For:
METex14 mNSCLC
Important Safety Information:


Interstitial Lung Disease (ILD)/Pneumonitis.
ILD/pneumonitis, which can be fatal, occurred in patients treated with TABRECTA™ (capmatinib) tablets. ILD/pneumonitis occurred in 4.5% of patients trea...

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Indication
TABRECTA™ (capmatinib) tablets is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

METex14

Why Mutations Leading to MET Exon 14 Skipping (METex14) Matter

METex14 is an oncogenic driver in mNSCLC1

METex14 has a prevalence of ~3%, representing ~4,000-5,000 patients with mNSCLC per year in the United States2-10*

  • NSCLC is a heterogeneous disease with many genomic mutations

  • The prevalence of METex14 is similar to that of other genomic mutations, such as ALK fusions (~3%-4%), BRAF mutations (~3%-4%), and ROS1 fusions (~1%-2%)

Patients with METex14 in mNSCLC face a poor prognosis11-13

  • Many of these patients may have bone, liver, and brain metastases, which are associated with poor outcomes

*This calculation is based on a 3% prevalence rate and mNSCLC–specific incidence and recurrence data from Kantar Health.


Testing

Knowledge of METex14 status can inform up-front treatment planning

METex14 testing is a critical component in the treatment of mNSCLC.

WHY TEST

  • Only patients with METex14 are eligible for biomarker-driven therapy with TABRECTA™ (capmatinib) tablets14

WHOM TO TEST

  • Patients with mNSCLC (stage IV)14

WHEN TO TEST

  • Test for METex14 upon diagnosis when a patient presents with mNSCLC14,15
  • METex14 is generally stable throughout the course of the disease16

HOW TO TEST

  • METex14 has a complex biological structure requiring a test that is specifically designed to detect it15,17
  • FoundationOne®CDx was validated and optimized to detect the specific mutations leading to MET exon 14 skipping that were studied in the clinical trial for TABRECTA14
    • Patients were enrolled in GEOMETRY mono-1 by central confirmation of METex14 using an RNA-based clinical trial assay. A 99% positive percentage agreement was demonstrated when those with evaluable specimens were retested using FoundationOne®CDx (72/73)*
  • Information on the FDA-approved test for the detection of METex14 in NSCLC is available at FDA.gov/CompanionDiagnostics or FoundationMedicine.com/F1CDx

 

FoundationOne®CDx 

CMS instituted an NCD for FDA-approved NGS tests, including FoundationOne®CDx, in March 201818

 

Assess for METex14 in mNSCLC in:

  • Patients with stage IV disease
  • Patients who have not received prior therapy or have progressed on treatment

 

 

FoundationOne®CDx is a next-generation sequencing based in vitro test intended for use by healthcare professionals for advanced cancer patients with solid tumors. The test analyzes 324 genes as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB) and is FDA-approved as a companion diagnostic to identify patients who may benefit from treatment with a specific list of therapies (listed in Table 1 in the Technical Information at www.foundationmedicine.com/f1cdx) in accordance with the approved therapeutic product labeling. Additional genomic findings, other than those listed in Table 1, may be reported and are not prescriptive or conclusive for labeled use of any specific therapeutic product. Use of the test does not guarantee a patient will be matched to a treatment or clinical trial option, or that all relevant alterations will be detected. Some patients may require a biopsy. For the complete label, including important risk information, please visit www.foundationmedicine.com/f1cdx.

CDx, companion diagnostic; CMS, Centers for Medicare and Medicaid Services; mNSCLC, metastatic non-small cell lung cancer; NCD, national coverage determination; NGS, next-generation sequencing.

*Of 78 specimens available to be retested, only 73 were evaluable. 

 

References: 1. Smyth EC, Sclafani F, Cunningham D. Emerging molecular targets in oncology: clinical potential of MET/hepatocyte growth-factor inhibitors. Onco Targets Ther. 2014;7:1001-1014. 2. Vuong HG, Ho ATN, Altibi AMA, Nakazawa T, Katoh R, Kondo T. Clinicopathological implications of MET exon 14 mutations in non-small cell lung cancer – A systematic review and meta-analysis. Lung Cancer. 2018;123:76-82. 3. Data on file. Kantar Health. CancerMPact: lung (non-small cell) metastatic stage IV incidence and newly recurrent. Updated December 15, 2018. my.khapps.com. 4. Chakravarty D, Gao J, Phillips SM, et al. OncoKB: a precision oncology knowledge base. JCO Precis Oncol. 2017. doi:10.1200/PO.17.00011. 5. Ross JS, Ali SM, Fasan O, et al. ALK fusions in a wide variety of tumor types respond to anti-ALK targeted therapy. Oncologist. 2017;22(12):1444-1450. 6. Gainor JF, Varghese AM, Ou SH, et al. ALK arrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res. 2013;19(15):4273-4281. 7. Awad MM, Oxnard GR, Jackman DM, et al. MET exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-Met overexpression. J Clin Oncol. 2016;34(7):721-730. 8. Lin Q, Zhang H, Ding H. The association between BRAF mutation class and clinical features in BRAF-mutant Chinese non-small cell lung cancer patients. J Transl Med. 2019;17(1):298. 9. Tissot C, Couraud S, Tanguy R, Bringuier PP, Girard N, Souquet PJ. Clinical characteristics and outcome of patients with lung cancer harboring BRAF mutations. Lung Cancer. 2016;91:23-28. 10. Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a molecular class of lung cancers. J Clin Oncol. 2012;30(8):863-870. 11. Hsu F, De Caluwe A, Anderson D, Nichol A, Toriumi T, Ho C. Patterns of spread and prognostic implications of lung cancer metastasis in an era of driver mutations. Curr Oncol. 2017;24(4):228-233. 12. Awad MM, Leonardi GC, Kravets S, et al. Impact of MET inhibitors on survival among patients with non-small cell lung cancer harboring MET exon 14 mutations: a retrospective analysis. Lung Cancer. 2019;133:96-102. 13. Awad MM, Leonardi GC, Kravets S, et al. Impact of MET inhibitors on survival among patients with non-small cell lung cancer harboring MET exon 14 mutations: a retrospective analysis. Supplementary Table 2. Lung Cancer (suppl). doi.org/10.1016/j.lungcan.2019.05.011. 14. Tabrecta [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2020. 15. Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med. 2018;142(3):321-346. 16. Ding G, Wang J, Ding P, Wen Y, Yang L. Case report: HER2 amplification as a resistance mechanism to crizotinib in NSCLC with MET exon 14 skipping. Cancer Biol Ther. 2019;20(6):837-842. 17. Frampton GM, Ali SM, Rosenzweig M, et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 2015;5(8):850-859. 18. Centers for Medicare and Medicaid Services. CMS finalizes coverage of next generation sequencing tests, ensuring enhanced access for cancer patients. https://www.cms.gov/newsroom/press-releases/cms-finalizes-coverage-next-generation-sequencing-tests-ensuring-enhanced-access-cancer-patients. Accessed March 6, 2020.

Indication

TABRECTA™ (capmatinib) tablets is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test.

 

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.


Important Safety Information

Interstitial Lung Disease (ILD)/Pneumonitis. ILD/pneumonitis, which can be fatal, occurred in patients treated with TABRECTA. ILD/pneumonitis occurred in 4.5% of patients treated with TABRECTA in the GEOMETRY mono-1 study, with 1.8% of patients experiencing grade 3 ILD/pneumonitis and 1 patient experiencing death (0.3%). Eight patients (2.4%) discontinued TABRECTA due to ILD/pneumonitis.

 

Monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, fever). Immediately withhold TABRECTA in patients with suspected ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis are identified.

 

Hepatotoxicity. Hepatotoxicity occurred in patients treated with TABRECTA. Increased alanine aminotransferase (ALT)/aspartate aminotransferase (AST) occurred in 13% of patients treated with TABRECTA in GEOMETRY mono-1. Grade 3 or 4 increased ALT/AST occurred in 6% of patients. Three patients (0.9%) discontinued TABRECTA due to increased ALT/AST.

 

Monitor liver function tests (including ALT, AST, and total bilirubin) prior to the start of TABRECTA, every 2 weeks during the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop increased transaminases or bilirubin. Based on the severity of the adverse reaction, withhold, reduce dose, or permanently discontinue TABRECTA.

 

Risk of Photosensitivity. Based on findings from animal studies, there is a potential risk of photosensitivity reactions with TABRECTA. In GEOMETRY mono-1, it was recommended that patients use precautionary measures against ultraviolet exposure, such as use of sunscreen or protective clothing, during treatment with TABRECTA. Advise patients to limit direct ultraviolet exposure during treatment with TABRECTA.

 

Embryo-Fetal Toxicity. Based on findings from animal studies and its mechanism of action, TABRECTA 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 treatment with TABRECTA and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with TABRECTA and for 1 week after the last dose.

 

Most Common Adverse Reactions. The most common adverse reactions (≥20%) were peripheral edema (52%), nausea (44%), fatigue (32%), vomiting (28%), dyspnea (24%), and decreased appetite (21%). The most common grade 3 adverse reactions (≥2%) were peripheral edema (9%), fatigue (8%), dyspnea (7%), nausea (2.7%), vomiting (2.4%), and noncardiac chest pain (2.1%).

 

Clinically Relevant Adverse Reactions. Clinically relevant adverse reactions observed in <10% of patients were pruritus (allergic and generalized), ILD/pneumonitis, cellulitis, acute kidney injury (including renal failure), urticaria, and acute pancreatitis.

 

Laboratory Abnormalities. Select laboratory abnormalities (≥20%) worsening from baseline in patients who received TABRECTA were decreased albumin (68%), increased creatinine (62%), decreased lymphocytes (44%), increased ALT (37%), increased alkaline phosphatase (32%), increased amylase (31%), increased gamma-glutamyltransferase (29%), increased lipase (26%), increased AST (25%), decreased hemoglobin (24%), decreased leukocytes (23%), decreased sodium (23%), decreased phosphate (23%), increased potassium (23%), and decreased glucose (21%).

 

Please see full Prescribing Information for TABRECTA.