Alisertib in patients with extensive-stage small-cell lung cancer: The phase 2 ALISCA-Lung1 study.
Authors: Taofeek K. Owonikoko, Alberto Chiappori, Ryan D. Gentzler, Stephen V. Liu, Adedayo A. Onitilo, Nathan A. Pennell, Jacob Sands, Bo Wang, Beth Hillary Lowenthal, Judith D. Bebchuk, Lisa DeFazio Eli, Elaine K. Wong, Afshin Dowlati
Journal: Journal of Clinical Oncology (2024)

TPS8128 Background: Treatment options are limited for patients (pts) with small-cell lung cancer (SCLC) whose disease has progressed on or after platinum-based chemotherapy. Therefore, there is an urgent need for evaluation of novel agents in this setting. Aurora kinase A (AURKA) is a key regulator of mitosis and AURKA expression is associated with worse prognosis in multiple solid tumor types. Alisertib is a highly selective, reversible, ATP-competitive, orally administered, small-molecule AURKA inhibitor under investigation for treating SCLC. Phase 1/2 clinical trials of alisertib as either monotherapy or in combination with paclitaxel for relapsed/refractory solid tumors (including SCLC) reported response rates of 21–22%. The most common treatment-related grade ≥3 AEs were neutropenia, febrile neutropenia, and leukopenia. Preclinically, greater alisertib sensitivity has been reported in models with high c-Myc expression and/or loss of RB1 function. In a clinical study of alisertib + paclitaxel vs placebo + paclitaxel in SCLC, either c-Myc expression or mutation in RB1, RBL1, RBL2, or CDK6 showed strong correlation with an improvement in both PFS and OS in the alisertib arm. Methods: ALISCA-Lung1(NCT06095505) is a phase 2 study to determine whether there is a biomarker-defined population of pts with extensive-stage SCLC that derives increased benefit from alisertib monotherapy. Key inclusion criteria: ≥18 years of age; progression on or after first-line treatment with platinum-based chemotherapy + anti-PD-L1 immunotherapy; ≥1 measurable lesion per RECIST v1.1; availability of tissue sample for retrospective biomarker evaluation. Key exclusion criteria: prior treatment with AURKA-specific or pan-Aurora-targeted agents; active infection; immunocompromise; unstable brain metastases; inability/unwillingness to swallow tablets. Primary objective: to determine whether any biomarker(s) correlate with increased benefit to alisertib monotherapy. Biomarkers will be assessed by next-generation sequencing, mRNA expression analysis, and immunohistochemistry. Candidate biomarkers include, but are not limited to, RB1 loss of function, c-Myc expression, TP53mutation, AURKA expression, and SCLC molecular subtype. Secondary objectives: to determine investigator-assessed efficacy, survival, safety, and population pharmacokinetics. Eligible pts will receive alisertib 50 mg orally BID d1−7 q21d (including primary prophylaxis with G-CSF) until disease progression, unacceptable toxicity, or withdrawal of consent. All pts will undergo sparse pharmacokinetic sampling. Recruitment is underway and up to 60 pts will be enrolled at ~20 centers in the USA. Findings are anticipated to identify a biomarker-defined pt population that derives the greatest clinical benefit from alisertib. Future development of alisertib in SCLC is anticipated to focus on this biomarker-defined population. Clinical trial information: NCT06095505 .