Cancer genomics and the rise in precision medicine continues to revolutionize our understanding of cancer and our approach to treatment. But to date, the focus in this space has predominantly been on finding targeted care solutions for patients with stage three and four advanced cancers.
There are multiple reasons for this concentration of efforts. In early cancer, the standard of care is potentially curative surgery alongside effective, but often toxic, chemotherapy and radiation. These strategies are less effective in advanced or metastatic cancer, and people tend to be sicker and less able to tolerate toxic therapies.
A significant proportion of people are only diagnosed after their cancer has progressed, despite advances in screening. Combined with those who have progressed or relapsed even with early intervention, this represents a significant population of cancer patients who need effective treatment options with acceptable tolerability.
We know that successful early cancer detection and treatment represents the strongest opportunity for potential cure or long-term tumor control, so in order to realize the full potential of precision medicine and eliminate long term toxicities associated with radiation and chemotherapy, we need to apply our deep genomics expertise to earlier stages of disease to identify patients at higher risk of relapse.
Building the evidence, traction and clinical landscape for precision medicine in early-stage disease is a core component of Foundation Medicine’s R&D strategy and this is reflected in the breadth of studies we are bringing to the American Society of Clinical Oncology (ASCO) Annual Meeting this year.
Gaining momentum for precision medicine in early cancer
Recent research shows growing opportunities to apply the wealth of discoveries in advanced disease to earlier stages of cancer. Particular progress has been made in early non-small cell lung cancer (NSCLC), where a deeper genomic understanding has already enabled an explosion of novel treatments in advanced disease that target EGFR, ALK, ROS1, BRAF, NTRK, MET, RET and KRAS gene mutations, as well demonstrating the vast potential of immunotherapy.
Results from multiple studies assessing the benefit of immunotherapy and targeted treatment in early NSCLC continue to demonstrate the superiority of a targeted approach versus the standard of care, when it comes to disease progression, recurrence risk and overall survival. In the past two years, the FDA has granted approvals for the first tyrosine kinase inhibitor (TKI) and the first checkpoint inhibitor in the adjuvant (post-surgery) setting and the first chemotherapy/checkpoint inhibitor combination in the neoadjuvant (prior to surgery) setting, ushering in the era of precision medicine in early-stage NSCLC.
Despite these encouraging milestones, there is still a long way to go before precision medicine is standard at diagnosis. To further support these new approvals in the adjuvant space, we are working with multiple partners to bring new data and insights that support the adoption of precision medicine at diagnosis.
In a real-world study being presented at ASCO this year, we collaborated with Flatiron Health and Cleveland Clinic Cancer Center to assess the clinical value of comprehensive genomic profiling (CGP) in early-stage NSCLC. Using the Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB), researchers investigated CGP results from nearly 1500 early-stage NSCLC tumor specimens to confirm the driver mutations identified and assess the role of CGP in the selection of appropriate precision therapies.
CGP identified EGFR, ALK, ROS1 and RET drivers in this early setting, and the resulting tumor profiling enabled optimization and timely initiation of precision therapies for first line treatment at recurrence. In addition, insights into the mutational profile of patients allowed for better identification of patients who were likely to be resistant to immunotherapy due to ALK or ROS1/RET mutations, or unlikely to benefit from TKI treatment, resulting in avoidance of unnecessary toxicity.
Maximizing actionability through collaboration
Data alone is not enough to drive change in clinical practice; key to securing the adoption of CGP in earlier stages of cancer is actionability. Genomic profiling at diagnosis must bring significant actionable benefit over and above current practice and give clinicians new tools, knowledge, and a range of novel therapeutic options to improve care for patients.
We recognize the importance of embedding our resources in the research and clinical trials needed to make progress in this space and are excited about our partnership with the Lung Cancer Research Foundation (LCRF) and the Lung Cancer Mutation Consortium (LCMC) on a new neoadjuvant screening trial – LCMC4 Evaluation of Actionable Drivers in EaRly Stage Lung Cancer (LEADER). The LEADER trial is utilizing an umbrella trial design to screen for 10 distinct actionable driver mutations in 1,000 patients with high-risk, resectable non-small cell lung cancer (NSCLC).
Comprehensive genomic profiling using our two FDA-approved CGP tests, the tissue-based FoundationOne®CDx, and the blood-based FoundationOne®Liquid CDx, will support identification of patients who harbor one or more of these mutations and match them into linked precision treatment trials. Generating data that clarifies the potential clinical utility of identifying and targeting these actionable mutations in early disease will help to accelerate the expansion of therapeutic options in this setting. Our Trial in Progress poster on the LEADER study at ASCO provides the opportunity to engage with stakeholders from across oncology to discuss the aims of the trial and explore further opportunities for pivotal research in early-stage cancer.
Earlier intervention demands advances in monitoring
People are living longer with cancer, especially those diagnosed in earlier stages of disease. Five-year survival rates have continued to rise in recent decades and there are more and more people living beyond the five-year mark with cancer as a ‘chronic disease.’ A precision-approach from diagnosis will undoubtedly increase these cases, introducing additional short and long-term considerations that will need to be factored into treatment decisions from diagnosis.
We know that what makes tumors so difficult to treat is that they are rarely static. They grow, evolve, find new ways to evade the body’s defenses and develop mechanisms to neutralize the effects of treatment. In order to achieve a balanced and sustained response to treatment, we need to track how a tumor is evolving at the genomic level and use those insights to modify the treatment approach in real time. This is where monitoring comes in.
Taking regular biopsies from diagnosis through the duration of treatment and beyond is not an option, and the need for a less invasive way to monitor tumor response and progression at the molecular level has driven significant advances in monitoring technology in recent years.
Detecting tumor DNA circulating in the blood (ctDNA), is a non-invasive way to track changes to the mutational profile of a tumor during treatment and monitor for signs of relapse further down the line. ctDNA monitoring uses include the detection of molecular residual disease, commonly known as MRD, in early-stage cancer after curative therapy, like surgery. This molecular detection can help guide further therapy decisions depending on MRD status and an individual’s risk of relapse.
Our monitoring test, FoundationOne Tracker, currently available for research use only, is a personalized assay that monitors the specific variants present in a patient’s tumor. In the future, we hope that this approach will provide physicians with effective monitoring combined with a streamlined solution that can more easily be integrated into existing systems and pathways. The use of FoundationOne Tracker is continuing to deliver evidence to support its potential in the clinic.
Expanding our genomic understanding into the future
In order to make significant advances in cancer treatment over the next decade, we need to build our knowledge of cancer genomics across the entire ‘lifespan’ of a tumor.
Our current approach gives us a static snapshot of the genomic landscape for a tumor that has reached middle age. If we take an end-to-end genomic approach using CGP at diagnosis to inform a personalized treatment strategy, alongside ongoing tumor monitoring with ctDNA monitoring technologies, we can map the genomic landscape of cancer from diagnosis through to metastasis. Instead of a genomic snapshot in time, we can understand the evolution of a tumor from its first steps to any eventual progression – how it begins to proliferate, adapts and evolves, responds to external pressures, learns to evade detection and metastasizes.
This mastery of cancer at the genomic level is now on the horizon. The next step in that journey is to firmly establish precision medicine as standard of care in early cancer. Working towards this goal will continue to be a priority for our team, as part of our mission to bring precision medicine to all patients living with cancer.