A phase Ib/II study of galunisertib in combination with nivolumab in solid tumors and non-small cell lung cancer

Abstract

Background In this phase Ib/II open-label study, tumor immune suppression was targeted in patients with advanced refractory solid tumors and patients with recurrent/refractory non-small cell lung cancer (NSCLC) using galunisertib with nivolumab. Methods Eligible patients were ≥ 18 years old, had an Eastern Cooperative Oncology Group performance status ≤ 1, and were treatment-naive for anti-programmed cell death-1, its ligand, or transforming growth factor β receptor 1 kinase inhibitors. Phase Ib was an open-label, dose-escalation assessment of the safety and tolerability of galunisertib with nivolumab in patients with advanced refractory solid tumors. Phase II evaluated the safety of galunisertib with nivolumab in NSCLC patients who had received prior platinum-based treatment but were immuno-oncology agent-naive. Results This trial was conducted between October 2015 and August 2020. No dose-limiting toxicities were observed in phase I. In the phase II NSCLC cohort (n = 25), patients received 150 mg twice daily galunisertib (14 days on/14 days off dosing schedule for all phases) plus nivolumab at 3 mg/kg (intravenously every 2 weeks). In this phase, the most frequent treatment-related adverse events (AEs) were pruritus (n = 9, 36%), fatigue (n = 8, 32%), and decreased appetite (n = 7, 28%). No grade 4 or 5 treatment-related AEs were observed. Six (24%) patients had confirmed partial response (PR) and 4 (16%) had stable disease; 1 additional patient had confirmed PR after initial pseudo-progression. The median duration of response was 7.43 months (95% confidence interval [CI]: 3.75, NR). Among the 7 responders, including the delayed responder, 1 had high PD-L1 expression (≥ 50%). The median progression-free survival was 5.26 months (95% CI: 1.77, 9.20) and the median overall survival was 11.99 months (95% CI: 8.15, NR). Interferon gamma response genes were induced post-treatment and cell adhesion genes were repressed, although the association of these observations with tumor response and clinical outcomes was not statistically powered due to limited samples available. Conclusions The study met its primary endpoint as galunisertib combined with nivolumab was well tolerated. Preliminary efficacy was observed in a subset of patients in the Phase 2 NSCLC cohort. Trial registration Trial registered with ClinicalTrials.gov (NCT02423343; 22.04.2015).

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“…Using galunisertib and the clinical anti-GD2 antibody dinutuximab, we showed that dual treatment could demonstrate dramatic reduction in tumour volume and metastatic burden by unleashing the ADCC capacity of NK cells in vivo . Our work highlights the importance of clinical trials such as NCT02423343 , 42 which has already shown promising patient outcomes for therapeutic antibodies and galunisertib dual therapy in solid tumours including lung cancer, and serve as rational for future considerations of this approach for malignant bladder cancers.…”

Small-molecule agents for cancer immunotherapy

“…In another phase II clinical trial, the combination of galunisertib and neoadjuvant chemoradiotherapy was well tolerated and was shown to increase the complete response rate to 32% in patients with locally advanced rectal cancer ( NCT02688712 ) 71 , thus advocating further evaluation in larger randomized clinical trials. The results of a phase Ib/II study of galunisertib combined with nivolumab in NSCLC showed that the combination was well tolerated and observed in a subset of patients in stage II NSCLC to the initial effect ( NCT02423343 ) 72 . In another phase II study of patients with recurrent glioblastoma, galunisertib in combination with lomustine failed to demonstrate an improvement in OS over lomustine alone ( NCT01582269 ) 73 .…”

Insights in Molecular Therapies for Hepatocellular Carcinoma

“…However, the phase II cohort, which included only one patient with HCC, showed a PFS of 5.4 months and an OS of 14.5 months. Hence, comprehensive efficacy results for the use of nivolumab and galunisertib in HCC patients are yet to be determined [339].…”