Phase II Trial of Palbociclib in Patients with Advanced Esophageal or Gastric Cancer.

LESSONS LEARNED: Palbociclib monotherapy demonstrated minimal clinical activity in patients with previously treated gastroesophageal cancers. Further clinical evaluation of palbociclib monotherapy is not warranted in gastroesophageal cancers, but improved understanding of resistance mechanisms may permit rational combination approaches. BACKGROUND: Dysregulation of the cell cycle is a hallmark of cancer. Progression through the G1/S transition requires phosphorylation of retinoblastoma (RB) by cyclin-dependent kinases (CDKs) 4 and 6, which are regulated by cyclins D and E. Amplifications of cyclin D loci and activating mutations in CDKs are frequent molecular aberrations in gastroesophageal malignancies. We conducted a phase II trial of the CDK4/6 inhibitor palbociclib as an initial test of efficacy. METHODS: Patients with previously treated metastatic gastroesophageal cancers with intact RB nuclear expression by immunohistochemistry were treated with 125 mg daily of palbociclib for days 1-21 of 28-day cycles. The primary endpoint was overall response rate. RESULTS: We screened 29 patients and enrolled 21 patients: 5 with gastric adenocarcinoma, 3 with gastroesophageal junction adenocarcinoma, 8 with esophageal adenocarcinoma, and 5 with esophageal squamous cell carcinoma. All 29 tumors screened had intact nuclear RB expression, and four treated patients tested positive for CCND1 overexpression. No objective responses were seen. Median progression-free survival was 1.8 months, and median overall survival was 3.0 months. All recurrent grade 3 or 4 toxicities were hematologic, with neutropenia in eight patients (38%), anemia in four patients (19%), and thrombocytopenia in two patients (10%). CONCLUSION: Palbociclib has limited single-agent activity in gastroesophageal tumors.

Recent advances in colorectal cancer therapy.

Colorectal cancer is the second most common cause of cancer-related mortality in the United States. The American Cancer Society projects that there will be 107,300 new diagnoses of colorectal cancer in the United States in 2002, and 48,100 deaths will be attributed to colorectal cancer.(1) Although for decades there was only one chemotherapeutic agent with any meaningful activity in colorectal cancer, significant research in the last five years has identified several additional active agents. This review will focus on the recently approved chemotherapeutic combinations including capecitabine, irinotecan and oxaliplatin. We will also discuss preliminary data of molecular targeted therapies and highlight ongoing studies that will likely change the treatment paradigm for colorectal cancer in the future.