Clinical Solutions Architect
Prognos Health
In today’s era of precision medicine, the management of most solid tumors is increasingly driven by biomarker testing, the results of which often drive treatment decisions. Perhaps the first real-world example of this is breast cancer, where biomarker testing has been well established for several decades. For virtually every newly diagnosed breast cancer patient, regardless of the patient’s tumor stage, tests are conducted to look for three key markers: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2).
More recently, tests for microsatellite instability (MSI) and mismatch repair genes (MMR) have been adopted in the management of patients with colorectal cancer (CRC). Guidelines from the National Comprehensive Cancer Network now recommend MSI or MMR testing in all patients newly diagnosed with CRC, and adjuvant (postsurgical) chemotherapy is recommended for patients with stage II high-risk tumors in patients who are MSI Stable (MSS) or MMR Proficient (pMMR). Several other organizations (American Society of Clinical Oncology, College of American Pathologists, Association for Molecular Pathology, Fight Colorectal Cancer) are developing joint guidelines on MSI/MMR testing for patients being considered for immune checkpoint inhibitor therapy in various tumor types, including CRC.
For most other solid tumors, biomarker testing has been adopted relatively recently, and most testing to date in these other malignancies has been limited to patients with advanced or metastatic (stage IV) disease. Commercially available targeted therapies and immunotherapies are generally approved only for patients with recurrent, advanced, or metastatic tumors. Yet, clinicians and biopharmaceutical manufacturers alike are actively investigating the use of targeted treatment (and hence biomarker testing) in earlier-stage cancers. This work could bring these therapies to a broader range of patients, creating additional market opportunities.
Currently, two immune checkpoint inhibitors targeting PD-1/L1 are approved for stage III unresectable non-small cell lung cancer (NSCLC)—pembrolizumab (Keytruda) and durvalumab (Imfinzi). Other therapeutics in this class include nivolumab (Opdivo), atezolizumab (Tecentriq), avelumab (Bavencio), and ipilimumab (Yervoy). All six currently available immune checkpoint inhibitors are in various phases of clinical development for early-stage disease across a variety of solid tumors, including NSCLC, breast cancer, bladder cancer, melanoma, and cancer of the esophagus or gastroesophageal junction.
This high level of interest is reflected at Prognos Health, where we have been contacted by a number of life sciences companies eager to better understand the current and evolving landscape for biomarker testing across several high-profile tumor types, including trends in earlier-stage disease.
We evaluated annual testing trends from 2018 through 2020 for key biomarkers in three common solid tumors: invasive breast cancer, CRC, and NSCLC, with results sorted by stage, where this information was available (Table 1). For this analysis, we leveraged the data assets of our prognosFACTOR platform.
With this platform, it is possible to query over 45 billion patient records covering over 325 million deidentified patients. Historical information is available for over 17 million cancer patients, including more than 6 million patients in the 2018–2020 time period. Also available is detailed information on multiple patient characteristics, such as laboratory test results and tumor stages, combined with claims data on drug therapy. All of this information can provide a comprehensive picture of the patient journey and market landscape.
Results and discussion
Our findings are outlined below for each tumor, followed by overall takeaways.
Breast cancer: According to the American Cancer Society, about 10–15% of patients with breast cancer have triple-negative breast cancer (TNBC). We have observed that PD-L1 testing in this tumor type is a more recent phenomenon and tends to occur in triple-negative patients. This development may be due to the recent FDA approvals for two immune checkpoint inhibitors (Keytruda and Tecentriq), which pertain to patients who have locally advanced or metastatic TNBC and who are PD-L1 positive.
These brands, as well as other members of this drug class, are in late-phase development as neoadjuvant therapy in combination with chemotherapy for patients with stage II or III disease. As Figure 1 shows, in 2020, PD-L1 testing occurred in nearly 5% of patients with earlier-stage tumors, as compared to less than 2% in 2018. This small but noticeable increase in testing in earlier-stage disease may be due in part to growing use of PD-L1 testing in patients with advanced or metastatic TNBC, as well as awareness of these potential future indications.
CRC: Here, testing for key genetic markers is more established as compared to PD-L1 in TNBC. In CRC, the results are more interesting, based on the biomarker in question. Based on our analysis, nearly all patients tested for RAS mutations continue to have metastatic tumors, whereas close to 40% of CRC patients currently being tested for MSI or MMR have earlier-stage disease (Figure 2).
Two brands (Erbitux and Vectibix) are specifically approved for treatment of metastatic CRC that is KRAS wild-type or RAS wild-type, respectively. Likewise, clinical guidelines from the National Comprehensive Cancer Network and similar organizations recommend that all metastatic CRC patients be tested for RAS and BRAF.
In contrast, and as pointed out earlier, National Comprehensive Cancer Network guidelines recommend testing for MSI or MMR in all patients diagnosed with CRC. In this tumor type, testing behavior closely mirrors existing product labeling and clinical practice guidelines.
NSCLC: We evaluated testing trends for three key biomarkers—ALK, EGFR, and PD-L1. In each case, we observed a small yet not insignificant increase in testing in 2020 vs. 2018, such that about 3% of testing occurred in early-stage NSCLC in the most recent year. For example, about 97% of early-stage patients were tested for EGFR in 2020 as compared to 99% in 2018 (Figure 3).
These trends may reflect the fact that several immune checkpoint inhibitors are in the final phase of development for adjuvant therapy in early-stage NSCLC. Also, many patients newly diagnosed with NSCLC undergo testing with multigene panels that evaluate multiple biomarkers. Finally, two brands are already cleared for use in stage III unresectable disease.
Overall and across all the tumors studied, we observed that most testing still occurs in patients with advanced or metastatic cancer. However, in most of these examples, there has been a modest increase in testing among earlier-stage patients from 2018 to 2020. Clinicians appear to generally adhere to product labeling and clinical practice guidelines that typically call for biomarker testing only in the presence of advanced or metastatic tumors.
Perhaps earlier-stage testing has been limited by potential issues with reimbursement, approval for which is in turn dependent on these same product labels and clinical guidelines. At the same time, the noticeable uptick in earlier-stage testing suggests that at least some oncologists are aware of the potential expansion of biomarker testing into the realm of earlier-stage cancer and are beginning to adjust their practice patterns accordingly.
The key exception among the malignancies and biomarkers studied involves MSI or MMR in colorectal cancer, where a large proportion of testing has been seen in earlier-stage patients. Yet, this also seems to be in line with recent clinical practice guidelines, which recommend testing for all newly diagnosed CRC patients.
We shall continue to monitor and report on biomarker testing trends in the oncology space, and on how these trends weave into the evolving narrative of precision medicine.
Bill Bowman is a clinical solutions architect at Prognos Health.