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

EURTAC Clinical Study Design

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

 Primary endpoint1:

  • Progression-free survival (PFS)

 Secondary endpoints included1,3:

  • Overall survival (OS)
  • Objective response rate (ORR)
  • Safety

PRIMARY ENDPOINT: Progression-free survival (PFS) as assessed by an investigator.

Tarceva doubled median PFS compared with chemotherapy1

 Tarceva Advanced NSCLC Progression-Free Survival

  • In the EURTAC study, treatment with Tarceva doubled median PFS compared with a standard-of-care platinum-based chemotherapy doublet.1

The PFS improvement demonstrated in the EURTAC study confirms the benefit of using Tarceva for patients with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.1

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.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 (hazard ratio [HR]=0.93; 95% CI=0.64-1.35).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

 Tarceva Advanced NSCLC Overall Response Rate

  • 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

Interactive online program

Explore a multidisciplinary approach to managing the treatment of patients who have metastatic NSCLC in the first-line setting.

Physician perspective

Roman Perez-Soler, MD, and David Jablons, MD, discuss the evidence for Tarceva as a first-line treatment in metastatic NSCLC.

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

Serious adverse reactions have occurred with Tarceva1

  • 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, myocardial infarction/ischemia, cerebrovascular accident, microangiopathic hemolytic anemia with thrombocytopenia, ocular disorders, hemorrhage in patients taking warfarin, and embryo-fetal toxicity. Tarceva is pregnancy category D.1

 Tarceva Side Effects in EURTAC Trial

*Platinum-based doublet chemotherapy (cisplatin or carboplatin with gemcitabine or docetaxel).1
Rash as a composite term includes: rash, acne, folliculitis, erythema, dermatitis acneiform, dermatitis, palmar-plantar erythrodysaesthesia syndrome, exfoliative rash, rash erythematous, rash pruritic, skin toxicity, eczema, rash follicular, skin ulcer.1

Hepatic toxicity: One patient treated with Tarceva experienced fatal hepatic failure and four additional patients experienced grade 3/4 liver test abnormalities.1

Tarceva Advanced NSCLC Adverse Reactions

Advanced Non-Small Cell Lung Cancer (NSCLC) Indications

Tarceva is indicated for:

  • The first-line treatment of patients with metastatic 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.
  • The maintenance treatment of patients with locally advanced or metastatic NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.
  • The treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen.

Limitations of use:

  • Tarceva is not recommended for use in combination with platinum-based chemotherapy.
  • Safety and efficacy of Tarceva have not been evaluated as first-line treatment in patients with metastatic NSCLC whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution.

Important Safety Information

DOSE MODIFICATIONS

  • Reduce Tarceva by 50 mg decrements:
    • If severe reactions occur with concomitant use of strong CYP3A4 inhibitors [such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole, or grapefruit or grapefruit juice] or when using concomitantly with an inhibitor of both CYP3A4 and CYP1A2 (eg, ciprofloxacin). Avoid concomitant use if possible.
    • When restarting therapy following withholding treatment for a dose-limiting toxicity that has resolved to baseline or grade ≤1.
  • Increase Tarceva by 50 mg increments as tolerated for:
    • Concomitant use with CYP3A4 inducers (such as rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, or St. John’s wort). Increase dose by 50 mg increments at 2 week intervals to a maximum of 450 mg. Avoid concomitant use if possible.
    • Concurrent cigarette smoking. Increase by 50 mg increments at 2 week intervals to a maximum of 300 mg. Immediately reduce the dose of Tarceva to the recommended dose (150 mg) upon cessation of smoking.
  • For drugs affecting gastric pH:
    • Avoid concomitant use of Tarceva with proton pump inhibitors if possible. Separation of doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI tract for an extended period.
    • If treatment with an H2-receptor antagonist is required, Tarceva must be taken 10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of the H2-receptor antagonist.
    • Although the effect of antacids on erlotinib pharmacokinetics has not been evaluated, the antacid dose and the Tarceva dose should be separated by several hours, if an antacid is necessary.

CONTRAINDICATIONS

None

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 and/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 value 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.
  • Myocardial Infarction (MI)/Ischemia:
    • In the pancreatic carcinoma trial, 6 patients (incidence 2.1%) in the Tarceva plus gemcitabine group developed myocardial infarction/ischemia. One of these patients died due to myocardial infarction. In comparison, 3 patients in the placebo/gemcitabine group developed myocardial infarction (incidence 1.1%), and one died due to myocardial infarction. The pooled incidence of myocardial infarction/ischemia in the 3 monotherapy lung cancer studies was 0.2% in the Tarceva arms and 0.4% in the control arms.
  • Cerebrovascular Accident:
    • In the pancreatic carcinoma trial, 7 patients in the Tarceva plus gemcitabine group developed cerebrovascular accident (incidence 2.5%). One of these was hemorrhagic and was the only fatal event. In comparison, in the placebo/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 0.9% 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:
    • Tarceva is pregnancy category D. Based on its mechanism of action, Tarceva can cause fetal harm when administered to a pregnant woman. If Tarceva is used during pregnancy, or if the patient becomes pregnant while taking Tarceva, the patient should be apprised of the potential hazard to a fetus.
    • Advise females of reproductive potential to use highly effective contraception during therapy and for at least 2 weeks after the last dose of Tarceva. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking 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. 
    • 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%). 
  • Advanced NSCLC – Maintenance Treatment:
    • Rash and diarrhea.
    • Grade 3/4 (NCI-CTC Version 3.0) adverse reactions were rash (9%) and diarrhea (2%). Rash and diarrhea resulted in dose reductions or interruption (5% and 3%, respectively) and discontinuation (1% and 0.5%, respectively) of Tarceva-treated patients.
  • Advanced NSCLC – Second/Third-Line Treatment:
    • Rash and diarrhea.
    • Grade 3/4 (NCI-CTC Version 2.0) adverse reactions were rash (9%) and diarrhea (6%). Rash and diarrhea each resulted in dose reductions (6% and 1%, respectively) and discontinuation in 1% of Tarceva-treated patients.

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.

For additional Important Safety Information, please see full Prescribing Information.

References

  1. Tarceva [package insert]. Northbrook, IL: OSI Pharmaceuticals, LLC, an affiliate of Astellas Pharma US, Inc.; 2014.
  2. 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 Ocologia 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.
  3. Data on file, OSI Pharmaceuticals, LLC, an affiliate of Astellas Pharma US, Inc.
  4. 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.