Clinical Newswire, October 20, 2009-Sequential administration of erlotinib following gemcitabine/platinum chemotherapy improves progression-free survival (PFS) by 53% in patients with Non-Small-Cell Lung Cancer (NSCLC), according to a study published in the.October 20 issue of the Journal of Clinical Oncology. Prior studies with erlotinib and chemotherapy given concurrently did not result in increased survival, likely due to cell cycle-based antagonistic effects of the drugs. The study is the first proof-of-concept, randomized, placebo-controlled phase II study to demonstrate an improvement in treatment outcome with a sequential combination of erlotinib and cytotoxic chemotherapy.
The study involved 154 previously untreated patients with stage IIIB or IV NSCLC and with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned to receive oral erlotinib (150mg/d, n=76pts) or placebo (n=78pts) on days 15 to 28 of a 4-week cycle that included gemcitabine (1,250 mg/m2 days 1 and 8) and either cisplatin (75 mg/m2 day 1) or carboplatin (5 X area under the serum concentration-time curve, day 1). Tumor response was determined by computed tomography or magnetic resonance imaging between days 22 and 28 of chemotherapy cycles 2, 4, and 6, and every 8 weeks following completion of chemotherapy. The primary end point was nonprogression rate (NPR) at 8 weeks. Secondary end points included tumor response rate, NPR at 16 weeks, duration of response, PFS, overall survival (OS), and safety. Patient baseline and disease characteristics were well balanced between arms.
At 8 weeks, the NPR was 80.3% in the -gemcitabine plus cisplatin or carboplatin (GC)-erlotinib arm and 76.9% in the GC-placebo arm (OR, 1.33; 95% CI, 0.57 to 3.10; P=0.51). NPR values at 16 weeks were 64.5% for GC-erlotinib and 53.8% for GC-placebo (OR, 1.70;95%CI, 0.84 to 3.41; P=0.14). The tumor response rate was higher in the GC-erlotinib arm vs. the GC-placebo arm (35.5% vs. 24.4%; respectively, OR, 1.75; 95% CI, 0.86 to 3.57; P =0.12). Patients given GC-erlotinib had a significantly longer median PFS than those given GC-placebo (29.4 weeks vs. 23.4 weeks, respectively; hazard ratio, 0.47; log-rank test, P =.0002), representing a 53% improvement. This benefit occurred across all clinical sub-groups with the exception of former smokers. Median response duration was also significantly longer in the GC-erlotinib group vs. the GC-placebo group (39.4 vs. 24.1 weeks, respectively; HR, 0.40; 95% CI, 0.20 to 0.79; log-rank test P=0.0057). There was no significant difference in median OS between the two arms (74.1 weeks for GC-erlotinib vs. 75.7 weeks for GC-placebo; HR, 1.09; 95% CI, 0.70 to 1.69; log rank test P =0 .42). The authors noted that the study was not powered to detect a difference in OS.
The addition of erlotinib to chemotherapy was well tolerated, with the majority of reported adverse events (AEs) grade 1 or 2. Additionally, there was no increase in hematologic toxicity and no treatment-related interstitial lung disease. Seventy patients in each arm had at least one AE that was possibly related to study treatment. Grade 3 treatment-related AEs occurred in 32% and 30% of the GC-erlotinib and GC-placebo arms, respectively, and 8% and 9%, respectively, had grade 4 treatment-related AEs primarily consisting of hematologic toxicity. Skin rash was more common in the GC-erlotinib arm vs. the CG-placebo arm (65% vs. 34%, respectively) but was primarily grade 1 to 2. The most common treatment-related serious AE was anemia, which occurred in 4 patients in each arm. There was one treatment-related death in the GC-erlotinib arm (bacterial pneumonia), while two were observed in the GC-placebo arm (thrombocytopenia; upper GI bleeding).
The authors concluded that sequential treatment with erlotinib and chemotherapy improves PFS and response rate in patients with NSCLC. This novel first-line sequential schedule may be used to avoid the potential issue of cell cycle-based antagonism between EGFR tyrosine kinase inhibitors and chemotherapeutic agents.
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