A combination of the immune checkpoint inhibitor (ICI) pembrolizumab with the histone deacetylase inhibitor (HDACi) vorinostat effectively fought tumors in patients with disease progression after previous ICI treatment for non-small cell lung cancer (NSCLC), according to the results of a phase 1/1b study published in Clinical Cancer Research.
“[HDACis] enhance tumor immunogenicity through several mechanisms and may improve response to [ICIs],” wrote the authors, led by Jhanelle Gray, MD, Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Moffitt Cancer Center, Tampa, FL.
Of the 33 patients enrolled in the study, 6 ICI-naïve and 24 ICI-pretreated patients evaluable for response were given intravenous pembrolizumab (200 mg every 3 weeks) along with oral vorinostat (200 or 400 mg/day). The primary outcome for the study was tolerability and safety; secondary outcomes included response rate, progression-free survival (PFS), overall survival (OS), and disease control rate (DCR). Additionally, T-cell density, tumor gene expression changes, and myeloid cell levels were assessed via serial tissue specimens.
DCR was 67%, with 13% of patient exhibiting partial response, 53%, stable disease, and 33%, progressive disease. Among those pretreated with ICIs, 3 patients exhibited partial response and 10 stable disease. In pretreated patients, CD8+ T-cell presence in tumor stromal regions was clinically beneficial.
“Given that the majority of patients with NSCLC will undergo ICI treatment in the first-line setting, a DCR of 58% in an ICI-pretreated patient population can be considered clinically significant,” wrote the authors.
In total, 73% of patient experienced treatment-related adverse events, with 15% occurring in ICI-naïve patients and 58% in ICI-pretreated patients. Fatigue and nausea/vomiting were the most frequent adverse events of any grade. Of note, no dose-limiting toxicities were noted.
The advent of ICIs, including anti–programmed cell death protein 1 (anti–PD-1) and anti–programmed cell death ligand 1 (anti–PD-L1), has expanded treatment options for patients with metastatic or otherwise advanced NSCLC.
Pembrolizumab, nivolumab, and atezolizumab have all been approved by the FDA for those previously treated for advanced NSCLC. Moreover, the FDA greenlighted pembrolizumab monotherapy for patients who received previous platinum-based doublet chemotherapy. The drug was also approved for patients with untreated metastatic or otherwise advanced nonsquamous NSCLC with no actionable mutations and a PD-L1 tumor proportion score ≥ 1.
The combination of pembrolizumab and platinum-doublet chemotherapy is significantly tied to longer median PFS and median OS vs platinum-doublet chemotherapy alone for non-squamous NSCLC and squamous cell NSCLC, as first-line treatment despite PD-L1 status.
“Despite these advancements, improving treatment options for NSCLC patients with progression after ICI therapy represents an area of need,” the authors wrote.
The absence or diminished number of T-cells is related to ICI-treatment resistance. Treatments that boost the number or functionality of T-cells are hypothesized to help patients who are resistant to ICI treatment, with epigenetic modulation of the tumor microenvironment an emerging trend. The immunostimulatory activity of HDACis has been elucidated, and preclinical studies have paired HDACis with immune-stimulating antibodies or adoptive T-cell transfer.
“Our ongoing randomized phase 2 study, which opened for enrollment in parallel with the phase 1b study, will determine whether pembrolizumab plus vorinostat improves [response rate] RR and PFS compared with pembrolizumab alone in ICI-naïve advanced/metastatic NSCLC patients,” concluded the authors.