NEW YORK – Researchers in Australia have developed a tool to guide treatment decisions for oncologists that they hope will improve patients' access to precision oncology drugs and clinical trials in the country.
The decision support tool, called TOPOGRAPH, was detailed in a paper published last month in NPJ Precision Oncology. The study authors, led by Frank Lin, senior research officer at the Garvan Institute of Medical Research in Sydney, hope to make it more widely available to clinicians after completing validation studies within a national precision oncology program in Australia called the Molecular Screening and Therapeutics, or MoST, program.
TOPOGRAPH, which stands for "Therapy-Oriented Precision Oncology Guidelines for Recommendation of Anticancer Pharmaceuticals," is a tool for matching patients to cancer drugs based on their tumor type, the biomarkers driving their tumors, and the evidence supporting the efficacy of drugs in their particular biomarker-defined tumor types, as well as the regulatory and reimbursement status of the therapeutic indications.
The tool sorts drugs into four tiers. Tier 1 drugs are approved by Australia's drug regulator, the Therapeutic Goods Administration, and are indicated for the treatment of biomarker-defined cancers. Within this tier, the tool also sorts drugs by whether they are funded by the Australian government, and therefore easily available for patients.
Tier 2 includes drugs not approved by the TGA but that have shown activity against the patient's cancer type or biomarker in large clinical trials. Tier 3 drugs have demonstrated clinical activity in tumors with the relevant biomarker in smaller, Phase II or earlier studies. Tier 4 includes drugs that have suggested activity in retrospective studies using exploratory biomarkers, but their activity has not been proven in clinical trials.
TOPOGRAPH also flags evidence on biomarkers that suggest that patients may not respond to certain drugs or develop resistance to them.
"Currently, there are many established resources for interpreting if a mutation is important for driving a patient’s cancer," Lin said. "However, most databases do not contain sufficient information about the usefulness of specific drugs, nor do they provide this information about the right clinical context. We believe that considering whether a drug is useful is as important as finding the mutation."
TOPOGRAPH was created to incorporate that information about a drug's "usefulness," which factors in results from clinical trials and other evidence on whether the therapy works against that biomarker or if the biomarker drives resistance to the treatment, as well as relevant clinical trials of the drug the patient is eligible for and its regulatory status.
While many oncologists are familiar with established biomarkers, like HER2 or PD-L1 expression, they also need to keep up with the constant stream of new research and relevant clinical trials. Lin and his colleagues believe that this tool, which is available online while they continue validation efforts, will help oncologists in Australia quickly synthesize the growing volume of published data on cancer biomarkers and drugs and improve their ability to identify the best treatment strategies for their patients.
"We designed TOPOGRAPH to fill this gap between mutations and therapy, enriching it with data from results of clinical trials and important preclinical studies," Lin said. "While it is relatively straightforward for experienced clinicians to find the best therapy when a common biomarker is present — for example, HER2-amplified cancers — it may be challenging to find the right information when a test returns a less common mutation."
The researchers have also developed a decision support algorithm in tandem with the TOPOGRAPH database to make it more accessible in the clinic. Lin said the hope is to "promote discussions about targeted therapy" between patients and their oncologists. The tool could also help oncologists find relevant clinical trials for their patients, which would contribute to further validation of new and existing biomarkers.
The algorithm would recommend therapies in a specific order based on the level of evidence on the biomarkers driving patients' cancers and the drugs available on the market and in clinical trials. For example, based on a patient's biomarker profile, TOPOGRAPH would first show doctors the drugs approved in that tumor type and for that biomarker, alongside therapies that the patient should avoid based on evidence on biomarker-driven resistance.
Next, the tool would present on- or off-label treatments based on lower tiers of evidence. Alongside each tier, the tool would also show clinical trials that the patient may be eligible for, in the hopes of encouraging research participation. "Part of efforts in addressing equity in cancer care should take into consideration clinical trials, and ongoing collaborative efforts between academia, pharma, and policymakers are needed," Lin said.
Ultimately, with the development of TOPOGRAPH, Lin and his colleagues are trying to raise Australia's precision oncology expertise on par with other nations leading in this space. Australia is sometimes behind other parts of the world because pharma companies tend to focus their precision oncology drug development and commercialization efforts in larger markets like the US, Europe, and China.
Once a drug has been approved and funded by regulators in Australia, access is usually straightforward, noted Agnes Vitry, a senior lecturer on medicines policies at the University of South Australia's School of Pharmacy and Health Sciences. The main barrier to accessing new cancer drugs is often the regulatory and reimbursement process in Australia, she said.
TOPOGRAPH's built-in information on the regulatory and reimbursement status of biomarker-driven treatments could help oncologists navigate and stay current on new drugs' approval and funding, so they aren't wasting time going after medications that may be time consuming or costly to procure and delay patient care.
A 2019 report from Australia's Center for Innovation in Regulatory Science found that there were some significant delays in cancer drugs being approved in Australia compared to other parts of the world, despite the TGA having a similar review timeline for drug applications as other regulatory agencies, according to Vitry. The report found a median "submission gap" of 535 days between when sponsors filed a regulatory application for a drug with the US Food and Drug Administration and the TGA.
That report flagged "significant delays in companies bringing new medicines to Australia," said Vitry, who is not involved in developing TOPOGRAPH. She observed that drug companies tend to launch drugs in the biggest markets first, such as in the US and Europe, because if they're successful in those places, they are more likely to garner approval elsewhere. But in pharma's prioritization process, Australia usually falls into those other, lower tier markets.
"Australia is on the side," Vitry said. "When [pharma companies] have time and when they have more resources, that's when they come to Australia."
While TOPOGRAPH won't change this reality, it can at least help oncologists identify the precision oncology drugs that are realistically accessible for their patients in Australia. In addition to regulatory status, a therapy's reimbursement status also impacts its accessibility. And there, too, TOPOGRAPH provides oncologists insights.
The tool would alert oncologists if a newly approved medicine has government funding through Australia's Pharmaceutical Benefits Scheme, which, based on the recommendations of an independent expert body called the Pharmaceutical Benefits Advisory Committee, provides certain drugs through the public healthcare system.
Vitry said there is often a gap between a drug's approval by the TGA, meaning the drug has been found to be safe and effective, and funding by the PBS, but recent initiatives have helped shorten that time period.
"A few years ago, the agencies began to try to streamline the process," she explained. "The new process] let a drug company apply at the same time for approval at the regulatory agency and for funding at PBAC. It means they didn't have to wait to get the [regulatory] approval to apply [for reimbursement]."
Once a drug is through the regulatory and funding review processes, accessing it becomes more straightforward and not costly for most patients, according to Vitry. Australians might have a small copay to receive a medicine, but it's often A$40 (around $29) or less since the public health insurance system caps an individual's annual spending on medicines.
Meanwhile, when patients' tumor biomarkers point to treatments that aren't approved or publicly funded in Australia, they will likely face higher costs. "In countries like Australia where a significant proportion of cancer drugs are publicly funded, the reimbursement or payment status strongly guides prescription choice and patterns of best practice," Lin noted. "Outside the reimbursement schedule, however, accessing certain approved medications, and drugs approved in other jurisdictions, can still be financially prohibitive for patients with less common cancers."
Some pharma companies offer medicine access programs, Vitry said, to help patients afford drugs in between TGA approval and funding, but she noted those programs are not very transparent on cost and can be difficult to navigate.
For the time being, Lin and his colleagues are continuing to study TOPOGRAPH and the decision support algorithm in the biomarker-informed platform trials being conducted within the MoST program, which Lin likened to the NCI-MATCH trial in the US. They're continuing to investigate how accurately TOPOGRAPH matches patients to treatments based on the biomarkers they harbor and whether the use of the tool is leading to treatment that improves their outcomes, he said.
In order for the tool to be broadly accessible to oncologists and easy to use, however, the TOPOGRAPH platform will eventually have to be integrated into "electronic tools that process treatment options and/or clinical trial referrals," he said in an email. Researchers are also exploring how to integrate the tool with electronic medical records systems in Australia, but Lin noted that those informatics tools are not yet mature.
"We hope that the web tool, in its current form, can gradually evolve into a trusted reference for oncologists to look up up-to-date evidence quickly in clinic, when interpreting a genomic report," Lin said. "We also hope to see TOPOGRAPH become a communication tool to help oncologists and patients decide together which treatments are valuable in a physician's office."