India's new clinical trial rules establish an accelerated pathway for new drug approvals, but affordability remains… https://t.co/uhVXDZGLfr
Complexities in personalised medicine: Key to new directions in oncology
In December of last year, I had the pleasure of attending the Personalised Medicine & Biomarkers 2015 conference, which presented a wide range of topics in the precision medicine arena, ranging from biomarker discovery and early phase trials design through to commercialisation, as explored in a number of interesting panel discussions and keynote presentations.
Unsurprisingly, the personalised medicine field is moving forward most quickly in oncology, where there is crucial need. The ideal practice of personalised medicine involves measurement of key tumour characteristics, which inform optimal therapy that benefits individual patients and prevent relapse. In reality, cancer is tremendously complex and heterogeneous, creating numerous obstacles for such visions to be realised. Even for a patient who responds well to a drug initially, cancer cells can become resistant to the medication after a while, owing to the additional DNA mutations that develop after a period of treatment that allow malignancy to progress - which in fact is also an active area in the development of companion diagnostics (CDx) as discussed at the meeting, in order to sequentially monitor genomic alterations and responsiveness to treatment (e.g. liquid biopsies test). On the upside, technological advancements in recent years have resulted in an explosion of data in biomarker research, and as a few speakers agreed, having good and properly validated biomarkers hugely decreases the chances of a drug's failure.
One presentation that was particularly interesting focused on the recent successful story of osimertinib (Tagrisso), an oral drug indicated for patients with non-small cell lung cancer whose tumours harbour a specific EGFR mutation (T790M) and whose disease has progressed after treatment with other EGFR-blocking treatment. The drug received FDA accelerated approval last month, after just 2.5 years since Tagrisso was first tested on humans. Tagrisso had also received breakthrough therapy designation in the US. At the same time, a CDx from Roche, Cobas EGFR Mutation Test v2, was approved to detect the mutation. The success of the programme was tied to both the drug and diagnostic test performance, as 1) drug approval in the US required the approval of a CDx, and 2) approval of the CDx relies on clinical utility data collected as part of the pivotal drug study.
A reliable test and an experienced diagnostic partner is key, and the two drug makers actually engaged in discussions long before they signed a collaboration agreement when Tagrisso completed Phase I. To have a win-win partnership, it is a case of matching both strategic interests and resources. Pharmaceutical companies need to understand the business models of the diagnostics partner, so as to find out what they strategically want to achieve in order to find a good fit for both. This echoes what several stakeholders told us in our recent study, Pathways to Precision Medicine: Navigating Payer Needs and Healthcare Systems through Molecular Diagnostics.
Discussions also revolved around the promise offered by cancer immunotherapy, which is likely to be the backbone of drug combination therapies for many cancers in the future. By targeting multiple pathways in the complicated process by which cells become cancerous, combinations of novel anti-cancer targeted drugs, such as compounds that are active at immune checkpoints, e.g. anti-CTLA4, anti-PD-1, and anti-PD-L1, have the potential to elicit durable, robust responses. In contrast to the Tagrisso story, the first wave of immune-oncology therapies (agents like Keytruda and Opdivo) have made their ways to major markets without pairing with any regulator-mandated diagnostic test; I cannot help but wonder about the role of CDx as the immune-oncology race continues to unfold. Part of the technical hurdle can be seen in the way that tests for PD-L1 are not perfectly predictive, with some PD-L1 negative tumours responding, and some PD-L1 positive tumours that don't respond. As clinical experts remain sceptical of PD-L1 status driving decision making, the need for post-marketing standardization of tests is evident. So far, only PD-L1 IHC 22C3 pharmDx has been approved by the FDA as a CDx for the use of pembrolizumab.
Technology is not sufficient on its own, however; the challenge remains as to how to bridge the gap between bench and bedside, and as one speaker at the conference said, tests for these highly promising medications will need to work within the existing healthcare workflow. As more new targeted therapies and their associated tests continue to become available, these will have to integrate into the clinical care pathway to determine the most effective treatment decisions for patients. There are other caveats with drug costs and the burden on the healthcare system, and the need to align stakeholders' interests. Indeed, it was commented upon in the meeting that the regulatory environment is not developing as fast as the science. Notably, even in countries where a lot of personalised medicine research and clinical development have made headway, regulatory activities are still in a formative state, leading to uneven market access. As personalised medicine continues to make strides, efforts should be focused to overcome the policy challenge which is necessary to foster innovation and the adoption of technologies into health systems.
Cecilia Chui is a life sciences senior analyst for IHS
Posted 11 January 2016
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