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.

MET Exon 14 Skipping

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

METex14 is an oncogenic driver in mNSCLC.1

METex14 has a prevalence of ~3%, representing ~4,000-5,000 patients with mNSCLC per year in the United States.2-10*

  • 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 prognosis.11-13

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

ALK, anaplastic lymphoma kinase; BRAF, v-raf murine sarcoma viral oncogene homolog B1; MET, mesenchymal-epithelial transition; mNSCLC, metastatic non-small cell lung cancer; ROS1, ROS proto-oncogene 1, tyrosine receptor kinase. 
*This calculation is based on a 3% prevalence rate and mNSCLC–specific incidence and recurrence data from Kantar Health.


Companion Diagnostics for TABRECTA

FoundationOne®CDx

With FDA-approved tissue- and blood-based diagnostics, there are options for determining METex14 status

 

To inform up-front treatment planning, test every patient with mNSCLC at diagnosis

 

Tissue-based FoundationOne®CDx 

  • In a retrospective analysis, FoundationOne®CDx demonstrated a 99% positive percentage agreement (n=72/73) with the RNA-based RT-PCR clinical trial assay (CTA) that confirmed METex14 in patients taking TABRECTA® (capmatinib) tablets in GEOMETRY mono-114*
    • Negative percentage agreement was 100% (125/125)15‡
99% positive percentage agreement (72/73)

Blood-based FoundationOne®Liquid CDx 

  • In a retrospective analysis, FoundationOne®Liquid CDx demonstrated a 71% positive percentage agreement (n=55/78) with the CTA that confirmed METex14 in patients taking TABRECTA in GEOMETRY mono-116§||
    • Negative percentage agreement was 100% (72/72)16¶
71% positive percentage agreement (55/78)

Reflex to tissue biopsy for negative findings on blood-based test results, if feasible.14

Clinical utility data in a retrospective analysis of patients with METex14 as confirmed by FoundationOne®Liquid CDx (n=55)

  • Clinical utility was analyzed in tissue diagnostic–positive patients from cohorts 4 and 5b who also tested positive for METex14 with FoundationOne®Liquid CDx16
  • This analysis of clinical utility was not designed to demonstrate the therapeutic effect or superiority of testing modalities

 

Clinical utility data of FoundationOne®Liquid CDx in treatment-naive patients (Cohort 5b, n=16)16,17:

81% ORR (95% CI, 54.4-96; n=13/16). 20.3 Months mDOR (95% CI, 4.2-NE; n=13).

In a retrospective analysis, clinical utility data demonstrated an overall response rate (ORR) of 81% and a median duration of response (mDOR) of 20.3 months in treatment-naive patients (n=16).

Of the 28 patients in Cohort 5b, 26 met the recommended sample requirement (≥30 ng) for retesting using FoundationOne®Liquid CDx. Twenty-five samples were determined to be valid, out of which 16 were confirmed to be METex14+ using FoundationOne®Liquid CDx. Thirteen of 16 patients had either complete response or partial response, and DOR was evaluated for those 13 patients only.

Highlights of Important Safety Information

TABRECTA® (capmatinib) tablets has Warnings and Precautions for interstitial lung disease (ILD/pneumonitis), hepatotoxicity, risk of photosensitivity, and embryo-fetal toxicity.

The most common adverse reactions (≥20%) are peripheral edema, nausea, fatigue, vomiting, dyspnea, and decreased appetite.

Please see additional Important Safety Information below.

Clinical utility data of FoundationOne®Liquid CDx in previously treated patients (Cohort 4, n=39)16,17:

51% ORR (95% CI, 34.8-67.6, n=20/39). 9.8 Months mDOR (95% CI, 4.2-19.5; n=20).

In a retrospective analysis, clinical utility data demonstrated an ORR of 51% and an mDOR of 9.8 months in previously treated patients (n=39).

Of the 69 patients in Cohort 4, 55 met the recommended sample requirement (≥30 ng) for retesting using FoundationOne®Liquid CDx. Fifty-three samples were determined to be valid, out of which 39 were confirmed to be METex14+ using FoundationOne®Liquid CDx. Twenty of 39 patients had either complete response or partial response, and DOR was evaluated for those 20 patients only.

 

Clinical utility data of FoundationOne®Liquid CDx: Noncomparative analysis of median PFS and OS17

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.

Due to the nonrandomized, noncomparative nature of the study, PFS and OS results are difficult to interpret. No statistical tests were made for PFS and OS, as there was no comparator arm. PFS and OS results are based on an interim analysis; results are subject to change pending longer trial follow-up.

In treatment-naive patients

  • 12.4-month median PFS (95% CI, 4.5-NE; n=16)
  • 17.9-month median OS (95% CI, 9.8-NE; n=16)

In previously treated patients

  • 5.4-month median PFS (95% CI, 4-6.9; n=39)
  • 11.5-month median OS (95% CI, 5.4-23.3; n=39)

 

Information on the FDA-approved tests for the detection of METex14 in mNSCLC is available at:
 FDA.gov/CompanionDiagnostics
 FoundationMedicine.com/F1CDx
 FoundationMedicine.com/F1LCDx

 

 

CDx, companion diagnostic; DOR, duration of response; mNSCLC, metastatic non-small cell lung cancer; NE, not estimable; OS, overall survival; PFS, progression-free survival; RT-PCR, reverse transcription-polymerase chain reaction.
*The primary concordance analysis was conducted on 204 samples (78 positive and 126 negative). The denominator is the total number of evaluable samples, and the numerator is the number of patients with agreement.15
Of 78 specimens available to be retested, only 73 were evaluable.
Of 126 specimens available to be retested, only 125 were evaluable.
§The primary concordance analysis was conducted on 159 samples (81 positive and 78 negative). The denominator is the total number of valid samples, and the numerator is the number of patients with agreement.16
||Of the 81 patients who were CTA positive and retested with FoundationOne®Liquid CDx, 55 results were positive, 23 were discordant (ie, negative), and 3 were invalid.16
Of the 78 patients who were CTA negative and retested with FoundationOne®Liquid CDx, 72 results were negative, 0 were positive, and 6 were invalid.16

 

FoundationOne®CDx and FoundationOne®Liquid CDx are qualitative next-generation sequencing based in vitro diagnostic tests for advanced cancer patients with solid tumors and are for prescription use only. FoundationOne CDx utilizes FFPE tissue and analyzes 324 genes as well as genomic signatures. FoundationOne Liquid CDx analyzes 324 genes utilizing circulating cell-free DNA and is FDA-approved to report short variants in 311 genes. The tests are companion diagnostics to identify patients who may benefit from treatment with specific therapies in accordance with the therapeutic product labeling. Additional genomic findings may be reported and are not prescriptive or conclusive for labeled use of any specific therapeutic product. Use of the tests does not guarantee a patient will be matched to a treatment. A negative result does not rule out the presence of an alteration. Some patients may require a biopsy for testing with FoundationOne CDx when archival tissue is not available which may pose a risk. Patients who are tested with FoundationOne Liquid CDx and are negative for companion diagnostic mutations should be reflexed to tumor tissue testing and mutation status confirmed using an FDA-approved tumor tissue test, if feasible.

For the complete label, including companion diagnostic indications and important risk information, please visit www.F1CDxLabel.com and www.F1LCDxLabel.com.  

 

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. Novartis Calculation. 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; 2022. 15. Foundation Medicine, Inc. FoundationOne®CDx Technical Information. Cambridge, MA: Foundation Medicine, Inc. 16. Data on file. Study CINC280A2201, Plasma CDx. Novartis Pharmaceuticals Corp; 2021. 17. Data on file. Study CINC280A2201, Statistical Analysis Results - Efficacy Analysis on F1LCDx Positive Patients for ASCO2021. Novartis Pharmaceuticals Corp; 2021.

 

Next: Testing for MET Exon 14 Skipping in mNSCLC

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%). Grade 4 dyspnea was reported in 0.6% of patients.  

 

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.