From scientific symposia and journal articles to blogs, podcasts, apps, teleconferences and roundtable discussions, the term “precision medicine” seems to be as ubiquitous as the daily unsolicited emails physicians generally delete on any number of topics. Call it “precision medicine” or “personalized medicine,” few avenues of clinical research in oncology have generated as much excitement and hope. And yet, the entire field is a cautionary tale. Yes, it has achieved some incredible milestones over the years and is poised to bring us closer to enhanced treatment strategies and improved outcomes. But how much of the progress is illusory?
Precision medicine has had some setbacks, notably in efforts to bring forth more effective vaccine strategies. For example, there have been three negative trials thus far of viral vectors that test vaccines in kidney cancer, transgene TG4010, MVA-5T4 and IMA901. These have, unfortunately, spanned the last decade in testing so it has been problematic to determine which tumor antigens are the optimal ones to target, which we should present to T cells to activate them, and which particular tumor antigens we should go after. The transgene virus vector presents a specific tumor antigen and there is one from the IMA901 study that presents about 10 different tumor antigens, but they are all prespecified and off-the-shelf. There has been one from Argos Therapeutics that is a dendritic cell vaccine, which takes both dendritic cells as well as tumor RNA from patients directly and integrates those, so that, when infused into the patient, the dendritic cells will activate the T cells based on the patient’s repertoire of tumor antigens.
That one showed promising results in the ADAPT phase 2 study and was undergoing a phase 3 trial in combination with sunitinib in the first-line setting. However, the company terminated its Phase 3 ADAPT trial assessing lead candidate Rocapuldencel-T, combined with sunitinib/standard-of-care, in newly diagnosed patients with metastatic renal cell carcinoma (RCC). The company made its decision after interim results indicated poor prospects of success. Despite these disappointing results, there are still more vaccine trials with reasonable prospects of showing benefit and their data could provide encouraging data. Overall, it is far too soon to rush to judgement on the viability of vaccines for kidney cancer. Too soon to count them out, but the results generally have not given us much to cheer about.
There is much more optimism surrounding the use of molecular biomarkers, not only to unravel more of the unknown characteristics of the tumor microenvironment, but to point the way toward improvements in prognostic models and selection of therapies . We are moving past the time—with its roots in the interferon era—when we rely primarily on clinicopathological variables like Karnofsky status to shape prognostic models such as the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model. Although recent studies are still emerging from the hypothesis-generating stage, molecular and genomic alterations are likely to be integrated into such prognostic models in the near future. Precision medicine and next generation sequencing are the increasingly used buzzwords to describe innovative strategies to deliver the right treatment to the right patient at the right time. As emerging data unravel more of the molecular underpinnings of RCC, the focus has turned toward tumor suppressor genes and the pivotal roles they play in determining outcomes. We are likely to see a broad impact on clinical trial design as these approaches update the paradigm of treatment in the immune-oncology era.
Within the last 5 years, particularly, emerging data have more clearly pointed toward potential strategies with translational impact as more studies target the genetic basis of a significant percentage of familial RCC that has remained unknown. There is precedent for genes mutated in the germline (such as VHL) that are also mutated in the sporadic setting. Consequently, somatically mutated genes may explain familial RCC if mutated in the germline. For a more detailed analysis of these trends, please review the content of this issue to keep current with critical reading on precision medicine.
So, what is the answer to the question posed in the headline: Is Precision Medicine the Wave of the Future or a Cautionary Tale? It looks like a bit of both. Stay tuned.
Robert A. Figlin, MD