Patients with non-small cell lung cancer (NSCLC) now have more improved treatment options compare to standard of care with the addition of several new agents called immune checkpoint inhibitors (ICI). Despite these changes, many patients still develop progressive disease after ICI treatment. In a new study publish in Clinical Cancer Research; Moffitt Cancer Center researchers describe promising results from an early clinical trial that may offer patients who progress after ICI an additional treatment option.
Models of lung cancer
Several ICI agents have been approved in recent years to treat NSCLC; including nivolumab, atezolizumab and pembrolizumab. ICIs function by stimulating the immune system to target cancer cells for destruction. However, patients may become resistant to ICIs and develop progressive disease. Many of these patients who have poor responses; so to ICIs have low numbers of T cells in their tumor environment. Therefore, the cancer community; so has trying to find drugs that work in conjunction with ICIs to increase the number and activity of T cells in a tumor.
Several preclinical studies, including studies conducted at Moffitt; which have shown that drugs call histone deacetylase inhibitors (HDAC inhibitors) are capable of stimulating the immune system and enhancing the response to ICIs. “In our preclinical studies; they reported that HDAC inhibitors improve response to PD-1 blockade in mouse models of lung cancer by increasing T cell trafficking to tumors and enhancing T cell function,” explained Amer Beg, Ph.D. senior member of the Department of Immunology at Moffitt.
“To our knowledge, this represents the first publication of the clinical trial; so combination of ICI with an HDAC inhibitor in lung cancer. We found that this combination was well tolerate; also demonstrate preliminary anti-tumor activity in patients who were refractory to prior ICI treatment,” said Jhanelle Gray, M. The researchers report that the most common adverse events; hence during treatment were fatigue, nausea and vomiting. Immune-activating drugs are often with adverse events relate to increase immune system activity.
The activity of pembrolizumab
The immune-relate adverse events experience by patients during; so the study were similar to those report previously for pembrolizumab, with the most common event being hypothryroidism in 15% of patients. The combination of pembrolizumab and vorinostat also demonstrate preliminary anti-tumor activity. Of 30 patients who were evaluable for efficacy; 4 had a partial response to treatment and 16 develop stable disease, for a disease control rate of 67%.
During the study, the researchers conduct a correlative analysis to determine; so if any blood or tissue biomarkers were with better patient outcomes to the combination treatment. They discover that patients who had higher levels of T cells within the stromal environment before treatment had improve outcomes to therapy. According to the researchers; these observations suggest that vorinostat may sensitize tumors to ICIs by causing the T cells to migrate from the stroma to the tumor bed.
The researchers will further investigate this hypothesis; also the activity of pembrolizumab and vorinostat in the ongoing phase 2 trial in patients with advanced/metastatic NSCLC who did not previously receive ICI treatment. “We believe our results lay the groundwork for future trials to assess impact of epigenetic agents on ICI response; also the discovery of biomarkers to assess the dynamic nature of the immune response; so early in patient’s treatment course,” said Beg.