Ki Y. Chung

PURPOSE: To establish evidence of activity, or lack thereof, of cetuximab-based therapy in patients with refractory colorectal cancer with tumors that do not demonstrate epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC). PATIENTS AND METHODS: Pharmacy computer records were reviewed to identify all patients who received cetuximab at Memorial Sloan-Kettering Cancer Center in a nonstudy setting during the first 3 months of cetuximab's commercial availability. Medical records of these patients were then reviewed to identify colorectal cancer patients who had experienced failure with a prior irinotecan-based regimen and who had a pathology report indicating an EGFR-negative tumor by IHC. Pathology slides from these patients were reviewed by a reference pathologist to confirm EGFR negativity, and computed tomography scans during cetuximab-based therapy were reviewed by a reference radiologist. Response rates were reported using WHO criteria. RESULTS: Sixteen chemotherapy-refractory, EGFR-negative colorectal cancer patients who received cetuximab in a nonstudy setting were identified. Fourteen of these patients received cetuximab plus irinotecan, and two received cetuximab monotherapy. In the 16 patients, four major objective responses were seen (response rate, 25%; 95% CI, 4% to 46%). CONCLUSION: Colorectal cancer patients with EGFR-negative tumors have the potential to respond to cetuximab-based therapies. EGFR analysis by current IHC techniques does not seem to have predictive value, and selection or exclusion of patients for cetuximab therapy on the basis of currently available EGFR IHC does not seem warranted.

PURPOSE: Safety and efficacy of tremelimumab (CP-675,206), a fully human anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) monoclonal antibody, were assessed in patients with treatment-refractory colorectal cancer. PATIENTS AND METHODS: A single-arm, multicenter, phase II trial was conducted in patients with Eastern Cooperative Oncology Group performance status <or= 1 and measurable colorectal carcinoma for whom standard treatments for metastatic disease had failed. Patients received 15 mg/kg tremelimumab intravenously every 90 days until progression. Primary end point was objective response status (per Response Evaluation Criteria in Solid Tumors). Secondary end points included safety, duration of response, progression-free survival, and overall survival. RESULTS: Forty-seven patients who had received extensive prior therapies (all had received fluoropyrimidines, oxaliplatin, and irinotecan; most [91%] had also received cetuximab) were treated. Grade 3/4 treatment-related adverse events (AEs) were diarrhea (n = 5; 11%), ulcerative colitis (n = 1; 2%), fatigue (n = 1; 2%), autoimmune thrombocytopenia (n = 1; 2%), and hypokalemia (n = 1; 2%), which resolved spontaneously or with interventions. Six patients discontinued because of an AE; two were considered treatment related. Of 45 response-evaluable patients, 44 did not reach second dose (43 progressive disease; one discontinuation). Twenty-one patients (45%) lived >or= 180 days after enrollment. One patient (2%; 90% CI, < 1% to 10%) had a stable pelvic mass and substantial regression in an adrenal mass (partial response). This patient received five tremelimumab doses; response duration was 6 months (enrollment to disease progression, 15 months). CONCLUSION: Tremelimumab did not demonstrate clinically meaningful single-agent activity in this patient population, although the number of survivors at 6 months and the one patient with confirmed partial response are potentially interesting. Further study of tremelimumab in combination with other agents may be warranted.

We report that patients treated with cetuximab, a monoclonal antibody against the epithelial growth factor receptor (EGFR), occasionally develop a magnesium wasting syndrome with inappropriate urinary excretion. We first observed this phenomenon in a 34-year-old male patient with metastatic colorectal cancer who developed profound fatigue and symptomatic hypocalcemia and hypomagnesemia while on cetuximab plus irinotecan therapy. Other medications with the potential to cause magnesium wasting had not been administered. Intravenous magnesium supplementation was required for the duration of cetuximab therapy, but electrolyte abnormalities resolved after discontinuation of treatment. This case prompted review of serum chemistry reports for a consecutive case series of 154 colorectal cancer patients treated with cetuximab. Thirty-four patients (22%) had at least one serum magnesium measurement during cetuximab treatment, and six had grade 3 (< 0.9 mg/dL) and two had grade 4 (< 0.7 mg/dL) hypomagnesemia. Because EGFR is strongly expressed in the kidney, particularly in the ascending limb of the loop of Henle where 70% of filtered magnesium is reabsorbed, EGFR blockade may interfere with magnesium transport. Because symptoms may be rapidly ameliorated with supplementation, we suggest that, when fatigue or hypocalcemia is encountered during cetuximab therapy, serum magnesium level be measured and repleted as necessary.