A phase II clinical trial of the CDK 4/6 inhibitor palbociclib (PD 0332991) in previously treated, advanced non-small cell lung cancer (NSCLC) patients with inactivated <i>CDKN2A</i>.

Abstract

8077 Background: The Retinoblastoma pathway is targeted for mutational or epigenetic inactivation in more than 70% of NSCLC. The most common event is loss of CDKN2A expression (p16 protein), usually by hypermethylation, resulting in deregulated CDK4/6 activity and cell cycle progression. Palbociclib is a highly specific CDK4/6 inhibitor and has been shown to inhibit cell cycle progression and promote cellular senescence. Methods: We conducted a phase II, single arm trial of palbociclib in 19 previously-treated patients with recurrent or metastatic NSCLC. Only patients whose tumors were negative for p16 expression by immunohistochemistry were eligible. The primary endpoint was response rate. A Simon’s 2-stage design was employed, with 2 or more responses required to proceed to the second stage. Palbociclib at 125 mg daily was given orally on days 1-21 of a 28-day cycle. Tumors were assessed by RECIST every 2 cycles. Secondary endpoints included overall survival, progression-free survival, toxicity and biomarker analysis. Results: Of the 16 evaluable patients who received at least one month of therapy, there were no responses, and the trial was closed to accrual. However, 8 patients with previously progressive NSCLC had stable disease (SD) lasting 16, 17, 20, 24, 35, 38, 41 and 42 weeks. The remaining 8 patients had progressive disease within 8 weeks. The median PFS was 12.5 weeks. There was no correlation between SD and histology or EGFR mutation status. One patient experienced grade 3 and 4 toxicities as a result of transaminitis and rhabdomyolysis (generalized muscle weakness and increased CPK) thought to be due to concomitant use of high-dose (80 mg) simvastatin. Three patients developed grade 3 or 4 neutropenia, and one patient developed grade 3 thrombocytopenia. All other toxicities were grade 1 or 2. Conclusions: Palbociclib therapy alone was well-tolerated, and stable disease (SD) was achieved in 50% of evaluable patients, suggesting the induction of cellular senescence. PFS was comparable to other second-line chemotherapeutic agents. Molecular predictors of clinical benefit (SD) are currently under investigation. Clinical trial information: NCT01291017.