Over the course of my career, I have worked to advance the development of novel cancer therapeutics through classic phase I, II, and III clinical trials at academic centers. More recently, leading a “hybrid” cancer research program in a community setting, including leadership of a precision medicine program, I realized the potential for real-world data (RWD) to accelerate not just our understanding of clinical outcomes, but also safety. The latter has become increasingly important as the FDA has successfully accelerated the approval of cancer therapies, leading to a greater challenge of clarifying efficacy and safety issues in the post-approval setting. This is particularly relevant to safety issues that manifest over a relatively long period of time. The plenary platform at the annual AACR meeting is a global stage intended for high-impact research presentations, and it is wonderful to see RWE featured in a plenary session. This, of course, is a most unusual year with this year’s meeting being entirely virtual due to the COVID-19 pandemic. The pandemic is not only changing the way we behave now, but will likely lead to long-lasting changes in our approach to cancer research, and the practice of oncology, in ways that we do not yet entirely comprehend. We at Syapse, along with others in the industry, are seeing that the approach to developmental therapeutics is changing. Clinical trials and regulatory processes are being rethought as we speak, and life sciences companies, cancer care providers, and regulators are all moving to adapt to this new reality. We believe this new reality likely includes a more prominent role for RWE, and with the COVID-19 pandemic in particular, the impactful role of timely RWE in safety of therapeutics has become clear.

Syapse has recognized the importance of RWE to regulatory stakeholders such as the FDA, and has engaged collaboratively to advance the field. Through our Research Collaboration with the FDA, we discussed with our collaborators, at the Center for Drug Evaluation and Research (CDER) and Office of Clinical Pharmacology (OCP) an important question facing oncologists today. Specifically, while immunotherapies have been approved at high rates, particularly using breakthrough designation based on phase II clinical trial results, the safety profile of immunotherapies in a broader population is less well understood. In lung cancer, pneumonitis is of particular concern due to its potential contribution to significant risk of morbidity and even increased mortality, as a result of baseline pulmonary dysfunction from the lung cancer itself, past therapeutic interventions, as well as underlying comorbidities. An important clinical question that impacts treatment decisions is whether post-treatment incidence of pneumonitis varies based on whether the patient has a prior medical history of pneumonitis, and whether there is a discernible difference between immunotherapy and more traditional and well-understood chemotherapies. While we did not know it at the time, this question would take on increasing importance following the submission of our late-breaking abstract in January.

In attempting to address this question, today at the AACR Virtual Annual Meeting, Dr. Qi Liu, PhD, MStat, FCP, Senior Science Advisor, OCP, Office of Translational Sciences at the FDA, will be presenting our research methodologies and results in an abstract jointly produced by Syapse, Advocate Aurora Health, and the FDA OCP within CDER. More information on this presentation, as well as a link to register for the free session can be found in our press release.

Our abstract, titled “Pneumonitis incidence in patients with non-small cell lung cancer treated with immunotherapy or chemotherapy in clinical trials and real-world data,” is a tangible result of the work Syapse and the FDA have done as part of the Research Collaboration Agreement (RCA) signed in August of 2019. We are honored that this work was selected for an oral presentation and discussion at the Clinical Plenary Session of AACR’s conference, a high-profile stage that allows us to make an important contribution to the existing body of evidence pertaining to lung cancer targeted therapies.

I want to take this opportunity to celebrate this accomplishment and also to share my own thoughts on why I find this work so exciting, how we were able to overcome the traditional challenges of conducting safety studies with RWD, and why Syapse is well-positioned to answer deeper questions in this area in the future.

Syapse regularly combines clinical and molecular data across a wide variety of source systems to develop a comprehensive, longitudinal picture of the care journey for each of the cancer patients within the Syapse Learning Health Network, both before and after a patient’s cancer diagnosis, and including both cancer and non-cancer care.

The team used this longitudinal view to compare the incidence of non-infectious pneumonitis in non-small cell lung cancer (NSCLC) patients treated with chemotherapy and immune checkpoint inhibitors (ICI) in the real-world, and segment these outcomes by whether the patients had a prior history of non-infectious pneumonitis. In doing so, the team aimed to understand the degree to which a prior history of pneumonitis might influence a patient’s likelihood of developing this treatment-related side effect in a real-world setting.

The study was conducted by performing the same retrospective analysis using two data sources in parallel: 1) RWD from Syapse on patients treated at Advocate Aurora Health, and 2) clinical trial data from pivotal studies previously submitted to the FDA. Most clinical trials enroll the healthiest possible patients, so this study represented an opportunity for us to determine whether the same risk assessed in the “pristine” clinical trial population would also be reflected in the real-world, where physicians are making difficult decisions about how to treat patients with more complicated clinical profiles. Syapse and FDA colleagues worked collaboratively to design the paired analyses of clinical trials data and RWD. We jointly created analytical methodologies for assessing pneumonitis incidence, including aligning the analysis of the RWD to the definitions used in the clinical trials. Issues such as consistency of index date, definition of pneumonitis, and decisions about whether to include or exclude radiation-associated pneumonitis necessitated a high degree of collaboration between the teams.

Our study found that clinical trial data and RWD generally align around the risk of treatment-associated pneumonitis, and the elevated risk in patients with a prior history of non-infectious pneumonitis. Given that this real-world risk factor is within the bounds of what has already been established as manageable in clinical trials, we have concluded that for physicians, the possibility of treatment associated pneumonitis should not be considered a reason to avoid a potentially beneficial therapy. Of note, within the RWD, a majority of patients with either a past medical history of pneumonitis or with treatment associated pneumonitis, had received radiation therapy at some point in time. This raises the question of the role of radiation therapy as a risk factor for ICI-associated pneumonitis, and treatment associated pneumonitis in general.

As I have mentioned, the rise of accelerated approvals in oncology has increased pressure on the post-market period and has opened up opportunities for RWD to provide clinically actionable insights such as those that our abstract delivers. RWD has the potential to demonstrate meaningful clinical effectiveness, characterize previously unidentified adverse events (especially those that take a long period of time to manifest), uncover new contra-indications, and help us calculate dosage adjustments for populations such as older patients or those with poor organ function.

Although the ability to establish real-world safety profiles would benefit stakeholders across the oncology ecosystem, these kinds of questions have historically been very difficult to answer with existing real-world datasets. This is mainly due to the high complexity involved in tracking patients over a long period of time. In order to meaningfully connect therapies with adverse events or outcomes, one needs to understand the full longitudinality of each treatment journey, including imaging, clinical labs, outpatient visits, primary care, and specialist visits.

At Syapse we have crafted a unique and comprehensive RWD platform that effectively addresses these challenges. Our close partnerships with the large community health systems in the Syapse Learning Health Network give us ongoing access to multiple clinical source systems, from which we build a complete picture of each cancer patient’s journey, encompassing both oncology and non-oncology care. Then we securely match that data to structured feeds received directly from the nation’s top molecular testing labs. Finally, the data is enriched with inputs from third-party sources such as the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program registries. The result of this RWD platform is a powerful RWE resource that can be leveraged for high-impact clinical research, such as that presented in this plenary session talk.

The depth and breadth of our RWD platform positions us to pursue other areas of safety research in collaboration with our health system, life sciences, and regulatory partners. Given the current COVID-19 pandemic, and the likelihood that many more patients in the future will report a prior history of infectious pneumonitis, i.e. pneumonia, we are planning to broaden our study to understand the extent to which a history of pneumonia leads to an increased risk for treatment related pneumonitis. In addition, we are looking at further extending this work to include other therapeutic classes beyond ICIs, and clarifying the role of radiation therapy as a predisposing risk factor for ICI-associated pneumonitis.

Another key area of interest for us is characterizing comorbidities among patients treated with targeted therapies, especially patients whose comorbidities would generally exclude them from clinical trials (such as renal and hepatic dysfunction, chronic lung disease, cardiovascular disease, or brain metastases). Using RWD, development of evidence on the clinical effectiveness and safety outcomes associated with these underrepresented populations has the potential to provide much needed insights to physicians evaluating trade-off decisions for these patients. It should be noted that although treatment associated incidence of pneumonitis was similar between clinical trial data and RWD in our study, the frequency of a past medical history of non-infectious pneumonitis was substantially higher in the RWD (0.7% in clinical trial data; 2.6% in RWD). This difference underscores the need to understand safety outcomes in a real-world setting in addition to the traditional clinical trial setting.

Syapse’s company mission is to enable healthcare providers to deliver the best care through precision medicine, and with the power of the Learning Health Network, our RWD platform, and working with our life sciences, regulatory, and research collaborators, we can continue to deliver safety insights to make our mission a reality.

Wishing you the best of health.

Thomas Brown, MD, MBA

Syapse, FDA, and Advocate Aurora Health to Present Safety Research at AACR Plenary Session