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Drug Information Summaries
NCI's drug information summaries provide consumer-friendly information about certain drugs that are approved by the U.S. Food and Drug Administration (FDA) to treat cancer or conditions related to cancer.
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FDA Approval for Erlotinib HydrochlorideBrand name(s): Tarceva®
Non-Small Cell Lung Cancer
On November 18, 2004, the U.S. Food and Drug Administration approved erlotinib hydrochloride (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 hydrochloride 150 mg p.o. daily to placebo. Survival was significantly prolonged on the erlotinib hydrochloride arm with a
median overall survival of 6.7 months and 4.7 months in the erlotinib hydrochloride and
placebo groups, respectively. The adjusted Hazard Ratio (HR) for death in the erlotinib hydrochloride group relative to the placebo group was 0.73, p = <0.001.
Progression-free survival (PFS) was significantly prolonged on the erlotinib hydrochloride arm with a median PFS of 9.9 weeks vs. 7.9 weeks in erlotinib hydrochloride and placebo groups, respectively. The adjusted HR for progression was 0.59, p < 0.001.
The objective response rate by RECIST in the erlotinib hydrochloride 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 hydrochloride prolonged survival compared to placebo (median 10.7 vs. 3.8 months, HR=0.65, p=0.033). No apparent erlotinib hydrochloride survival effect was observed in the EGFR negative subgroup (erlotinib hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride-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.
Full prescribing information is available, including clinical trial
information, safety, dosing, drug-drug interactions and contraindications.
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Pancreatic Cancer
On November 2, 2005, the U.S. Food and Drug Administration approved erlotinib hydrochloride (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 hydrochloride 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 hydrochloride 100 mg cohort and 48 patients in the erlotinib hydrochloride 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 hydrochloride arm with a median overall survival of 6.4 months and 6.0 months in the 100 mg erlotinib hydrochloride/gemcitabine and placebo/gemcitabine groups, respectively. The adjusted Hazard Ratio (HR) for death in the erlotinib hydrochloride 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 hydrochloride/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 hydrochloride/gemcitabine were fatigue, rash, nausea, anorexia, and diarrhea. Severe rash and diarrhea were more frequently observed in the erlotinib hydrochloride/gemcitabine arm. Other newly recognized severe adverse reactions observed with the erlotinib hydrochloride/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.
Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
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This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products, or Patricia Keegan, M.D., director of the FDA's Division of Clinical Trials Design and Analysis.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other
products. (See "Understanding the Approval Process for New Cancer Treatments.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.
For further information related to oncology drug approvals, regulatory information and other oncology resources, please refer to the FDA's Oncology Tools Web site.
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