FDA Corner – Interview with Gideon Blumenthal, MD

By Erik J. Mac Laren, PhD

In 2015, the US Food and Drug Administration (FDA) approved an unprecedented 7 new drugs or new uses for drugs for patients with lung cancer, an increase driven by the proliferation of targeted therapies in the area of thoracic oncology. The advent of precision medicine in oncology has raised new questions about how to adapt the evaluation and approval process to capitalize on the potential of these new technologies. IASLC Lung Cancer News spoke with Gideon Blumenthal, MD, from the FDA’s Office of Hematology and Oncology Products (OHOP) about these challenges, including the use of surrogate endpoints in lung cancer trials and the emergence of next-generation sequencing (NGS) in oncology.

Q: Last year, you and your colleagues published a meta-analysis of NSCLC trials in the Journal of Clinical Oncology1 that showed a strong association between overall response rate (ORR) and progression-free survival (PFS), but not between either of these surrogate endpoints and overall survival (OS). Are there ways to improve how surrogate endpoints are used in clinical trials?

A: That is a great question, and certainly something we ruminate over all the time.
While it is true that we did not observe associations on a trial level between ORR and OS or between PFS and OS, there are some caveats to those results. High rates of crossover might wash out the effect on OS, and if the target population is small, it may be hard to power a study to see a survival benefit. Also, patients with oncogeneaddicted malignancies such as EGFR or ALK can live a long time after progression, contributing to the difficulties of designing a study to detect a survival gain. Particularly in trials of some immunotherapies, ORR and PFS do not seem to fully capture the clinical benefits of some of these agents. Are there new ways to measure responses to these treatments? That is an area in OHOP that we are definitely investigating. We are also talking to thought leaders in the lung cancer community because we know there are others in the academic community looking at this issue as well.

Q: NGS offers new opportunities to dramatically expand the genetic characterization of both patients and tumors. How do you think these technologies will affect the way new cancer therapies are tested and used in the clinic?

A: I have recently co-written an article in JAMA Oncology on this issue.2 I think lung cancer doctors are at the forefront of using NGS both in terms of selecting patients for trials and in using information derived from NGS in the clinic because there are at least 2 actionable mutations in lung cancer, EGFR and ALK, and in the near future there may be others. Using a single multiplex platform makes a lot of sense in lung cancer patients because tissue is scarce in the metastatic setting and we could potentially spare patients repeated biopsies.
From a drug development standpoint, the model of 1 companion diagnostic for a single drug may soon give way to a model using a single platform that has several companion diagnostic indications with several drugs tied to it. That way, drug developers and device manufacturers don’t have to reinvent the wheel with every development program. It also makes a lot of sense from a research perspective because you can see many different genomic changes at the same time with a single test. There was a public workshop on February 25, 2016 to discuss some of these NGS-based oncology panels. We hope that there will be many platforms that can be used, but the key issue is standardizing these platforms so that the calls you get on one platform are the same as the calls you get from a different vendor.

Q: Are there any big developments on the horizon in the development of precision medicine for lung cancer treatment such as testing circulating tumor DNA (ctDNA), and if so, how will this be integrated into the approval process?

A: I think ctDNA is a very exciting emerging technology because it has a lot of potential clinical applications: early detection, risk stratification of patients after surgical resection, monitoring patients, and even potentially down the road as a surrogate endpoint to discern drug activity. The FDA is in the early planning stages of a workshop on ctDNA in lung cancer this summer. The other big development has been the emergence of immunotherapies in lung cancer. We approved our first 2 immunotherapies for the treatment of certain types of lung cancer in 2015, and there is a lot of interest in combining various immunotherapies, developing biomarkers to identify patients more likely to respond or not respond to an immunotherapy, and enhancing the immune response.

1. Blumenthal GM, Karuri SW, Zhang H, et al. Overall response rate, progression-free survival, and overall survival with targeted and standard therapies in advanced non-small-cell lung cancer: US Food and Drug Administration trial-level and patient-level analyses. J Clin Oncol. 2015;33(9):1008-1014.
2. Blumenthal GM, Mansfield E, Pazdur R. Next-Generation Sequencing in Oncology in the Era of Precision Medicine. JAMA Oncol. 2016;2(1):13-14.