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In the world of personalized diagnostics, history does not necessarily predict the future. Following the much anticipated FDA approval of the first immuno-oncology drug Keytruda® (Merck) for NSCLC patients in October 2015 as a Companion Diagnostic (CDx) for PD-L1 testing , all eyes then went to Bristol Myers Squibb with competitor OPDIVO® as the CheckMate 057 trial data emerged for non- squamous NSCLC patient use. Much to the surprise of the oncology community, only two weeks following the Keytruda CDx approval, OPDIVO was approved as a “complementary diagnostic,” a classification unfamiliar in diagnostics not requiring PD-L1 testing for clinical use in nsNSCLC. Really ? What are the implications of a complementary diagnostic test vs a CDx?

Since the development of the first companion diagnostic in 1998, HercepTestTM (Dako North America, an Agilent Company) to select breast cancer patients eligible for Herceptin, the field of personalized diagnostics has evolved significantly. Today with advances in molecular diagnostics, FISH and PCR technologies are commonplace in Companion Diagnostics for HER2 FISH and kRAS/ BRAF respectively. Immunohistochemistry continues to be the mainstay for HER2, EGFR and the new PD-L1 companion diagnostic tests. In the future, we can expect Genome signature assays with techniques such as next generation sequencing (NGS) to become relevant in the personalized diagnostics space.

Going back to the “complementary diagnostic” classification, the field of oncology diagnostics was left with questions about this new category of “complementary” tests:

    1. What is a complementary diagnostic?
    2. Is the complementary diagnostic testing required to order the drug?
    3. What are the implications to test reimbursement, etc.?

What is a complementary diagnostic?

The term “Complementary Diagnostic” was introduced in June 2015 by Elizabeth Mansfield, Deputy Director for Personalized Medicine at FDA, during a DIA panel discussion regarding the regulation of laboratory-developed tests (LDTs). During the discussion, she announced that FDA will be increasingly focused on what she called "complementary diagnostics." The “complementary” category of tests was defined as distinct from companion diagnostics in that it will provide additional information about how a drug might be used, or whether someone should receive a class of drugs, rather than being required for the safe and effective use of a drug.

This complementary approach resonated with industry as a practical approach. A complementary diagnostic test would be informative but due to the low safety risk, there would be no need to elevate it to a CDx, a higher level test requiring results prior to clinicians initiating treatment. The PMA requirement in the US remains in place as a way to ensure that FDA review takes place to confirm there is indeed no safety risk. It makes sense that as personalized medicine becomes the norm, it won’t be practical to tie all biomarker testing to a companion diagnostic. Today there are estimated to be 11,000 biomarkers informing treatment and this complementary category may be a prudent approach to managing the onslaught of biomarkers tied to patient stratification.

Is the complementary diagnostic test required to order the drug?

While the Companion Diagnostic FDA label for Keytruda determines that PD-L1 testing is required, a complementary label does NOT require testing. However, it might be important to consider PD-L1 status when oncologists select patients to treat. Specifically, the CheckMate 057 trial for non-squamous NSCLC demonstrated OPDIVO benefit in overall survival in patients with PD-L1 expression at various levels, while patients in the squamous NSCLC trial 017 benefited from OPDIVO regardless of expression. Both of these trials demonstrated that expression, while informative to clinicians, was not required. In contrast Keytruda demonstrated response based on 50% expression consistently requiring a CDx test designation. To build on the complementary momentum, May 2016 Ventana received FDA approval for PD-L1 in urothelial cancer as a complementary diagnostic to TECENTRIQTM; indicated to shrink tumors in 26% of those patients with mid to high level expression. These recent approvals emphasize the point that while testing is important since both these immuno-oncology drugs have been scrutinized in exhaustive clinical studies relative to test expression , clinicians are not required to test in advance of treatment. These recent immuno-oncology trials have spawned active discussion on the importance of the biomarker testing for optimal patient selection and are making a case for the importance of testing.

While it is too early to know where the field of personalize diagnostics will land, it is clear that testing will be critical for stratification of patients. Where the field of personalized medicine evolves remains to be seen.

Contact Market Ready Rx for more information on how we can support your companion or complementary diagnostic go-to-market planning.