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Authors Priya Kadambi Gopalan, Mary Colleen Pinder, Alberto Chiappori, Alison Marguerite Ivey, Andres Gordillo Villegas, Frederic J. Kaye
Title 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 CDKN2A.
Abstract Text 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.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CDKN2A loss lung non-small cell carcinoma predicted - sensitive Palbociclib Phase II Actionable In a Phase II trial, treatment with Ibrance (palbociclib) resulted in stable disease in 50% (8/16) of non-small cell lung cancer patients with CDKN2A loss (J Clin Oncol 32:5s, 2014 (suppl; abstr 8077)). detail...