FDA Approval for Erlotinib Hydrochloride
- Approved for first-line treatment of non-small cell lung cancer
- Approved for maintenance treatment of non-small cell lung cancer
- Approved for pancreatic cancer
- Approved for non-small cell lung cancer
Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
On May 14, 2013, the Food and Drug Administration (FDA) approved erlotinib (Tarceva®, made by Astellas Pharma Inc.) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations. This indication for erlotinib is being approved concurrently with the cobas® EGFR Mutation Test, a companion diagnostic test for patient selection.
The approval was based on the results of a randomized, multicenter open-label trial comparing erlotinib (n=86) to platinum-based doublet chemotherapy (n=88) in patients with metastatic NSCLC whose tumors had EGFR exon 19 deletions or exon 21 (L858R) substitution mutations determined by a clinical trial assay (CTA). Eligible patients were randomly assigned (1:1) to receive erlotinib, 150 mg/day orally, or platinum-based doublet chemotherapy. Randomization was stratified by EGFR mutation [exon 19 deletion or exon 21 (L858R) substitution] and ECOG Performance Status (PS 0 vs. PS 1 vs. PS 2). Tumor samples from 134 patients were tested retrospectively with the cobas® EGFR Mutation Test.
The median age of the patients was 65 years. The majority were female (72 percent), Caucasian (99 percent), never-smokers (69 percent), and had adenocarcinoma histology (93 percent).
The median PFS was 10.4 months in the erlotinib arm and 5.2 months in the platinum-based chemotherapy arm [HR 0.34 (95 percent confidence interval [CI]: 0.23, 0.49), p <0.001]. The median OS was 22.9 months in the erlotinib arm and 19.5 months in the platinum-based chemotherapy arm [HR 0.93 (95 percent CI: 0.64, 1.35), p=0.6482]. The ORR was 65 percent in the erlotinib arm and 16 percent in the platinum-based chemotherapy arm. The majority of patients in the platinum-based chemotherapy arm (82 percent) subsequently received an EGFR tyrosine kinase inhibitor following investigator-determined disease progression. Analysis of PFS in the cobas® EGFR Mutation Test-positive patients was consistent with the primary analysis.
The most frequent (at least 30 percent) adverse reactions of any grade in the erlotinib arm were rash, diarrhea, asthenia, cough, dyspnea and decreased appetite. The most frequent (at least 5 percent) grade 3-4 adverse reactions in the erlotinib arm were rash and diarrhea.
The recommended daily dose of erlotinib for NSCLC is 150 mg taken orally at least one hour before or two hours after eating a meal. Treatment should continue until disease progression or unacceptable toxicity.
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On April 16, 2010, the FDA approved erlotinib (Tarceva®) tablets for maintenance treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. This approval is erlotinib’s second indication in locally advanced or metastatic NSCLC. Erlotinib was originally approved in November, 2004 for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen.
The efficacy and safety of erlotinib as maintenance treatment were demonstrated in a randomized, double-blind, placebo-controlled, multinational trial. A total of 889 patients with locally advanced or metastatic NSCLC whose disease did not progress during first-line platinum-based chemotherapy were randomly assigned (1:1) to receive either erlotinib (150 mg) or placebo orally once daily until disease progression or unacceptable toxicity. The trial’s primary objective was to determine if the administration of erlotinib after standard platinum-based chemotherapy resulted in improved progression-free survival (PFS) when compared to placebo in either all patients or in patients with EGFR immunohistochemistry (IHC) positive tumors. Overall survival (OS) was a secondary endpoint in the trial but was designated as the regulatory endpoint for approval of this indication.
Patient demographics and disease characteristics were balanced between the two groups. Approximately 70 percent of patients’ tumors were EGFR positive. The hazard ratio (HR) for PFS was 0.71 (95 percent CI: 0.62, 0.82, p<0.0001). The HR for OS was 0.81 (95 percent CI: 0.70, 0.95, p=0.0088). Patients with EGFR IHC-positive tumors had PFS hazard ratio of 0.69 (95 percent CI: 0.58, 0.82) and OS hazard ratios of 0.77 (95 percent CI: 0.64, 0.93). Patients with IHC-negative tumors had PFS hazard ratios of 0.77 (95 percent CI: 0.51, 1.14) and OS hazard ratios of 0.91 (95 percent CI: 0.59, 1.38).
Following disease progression, a greater proportion of patients in the placebo group (57 percent) received second-line treatment for NSCLC compared to the erlotinib group (47 percent). Of the 259 patients in the placebo group who received second-line treatment, thirty-seven (14 percent) received either erlotinib or gefitinib at first progression, 31 percent received docetaxel, and 14 percent received pemetrexed. In total, 59 percent of patients in the placebo group who received treatment at the time of tumor progression received FDA-approved second-line NSCLC drugs.
The safety results for patients treated with erlotinib were consistent with the known safety profile previously described in product labeling. The most common (more than 20 percent) adverse reactions in patients receiving erlotinib were rash-like events and diarrhea.
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On November 2, 2005, the FDA 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.
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On November 18, 2004, the FDA 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.
This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.
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 "Learn How Drugs and Devices Get Approved.") 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.