As reported in the Journal of Clinical Oncology by Pamela L. Kunz, MD, and colleagues, the phase II ECOG-ACRIN E2211 trial has shown significantly prolonged progression-free survival with the addition of capecitabine to temozolomide in patients with advanced pancreatic neuroendocrine tumors.
The median progression-free survival and response rate observed with capecitabine/temozolomide are the highest reported in a randomized study for pancreatic neuroendocrine tumors.— Pamela L. Kunz, MD, and colleagues
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Study Details
The open-label multicenter trial included 133 eligible patients. They were randomly assigned between April 2013 and March 2016 to receive capecitabine at 750 mg/m2 twice daily on days 1 to 14 and temozolomide at 200 mg/m2 on days 10 to 14 every 28 days (n = 68) or temozolomide at 200 mg/m2 on days 1 to 5 every 28 days (n = 65).
The primary endpoint was progression-free survival, with the objective of achieving a hazard ratio (HR) of 0.64 for the combination group vs the control group.
Progression-Free Survival
The study met the primary endpoint at interim analysis; median progression-free survival was 22.7 months (95% confidence interval [CI] = 15.3–29.0 months) in the capecitabine/temozolomide group vs 14.4 months (95% CI = 6.5–20.3 months) in the temozolomide group (HR = 0.58, 95% CI = 0.36–0.93, P = .022).
Objective response was observed in 27 patients (39.7%) in the combination group vs 22 (33.8%) in the control group (P = .59), with complete response seen in 1 patient in each group. An additional 44.1% vs 40.0% of patients had stable disease. Median duration of response was 16.6 months (interquartile range [IQR] = 11.4–24.7 months) vs 12.6 months (IQR = 8.6–30.7 months).
Among all patients with available data, objective response was observed in 33 (52%) of 63 patients with low MGMT and 5 (15%) of 34 with high MGMT on immunohistochemistry (odds ratio [OR] = 6.38, P = .0004) and in 19 (38%) of 50 with MGMT deficiency defined as negative for promoter methylation vs 6 (85%) of 7 positive for promoter methylation (OR = 9.79, P = .04).
At final analysis, with a median follow-up of 59.9 months, median overall survival was 58.7 months (95% CI = 44.7 months to not evaluable) in the combination group vs 53.8 months (95% CI = 35.7 months to not evaluable) in the control group (HR = 0.82, 95% CI = 0.51–1.33, P = .42).
KEY POINTS
- Capecitabine/temozolomide prolonged progression-free survival vs temozolomide alone.
- MGMT deficiency was associated with greater likelihood of objective response.
Adverse Events
Grade 3 or 4 treatment-related adverse events occurred in 45% of patients in the capecitabine/temozolomide group vs 22% of the temozolomide group, with the most common in the combination group being decreased neutrophils (13%) and decreased platelets (10%). Adverse events led to discontinuation of treatment in 15% vs 6% of patients. Second primary malignancies were observed in four patients in the combination group and three in the control group, including myelodysplastic syndrome in one patient in the combination group. No treatment-related deaths were reported.
The investigators concluded, “The combination of capecitabine/temozolomide was associated with a significant improvement in progression-free survival compared to temozolomide alone in patients with advanced pancreatic neuroendocrine tumors. The median progression-free survival and response rate observed with capecitabine/temozolomide are the highest reported in a randomized study for pancreatic neuroendocrine tumors. MGMT deficiency was associated with response and, although, routine MGMT testing is not recommended, it can be considered for select patients in need of objective response.”
Dr. Kunz, of Yale Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by grants from the National Cancer Institute. For full disclosures of the study authors, visit ascopubs.org.
