What’s key to the next cancer breakthrough? The answer may lie in pan-tumor biomarkers
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By Brian Alexander, MD, MPH, Chief Medical Officer, Foundation Medicine, Inc.
Targeted cancer treatments, especially immunotherapies, are complex. Understanding in which patients they will work, and just as importantly in which they won’t, is not easy. However, when patients are matched with a treatment approach based on the genomic insights from his or her individual tumor profile, the outcomes can be significant.
Single biomarkers, typically confined to a specific cancer type, have proven powerful in navigating eligible patients to the right treatments. However, as our knowledge of cancer biology grows, we understand the value of additional and more complex biomarkers, whether they are quantitative in nature or inclusive of multiple genes. Sometimes, grouping tumors by molecular biomarkers, rather than tissue of origin, is more effective in predicting response to novel therapies.
At Foundation Medicine, we believe such pan-tumor biomarkers are key to providing additional clinical insight and will prove a tremendous tool for making precision medicine a reality for many cancer patients.
Success to Date
Pan-tumor biomarkers have helped usher in a potential transformation of cancer care from tissue-specific to tumor-agnostic. In the last five years, Merck’s Keytruda® (pembrolizumab), indicated for tumors with the pan-tumor biomarker microsatellite instability (MSI), has been the poster child of this transformation.
The role of a pan-tumor biomarker more recently shown to be clinically relevant, NTRK (neurotrophic tropomyosin receptor kinase) gene fusion, is also garnering a lot of attention, especially with last fall’s FDA approval of the first TRK-inhibitor, Vitrakvi® (larotrectinib), which was developed and launched by Bayer and Loxo Oncology. While NTRK fusion-driven cancers are rare — less than 1% of all solid tumors — the impact of this drug has been shown to be significant, which is an important factor when considering the breadth of the genomic testing required for each patient.[i]
Measuring Pan-Tumor Biomarkers
At Foundation Medicine, we believe biomarkers are ideally evaluated with the breadth provided by comprehensive genomic profiling (CGP). Unlike single-marker testing, our tissue CGP test FoundationOne®CDx analyzes hundreds of cancer-related genes. This breadth and depth of sequencing allows for improved discovery of targetable mutations, like NTRK, as well as the quantification of the number of mutations present across a significant part of the tumor genome. By interrogating a large panel of genes in this way, we are able to estimate the quantitative biomarker tumor mutational burden (TMB), for example, which is being extensively studied by us and others for its utility as a pan-tumor biomarker for predicting response to immunotherapy. Similarly, both FoundationOne CDx and our liquid biopsy test, FoundationOne®Liquid, are able to report microsatellite instability high (MSI-H) status indicating eligibility for pembrolizumab regardless of tumor type. We are using the power of CGP to help physicians match patients to the most appropriate approved and investigational therapies as well as to accelerate research of pan-tumor biomarkers.
We are proud to be a leader in developing companion diagnostic tools that form the bridge between eligible patients and precision oncology treatments. To that end we are particularly proud to have entered into multiple partnerships, including one with Merck to develop a companion diagnostic for use with Keytruda measuring MSI and TMB and most recently a partnership with Bayer to develop and launch a companion diagnostic for Vitrakvi.
The Latest Research
Research around pan-tumor biomarkers has been growing exponentially. In addition to better understanding pan-tumor biomarkers MSI and NTRK, scientific data has been mounting around other potential pan-tumor biomarkers, specifically TMB and FGFR (fibroblast growth factor receptor).
We are committed to continue supporting this important area of research and development. For years, we have been presenting compelling data on TMB, measured from tumor tissue via FoundationOne®CDx or blood via a forthcoming version of our liquid biopsy test, which has led to landmark publications in Nature Medicine[ii] and Genome Medicine[iii].
This year, we will present data around both TMB and FGFR at the annual meeting of the American Society of Clinical Oncology (ASCO) and are particularly excited to share the results of a collaboration with Friends of Cancer Research to further characterize TMB as a continuous variable and predictor of immunotherapy response.[iv] We will also present data analyzing the landscape of immunotherapy predictive biomarkers like TMB, as well as biomarkers with evidence in other tumor types, in the setting of three subtypes of metastatic breast cancer.[v] And we will present a study which screened more than 200,000 cancer cases and found that FGFR2 genomic alterations are most frequent in bile duct, breast, gastrointestinal tract and lung cancer, further supporting a role for FGFR as a pan-tumor biomarker.[vi]
We’ve also seen the research in support of TMB as a predictive biomarker substantiated through real-world evidence, as shown in our collaboration study with Flatiron Health recently published in the Journal of the American Medical Association (JAMA)[vii]. This study confirmed that patients with non-small cell lung cancer (NSCLC) and high TMB responded to immunotherapy in a real-world setting, regardless of their PD-1 high or low status. The study also showed that high TMB was associated with longer survival on immunotherapy. Another study in collaboration with the City of Hope National Medical Center (Duarte, CA) recently published in Annals of Oncology[viii] showed how TMB may be used in patients with metastatic colorectal cancer who have high levels of MSI, to further improve the stratification of patients predicted to respond to immunotherapy.
Collaborating to Advance Cancer Care
We believe it is our responsibility to help inform precision medicine and learn from every patient today to accelerate research that drives the development of future therapeutic options. Our passion for this goal has led us to collaborations across the entire oncology ecosystem.
We partner with physicians to create access to CGP, who then utilize that information to help guide patients to the treatments of today as well as those of tomorrow through clinical trial options. Our long-standing partnerships with the leading biopharma companies in oncology have allowed us to collaborate in expanding labels for existing therapies and advance the development of cutting-edge cancer treatments including those with pan-tumor indications.
Using Foundation Medicine’s highly validated portfolio of tests — including the first FDA-approved comprehensive genomic profiling test for all solid tumors, FoundationOne CDx — we provide clinically relevant genomic results regardless of specimen type. We remain dedicated to further the discovery and utility of precision cancer care through our collaborations with other leaders in the field. We believe that advancing the utility of pan-tumor approvals and investigational biomarkers — including in cancers not historically treated with targeted therapies, will help inform the treatment plan for more patients — ultimately improving patient outcomes and advancing precision medicine.
[i] Okamura R, Boichard A, Kato S, et al. Analysis of NTRK Alterations in Pan-Cancer Adult and Pediatric Malignancies: Implications for NTRK-Targeted Therapeutics. JCO Precis Oncol. 2018; doi: 10.1200/PO.18.00183.
[ii] Gandara DR, Paul SM, Kowanetz M et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nature Medicine, 2018;24:1441-1448.
[iii] Chalmers ZR, Connelly CF, Fabrizio D et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.Genome Med. 2017;9(1):34. doi: 10.1186/s13073-017-0424-2.
[iv] Merino, et al. TMB Standardization by Alignment to Reference Standards: Phase 2 of the Friends of Cancer Research TMB Harmonization Project. Poster presented at American Society of Clinical Oncology (ASCO) Annual Meeting; June 2019; Chicago, IL.
[v] Ross J, Sokol E, Albacker LA, et al. Immunotherapy Predictive Biomarkers in Metastatic Breast Cancer (mBC). Poster presented at American Society of Clinical Oncology (ASCO) Annual Meeting; June 2019; Chicago, IL.
[vi] Madison R, Sokol E, Schrock AB, et al. FGFR2: A Pan-Genomic Target. Poster presented at American Society of Clinical Oncology (ASCO) Annual Meeting; June 2019; Chicago, IL.
[vii] Singal G, Miller PG, Agarwala V, et al. Association of patient characteristics and tumor genomics with clinical outcomes in patients with non-small cell lung cancer using a clinico-genomic database derived from routine clinical care. JAMA. 2019;321(14):1391-1399.
[viii] Schrock AB, Ouyang C, Sandhu J, et al. Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer. Ann Oncol. 2019. pii: mdz134. doi: 10.1093/annonc/mdz134. [Epub ahead of print]