How to Test

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Testing specifically designed to detect certain DNA mutations that lead to METex141

 

FoundationOne®CDx is the FDA-approved companion diagnostic clinically validated and optimized for detecting mutations leading to mesenchymal-epithelial transition (MET) exon 14 skipping (METex14) in metastatic non-small cell lung cancer (mNSCLC)2

 

The complex biological structure of METex14 requires a test that is specifically designed for its detection3,4

 

  • Skipping of exon 14 of MET is due to DNA mutations at splice sites, which flank this exon5

    • DNA mutations leading to METex14 are diverse and can include a variety of substitutions or indels3,5

 

Various point mutations leading to skipping of exon 14 of MET Various point mutations leading to skipping of exon 14 of MET

 

The FoundationOne®CDx is an FDA-approved test that has been clinically validated to identify patients who are eligible for treatment with TABRECTA.1

 

 

It is imperative to use a test specifically designed to detect METex14 to identify patients who are eligible for treatment with TABRECTATM (capmatinib) 150 mg, 200 mg tablets3

 

 

The ability of FoundationOne®CDx to detect METex14 in patients with mNSCLC was demonstrated in a retrospective analysis1,2

 

FoundationOne®CDx demonstrated agreement with the RNA-based RT-PCR clinical trial assay, which confirmed METex14 for TABRECTA1,2

 

FoundationOne®CDx positive, negative, and overall percent agreement with the RNA-based RT-PCR clinical trial assay FoundationOne®CDx positive, negative, and overall percent agreement with the RNA-based RT-PCR clinical trial assay

 

RT-PCR, reverse transcription-polymerase chain reaction.
The primary concordance analysis was conducted on 204 samples (78 positive and 126 negative).2
*The denominator is the total number of evaluable samples, and the numerator is the number of patients with agreement.
†Of 78 specimens available to be retested, only 73 were evaluable.

 

The limit of detection of alterations assessed by FoundationOne®CDx

 

The limit of detection (LoD) of alterations was assessed using a single FFPE tumor sample.2

  • Five levels of MAF, with 10 replicates per level, were evaluated for a total of 50 replicates per sample2

Summary of LoD for alterations associated with METex14 CDx claims (short variants)2

 

Alteration

LoDa
allele fraction (%)
(probit)

METex14 SNVsb

<2.9% (all detected)

METex14 insertions and deletions

5.7%

 

FFPE, formalin-fixed paraffin-embedded; MAF, mutant allele frequency; SNV, single nucleotide variant.
aLoD calculations for the CDx variants were based on the probit approach with 95% probability of detection.
bFor each sample, five levels of MAF, with 10 replicates per level, were evaluated for a total of 50 replicates per sample.

Preparing the test sample

FFPE tumor tissue specimens are collected and prepared following standard pathology practices. FFPE specimens may be received as either unstained slides or an FFPE block.6

FoundationOne®CDx uses DNA isolated from FFPE tumor tissue specimens.1

Acceptable samples

  • FFPE specimens, including cut slide specimens, are acceptable6

  • Use standard fixation methods to preserve nucleic acid integrity. Ten percent neutral-buffered formalin for 6 to 72 hours is industry standard. DO NOT use other fixatives (eg, Bouins, B5, AZF, Holland’s)6

  • Do not decalcify6

When feasible, please send6:

FFPE tissue block + 1 H&E slide‡

Graphic of FFPE tissue block and stained slide


OR

10 unstained slides (positively charged and unbaked at 4-5 microns thick) + 1 H&E slide‡

Graphic of unstained slides

 

H&E, hematoxylin and eosin stained.

Surface area6

MINIMUM: 25 mm2

  • If sending slides, provide 10 unstained slides cut at 4 to 5 microns thick to achieve a tissue volume of 1 mm3§
Graphic of Slide Surface Area

Tumor content6

OPTIMUM: 30% tumor nuclei
MINIMUM: 20% tumor nuclei
Percent tumor nuclei is the number of tumor cells divided by total number of all cells with nuclei.

Note for liver specimens: Higher tumor content may be required because hepatocyte nuclei have twice the DNA content of other somatic nuclei.
‡For smaller samples, providing the original H&E will preserve material for testing.
§Specimens with a smaller surface area may meet volume requirements by submitting additional unstained slides (USS) or blocks.
References: 1. Data on file. Study 7227b. Novartis Pharmaceuticals Corp; 2020. 2. Foundation Medicine, Inc. FoundationOne®CDx Technical Information. Cambridge, MA: Foundation Medicine, Inc. 3. 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. 4. 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. 5. Pruis MA, Geurts-Giele WRR, von der TJH, et al. Highly accurate DNA-based detection and treatment results of MET exon 14 skipping mutations in lung cancer. Lung Cancer. 2020;140:46-54. 6. Foundation Medicine, Inc. Specimen instructions. https://assets.ctfassets.net/vhribv12lmne/6ms7OiT5PaQgGiMWue2MAM/52d91048be64b72e73ffa0c1cab043c0/F1CDx_Specimen_Instructions.pdf. Accessed May 12, 2020. 

Indication

TABRECTA™ (capmatinib) 150 mg, 200 mg 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.

FoundationOne® is a qualitative next-generation sequencing based in vitro diagnostic test for advanced cancer patients with solid tumors and is for prescription use only. The test analyzes 324 genes as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB) and is a companion diagnostic to identify patients who may benefit from treatment with specific therapies in accordance with the approved 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 test 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 the complete label, including companion diagnostic indications and important risk information, please visit www.F1CDx.com.

 

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