The Binding of Isaac! The BINDING of ISAAC!
It’s a massive pivot for Edmund McMillen from his work on Super Meat Boy, and while I can point to their shared DNA - the debt they owe to well-established genres and NES classics, the aesthetic, the difficulty - there’s very little they share mechanically, and it’s refreshing and impressive to watch a developer effectively revolutionize a whole other genre after having done it once.
I think The Witness fits here too; I know some of the Waypoint crew took exception to some of that games thematic underpinnings, which is maybe the piece it shares with Jonathan Blow’s first tile, but it’s a wonderful puzzler and wonderful in a wholly different way from Braid.
I haven’t played it yet, but Heat Signature is another pretty big departure from Tom Francis’s first title, Gunpoint.
I have serious problems with the idea of the “auteur”, but maybe there’s something to the fact that a lot of these pivots come from small studios, and that I can associate the three in this post (and a few of the titles Austin mentioned) with single creators whose personalities seem to permeate their games. Obviously having less publisher pressure means more freedom to try new things, but maybe it also has to do with the agility of small teams, or the inertia of big ones.