Cancer Medications : Tarceva

by National Cancer Institute

(Page 15 of 18)

Tarceva for NSCLC

On November 18, 2004, the FDA approved erlotinib (Tarceva™ tablets, made by OSI Pharmaceuticals Inc.) for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen.

Safety and efficacy were demonstrated in a 731 patient double-blind, multinational, randomized trial comparing erlotinib 150 mg p.o. daily to placebo. Survival was significantly prolonged on the erlotinib arm with a median overall survival of 6.7 months and 4.7 months in the erlotinib and placebo groups, respectively. The adjusted Hazard Ratio (HR) for death in the erlotinib group relative to the placebo group was 0.73, p = <0.001. Progression-free survival (PFS) was significantly prolonged on the erlotinib arm with a median PFS of 9.9 weeks vs. 7.9 weeks in erlotinib and placebo groups, respectively. The adjusted HR for progression was 0.59, p < 0.001.

The objective response rate by RECIST in the erlotinib group was 8.9 percent (95 percent CI: 6.4 to 12.0 percent). (RECIST stands for Response Evaluation Criteria In Solid Tumors, a widely accepted set of rules that define when cancer patients improve ["respond"], stay the same ["stable"], or worsen ["progression"] during treatments.) The median response duration was 34.3 weeks, ranging from 9.7 to 57.6+ weeks. Two responses (0.9 percent, 95 percent CI: 0.1 to 3.4) were reported in the placebo group.

An exploratory analysis of Epidermal Growth Factor Receptor (EGFR) protein expression status on treatment survival effect was performed; however, EGFR status was known for only 33 percent of patients. The EGFR expression was determined using the DAKO EGFR pharmDx™ kit. About half of the patients with known EGFR status were positive and half were negative.

In the EGFR positive subgroup, erlotinib prolonged survival compared to placebo (median 10.7 vs. 3.8 months, HR=0.65, p=0.033). No apparent erlotinib survival effect was observed in the EGFR negative subgroup (erlotinib median: 5.2 months vs. placebo median: 7.5 months; HR=1.01, p=0.958). However, the confidence intervals for the EGFR positive and negative subgroups are wide and overlap. Thus, an erlotinib survival effect in the EGFR negative subgroup cannot be excluded. Post-approval clinical trials will prospectively examine the relationship of EGFR status and survival effects.

An additional subgroup survival analysis examining the effect of smoking status showed that the erlotinib survival benefit was greater in patients who had never smoked (HR 0.42; 95 percent CI: 0.3, 0.6) than in smokers (HR 0.87; 95 percent CI: 0.7, 1.1).

The most common adverse reactions in patients receiving erlotinib were diarrhea and rash. Grade 3/4 rash and diarrhea occurred in 9 percent and 6 percent, respectively. Rash and diarrhea each resulted in study discontinuation in 1 percent of erlotinib-treated patients. Only 6 percent and 1 percent of patients required dose reductions for rash and diarrhea, respectively. The median time to onset of rash was eight days; the median time to onset of diarrhea was 12 days.

Tarceva for Pancreatic Cancer

On November 2, 2005, the FDA approved erlotinib (Tarceva® tablets, made by OSI Pharmaceuticals Inc.) in combination with gemcitabine for the treatment of patients with locally advanced, unresectable or metastatic pancreatic carcinoma.

Safety and efficacy were demonstrated in a single, multicenter (U.S. and international), double-blinded, placebo-controlled, randomized, phase III study of erlotinib plus gemcitabine (EG) versus gemcitabine plus placebo (PG) as first-line chemotherapy for locally advanced or metastatic pancreatic carcinoma.

The study involved 569 patients with 521 patients in the erlotinib 100 mg cohort and 48 patients in the erlotinib 150 mg cohort. There were too few patients for analysis in the 150 mg cohort. Results are presented for the 100 mg cohort.

The primary endpoint of the trial was overall survival. Survival was significantly prolonged on the erlotinib arm with a median overall survival of 6.4 months and 6.0 months in the 100 mg erlotinib/gemcitabine and placebo/gemcitabine groups, respectively. The adjusted Hazard Ratio (HR) for death in the erlotinib group relative to the placebo group was 0.81, p = 0.028.

Secondary endpoints were progression-free survival (PFS), tumor response rate, duration of response, role of EGFR status and survival and quality of life. The combination of erlotinib/gemcitabine had a longer median PFS for 100 mg cohort (EG 3.8 months and PG 3.5 months) with an adjusted HR: 0.76, p =0.006. In contrast, there was no statistically significant difference in tumor response (EG 8.6 percent and PG 7.9 percent) or response duration (EG 24 weeks and PG 23 weeks).

There was no relationship between EGFR tumor expression and survival in this trial, but the number of available EGFR samples was small (less than one-third of cases had available EGFR status).

The most common adverse reactions in patients receiving erlotinib/gemcitabine were fatigue, rash, nausea, anorexia, and diarrhea. Severe rash and diarrhea were more frequently observed in the erlotinib/gemcitabine arm. Other newly recognized severe adverse reactions observed with the erlotinib/gemcitabine combination included stroke, syncope, microangiopathic anemia with thrombocytopenia, myocardial infarction/ischemia, arrhythmias, renal insufficiency, ileus, pancreatitis, and neuropathy.

This sNDA was presented at the ODAC meeting on September 13, 2005 and the committee voted 10 to 3 in favor of approval for this application.

About the Author

www.nci.nih.gov
The National Cancer Institute's research programs are extensive and contain many innovative initiatives. I invite you to explore our Web site to find out more about the exciting work being conducted here at NCI and by NCI-supported scientists throughout the country.