Barbara J. Gitlitz, MD
Stephen V. Liu, MD
Peter A. Jones, PhD, DSc
USC Norris Comprehensive Cancer Center, Los Angeles, California
As oncologists practicing in an era of “genomic medicine,” when we consider alterations in gene expression, we generally default to DNA mutation as the primary mechanism. Gene expression can also be regulated by epigenetic changes, such as DNA methylation and histone modification. These changes dysregulate gene function without actually altering the underlying DNA sequence. In principle, these modifications are reversible (restoring gene function) and “druggable.” Epigenetic modifications have been strongly implicated in carcinogenesis and maintenance of a malignant clone by silencing key tumor suppressor genes.
Peter A. Jones, PhD, DSc, University of Southern California (USC), and Stephen Baylin, MD, Johns Hopkins University, are well known for their pioneering work in cancer epigenetics and are the leaders of the American Association for Cancer Research Stand Up To Cancer (SU2C) Epigenetics Dream Team. The goal of this Dream Team is to bring the promise of epigenetic therapy to clinical practice to treat leukemia, breast, colon, and lung cancers.
Preclinical studies suggest that combining inhibitors of DNA methyltransferase, such as 5-azacytidine, with inhibitors of histone deacetylase (HDAC), such as entinostat, synergistically induces re-expression of epigenetically silenced tumor suppressor genes. A phase I/II clinical trial showed that combining these agents in heavily pretreated patients with advanced non–small cell lung cancer (NSCLC) proved feasible, tolerable, and active (Cancer Discov
. 2011;1:598-607). Durable objective responses were observed, including a complete response lasting 14 months and a partial response with complete resolution of multiple liver metastases lasting 8 months. Ten patients had stable disease lasting at least 12 weeks with two patients having disease stabilization for 18 and 14 months. Updated median overall survival (OS) in an intent-to-treat analysis was 6.28 months, comparing quite favorably with any salvage therapy in this patient population.
Another major focus of the Epigenetics Dream Team is the identification of predictive markers of benefit to epigenetic therapy. Demethylation of a set of four epigenetically silenced genes known to be associated with lung cancer was detectable in serial blood samples in these patients. Of those patients with methylated target genes pretreatment, a decrease in methylation posttreatment was associated with improved progression-free survival (P
= .034) and OS (P
= .035) as compared with patients without methylated genes at baseline.
An intriguing observation from the study was the magnitude of benefit to systemic therapy following disease progression on protocol (Figure
). Many of the patients receiving subsequent treatment have had major objective responses to both salvage chemotherapy and immunotherapy targeting the PD-1/ PD-L1 pathway. Median survival among patients who completed at least one cycle of epigenetic therapy was 8.6 months and included long-term survivors of 44 and 52 months, both having received only one post-study treatment regimen.
Figure. Best Response to Therapy Subsequent to Epigenetic Therapies
In a phase I/II trial, Juergens et al examined combined epigenetic therapy with entinostat, an HDAC inhibitor, and azacitidine, an inhibitor of DNA methylation, in heavily pretreated patients with non–small cell lung cancer. The waterfall plot shows response to treatments immediately following epigenetic therapy, as determined by changes in defined target lesions. (*) indicates progression defined by a new lesion.
Adapted from Juergens RA et al. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov. 2011;1(7):598-607.
At USC, we are proud to offer our lung cancer patients participation in ongoing and planned clinical trials in partnership with Johns Hopkins and the SU2C Epigenetics Dream Team. There are four trials overall. The first is an expanded cohort of the phase I/II trial seeking additional clinical outcomes and predictive epigenetic information. Next, we will move this regimen of epigenetic therapy forward to an earlier line of therapy, offering it as an adjuvant for completely resected early-stage NSCLC. Also of great interest is testing the concept of epigenetic “priming” as a strategy to sensitize tumors to subsequent therapy. Two very exciting clinical/translational trials are planned in this area:
A Randomized Phase II Trial of Cytotoxic Chemotherapy With or Without Epigenetic Priming in Patients with Advanced Non–Small Cell Lung Cancer Unlike the phase I/II trial, this study will be for patients with only one prior line of therapy. Patients will be randomized to receive chemotherapy alone or chemotherapy preceded by epigenetic priming. Preliminary data suggest that the reversal of epigenetic gene silencing could increase the efficacy of cytotoxic drugs with known activity in NSCLC. Approximately 110 patients will be randomized.
Phase II Study of Epigenetic Priming with Azacitidine and Entinostat Prior to BMS-936558 in Subjects with Recurrent Metastatic Non–Small Cell Lung Cancer BMS-936558 (MDX-1106) is a fully human IgG4:κ monoclonal antibody that blocks PD-1. Phase I testing of BMS-936558 has been associated with objective responses in multiple solid tumors including NSCLC. There are currently many planned and ongoing trials of various PD-1 inhibitors and PD-L1 inhibitors, as these agents have shown exciting preliminary results in NSCLC.
The goal of this study is to assess whether two cycles of epigenetic therapy can serve to “prime” metastatic NSCLC to better respond to the PD-1 inhibitor. The study is a single-arm phase II trial in patients with stage IIIB/IV NSCLC after one or two prior therapies. Preliminary data suggest epigenetic therapy leads to re-expression of silenced promoters of key cytokine genes in T cells such as interferon-gamma and IL-2 and may induce tumor antigen expression.
In addition to clinical outcomes, biomarker analysis will be explored in all of these trials. If these proposed projects verify the striking observations seen in the patients in the original phase I/II epigenetic trial, including durable responses, and there are promising outcomes with subsequent therapy, this strategy may positively impact the paradigm of NSCLC treatment.