I am 6 ft. and 154 lb. and last week I had a headache. I grabbed my trusted Paracetamol and read the On-label: “1-2 capsules every 4-6 hours,” it said. NBA legend Shaquille O’Neal, at 7 ft. 1 in and 325 lb. would have read the same recommendation. Would a drug’s pharmacodynamics and pharmacokinetics profile be identical in two individuals with physical profiles of such dichotomy? A priori knowledge says NO.
And yet, everyday, people use the internet to self-diagnose and prescribe themselves drugs marketed as miracle capsules. In this article, we will go through the current stage of personalized medicine and then explore the importance of proper testing for diagnostics and how the two components can work together to provide a more effective medicinal and economic value for patients.
The Right Drug For The Right Patient at The Right Time
A variety of reasons including notably stretched public healthcare systems, high rates of attrition in pharmaceutical drug development and a knowledgeable patient population are driving the personalized medicine movement. In my research field of oncology, this movement has reached fever pitch.
In the past decade, The Cancer Genome Atlas (TCGA) project has characterized many cancers. Thus, we know more about the cancer genome than we ever had. Commercial and academic entities have taken advantage of the data generated by TCGA to develop drugs on actionable genomic lesions that cancers exhibit. Despite this influx of knowledge about the genomic alterations that drive cancers and an ever-increasing armamentarium of drugs to combat this disease, drug development costs have skyrocketed. Moreover, the most important stakeholder, patients, take on the costs of treatments, which in turn deters proper treatment.
Applying Precision Medicine Early in Drug Development – Identifying Biomarkers Yields Results
In the recent 2016 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, a meta-analysis of 346 Phase I clinical trials involving more than 13 000 patients found that patients whose treatments were selected based on their tumor lesions experienced significantly better outcomes. Treatment arms employing precision medicine yielded a tumor regression rate of 30.6% compared to 4.9% in those that did not. This study suggests that applying precision medicine even at the earliest stage of clinical trials (Phase 1 traditionally explores drug safety profiles) may stratify for patient populations that stand to benefit most from a drug.
Ex-President Jimmy Carter and The Keytruda® Experience Mirrors the “Angelina Jolie Effect”
More often than, the mainstream media tells us about a miraculous new drug that has ‘cured’ cancer. If the patient in question happens to be a former US president, the hype will gain momentum, as it did with the drug, Keytruda®. We live in an era where patients ‘self-diagnose’ their ailments through what they read on the Internet and mainstream media, even before consultation with their healthcare professional. It is not that simple of course.
Why Are Companion Diagnostics (CDx) So Important?
Unfortunately, not everyone will benefit from Keytruda®, the drug that former president Jimmy Carter said made his melanoma disappear. Keytruda® blocks a receptor on T-cells called PD-1. Many tumors express another protein called PD-L1 and to a lesser extent, PD-L2, which when engages PD-1 on T-cells, renders T-cells ‘exhausted’ and do not see tumors as a threat. Patients treated with Keytruda® is akin to having “brakes taken off” in T-cells, and regaining cytotoxic activity to kill tumors.
The caveat is that not every patient’s tumor expresses enough of the PD-L1 protein. These patients are unlikely to respond to Keytruda®. These drugs are very costly and there are risks of side effects. Thus, it is so important to administer these therapies to patients with the best chance of benefiting from them. This is where Companion Diagnostics (CDx), an in vitro procedure, comes into the equation. Keytruda®’s CDx test is based on a immunohistochemical method of staining patient tumors with an anti-PD-L1 antibody. Beyond Keytruda®, the use of CDx testing has improved the success of a number of cancer targeted therapies.
Limitations of Current CDx – Testing For One Marker Only
CDx testing has undoubtedly improved tumor response rates. However, there are a proportion of patients who although express the target protein, do not respond to the targeted therapy in question.
Why is this so?
It is because the majority of CDx tests the patient’s tumor expression of the protein to be targeted only, which does not take into account downstream events of the protein in question that could lead to intrinsic resistance to the targeted therapy. Take the example of Erbitux® (Cetuximab), an epidermal growth factor receptor (EGFR) antibody used for the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer and head and neck cancer. For eligibility, tissue is assessed for EGFR expression using the DAKO EGFR PharmDx Kit. Patients who are selected based on this CDx test proceed with Erbitux® treatment. There is however a proportion of patients who do not respond. Studies have shown that the overexpression of another protein, AXL, and mutational status of K-ras, a small G-protein downstream of the EGFR pathway, mediates response to Erbitux®. This shows the value of preclinical and clinical research to understand potential compensatory resistance pathways to drugs. This knowledge directly translates into improved patient management that will prevent over-treatment with drugs that are unlikely to work.
In my own research, I hypothesized another approach to overcome this limitation – to develop a gene signature –based CDx. A gene signature is able to capture multiple downstream messenger RNA events, when calculated into a proprietary score, can provide a “transcriptomic snapshot”. In theory, this approach is more robust than the current general CDx model of measuring for one therapeutic marker.
Risk vs Reward
In oncology, targeted drug therapies and immunotherapies have been hailed as less toxic, with potentially minimized side effects, compared to chemotherapy. While it may be true in certain cases, this is stretching the truth. Cancer Immunotherapy in particular, holds a double-edged sword; tipping the balance of anti-tumor immune activity not to the point of disastrous immune-related adverse events is something clinicians continue to optimize. What these newer therapies provide though are more options than in the past where radiotherapy, chemotherapy and surgery were the main options.
The future of personalized medicine in oncology looks bright; as an active researcher in the field I am excited to contribute to novel tools and potential drug targets for clinicians to tailor the right treatment to the right patients at the right time. That is the ultimate goal.
