Targeting epidermal growth factor receptors (EGFRs) has been a novel strategy in treating non-small-cell lung cancer (NSCLC). This multicenter, community-based trial was designed to examine the role of cetuximab in combination with a nonplatinum regimen. Eligibility criteria were newly diagnosed unresectable stage III/IV NSCLC, all histologies, measurable disease, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2. Treatment premedication included dexamethasone 20 mg orally 12 and 6 hours before treatment, and 4 mg 12 hours following treatment; diphenhydramine 50 mg intravenously (I.V.) and cimetidine 300 mg I.V. before cetuximab. Treatment medication included docetaxel 30 mg/m2 I.V. days 1 and 8; gemcitabine 1000 mg/m2 I.V. days 1 and 8; and cetuximab 400 mg/m2 I.V. day 1, then 250 mg/m2 I.V. weekly. Patients received up to 6 cycles with restaging every 6 weeks. The primary endpoint was an overall response rate (ORR) > or = 25%. Sixty-nine patients enrolled from July 2005 to October 2007. Patients had a median age of 69 years; 70% were male and 30% were female; ECOG PS was 0 in 42%, 1 in 51%, and 2 in 7%; patients had adenocarcinoma (42%), squamous cell (30%), large cell (6%), mixed (1%), and not otherwise specified (20%) disease. The ORR was 17% (95% CI, 9%-29%). Thirty-five patients (54%) had stable disease; 14 patients (22%) had progressive disease. With a median follow-up of 17.8 months, the median progression-free and overall survivals were 4 months and 9.4 months, respectively. The most common (> 10%) grade 3/4 toxicities were neutropenia (25%), rash (22%), and fatigue (12%). Accrual in our middle Tennessee offices was temporarily suspended and ultimately stopped because of a higher-than-anticipated rate of cetuximab-related severe hypersensitivity reactions (HSRs) in 4 patients among the first 12 enrolled, including 1 fatal event. Cetuximab/docetaxel/gemcitabine was relatively well-tolerated and associated with efficacy similar to chemotherapy alone. Additional study with cetuximab/chemotherapy in NSCLC should focus on new potentially predictive biomarkers. Also, additional study is needed to better understand and prevent the severe HSRs that appear to be endemic to specific regions of the United States.
Spigel DR, Greco FA, Waterhouse D, Shipley D, Lane CM, et al.
Clinical advances in hematology & oncology : H&O •
To examine FOLFOX/bevacizumab/cetuximab in the first-line treatment of metastatic colorectal cancer (mCRC). Randomized phase II trial aimed at achieving a 60% objective response rate (ORR). Due to frequent cetuximab-related hypersensitivity reactions the trial was amended to a single-arm design. Eligibility: Previously untreated mCRC, measurable disease, Eastern Cooperative Oncology Group performance status (ECOG-PS) 0-1. Modified FOLFOX6 (oxaliplatin 85 mg/m², leucovorin 350 mg, and 5-fluorouracil 400 mg/m² bolus; 2.4 g/m² infusion, 46 h) day 1; bevacizumab 5 mg/kg on day 1; cetuximab 400 mg/m² on day 1, then 250 mg/m² on days 1 and 8, every 14 days (1 cycle) until progressive disease (PD); restaging occurred every 4 cycles. With emerging negative progression-free survival (PFS) data from a similarly designed trial, this trial closed early. Enrollment (N=31) was from August 2005-June 2008. Median age was 55 years (29-78); 58% were male; 71% were ECOG-PS 0. Ten cycles (median) were completed (range 2-62). The ORR was 55% (95% confidence interval [CI], 36-73%); 11 patients (35%) had stable disease; 1 patient (3%) had PD; 2 patients (6%) were unevaluable. Median PFS was 9 months (95% CI, 8.3-15.2 months); median overall survival was 25.7 months (95% CI, 15.4-27.6 months). Grade 3/4 toxicities (>1 patient) included neutropenia (25%), rash (23%; grade 2 events, 45%), diarrhea (19%), fatigue (16%), pain (16%), anemia (13%), sensory neuropathy (13%), deep-vein thrombosis (10%), nausea (10%), pulmonary embolism (7%), anorexia (6%), and vomiting (6%). In this limited trial, it is unclear whether cetuximab contributed to FOLFOX/bevacizumab efficacy, although the response rate, PFS, and overall survival were high. The regimen was generally well-tolerated, with expected skin effects; thromboembolic rates should be assessed in larger analyses. Cetuximab's role in first-line mCRC treatment is likely best guided by K-RAS testing in future clinical trials.
O'Neil BH, Allen R, Spigel DR, Stinchcombe TE, Moore DT, et al.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology •
To confirm the anecdotal observation that patients in North Carolina (NC) and Tennessee (TN) treated with cetuximab experience hypersensitivity reactions (HSR) at a much higher rate than are reported nationally and internationally (<or= 3%). Data from patients treated with cetuximab on clinical trials (n = 88) at three research sites were analyzed for grade 3 or 4 HSR. Additional information was obtained from medical records for patients treated with cetuximab at the University of North Carolina (Chapel Hill, NC) to determine whether history of other significant allergy was a risk factor for HSR to cetuximab. Data for 88 patients on clinical trials and an additional 55 patients treated outside of trials were included in this analysis. Patients had a variety of tumor types. For the clinical trial group (n = 88), the overall rate of grade 3 to 4 HSR was 22%, significantly higher than the rate noted in any large published trial. All HSRs occurred during the first dose. There was a strong relationship between prior allergy history and chance of HSR. At the sites in neighboring NC and TN studied, HSR was far more common than reported in national studies. History of prior allergy is a strong predictor of HSR. Further investigation of more specific predictors of HSR in the US middle south region is warranted, and patients being treated with cetuximab in this area should be observed particularly closely during their first infusion.