Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer

Abstract

Epigenetic alterations are strongly associated with the development of cancer. We conducted a phase I/II trial of combined epigenetic therapy with azacitidine and entinostat, inhibitors of DNA methylation and histone deacetylation, respectively, in extensively pretreated patients with recurrent metastatic non-small cell lung cancer. This therapy is well tolerated, and objective responses were observed, including a complete response and a partial response in a patient who remains alive and without disease progression approximately 2 years after completing protocol therapy. Median survival in the entire cohort was 6.4 months (95% CI 3.8-9.2), comparing favorably with existing therapeutic options. Demethylation of a set of 4 epigenetically silenced genes known to be associated with lung cancer was detectable in serial blood samples in these patients and was associated with improved progression-free (P = 0.034) and overall survival (P = 0.035). Four of 19 patients had major objective responses to subsequent anticancer therapies given immediately after epigenetic therapy.

Significance: This study demonstrates that combined epigenetic therapy with low-dose azacitidine and entinostat results in objective, durable responses in patients with solid tumors and defines a blood-based biomarker that correlates with clinical benefit.

Figure 1. Serial CT scan images from patient with a complete response

Scans show progressive resolution of a prevascular tumor (top) and a right hilar mass (bottom) over the course of one year on therapy. Red circles indicate areas of measurable disease.

Figure 2. Serial CT scan images from patient with a partial response

Scans demonstrate gradual resolution of sites of disease including a lung mass, matted hilar lymph nodes, and one of the liver metastases. Although he was taken off study for treatment of an intercurrent small cell lung cancer, he remains alive and was without evidence of disease recurrence nearly 2 years after completion of this therapy. Red arrrows indicate areas of measurable disease.

Figure 3. Kaplan Meier survival analyses (intent-to-treat)

All patients on study are included in these analyses. A. Progression-free survival. B. Overall survival.

Figure 4. Survival, subsequent therapies, and response

A Duration of survival on and after protocol therapy. The height of the gray bar indicates duration of survival. Light gray bars indicate patients who are still alive. The colored portion of the bar represents the duration of therapy received on trial. NE: non-evaluable for response, PD: progressive disease, SD: stable disease, PR: partial response, CR: complete response. If a patient received subsequent chemotherapy within 6 months, it is listed above the patient’s survival bar. Letters identify corresponding patients in panel B. B. Waterfall plot of response to immediate subsequent therapy. The best change in defined target lesions to subsequent systemic anti-cancer treatment following epigenetic therapy is shown. Green: PR, blue: SD, red: PD. (*) indicates progression defined by a new lesion. Two patients, indicated at right, died without follow-up imaging.

Figure 5. Survival stratified by target gene methylation status

Promoter methylation of APC, CDH13, RASS1a, and CDKN2A were evaluated in circulating plasma DNA from patients at pre-treatment and on day 29. Red: patients with pre-treatment methylation of ≥2 of these 4 genes that demonstrate demethylation by day 29. Blue: all other patients with detectable circulating DNA (total N = 26). A. Overall survival. B. Progression-free survival.