First-line efficacy and safety in EGFR exon 19 deletion and exon 21 (L858R) metastatic NSCLC
The EURTAC trial
The EURTAC trial study design
EURTAC was a phase III, randomized, open-label trial designed to assess the efficacy and safety of Tarceva compared with standard chemotherapy for first-line treatment of White patients with metastatic NSCLC whose tumors had EGFR exon 19 deletions or exon 21 (L858R) substitution mutations1,2
Demographics and disease characteristics1:
- The EURTAC trial population included White patients of varying sex, age, smoking status, Eastern Cooperative Oncology Group (ECOG) performance status (0-2), location and type of mutation (exon 19 deletions or exon 21 [L858R] substitution), histological classification, and stage of NSCLC (IIIB with pleural effusion or IV) at baseline.1
- Progression-free survival (PFS)
Secondary endpoints included1,3:
- Overall survival (OS)
- Objective response rate (ORR)
SECONDARY ENDPOINT: Overall survival (OS)
Median OS in the EURTAC trial
- The median OS was 22.9 months (95% confidence interval [CI]=17.0-26.8) in the Tarceva arm and 19.5 months (95% CI=17.3-28.4) in the chemotherapy arm (hazard ratio [HR]=0.93; 95% CI=0.64-1.35).1
- A protocol-specified analysis of OS conducted at the time of the final analysis of PFS showed no statistically significant difference between the Tarceva and chemotherapy arms.1
- 82% of the patients in the chemotherapy arm received subsequent treatment with a tyrosine kinase inhibitor (TKI), with all but 2 of these patients receiving Tarceva. This may have confounded the OS results.3,4
- In the Tarceva arm, 66% of patients received at least one subsequent treatment.1
- The study was not powered for OS.3
SECONDARY ENDPOINT: Objective response rate (ORR)
The objective response rate was 65% for Tarceva and 16% for chemotherapy1
- The objective response rate was 65% (95% confidence interval [CI]=54.1%-75.1%) for patients treated with Tarceva and 16% (95% CI=9.0%-25.3%) for patients treated with chemotherapy.1
Tarceva has a consistent safety profile across therapeutic settings in advanced NSCLC1
Serious adverse reactions have occurred with
- Warnings and precautions, which include fatalities, associated with Tarceva in metastatic NSCLC include interstitial lung disease (ILD), renal failure, hepatotoxicity with or without hepatic impairment, gastrointestinal perforation, bullous and exfoliative skin disorders, cerebrovascular accident, microangiopathic hemolytic anemia with thrombocytopenia, ocular disorders, hemorrhage in patients taking warfarin, and embryo-fetal toxicity.1
The most common adverse reactions associated with Tarceva in the EURTAC trial were consistent with those reported in previous phase III trials of Tarceva1,3
*None of the adverse reactions in this table, except back pain (one patient with Tarceva), were grade 4 in severity.3
†Rash as a composite term includes: rash, acne, folliculitis, erythema, dermatitis acneiform, dermatitis, palmar-plantar erythrodysesthesia syndrome, exfoliative rash, rash erythematous, rash pruritic, skin toxicity, eczema, rash follicular, skin ulcer.1
‡Platinum-based doublet chemotherapy (cisplatin or carboplatin with gemcitabine or docetaxel).1
Hepatic toxicity: One patient treated with Tarceva experienced fatal hepatic failure and four additional patients experienced grade 3/4 liver test abnormalities.1
The most common adverse reactions in patients with metastatic NSCLC receiving Tarceva as first-line therapy, rash and diarrhea, can usually be managed.1
- Withhold Tarceva for persistent severe diarrhea or severe rash not responsive to medical management.
- In Tarceva-treated patients, the most frequently reported adverse reactions leading to dose modification were rash (13%), diarrhea (10%), and asthenia (3.6%).
- Get the latest information about Tarceva
Tarceva is indicated for:
- The 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 as detected by an FDA-approved test receiving first-line, maintenance, or second or greater line treatment after progression following at least one prior chemotherapy regimen.
Limitations of use:
- Safety and efficacy of Tarceva have not been established in patients with NSCLC whose tumors have other EGFR mutations.
- Tarceva is not recommended for use in combination with platinum-based chemotherapy.
WARNINGS AND PRECAUTIONS
- Interstitial Lung Disease (ILD):
- Cases of serious ILD, including fatal cases, can occur with Tarceva treatment. The overall incidence of ILD in approximately 32,000 Tarceva-treated patients in uncontrolled studies and studies with concurrent chemotherapy was approximately 1.1%. In patients with ILD, the onset of symptoms was between 5 days to more than 9 months (median 39 days) after initiating Tarceva therapy.
- Withhold Tarceva for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever pending diagnostic evaluation. If ILD is confirmed, permanently discontinue Tarceva.
- Renal Failure:
- Hepatorenal syndrome, severe acute renal failure including fatal cases, and renal insufficiency can occur with Tarceva treatment. Renal failure may arise from exacerbation of underlying baseline hepatic impairment or severe dehydration.
- The pooled incidence of severe renal impairment in the 3 monotherapy lung cancer studies was 0.5% in the Tarceva arms and 0.8% in the control arms. The incidence of renal impairment in the pancreatic cancer study was 1.4% in the Tarceva plus gemcitabine arm and 0.4% in the control arm.
- Withhold Tarceva in patients developing severe renal impairment until renal toxicity is resolved. Perform periodic monitoring of renal function and serum electrolytes during Tarceva treatment.
- Hepatotoxicity With or Without Hepatic Impairment:
- Hepatic failure and hepatorenal syndrome, including fatal cases, can occur with Tarceva treatment in patients with normal hepatic function; the risk of hepatic toxicity is increased in patients with baseline hepatic impairment.
- Hepatic Toxicity: One Tarceva-treated patient experienced fatal hepatic failure and four additional patients experienced grade 3-4 liver test abnormalities.
- In clinical studies where patients with moderate to severe hepatic impairment were excluded, the pooled incidence of hepatic failure in the 3 monotherapy lung cancer studies was 0.4% in the Tarceva arms and 0% in the control arms. The incidence of hepatic failure in the pancreatic cancer study was 0.4% in the Tarceva plus gemcitabine arm and 0.4% in the control arm.
- Perform periodic liver testing (transaminases, bilirubin, and alkaline phosphatase) during treatment with Tarceva. Increased frequency of monitoring of liver function is required for patients with pre-existing hepatic impairment or biliary obstruction.
- Withhold Tarceva in patients without pre-existing hepatic impairment for total bilirubin >3 x ULN or transaminases >5 x ULN. Withhold Tarceva in patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases values over baseline.
- Discontinue Tarceva in patients whose abnormal liver tests meeting the above criteria do not improve significantly or resolve within 3 weeks.
- Gastrointestinal Perforation:
- Gastrointestinal perforation, including fatal cases, can occur with Tarceva treatment. Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, or taxane-based chemotherapy, or who have prior history of peptic ulceration or diverticular disease may be at increased risk of perforation.
- The pooled incidence of gastrointestinal perforation in the 3 monotherapy lung cancer studies was 0.2% in the Tarceva arms and 0.1% in the control arms. The incidence of gastrointestinal perforation in the pancreatic cancer study was 0.4% in the Tarceva plus gemcitabine arm and 0% in the control arm.
- Permanently discontinue Tarceva in patients who develop gastrointestinal perforation.
- Bullous and Exfoliative Skin Disorders:
- Bullous, blistering and exfoliative skin conditions, including cases suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis, which in some cases were fatal, can occur with Tarceva treatment.
- The pooled incidence of bullous and exfoliative skin disorders in the 3 monotherapy lung cancer studies was 1.2% in the Tarceva arms and 0% in the control arms. The incidence of bullous and exfoliative skin disorders in the pancreatic cancer study was 0.4% in the Tarceva plus gemcitabine arm and 0% in the control arm.
- Discontinue Tarceva treatment if the patient develops severe bullous, blistering or exfoliating conditions.
- Cerebrovascular Accident:
- In the pancreatic carcinoma trial, 7 patients in the Tarceva plus gemcitabine group developed cerebrovascular accidents (incidence: 2.5%). One of these was hemorrhagic and was the only fatal event. In comparison, in the placebo plus gemcitabine group there were no cerebrovascular accidents. The pooled incidence of cerebrovascular accident in the 3 monotherapy lung cancer studies was 0.6% in the Tarceva arms and not higher than that observed in the control arms.
- Microangiopathic Hemolytic Anemia With Thrombocytopenia:
- The pooled incidence of microangiopathic hemolytic anemia with thrombocytopenia in the 3 monotherapy lung cancer studies was 0% in the Tarceva arms and 0.1% in the control arms. The incidence of microangiopathic hemolytic anemia with thrombocytopenia in the pancreatic cancer study was 1.4% in the Tarceva plus gemcitabine arm and 0% in the control arm.
- Ocular Disorders:
- Decreased tear production, abnormal eyelash growth, keratoconjunctivitis sicca or keratitis can occur with Tarceva treatment and can lead to corneal perforation or ulceration.
- The pooled incidence of ocular disorders in the 3 monotherapy lung cancer studies was 17.8% in the Tarceva arms and 4% in the control arms. The incidence of ocular disorders in the pancreatic cancer study was 12.8% in the Tarceva plus gemcitabine arm and 11.4% in the control arm.
- Interrupt or discontinue Tarceva therapy if patients present with acute or worsening ocular disorders such as eye pain.
- Hemorrhage in Patients Taking Warfarin:
- Severe and fatal hemorrhage associated with International Normalized Ratio (INR) elevations can occur when Tarceva and warfarin are administered concurrently.
- Regularly monitor prothrombin time and INR during Tarceva treatment in patients taking warfarin or other coumarin-derivative anticoagulants.
- Embryo-Fetal Toxicity:
- Based on animal data and its mechanism of action, Tarceva can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus.
- Advise females of reproductive potential to use effective contraception during therapy and for one month after the last dose of Tarceva.
MOST COMMON ADVERSE REACTIONS
- Metastatic NSCLC – First-Line Treatment of Patients With EGFR Mutations:
- Most frequent (≥30%) adverse reactions were diarrhea, asthenia, rash, cough, dyspnea, and decreased appetite.
- Most frequent Grade 3/4 (NCI-CTC Version 3.0) adverse reactions were rash (14%) and diarrhea (5%). In Tarceva-treated patients, the most frequently reported adverse reactions leading to dose modification were rash (13%), diarrhea (10%), and asthenia (3.6%).
You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555.
Please see the Tarceva full Prescribing Information for additional Important Safety Information.
- Tarceva [package insert]. Northbrook, IL: OSI Pharmaceuticals, LLC, an affiliate of Astellas Pharma US, Inc.; 2016.
- Rosell R, Carcereny E, Gervais R, et al; on behalf of the Spanish Lung Cancer Group in collaboration with the Groupe Français de Pneumo-Cancérologie and the Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239-246.
- Data on file, OSI Pharmaceuticals, LLC, an affiliate of Astellas Pharma US, Inc.
- Center for Biologics Evaluation and Research. Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. Rockville, MD: Center for Biologics Evaluation and Research, US Dept of Health and Human Services; 2007.