ABSTRACT
BACKGROUND: In 2019, we reported the first efficacy and safety analysis of EUCROSS, a phase II trial investigating crizotinib in ROS1 fusion-positive lung cancer. At that time, overall survival (OS) was immature and the effect of crizotinib on intracranial disease control remained unclear. Here, we present the final analysis of OS, systemic and intracranial activity, and the impact of co-occurring aberrations. MATERIALS AND METHODS: EUCROSS was a prospective, single-arm, phase II trial. The primary endpoint was best overall response rate (ORR) using RECIST 1.1. Secondary and exploratory endpoints were progression-free survival (PFS), OS, and efficacy in pre-defined subgroups. RESULTS: Median OS of the intention-to-treat population (N = 34) was 54.8 months [95% confidence interval (CI) 20.3 months-not reached (NR); median follow-up 81.4 months] and median all-cause PFS of the response-evaluable population (N = 30) was 19.4 months (95% CI 10.1-32.2 months). Time on treatment was significantly correlated with OS (R = 0.82; P < 0.0001). Patients with co-occurring TP53 aberrations (28%) had a significantly shorter OS [hazard ratio (HR) 11; 95% CI 2.0-56.0; P = 0.006] and all-cause PFS (HR 4.2; 95% CI 1.2-15; P = 0.025). Patients with central nervous system (CNS) involvement at baseline (N = 6; 20%) had a numerically shorter median OS and all-cause PFS. Median intracranial PFS was 32.2 months (95% CI 23.7 months-NR) and the rate of isolated CNS progression was 24%. CONCLUSIONS: Our final analysis proves the efficacy of crizotinib in ROS1-positive lung cancer, but also highlights the devastating impact of TP53 mutations on survival and treatment efficacy. Additionally, our data show that CNS disease control is durable and the risk of CNS progression while on crizotinib treatment is low.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Crizotinib/pharmacology , Crizotinib/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Protein-Tyrosine Kinases/genetics , Prospective Studies , Proto-Oncogene Proteins/genetics , Central Nervous SystemABSTRACT
Ca(2+)-induced inactivation of L-type Ca(2+) is differentially mediated by two C-terminal motifs of the alpha(1C) subunit, L (1572-1587) and K (1599-1651) implicated for calmodulin binding. We found that motif L is composed of a highly selective Ca(2+) sensor and an adjacent Ca(2+)-independent tethering site for calmodulin. The Ca(2+) sensor contributes to higher Ca(2+) sensitivity of the motif L complex with calmodulin. Since only combined mutation of both sites removes Ca(2+)-dependent current decay, the two-site modulation by Ca(2+) and calmodulin may underlie Ca(2+)-induced inactivation of the channel.
