The Era of Genetically-Targeting Therapies and Diagnostic Challenges: What Have We Learned?
When the FDA approved Keytruda for use in any tumor with the biomarker, I decided to investigate how a doctor and patient would diagnose the patient as a candidate for this treatment. This investigation, Diagnostic Challenges in the Era of Genetically-Targeting Master Brands, was published in Pharmaceutical Executive on May 26. In the following post, I would like to share the key learnings behind the article with you.
I summarized two very good articles on the reliability of PD-L1 testing in my PharmExec article.1,2 I also referenced Stanford University, addressing the acute shortage of laboratories that could test for the specific genetic marker for familial hypertension; this hampered the successful uptake of Repatha and Praluent. The Pharmaceutical Executive article further illustrated the challenges related to FISH testing with Herceptin that Genentech and Roche faced at launch.
For those involved in bringing genetically-targeting therapies to market, these three examples and related experiences form the basis of shared learning:
- Prior to launching, companies need to ensure the availability of the tests. In fact, pharmaceutical companies need to involve diagnostic test planning along with the clinical R&D development plan of the drug.
- Companies also need to ensure standardization of the tests across multiple laboratory systems, platforms and diagnostics.
- To reduce variability and improve reliability of results, laboratory technicians may need extensive training on how to process the biopsy or blood sample for analysis, storage, handling, and processing.
- Governments must be willing to reimburse for the diagnostics, including them in the value-based care proposition for pricing approval of the genetically-targeting therapy.
- Doctors’ willingness and understanding of how and what tests to order, and how to interpret the results for the patient, need to be as much a part of the MDs’ education as understanding the therapy.
- Patients need to know about and understand the benefits of the testing.
- If the patients do test positive (i.e. they may respond to the genetically-targeting therapy), longer-term care plans need to be developed, including: sustainability and affordability of maintenance on the drug, how often they need to be monitored in case of further mutations that may render the drug ineffective, and subsequent impact on therapeutic options.
- Companies need to involve diagnostic test planning along with the clinical R&D development plan of the drug.
Further questions to consider:
- How willing are patients to pay for the test or a portion of it, especially when results are negative?
- How can the investigators and company help shape the language used by the regulatory authorities about the drug’s use of a companion diagnostic?
- What are the implications for doctors and patients if tests are unreliable, or if there is a lack of access? How does this impact strategy, forecasts, MD education and messaging/promotion?
- How can the language used by the regulatory authorities be shaped about when the drug could be used in a patient (e.g. stage of disease)?
I still question why a patient has to wait for first line treatment failure or metastatic disease to reap the benefits of an immunologic or other genetically-targeting therapy. Earlier diagnosis and use are proven to be much better for the patient. Herceptin is now first line therapy, but that was not the case for years. Many, many deaths could have been prevented had Herceptin not been initially reserved for metastatic disease.
In the case of immunotherapies such as Keytruda, some research indicates that early diagnosis and treatment are more effective at stopping the replication of cancer cells and essentially killing them before they can grow to radiologically-detectable tumors. In other solid tumor research, Circulating Tumor Cells (CTCs) have been used to detect for early potential of primary cancer metastasis. CTCs and earlier use of other blood-based assays could potentially result in treatment with targeted therapies before a radiologically identifiable tumor is detected. This would then allow the drug and the patient to get ahead of the curve in terms of cancer cell replication.
However, the FDA and other agencies are unlikely to allow immunotherapies to be approved for prophylaxis until they understand the longer-term sequelae of such immunomodulation. Although not stated outright, long-term costs must also be a concern. The amount of time a patient should spend on immunotherapies also can be highly variable. Furthermore, different immunotherapies require different tests to determine biomarker inhibition status.
This has further implications in terms of the patient journey. We now may anticipate how immunotherapies could be excellent prospective examples of upstream marketing strategy. Potentially, much earlier diagnosis and use could not only save lives, but also preserve the quality of life and productivity of individuals for decades to come from initiation of treatment.
How this journey will unfold, particularly the affordability vs. benefits of lifelong monitoring and alternating uses of immunotherapies, will make this for a most interesting ride indeed.
1. Diggs LP, Hsueh EC. Utility of PD-L1 immunohistochemistry assays for predicting PD-1/PD-L1 inhibitor response. Biomarker Research (2017) 5:12
2. Grigg C, Rizvi NA. PD-L1 biomarker testing for non-small cell lung cancer: truth or fiction? Journal for ImmunoTherapy of Cancer (2016) 4:48