Discussion
NSCLC, tumor, cancer, cardiac toxicity, lung cancer
DISEASE PROGRESSION, TUMOR, INFILTRATION, CANCER, DISEASE, RECRUITMENT, LUNG CANCER, TUMOR PROGRESSION, NSCLC, RECURRENT NSCLC, SECONDARY MALIGNANCIES
Immune checkpoint molecules are established targets for cancer immunotherapies. Blocking PD-(L)1 signaling has become standard of care in patients with lung cancer in different clinical settings, but still not all patients benefit from these therapeutic approaches [Overall, in this study we did not observe significant PFS or OS benefit suggesting a delay in disease progression, although some patients that had elevated baseline expression of TGF-β pathway genes tended to have longer PFS and OS benefits than patients who did not (Fig. Given the immune suppressive role of TGF-β on cytotoxic T-cells, our clinical hypothesis was that dual blockade of both TGF-β and PD-1 may overcome the immunosuppressive nature of the tumor microenvironment and lead to T-cell infiltration and activation [The 2-week treatment break and a maximum dose of 150 mg BID was introduced not to exceed area under the curve (AUC) levels corresponding to levels where valvulopathies were observed in animals. Although we did not observe major cardiovascular signals or emergence of secondary malignancies in our study, it is plausible higher doses might have led to better target inhibition and thus higher response rates. Interestingly, TGF-β pathway genes were not modulated but changes were seen in interferon gamma gene expression that is likely related to PD-1 blockade. Although most patients had tumor target reduction, overall, the efficacy data were not different than PD-(L)1 monotherapy in the same disease setting.The median OS was 11.99 months (95% CI: 8.15, NR) for patients treated with galunisertib plus nivolumab. This is not different than survival data observed in multiple large studies showing median OS to be between 12–14 month for anti PD-1 (nivolumab, pembrolizumab) and anti PD-L1 (durvalumab, atezolizumab) single agent treatment [DNA sequencing was performed to assess for associations between genetic variants and clinical response. Both Patients were not selected prospectively based on TGF-β gene expression, therefore the appropriate patient population may not have been treated to see changes in the expression of TGF-β pathway genes. Higher doses may have modulated gene expression but were associated with higher risk of inducing cardiac toxicity. Notwithstanding, we detected increased transcription and serum levels of T-cell activation and migration markers IP-10 (These findings demonstrate combination treatment with galunisertib plus nivolumab has an acceptable safety profile in patients with refractory or recurrent NSCLC who received prior platinum-based treatment and were treatment-naive for anti-PD-(L)1 or TGF-β receptor 1 kinase inhibitors. Notwithstanding, this study has several limiting factors. The primary limitation is the low number of patients. While this study contributes to research in the field, analysis of a larger cohort of patients would provide further data on the safety and efficacy of the combination treatment in NSCLC. Another limitation is the low number of paired baseline and on-treatment tumor samples for exploratory comparative analysis. Collection of baseline and on-treatment biopsies were required for participation in this study, however, limited on-treatment tissue was submitted due to tumor progression, clinical deterioration, insufficient tumor, and patient decision. Thus, although these results identify potential predictive markers of therapeutic effect in recurrent or refractory NSCLC, more patient samples are needed to support the translational work.In conclusion, combination treatment of galunisertib with nivolumab was well tolerated and the study met its primary endpoint of safety. Preliminary efficacy activity was observed in a subset of patients and was not associated with tumor PD-L1 expression. Increased levels of T-cell activation and migration markers were indicative of potential treatment-driven T-cell recruitment. However, the sample size was small and the magnitude of response or benefit in survival outcomes do not clearly differentiate from nivolumab monotherapy in the second line IO-naïve setting. In this unselected cohort of NSCLC patients, a few patients exhibited a baseline increase in TGF-β activity that may have benefited from this combination treatment. Further studies that select patients based on TGF-β pathway expression may yield higher response rates to TGF-β and immune checkpoint inhibitor combination treatment.