Not including cheat methods that let you avoid a majority of the fight mechanics, like asphalt bridges, I think the hardest fight for the stage of the game you're supposed to fight it at, is Queen Slime (pre mech) or possibly Queen Bee (after eye of cthulhu)
I find it so tremendously difficult to avoid all the slimes she spawns, all the projectiles they spawn, her massive amount of projectiles herself, and the high damage they deal. Not to mention she has a few moves like Heavenly Smash which deal huge damage also, and are an ever-present threat if you stop moving.
For Summoner, the class that benefits the most from the drops, it's even more brutal, Summoner doesn't have many reliable options for her fight.
Same for Queen Bee, really.