Molecular testing may guide treatment for EGFR mutation-positive NSCLC1-3

Collaborative care for a complex disease

Recent diagnostic and treatment options in metastatic NSCLC have increased the importance of interdisciplinary care4

Pathologists play an especially important role in the diagnosis and treatment of metastatic NSCLC4

Collaborating with peers

Pulmonologists, Thoracic Surgeons, and Interventional Radiologists

  • Maintain a dialogue with pulmonologists, thoracic surgeons, and interventional radiologists about the importance of obtaining tissue samples of adequate size and quality to help obtain accurate results.4

Oncologists

  • Because mutation status is one of the key factors for determining treatment decisions, it’s important to clearly communicate results with oncologists.2

Other Pathologists

  • Speak to other pathologists about the importance of EGFR-mutation testing.3

Selected best practices

The pathologist and metastatic NSCLC: the important impact of mutation testing

  • Because patients with metastatic NSCLC and EGFR exon 19 deletions or exon 21 (L858R) substitution mutations may benefit more from erlotinib (Tarceva) than conventional chemotherapy in the first-line setting, it’s important to determine mutation status as soon as possible.1,3

Tissue- and plasma-based tests are FDA-approved options for detecting EGFR mutations and to determine eligibility for treatment with Tarceva.1

  • Determining EGFR mutation status from tissue is preferred, but not always possible.5-12
  • CAP/IASLC/AMP guidelines recommend using tissue specimens for testing to detect EGFR mutations.2
  • If plasma-sample testing results in “No Mutation Detected,” tissue testing should be performed if available.1,8

Learn more about the FDA-approved tissue- and plasma-based diagnostic for EGFR mutations.

The College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology (CAP/IASLC/AMP) Guideline recommends making EGFR-mutation testing a priority2

  • The CAP/IASLC/AMP Guideline recommends testing for EGFR mutations in all adenocarcinomas and mixed lung cancers with an adenocarcinoma component regardless of histologic grade.2
  • According to the CAP/IASLC/AMP Guideline, the decision to test should not be based on clinical characteristics, as EGFR mutations can occur across a range of patient types.2
  • According to the CAP/IASLC/AMP Guideline, in the setting of fully excised lung cancer specimens, EGFR testing is not recommended in lung cancers that lack any adenocarcinoma component, such as pure squamous cell carcinomas, pure small cell carcinomas, or large cell carcinomas lacking any immunohistochemistry evidence of adenocarcinoma differentiation.2

Testing all appropriate tumors for EGFR mutations is critical in metastatic NSCLC

The Prevalence of mNSCLC Tumors that are EGFR Mutation-Positive Graph

Accurate testing methods are especially important in metastatic NSCLC2,4

  • Rapid molecular results are essential for metastatic NSCLC tumors because of the urgent need to initiate therapy that is most appropriate to disease type.2,14
  • According to the CAP/IASLC/AMP Guideline, neither immunohistochemistry (IHC) for total EGFR nor an EGFR copy number analysis (eg, fluorescence in situ hybridization [FISH] or chromogenic in situ hybridization [CISH]) is recommended for the selection of EGFR tyrosine kinase inhibitor (TKI) therapy.2
  • The CAP/IASLC/AMP Guideline states that Kirsten rat sarcoma (KRAS)–mutation testing is not recommended as the sole determinant of EGFR TKI therapy.2

Selected best practices for EGFR-mutation testing

  • EGFR results should be available within 2 weeks (10 working days) of receiving the specimen in the testing laboratory.2
  • Laboratories with average turnaround times beyond 2 weeks need to make available a more rapid test— either in-house or through a reference laboratory—in instances of clinical urgency.2
  • Laboratory departments should establish processes to ensure that specimens which have a final histopathologic diagnosis are sent to outside molecular pathology laboratories within 3 working days of receiving requests and to internal molecular pathology laboratories within 24 hours.2

Indication

Metastatic NSCLC

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.

Important Safety Information

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.

References

  1. Tarceva [package insert]. Northbrook, IL: OSI Pharmaceuticals, LLC, an affiliate of Astellas Pharma US, Inc.; 2016.
  2. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol. 2013;8(7):823-859.
  3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.4.2017. © National Comprehensive Cancer Network, Inc 2017. All rights reserved. Accessed January 24, 2017. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.
  4. Ellis PM. The importance of multidisciplinary team management of patients with non-small-cell lung cancer. Curr Oncol. 2012;19(suppl 1):S7-S15.
  5. Bordi P, Del Re M, Danesi R, Tiseo M. Circulating DNA in diagnosis and monitoring EGFR gene mutations in advanced non-small cell lung cancer. Transl Lung Cancer Res. 2015;4(5):584-597.
  6. Douillard J-Y, Ostoros G, Cobo M, et al. Gefitinib treatment in EGFR mutated caucasian NSCLC. J Thorac Oncol. 2014;9(9):1345-1353.
  7. Fenizia F, De Luca A, Pasquale R, et al. EGFR mutations in lung cancer: from tissue testing to liquid biopsy. Future Oncol. 2015;11(11):1611-1623.
  8. Mao C, YuanJ-Q, Yang Z-Y, et al. Blood as a substitute for tumor tissue in detecting EGFR mutations for guiding EGFR TKIs treatment of nonsmall cell lung cancer. Medicine. 2015;94(21):e775. doi: 10.1097/MD.0000000000000775.
  9. Marchetti A, Palma JF,Felicioni L, et al. Early prediction of response to tyrosine kinase inhibitors by quantification of EGFR mutations in plasma of NSCLC patients. J Thorac Oncol. 2015;10(10):1437-1443.
  10. Sholl LM, Aisner DL, Allen TC, et al. Liquid biopsy in lung cancer: a perspective from members of the Pulmonary Pathology Society [published online May 19, 2016]. Arch Pathol Lab Med. doi:10.5858/arpa.2016-0163-SA.
  11. Sorber L, Zwaenepoel K, Deschoolmeester V, et al. Circulating cell-free nucleic acids and platelets as a liquid biopsy in the provision of personalized therapy for lung cancer patients. Lung Cancer. 2016 May 4. pii: S0169-5002(16)30312-9. doi: 10.1016/j.lungcan.2016.04.026.
  12. Westwood M, Joore M, Whiting P, et al. Epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation testing in adults with locally advanced or metastatic non-small cell lung cancer: a systematic review and cost-effectiveness analysis. Health Technol Assess. 2014;18(32):1-166.
  13. Socinski MA. The emerging role of biomarkers in advanced non–small-cell lung cancer. Clin Lung Cancer. 2010;11(3):149-159.
  14. Lopez-Rios F, Angulo B, Gomez B, et al. Comparison of molecular testing methods for the detection of EGFR mutations in formalin-fixed paraffin-embedded tissue specimens of non-small cell lung cancer. J Clin Pathol. 2013;66(5):381-385.