Importance of EGFR Testing

For the treatment of metastatic EGFRm NSCLC

Importance of EGFR Testing

Optimal treatment starts with a full molecular profile

~1 in 3 patients with metastatic lung adenocarcinoma has an actionable mutation, a genetic alteration that1-4

  • Drives the growth and spread of metastatic NSCLC
  • Can be targeted with therapy specific to the mutation

One missed patient is one too many—test all your mNSCLC patients for actionable mutations like EGFR

Phenotype is not genotype—test every patient with metastatic NSCLC for an EGFR mutation

Patients with mNSCLC should get EGFR testing, regardless of

SMOKING STATUS
Up to 38% of EGFR mutations could be missed if patients with smoking history are not tested5,6*

GENDER
~1/3 of EGFR mutations could be missed if men are not tested7†

RACE

    EGFR mutations in adenocarcinoma NSCLC are present in various racial backgrounds5,8-10
  • Caucasians: ~20%
  • Latinos: ~23%§
  • African-Americans: ~19%||
  • Asians: ~51%

AGE
Up to 37% of EGFR mutations could be missed if patients ≥65 years old are not tested11-13¶

*Based on 2 ex-US studies of 13,160 patients with stage IIIB or IV NSCLC, 92% of whom had stage IV disease. 7925 patients had an EGFR mutation.6,7Based on a retrospective US study of patients with EGFRm NSCLC selected from the Flatiron database; 961 patients were selected for this study, and 94% had stage IV disease.7Based on a meta-analysis of 456 multinational studies with 115,815 patients; 153 studies included patients with stage III or IV disease. 30,466 patients had an EGFR muation.5§Rate includes all histologies. Based on a multinational study of 642 patients, 480 of whom were tested for EGFR. 93% of patients tested for EGFR had stage IIIB or IV disease. 105 patients had an EGFR mutation.9||Based on a review of 151 multinational studies including 33,162 patients. 9749 patients had EGFRm adenocarcinoma.10Based on 4 multinational studies of 1334 patients with EGFRm NSCLC, 96% of whom had stage IIIB or IV disease.11-13

NCCN® recommends clinicopathologic features such as ethnicity, smoking status, or histology NOT be used to select patients for molecular testing14

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend14

  • Testing for actionable molecular alterations in patients with metastatic nonsquamous NSCLC at diagnosis
  • Treating patients based on test results

PD-L1 positive does not mean EGFR negative15,16

Patients with an EGFR mutation may also express PD-L1

  • PD-L1 is not an actionable mutation—it is a protein expressed on the tumor cell surface

UP TO 70% OF EGFRm mNSCLC PATIENTS ALSO EXPRESS AT LEAST 1% PD-L117-21

Up to 70% of EGFRm mNSCLC patients also express at least 1% PD-L1

No single-agent or combination immunotherapies are FDA-approved for treatment-naïve EGFRm mNSCLC patients22-24

Treatment-naïve metastatic EGFRm NSCLC patients were excluded in 8 pivotal first-line immunotherapy trials25-32*

*KEYNOTE-189, KEYNOTE-021 Cohort G, KEYNOTE-042, KEYNOTE-024, CHECKMATE 026, CHECKMATE 227, IMpower130, IMpower150. In the IMpower130 and IMpower150 trials, EGFRm positive patients were allowed only after progression on EGFR-TKI therapy or intolerance to EGFR TKI treatment.22-24

How to test for mNSCLC mutations

Testing tissue and plasma concurrently increased detection of actionable mutations Testing tissue and plasma concurrently increased detection of actionable mutations

Ensure
adequate tissue collection—quantity and quality matter14,33

Prioritize
actionable mutations for optimal treatment34

Integrate

plasma testing to detect more actionable mutations

  • Plasma testing has >98% concordance with tissue testing across 4 actionable mutation types, with a median turnaround time of 9 days35
  • Testing plasma and tissue concurrently increased detection of actionable mutations by 17% over mutations found in tissue36
  • In patients who were unable to have a tissue biopsy, ~1 of 5 were found to have actionable mutations with plasma testing36*

*Single-center, prospective US study pf 323 patients with stage IV NSCLC using next-generation sequencing as the testing platform.36

Test. Know. Treat.

In mNSCLC, optimal treatment starts with knowing the driver of your patient’s disease

TEST

for actionable mutations
  • NCCN® recommends testing all patients with metastatic nonsquamous NSCLC for actionable mutations, including EGFR, ALK, ROS1, and BRAF14
  • Using both tissue and plasma testing can help identify more patients with actionable mutations34,35

KNOW

Your patient’s full molecular profile
  • Obtain all molecular test results before first-line treatment, if clinically feasible14
  • Molecular testing results should be used to determine the optimal first-line therapy option15,37

TREAT

EGFRm mNSCLC patients with an EGFR TKI
  • EGFR TKIs are the standard of care for first-line therapy in metastatic EGFRm NSCLC33
Don’t miss a patient who could be eligible for first-line TAGRISSO

TAGRISSO is indicated 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 mutations, as detected by an FDA-approved test.

MOA

TAGRISSO is designed to inhibit EGFR sensitizing and resistance mutations38-41

TAGRISSO is a third-generation, irreversible EGFR TKI designed to

  • Inhibit EGFR sensitizing mutations—exon 19 del and L858R mutations
  • Inhibit mutated EGFR with the T790M resistance mutation
  • Have lower activity against wild-type EGFR
TAGRISSO (osimertinib) Mechanism of Action TAGRISSO (osimertinib) Mechanism of Action

TAGRISSO crossed the blood-brain barrier (BBB) in preclinical models.38,42,43 TAGRISSO crossed the intact BBB in a study of healthy humans44*

||Study description: Eight (8) healthy male volunteers (age 52±8 years) were examined for ~90 minutes with PET imaging after single intravenous microdose (1.3 mcg; range 1.1-1.4 mcg) of 11C-labeled TAGRISSO. Concentrations of 11C-labeled TAGRISSO were also measured in arterial and venous blood and plasma. Brain MRI was acquired and used for co-registration of PET data and automatic delineation of regions of interest in the brain. PK parameters Cmax (brain), Tmax (brain) and AUC0–90 min brain/blood ratio were calculated. Safety and tolerability monitoring included recording of AEs, vital signs and ECG.44

ALK, anaplastic lymphoma kinase; BRAF, B-Raf proto-oncogene; EGFR, epidermal growth factor receptor; EGFRm, epidermal growth factor receptor mutant; IO, immunotherapy; L858R, substitution of lysine for arginine at amino acid position 858; mNSCLC, metastatic non-small cell lung cancer; NSCLC, non-small cell lung cancer; PD-L1, programmed death-ligand 1; ROS1, ROS proto-oncogene 1; TKI, tyrosine kinase inhibitor; T790M, substitution of threonine for methionine at position 790; WT, wild-type

References: 1. Sholl L, Aisner D, Varella-Garcia M, et al. Multi-institutional oncogenic driver mutation analysis in lung adenocarcinoma: The Lung Cancer Mutation Consortium experience. J Thorac Oncol. 2015;10(5):768-777. 2. Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. The landscape of kinase fusions in cancer. Nat Commun. 2014;5:4846. doi:10.1038/ncomms5846. 3. Bergethon K, Shaw A, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol. 2012;30:863-870. 4. Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol. 2011;12:175-80 5. Shi Y, Au JS, Thongprasert S, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol. 2014;9(2):154-162. 6. Tseng CH, Chiang CJ, Tseng JS, et al. EGFR mutation, smoking, and gender in advanced lung adenocarcinoma. Oncotarget. 2017;8(58):98384-98393. 7. Li Y, Appius A, Pattipaka T, et al. Real-world management of patients with epidermal growth factor receptor (EGFR) mutation-positive non–small-cell lung cancer in the USA. PLoS ONE. 2019;14(1):e0209709. 8. Zhang Y, Yuan J, Wang K, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget. 2016;7(48):78985-78993. 9. Lopez-Chavez A, Thomas A, Evbuomwan M, et al. EGFR mutations in Latinos from the United States and Latin America. J Glob Oncol. 2016;2(5):259-267. 10. Midha A, Dearden S, McCormack R. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res. 2015;5(9):2892-2911. 11. Wu YL, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(11):1454-1466. 12. Yang JC, Wu YL, Schuler M, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015;16(2):141-151. 13. Rosell R, Carcereny E, Gervais R, et al. 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. 14. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NSCLC V.7.2019. ©National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed August 30, 2019. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 15. Brahmer JR, Govindan R, Anders RA, et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC). J Immunother Cancer. 2018;6(1):75. 16. Ribas A, Hu-Lieskovan S. What does PD-L1 positive or negative mean? J Exp Med. 2016;213(13):2835-2840. 17. Akamine T, Takada K, Toyokawa G, et al. Association of preoperative serum CRP with PD-L1 expression in 508 patients with non-small cell lung cancer: a comprehensive analysis of systemic inflammatory markers. Surg Oncol. 2018;27(1):88-94. 18. D’Incecco A, Andreozzi M, Ludovini V, et al. PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients. Br J Cancer. 2015;112(1):95-102. 19. Liu SY, Dong ZY, Wu SP, et al. Clinical relevance of PD-L1 expression and CD8+ T cells infiltration in patients with EGFR-mutated and ALK-rearranged lung cancer. Lung Cancer. 2018;125:86-92. 20. Yoneshima Y, Ijichi K, Anai S, et al. PD-L1 expression in lung adenocarcinoma harboring EGFR mutations or ALK rearrangements. Lung Cancer. 2018;118:36-40. 21. Brown H, Vansteenkiste JF, Nakagawa K, et al. PD-L1 expression in untreated EGFRm advanced NSCLC and response to osimertinib and SoC EGFR-TKIs in the FLAURA trial. Presented at: IASLC WCLC; September 23-26, 2018; Toronto, Canada. 22. Keytruda [package insert]. Whitehouse Station, NJ: Merck & Co., Inc; 2019. 23. Tecentriq [package insert]. South San Francisco, CA: Genentech Inc; 2019. 24. Opdivo [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2019. 25. Reck M, Rodríguez-Abreu D, Robinson AG, et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1–positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823-1833. 26. Clinicaltrials.gov. Study of pembrolizumab (MK-3475) versus platinum-based chemotherapy for participants with programmed cell death-ligand (PD-L1)-positive advanced or metastatic non-small cell lung cancer (MK- 3475-042/KEYNOTE-042). https://clinicaltrials.gov/ct2/show/NCT02220894. Accessed January 9, 2019. 27. Langer CJ, Gadgeel SM, Borghaei H, et al; KEYNOTE-021 Investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497-1508. 28. Broderick JM. Frontline pembrolizumab combo improves survival in phase III NSCLC trial. https://www.onclive.com/web-exclusives/frontline-pembrolizumab-combo-improves-survival-in-phase-iii-nsclc-trial. Published January 16, 2018. Accessed January 9, 2019. 29. Carbone DP, Reck M, Paz-Ares L, et al; CheckMate 026 Investigators. First-line nivolumab in stage IV or recurrent non–small-cell lung cancer. N Engl J Med. 2017;376(25):2415-2426. 30. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378(22):2093-2104. 31. EU Clinical Trials Register. A phase III clinical study to evaluate the efficacy and safety of atezolizumab in combination with carboplatin + nab-paclitaxel compared with carboplatin + nab-paclitaxel in patients with stage IV non-squamous non-small cell lung cancer. EudraCT number 2014-003206-32. https://www.clinicaltrialsregister.eu/. Accessed January 28, 2019. 32. Kowanetz M, Socinski MA, Zou W, et al. Impower150: efficacy of atezolizumab plus bevacizumab and chemotherapy across PD-L1 expression subgroups defined by the SP142 and SP263 IHC assays confirm all-comer benefit in 1L metastatic NSCLC. Presented at: AACR; April 14-18, 2018; Chicago, IL. 33. Planchard D, Popat S, Kerr K, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(suppl 4):iv192-iv237. 34. Barlési F, Mazieres J, Merlio JP, et al. Routine molecular profiling of cancer: results of a one-year nationwide program of the French Cooperative Thoracic Intergroup (IFCT) for advanced non-small cell lung cancer (NSCLC) patients. Lancet. 2016;387:1415-1426. 35. Leighl NB, Page RD, Raymond VM, et al. Clinical utility of comprehensive cell-free DNA analysis to identify genomic biomarkers in patients with newly diagnosed metastatic non–small cell lung cancer. Clin Cancer Res. 2019;25(15):4691–4700. 36. Aggarwal C, Thompson JC, Black TA, et al. Clinical implications of plasma-based genotyping with the delivery of personalized therapy in metastatic non-small cell lung cancer. JAMA Oncol. 2019;5(2):173-180. 37. Kalemkerian GP, Narula N, Kennedy EB, et al. Molecular testing guideline for the selection of patients with lung cancer for treatment with targeted tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Clinical Practice Guideline update. J Clin Oncol. 2018;36(9):911-919. 38. TAGRISSO [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2018. 39. Soria JC, Ohe Y, Vansteenkiste J, et al; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. 40. Cross DA, Ashton SE, Ghiorghiu S, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4(9):1046-1061. 41. Finlay MR, Anderton M, Ashton S, et al. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J Med Chem. 2014;57(20):8249-8267. 42. Ballard P, Yates JW, Yang Z, et al. Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res. 2016;22(20):5130-5140. 43. Colclough N, Ballard PG, Barton P, et al. Preclinical comparison of the blood brain barrier (BBB) permeability of osimertinib (AZD9291) with other irreversible next generation EGFR TKIs. Eur J Cancer. 2016;69:S28. 44. Varrone A, Varnäs K, Jucaite A, et al. A PET study in healthy subjects of brain exposure of 11C-labeled osimertinib: A drug intended for treatment of brain metastases in non-small cell lung cancer. J Cereb Blood Flow Metab. 2019 Apr 20:271678X19843776.

Important Safety Information Expand

  • There are no contraindications for TAGRISSO

  • Interstitial lung disease (ILD)/pneumonitis occurred in 3.9% of the 1142 TAGRISSO-treated patients; 0.4% of cases were fatal. Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (eg, dyspnea, cough and fever). Permanently discontinue TAGRISSO if ILD is confirmed

  • Heart rate-corrected QT (QTc) interval prolongation occurred in TAGRISSO-treated patients. Of the 1142 TAGRISSO-treated patients in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. No QTc-related arrhythmias were reported. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia

  • Cardiomyopathy occurred in 2.6% of the 1142 TAGRISSO-treated patients; 0.1% of cardiomyopathy cases were fatal. A decline in left ventricular ejection fraction (LVEF) ≥10% from baseline and to <50% LVEF occurred in 3.9% of 908 patients who had baseline and at least one follow-up LVEF assessment. Conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in patients with cardiac risk factors. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure, permanently discontinue TAGRISSO

  • Keratitis was reported in 0.7% of 1142 patients treated with TAGRISSO in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist

  • Verify pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose

  • Most common adverse reactions (≥20%) were diarrhea, rash, dry skin, nail toxicity, stomatitis, fatigue and decreased appetite

Indications

  • TAGRISSO is indicated 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 mutations, as detected by an FDA-approved test

  • TAGRISSO is indicated for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy


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