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December 25, 2017 – The American Food & Drug Administration (FDA) has approved two genetic tests to identify genetic alterations in tumors. The FoundationOne CDx (F1CDx) genomic test and the MSK-IMPACT Tumor Profiling test both can help to guide physicians in clinical trial enrollment and in cancer treatment.
The FoundationOne CDx (F1CDx) genomic test can identify cancer-associated alterations in 324 genes and two types of genomic signatures in any type of solid tumor, irrespective of the tissue the tumor initially originated from. Moreover, F1CDx can be used as a companion diagnostic test for 15 different targeted therapies used to treat five types of cancer (see table at bottom). A companion diagnostic is used to determine whether a patient is a candidate for a specific therapy by identifying whether their tumor has a specific genetic alteration. Data that led to the test’s approval showed that it could accurately detect selected mutation types about 95% of the time.
A couple of days before the F1CDx, FDA had cleared the MSK-IMPACT Tumor Profiling Test. This test. which was developed for use only at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, can scan tumor samples for 468 different cancer-associated mutations or alterations. Laboratory tests developed by and used only at a single hospital currently do not require FDA review and authorization to be offered to patients.
This latter test was at the base of research using the concept of a basket clinical study, which harnessed the power of precision medicine by assigning treatments to patients based on the genetic alterations and led to the recent approval of Vemurafenib (Zelboraf) for the treatment of BRAF V600E positive Erdheim-Chester Disease (ECD) based on the data of 22 ECD patients enrolled in the phase II VE-BASKET study.
Of note in this context is that the Centers for Medicare & Medicaid Services (CMS) proposed national coverage of F1CDx and certain other diagnostic tests that use next-generation sequencing technology, which can rapidly analyze many genes simultaneously. The proposed coverage includes the use of these tests in patients with recurrent or metastatic solid cancers who have not previously used the test and who wish to pursue further treatment for which the test can serve as a companion diagnostic. Still, CMS’ coverage proposal, known as a national coverage determination, is subject to a 30-day public comment period before it can be finalized.
Under the newly emerging concept of “One Clinical Trial, Many Cancer Types” clinical trials in cancer (also coined “basket trials”) are increasingly enrolling patients based not on the organ in which a tumor initially arose, such as the breast, colon, lung, or liver, but on the specific genetic alterations that allow the tumor to survive and spread. These targets can include mutations in single genes or genomic signatures such as microsatellite instability or mutation burden (the number of mutations in a single tumor). Research published earlier this year showed that MSK-IMPACT identified actionable genetic changes in 37% of patients with advanced solid cancers. An actionable mutation is one that can be targeted with either an approved drug or one being tested in clinical trials. Taken together, patients with a variety of rare but actionable mutations do really add up to significant subsets of patients, and it would never be cost-effective to screen for these alterations one at a time.
|Cancer Type||Gene Containing Targeted Mutations||Drug|
|Non-small cell lung cancer||EGFR||Erlotinib (Tarceva®), Afatinib (Gilotrif®), or Gefitinib (Iressa®)|
|Non-small cell lung cancer||EGFR||Osimertinib (Tagrisso®)|
|Non-small cell lung cancer||ALK||Crizotinib (Xalkori®), Alectinib (Alecensa®) or Ceritinib (Zykadia®)|
|Non-small cell lung cancer||BRAF||Dabrafenib (Tafinlar®) in combination with Trametinib (Mekinist®)|
|Melanoma||BRAF||Vemurafenib (Zelboraf®) or Dabrafenib|
|Melanoma||BRAF||Trametinib (Mekinist®) or Cobimetinib (Cotellic®) in combination with Vemurafenib (Zelboraf®)|
|Breast cancer||HER2 (ERBB2)||Trastuzumab (Herceptin®, Ogivri™), Pertuzumab (Perjeta®), or Ado-trastuzumab emtansine (Kadcyla®)|
|Colorectal cancer||KRAS||Cetuximab (Erbitux®)|
|Colorectal cancer||KRAS, NRAS||Panitumumab (Vectibix®)|
|Ovarian cancer||BRCA1, BRCA2||Rucaparib (Rubraca®)|