galunisertib + nivolumab

The drug combination "galunisertib + nivolumab" is an investigational therapy that combines two distinct mechanisms of action to target tumor immune suppression. This combination has been studied in clinical trials for various advanced refractory solid tumors, with specific focus on non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), and glioblastoma. ## Mechanism of Action Galunisertib (LY2157299) is a TGF beta R1 kinase inhibitor that selectively blocks TGF beta signaling in vitro[9]. TGF-beta is known to play a role in tumor immune suppression, and blocking this pathway may enhance anti-tumor immune responses. Nivolumab (Opdivo) is a human programmed death receptor-1 (PD-1) blocking antibody that binds to the PD-1 receptor expressed on activated T-cells[9]. By blocking the PD-1 pathway, nivolumab helps restore T-cell function and anti-tumor immune responses. The combination aims to simultaneously target two immune suppression pathways to potentially enhance efficacy against various cancers. ## Clinical Development A Phase Ib/II open-label study evaluated the safety, tolerability, and efficacy of galunisertib in combination with nivolumab in patients with advanced refractory solid tumors and in recurrent or refractory NSCLC, HCC, or glioblastoma[7]. The Phase Ib portion was a dose-escalation study in patients with advanced refractory solid tumors, while Phase II focused on specific cancer types including NSCLC, HCC, and glioblastoma[2][4]. ### Study Design and Dosing In the Phase II NSCLC cohort (n=25), patients received 150 mg twice daily galunisertib (14 days on/14 days off dosing schedule) plus nivolumab at 3 mg/kg intravenously every 2 weeks[7]. The trial was conducted between October 2015 and August 2020[7]. ### Results The study met its primary endpoint as galunisertib combined with nivolumab was well tolerated[1]. No dose-limiting toxicities were observed in Phase I[7]. In the Phase II NSCLC cohort, the most frequent treatment-related adverse events were pruritus (36%), fatigue (32%), and decreased appetite (28%). No grade 4 or 5 treatment-related adverse events were observed[7]. Efficacy results showed that 6 patients (24%) had confirmed partial response and 4 (16%) had stable disease. One additional patient had confirmed partial response after initial pseudo-progression. The median duration of response was 7.43 months[7]. Due to low enrollment, the HCC cohort was terminated early[6]. ## Development History This combination therapy emerged from a clinical trial collaboration between Bristol-Myers Squibb Company and Eli Lilly and Company, announced on January 13, 2015[9]. The collaboration aimed to evaluate the safety, tolerability, and preliminary efficacy of this combination in advanced glioblastoma, hepatocellular carcinoma, and non-small cell lung cancer[9]. The global end of trial date was July 8, 2020, and the trial was not ended prematurely according to the clinical trial results[6].