Having spent nearly 30 years working in the field of lung cancer, I have seen how advances in genomic profiling, a key element in precision medicine, have led to some amazing success stories.
A patient named Mary
In 2014, a patient named Mary was diagnosed with advanced non-small cell lung cancer. She was only 57 years old and had never smoked cigarettes. After testing negative for all of the clinical guideline-recommended biomarkers that could match her with an FDA-approved targeted therapy, she believed chemotherapy was her only option. Then a friend told her about the FoundationOne® comprehensive genomic profiling test that analyzes more than 300 cancer-related genes using a single tissue sample.
Her FoundationOne report revealed a MET exon 14 splice-site mutation. At that time, the MET-inhibitor crizotinib was still being studied in a Phase I trial, and because of her genomic alterations, she was able to enter the study. Within 48 hours her cough subsided, and a CT scan one month later showed her cancer had shrunk by 75 percent.
It is important to realize that this kind of success will not happen for every patient. Even though we have made great strides in diagnosing and treating cancer, not all patients will find a therapy option or clinical trial with genomic profiling. But it is stories like Mary’s that give us confidence that we are on the right track. Matching therapies with molecular alterations is helping redefine clinical trials from a “last ditch resort” to, in many cases, a rational treatment option. While they offer no guarantee, they do provide hope and potentially a better outcome – which is critical to so many cancer patients, their loved ones and their caretakers.
The role of lung cancer in precision medicine
The treatment of non-small cell lung cancer has served as somewhat of a roadmap for the incorporation of precision medicine into cancer care. Through advances in genomic profiling, the field has identified several molecular biomarkers, such as EGFR mutations or ALK rearrangements that are predictive of treatment efficacy in certain therapies and have laid the foundation for the standard of care in lung cancer treatment by allowing oncologists and patients to make more informed treatment decisions. Now, with continued biomarker discovery, the opportunities to be matched with personalized treatment are continuing to grow.
Our learnings in lung cancer have translated to important advances across many other cancer types. Today when someone receives a cancer diagnosis, it does not just matter where the tumor is. Oncologists need to understand the genomic alterations driving each person’s unique cancer, which can give insight into the most effective treatment. If a tumor has a mutation in a specific gene that leads to uncontrolled growth, there may be an approved targeted therapy that directly targets that mutation to stop or slow the progression of the disease.
More recently, the field has identified mutations that exist across multiple cancer types, setting the stage for pan-cancer treatment approaches. Indeed, 2017’s historic approval of pembrolizumab for any microsatellite instability (MSI) high solid tumors represented a milestone in our understanding of cancer genomics. Most recently, the FDA approved another treatment (larotrectinib) as a pan-cancer therapy for adult and pediatric solid tumors with an NTRK fusion.
Applying precision medicine approaches to immunotherapy
Immunotherapy approaches have also contributed significantly to our progress in treating lung cancer. However, the reality is that immunotherapy only works in a subset of the population, again underscoring the need to stratify patients and help guide the right therapy to the right people. A growing body of research is helping to identify and validate predictive biomarkers of immunotherapy response.
One such biomarker, tumor mutational burden (TMB), has been shown to predict response to immunotherapy across a growing number of cancer types. A retrospective analysis showed that in 151 patients treated with immunotherapy across 21 different types of cancer, those with high TMB had better outcomes than those with low TMB. Moreover, a study of more than 100,000 human cancer genomes found 20 tumor types for which at least 10 percent of patients had high TMB, suggesting the broad potential of this biomarker to guide immunotherapy use.
This year, data from the first prospective clinical trial showed that non-small cell lung cancer (NSCLC) patients with high TMB showed statistically significant improvement in progression-free survival upon treatment with nivolumab and ipilimumab as opposed to chemotherapy. Other studies are ongoing to better understand the predictive role of TMB across more cancer types.
Moving forward, it will be important for the field to establish TMB standards across platforms and new biomarkers to determine which patients will respond to immunotherapies. Foundation Medicine is part of a consortium led by the Friends of Cancer Research, which aims to standardize the definition and analytic validation requirements for TMB for consistent and accurate reporting. We have also collaborated with Flatiron Health to build a clinico-genomic database that integrates genomic information with patient outcomes to better monitor real-world data. Initiatives like these help to ensure that the field can move forward in a valid and meaningful way.
Expanding opportunities with liquid biopsy
Traditionally, comprehensive genomic profiling has relied on a tissue biopsy to profile the cancer but unfortunately, not all patients have tissue available for testing. For example, up to 30 percent of patients with non-small cell lung cancer (NSCLC) do not have adequate tissue available at diagnosis for standard biomarker testing. This is why liquid biopsy is becoming such an important tool for advancing precision oncology to as many patients as possible, as it can provide genomic information using a blood sample.
Liquid biopsy is being incorporated in an increasing number of clinical trials. For example, Foundation Medicine is using liquid biopsy to identify eligible patients for one of a number of targeted therapies to treat NSCLC in a prospective clinical trial. This analysis includes the genomic biomarker blood tumor mutational burden (bTMB). Assessing bTMB through a blood sample could help even more people have the opportunity to receive the treatment most likely to benefit their cancer.
Treatment of non-small cell lung cancer has paved the way
The rapid progress we are making in the treatment of non-small cell lung cancer has paved the way for several other types of cancer. Each of these avenues of research represents decades of effort, but we still have work to do. However, reflecting on the enormous progress made to date and the fact that there are more than 600 late-stage therapies for cancer in development, I am very optimistic about a future where we can continue to match an increasing number of patients with better, more precise and more effective treatments.