Over the last two decades, we have seen a surge of targeted treatments for cancer. Beginning with Herceptin (which is used to treat HER2-receptor positive breast cancer), the field has grown to include a wide range of targeted therapies, along with companion diagnostic tests.
Gleevec, for instance, treats forms of leukaemia that test positive for the Philadelphia chromosome. Erbitux treats colon cancer in tumours where the KRAS gene is not mutated. Xalkori treats certain non-small cell lung cancers that express an abnormal ALK gene, and Tafinlar treats cancers associated with a mutated BRAF gene.
The list could go on. In fact, of all the new drugs approved by the US Food and Drug Administration (FDA) in 2016, 27% were targeted therapeutics. What links treatments of this kind is that, rather than being administered to all patients with a particular disease, they use a biomarker to identify which patients are likely to respond.
“When you understand a molecular pathway then you can target individual steps in that pathway, and that’s what many of the oncology biomarker-guided drugs actually do,” explains Dr David Parker, senior vice-president of diagnostic solutions at diagnostics development firm Precision for Medicine. “We know the pathway of the signal that causes the cell to divide in a cancerous way, and we target drugs to interrupt that signalling pathway.”
Many of these drugs have been highly successful. Herceptin, for instance, has significantly improved survival rates for patients with HER2-positive cancer. In one major long-term study, overall survival was 37% better in women who received Herceptin plus chemotherapy, compared to women who only received chemotherapy.
Biomarkers also play an important role in immunotherapy. Take Merck’s drug Keytruda, which was originally approved to treat metastatic melanoma. Last year, it was approved for any cancer with a particular genetic anomaly, marking the first time a drug had been approved based on tumour genetics rather than cancer type.
“PD-L1 and PD-1 inhibitors like Opdivo, Keytruda, and Tecentriq have used a number of different biomarkers to guide the selection of patients for treatment,” explains Parker. “Those drugs have continued to expand their indications to a wide variety of cancers. Among all the biomarker-guided drugs, these immuno-oncology agents are perhaps the greatest success story that we’ve seen.”
Clinical and commercial benefits
The advantages are clear. Firstly, and most obviously, biomarkers have therapeutic benefits, ensuring the right groups of patients are given the right treatments. Not only does this improve the odds that they’ll respond, it also means non-responders won’t have to deal with unnecessary side effects.
On top of this, there are economic benefits. As Parker explains, this is part of the reason why biomarker-guided therapies are more prevalent in oncology than anywhere else.
“Cancer treatment is very expensive – it was expensive before biomarker-guided therapies became available, and it has only become more expensive since then,” he says. “There is a confluence of advanced scientific understanding and economic need present in cancer that has concentrated biomarker guidance in that area.”
He adds that these economic advantages become apparent long before the drugs reach market. In essence, biomarkers enable the pharma company to take some of the risk out of their clinical trial.
“The pharma company needs to invest tens of millions of dollars in clinical trials for a new therapeutic, and traditionally they have done so on a population basis without biomarker stratification,” he says. “Those trials frequently fail at the pivotal phase 3 stage. If you have a biomarker that predicts response to that drug, and if you can screen the patients for that biomarker before enrolment, then obviously you have a much better chance that the patients will respond.”
Once the drug is commercialised, the economic benefits extend to the payer or budget holder. They now have an objective clinical measure they can use to manage access, and are less likely to waste money on ineffective drugs.
Clinical trial design
As Parker explains, the role of the biomarker begins at the earliest stages of drug development.
“During the preclinical testing stage, researchers will want to see if there is an association between the biomarker and some measurable effect of the drug candidates in vitro,” he says. “In the phase 1 studies, the drug company will assess the biomarker with a clinical trial assay. They will assess a relatively broad population of patients, and look for an association between the biomarker and patient response.”
Over the course of the trial, the clinical trial assay may continue to evolve until it reaches its final form. By phase 2, it should closely resemble the companion diagnostic that will be marketed along with the drug.
“At this stage, drug companies will take one of two strategies – either they will enrol patients with the biomarker as a selection criterion, or they will enrol patients in a bigger trial and only require a subset to have the biomarker,” says Parker. “With the second strategy, they are hedging their bets by ensuring a biomarker-positive subgroup will give significant results if the overall results are not sufficient for drug approval.”
Trials of this nature, unsurprisingly, can be challenging to design, the main issue being finding enough patients who fit the enrolment criteria.
“If patients enrol very slowly the costs skyrocket and the market entry of the drug is delayed,” says Parker. “When you introduce a biomarker test into the clinical trial that’s one more factor that has to be taken into account. So introducing a biomarker can cause the rate of enrolment to slow down and the calendar length of the trial to go up.”
Typically, drug companies address this issue by expanding the number of sites used in the trial, allowing them to accrue biomarker-positive patients more easily.
Parker believes that, in the years to come, we are likely to see biomarker-guided trials extend beyond oncology.
“With other conditions, we don’t have as deep an understanding of the molecular causes of disease, but research is progressing,” he says. “Eventually I believe we will reach a stage of scientific understanding that allows us to develop specific molecule targeted drugs in other clinical areas.”
Within oncology, he thinks biomarker testing will continue to increase, not least because biomarker-guided therapies can command a higher price than conventional drugs.
“Biomarker guidance can support higher drug prices per efficacious treatment, so I think that’s a mechanism by which pharma companies will be looking to justify their pricing,” says Parker. “It’s another incentive for pharma companies to incorporate biomarker guidance in their clinical trials.”
As he explains, without a biomarker, two patients might both receive a treatment valued at $1,000 – but if only one of them ends up responding, the budget holder will pay $2,000 per response. With a biomarker, only the responding patient would receive the treatment. Assuming you’re still willing to pay $2,000 per response, this equates to $2,000 for the one treatment.
Of course, the high costs of targeted therapies is a controversial subject, and beyond the remit of this article to discuss. However, it’s clear that in today’s value-focused environment, pharma companies need new ways to achieve their commercial goals. Factor in the clinical benefits, and we can expect biomarker-guided trials to become even more prevalent in future.