I have an OpenVPN connection, and I use the update-systemd-resolved to correctly fetch the DNS from the VPN. The issue arose updating my Ubuntu 18.04: the script is no longer invoked, and even invoking it manually (sudo openvpn myfile.ovpn) does not work anymore, even if in that case systemd-resolve --status shows the new DNS on the interface correctly.
As suggested in https://bugs.launchpad.net/ubuntu/+source/network-manager/+bug/1211110/comments/99, reverting to 1.10.6-2ubuntu1.1 fixes the issue.
Thanks for new report and confirming that downgrading fixes the issue