibitor MLN8237 (alisertib) in patients (pts) with non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), breast cancer (BrC), head/neck cancer (H&N), and gastroesophageal (GE) adenocarcinoma: Preliminary phase II results. J Clin Oncol. 2012;30(suppl; abstr 3010).
• Alisertib (MLN8237) or Investigator’s Choice in Patients With Relapsed/Refractory Peripheral T-Cell Lymphoma. ClinicalTrials.gov. Available at: http://clinicaltrials.gov/ct2/show/NCT01482962?term=nct01482962&rank=1.
• MLN8237 in Head and Neck Cancer. ClinicalTrials.gov. Available at: http://clinicaltrials.gov/ct2/show/NCT01540682?term=mln8237+hnscc&rank=2.