Alisertib in patients with extensive-stage small-cell lung cancer: The phase 2 ALISCA-Lung1 study.

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 .