Adding Vorinostat May Improve Efficacy of Pembrolizumab in NSCLC

Patients with advanced/metastatic non­—small cell lung cancer (NSCLC) who previously progressed after treatment with immune checkpoint inhibitors (ICI) may have an additional treatment option. A new study published in Clinical Cancer Research showed that combining pembrolizumab, a programmed cell death protein 1 inhibitor, with vorinostat, a histone deacetylase (HDAC) inhibitor, is safe and effective.

Researchers at the Moffitt Cancer Center were continuing previous research that showed HDAC inhibitors were capable of enhancing the response to ICI. In the phase 1/1b trial, 33 patients were treated with 200 mg intravenous pembrolizumab every 3 weeks plus oral vorinostat (200 mg/day or 400 mg/day).

"To our knowledge, this represents the first publication of the clinical trial combination of ICI with an HDAC inhibitor in lung cancer. We found that this combination was well tolerated and demonstrated preliminary anti-tumor activity in patients who were refractory to prior ICI treatment," study author Jhanelle Gray, MD, assistant member of the Department of Thoracic Oncology at Moffitt, said in a statement.

Only 30 patients were evaluable for response: 6 ICI-naïve patients and 24 ICI-pretreated patients. Of the evaluable patients, 4 (13%) had partial response, 16 (53%) had stable disease, and 10 (33%) had progressive disease. The overall disease control rate was 67%.

Patients with higher levels of pretreatment T cells within the stromal environment had improved outcomes, which may suggest that vorinostat sensitizes tumors to ICIs by causing the T cells to migrate, according to the authors.

No dose-limiting toxicities were observed. The most common adverse events (AEs) were fatigue (33%), nausea (27%), and vomiting (27%). The immune-related AEs observed were similar to those reported previously for pembrolizumab.

The recommended dose for a phase 2 trial were 200 mg of pembrolizumab and 400 mg of vorinostat.

"We believe our results lay the groundwork for future trials to assess impact of epigenetic agents on ICI response, and the discovery of biomarkers to assess the dynamic nature of the immune response early in patient's treatment course," said Amer Beg, PhD, senior member of the Department of Immunology at Moffitt.

Reference

Gray JE, Saltos AN, Tanvetyanon T, et al. Phase 1/1b study of pembrolizumab plus vorinostat in advanced/metastatic non-small cell lung cancer [published online August 13, 2019]. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-19-1305.