Commentary: How genomic testing is redefining cancer research
By Dr. Gaurav Singal of Foundation Medicine
The clinical development process is long, arduous and risky, especially in the oncology field. Cancer drugs have a 5 percent chance of making it from a Phase 1 clinical trial to FDA approval, the lowest likelihood of all major disease areas.[1] This poor success rate has been a major roadblock to improving cancer outcomes.
However, improved genomic sequencing techniques are increasing the rigor of the clinical development process. Genomic profiling is helping to identify new therapeutic targets as well as biomarkers of treatment response. These insights help bring new medicines to market and ensure they get to the right patients, which ultimately advances precision cancer care.
Novel therapeutic targets
Genomic testing has uncovered numerous molecular drivers of cancer, many of which can now be targeted by treatment. In the last five years, 68 different targeted agents have been approved for over 22 different cancer types.[2]
Meanwhile, a wealth of new knowledge about the molecular drivers of cancer has the potential to reveal even more therapeutic targets. On April 5, the National Institutes of Health published new findings from the Pan-Cancer Atlas, a comprehensive genomic analysis spanning 10,000 tumors across 33 cancer types.
These developments are leading us toward a pan-cancer treatment approach, in which therapeutic decisions are based on the presence of genomic alterations rather than the tumor site.
One particularly compelling example comes from recent clinical findings with larotrectinib, which targets TRK gene fusions. In February 2018, the New England Journal of Medicine published findings showing that larotrectinib treatment led to a 75 percent response rate in 55 adult patients with 17 different TRK fusion-positive tumor types.[3] More recently, researchers reported in The Lancet Oncology that 14 of 15 pediatric patients (93 percent) with TRK fusion-positive cancers achieved an objective response.[4]
While this type of genomic alteration is rare, these results show that the use of comprehensive genomic profiling to identify therapeutic targets for clinical development can lead to important new treatment options for patients. Larotrectinib was recently submitted to the FDA for approval for the treatment of adult and pediatric patients with locally advanced or metastatic solid tumors harboring a TRK gene fusion.
Optimizing clinical trials through biomarkers
In addition to uncovering new targets, genomic profiling has identified biomarkers of treatment response. Historically, biomarkers have been used to develop companion diagnostics, which provide information essential for safely and effectively matching patients with targeted treatments based on the genomic profile of their tumor.
Today, however, biomarkers are not only making an impact on treatment decisions—they are informing clinical trials. This is particularly important for cancer immunotherapy trials, where we are still trying to understand the underlying biology of this treatment approach and why only a subset of patients respond.
However, when a Phase 3 trial that used PD-L1 expression levels to evaluate response to the checkpoint inhibitor immunotherapy nivolumab in non-small cell lung cancer (NSCLC) patients did not meet its primary endpoint, it raised the concern that PD-L1 expression alone may be an insufficient biomarker to predict those patients who will or won’t respond to these new therapies.
More recent data suggest that tumor mutational burden (TMB), a measure of the number of mutations in a person’s tumor, may improve our ability to identify patients likely to respond to cancer immunotherapies. TMB has been shown to help predict response to immunotherapy in several cancer types, including lung, melanoma and bladder.[5],[6],[7] Based on this growing evidence, TMB was used as a biomarker in a different Phase 3 trial of nivolumab. Indeed, the study found that high TMB was associated with statistically improved progression-free survival of NSCLC compared with chemotherapy, regardless of PD-L1 expression levels.
The future of cancer research
These results demonstrate the impact that biomarkers can have on the success or failure of a clinical trial by revealing which patients are most likely to benefit from a treatment. Several pan-cancer, biomarker-driven clinical trials are now underway that assign treatment to a broad array of patients based on the genomic alterations found in their tumors. For example, the National Cancer Institute–Molecular Analysis for Therapy Choice (NCI-MATCH) trial consists of 18 treatment arms to study how genomic alterations affect response to treatment across different solid tumor types. The study will not only advance our understanding of treatments that are already FDA-approved, but could help expand their usage to other cancer types.
Meanwhile, the predictive power of TMB is also being extended to more patients. For example, Foundation Medicine has developed a blood-based test that measures TMB using only a blood sample, rather than a tissue sample. Because many advanced cancer patients cannot safely undergo a tissue biopsy, this assay could serve as an alternative option for measuring this biomarker. This blood tumor mutational burden (bTMB) assay is now being used in a Roche/Genentech Phase 3 study to investigate bTMB as a non-invasive biomarker of response to first-line checkpoint inhibitor immunotherapy (atezolizumab) in advanced NSCLC patients. If successful, bTMB could be used to identify lung cancer patients likely to respond to this treatment, even when a tissue biopsy is unavailable.
In March, the Centers for Medicare and Medicaid Services announced a national coverage determination for eligible Medicare patients with cancer to have next-generation sequencing testing. This marks a significant milestone in expanding access to precision care as we continue to discover new molecular insights that can improve treatment.
But the value of genomic testing in cancer treatment is just the tip of the iceberg. Genomics also has enormous power to transform cancer drug discovery and development. By driving new advances across the entire cancer ecosystem, genomic testing could help us achieve the full potential of precision medicine in cancer.
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Gaurav Singal, M.D., is vice president of data strategy and product development at Foundation Medicine.
References
[1] Thomas et al. Clinical Development Success Rates 2006-2015. Available at: https://www.bio.org/sites/default/files/Clinical%20Development%20Success%20Rates%202006-2015%20-%20BIO,%20Biomedtracker,%20Amplion%202016.pdf
[2] Aitken M, Kumar S, Kleinrock M. IQVIA Institute for Human Data Science. Global Oncology Trends 2017: Advances Complexity and Cost. June 2017.
[3] Drilon et al. Efficacy of larotrectinib in TRK fusion-positive cancers. NEJM. 2018;378:731-739.
[4] Burki et al. Larotrectinib in TRK fusion-positive cancers. Lancet Oncology. 2018;19(4):e187.
[5] Rizvi et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124-128.
[6] Snyder et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. NEJM. 2014;371:2189-2199.
[7] Rosenberg et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre phase 2 trial. Lancet. 2016;387(10031):1909-1920.
