Not the biggest but..
Resident Evil 6. Weather RE 6 is a bad game or not dosen't matter, but I think it was a huge miss of what could have been a mega hit. Had RE6 been a good game with really good word of mouth, I think we would have seen a huge game sales wise. I mean think about it, zombies right now are just on the top of pop culture. There had been a decent gap since 5- which I think was decently received as well-that a new RE would seem very new and worth hyping. It looked great, it looked flashy enough to win that crowd that likes explosions, and RE is just a name people know even if they don't play the games. I mean it was also the year of RE basically. A cg movie, a side game, and a live action movie all had come out. RE's name was pretty much everywhere. This was also a return to zombies on top of it all. Really had RE6 been some great game, I really think it would have had those "CoD" sales Capcom is hungry for. Had word of mouth been so positive I think people caught up in all the present zombie stuff would have heard about it and thought to themselves "maybe I should try this RE thing finally".
Capcom in general has been so off and on as this gen went on. I remember in the begining when LP1 and Dead Rising were coming out. Those demos came and people loved them. LP1 looked great. DMC 4 looked great. While it was coming apparent that Japanese developers were having trouble it looked like Capcom knew it's shit and people loved them. They've made some poor choices I guess, but are still better off then most. Still there seems to have been a total reveral on people's views of the company in the 2nd half of this gen.
Ghost Recon Advanced Warfighter is another one. I'm not sure how much it sold, but I doubt it was a big hit and the game seems mostly forgotten. It took so long for it to come at as well and obviously went through many revisions. What we ended up getting was a game with an identity crisis. Wanting to appease the CoD crowd with small maps and more streamlined mechanics all while trying to still be GR. What we ended up getting was a meh CoD wannabe that feels like a downgrade from even Advanced Warfighter. The game came out quietly and then diapered quietly, not even carving or catering to that tactical tps crowd.
Speaking of games like GR, there was also Socom 4. I don't know if Socom 4 would have even been a huge hit, but I'm sure coming out during the time PSN was down didn't help. I don't think the game ever recovered.
Brink for all it's supposed freshness and good looks never went anywhere. And cheap copies are abundant in your local gamestop.
Force Unleashed 2. People seemed to like the 1st one, but talk about an awful sequel.