Bob and Georgeaverted this when the originally planned comic failed and the Mega Man sprite comic, originally used simply for filler, proved more popular by merging portions of the Bob and George plot, including characters, with the Mega Man sprite comic. Bob and George were even given Plot Armor as long as they were in the title, which lead to a joke of a character "dying" thus leading to his name being removed from the title.
Bob and George is a very interesting example. The Mega Man sprite comic originally had no mention of the title characters at all; according to the author's notes for the first few hundred comics, he hadn't planned on making Bob and George characters at all once the strips became 100% Mega Man sprite comics. But he realized that he already had a developing fanbase and it was too late to change the comic title, and he didn't want to keep a title that was irrelevant to the story, so he added Bob and George, completely changing the story. So he tried so hard to avert this trope that he ended up drastically changing his comic and adding in two characters that ended up being way more important than Mega Man.
8-Bit Theater was originally going to feature several video game parodies, an idea abandoned by Clevinger when the Final Fantasy comic became popular; hence the title which seems to suggest more 8-bit stories that were never made (and never will be).
This was slightly averted by the brief side comic Field of Battle (included in the 8-Bit archives here), which features the sprite comic style but is otherwise unconnected to 8-Bit Theater.
Only the first panel of the first adventure is done in MS Paint. The rest are done in Photoshop and Flash.
Andrew Hussie: I am so good, I can emulate pressure sensitivity with MS Paint.
Thoroughly zig-zagged by Homestuck, being both a title reflecting the state of the protagonists at the beginning and a reference to Earthbound, as the protagonists are very often stuck in places which could be considered home, but not always.
Finally given meaning when it's revealed that Bun-bun used to be a god named Sluggy, but he declared, after a near-apocalypse, that he was going freelance.
The Whiteboard. Although the comic started as doodles on a whiteboard, it stopped after only five "strips", and there was one later on to celebrate a holiday, for a grand total of six — less than three and a half permilnote 10 permil is 1 percent of the now 1700+ strip archive.
Polk Out, where polking out (Named after James K. Polk) is a phrase the Polkster coined to refer to pulling out when the job is done. This was to refer to the rotating comics which have long since stopped doing any rotating. It just might apply again in the near future.
Christian Weston Chandler's Sonichu comic is named for a Sonic/Pikachu hybrid that the creator made. Said character was Demoted to Extra in the third issue. However, considering how Sonichu is also the name of the species he's part of, it's not that much of an artifact considering the Spotlight-Stealing Squad has the ability to morph into a Sonichu.
Jix is named for a character, but several story arcs have nothing to do with her. Often times, her human friend Lauren takes over the story. This trope is sometimes lampshaded by the characters knowing Jix's change to her any of her other personalities isn't permanent because of the name of the comic, thus breaking the fourth wall.
When it first started in 2007, This Is Not Fiction was titled after the main character's favourite novel. But in the 2010 rewrite, the book makes but one brief appearance and is never named, making the title rather mysterious to new readers.
Irregular Webcomic! was originally intended to be a fun side project for the creator that he would update simply whenever he got the time. It went on to become one of the most consistently regular webcomics of all time, until its end in 2011... upon which it has still be regularly updated every day with longer scientific/mathematic posts on Sundays and reruns with new commentary of old strips other days.
Inverted in Coach Random. The character in the title shows up in the penultimate official strip. This was lampshaded.
Oglaf appeared in exactly two early comics of the strip that bears his name.
Looking for Group was originally conceived as a World of Warcraft parody, and the name was fitting. But over time, the series began moving away from Warcraft by parodying other fantasy franchises and developing its own universe. Nowadays, the strip is more of a Dramedy, and parody gags of any kind are few and far between.
Girls with Slingshots: The two main characters are still female, but the Slingshots in question are drinks. The Slingshot is the specialty beverage of a drag bar where Jamie and Hazel went once, and had one Slingshot each. Neither the bar nor the beverage has been mentioned since.