Cambridge boss John Taylor experimented with a system which had three players in positions in which they had never featured before and it failed badly as his team were overpowered by Orient.
Taylor was trying to plug the gaps caused by half a dozen injuries, including top scorer Dave Kitson, but the disorganised team was carved up by an Orient side who had much more experience.
Two goals came from straightforward corner kicks in the first half as Orient quickly took a grip on their way to their first victory at the Abbey Stadium for 18 years.
Wayne Purser was the man who scored from the set pieces, hammering the ball in from close range when unmarked at the far post in the 17th minute, then powering a header in off the keeper just before the break after Gary Alexander drove the ball across the face of goal.
In between Lee Thorpe took advantage of basic mistakes in the Cambridge defence, before hitting an angled drive from the right hand side of the box which flashed inside the far post.
Cambridge re-organised after the break but it was as good as over in the 54th minute when a posse of defenders stood and stared as Justin Miller hit a 20-yard effort in off the post.
Cambridge's desperation was illustrated by the use of 46th minute substitute, 18-year-old Brian Dutton making his league debut after just a week at the club from minor non-league side Pickering Town.
It was a scrap of consolation for the home side, when youngster John Turner flighted a 25-yard effort over goalkeeper Glen Morris eight minutes from time.
Taylor: "It was unacceptable. We practised the new formation all week but once they crossed the white line too many players just failed to do what they had been told.
"There was more spirit in the second half but it was a poor display and places are now under threat. We are in danger of being pulled down into the relegation fight." Orient caretaker-boss Martin Ling called his team's first-half display "a complete performance".
He added: "We made the most of Cambridge's mistakes and we dominated the match from early on. To go 3-0 up away from home by half time was impressive.
"We failed to win last week after having a 2-0 half time lead and everybody was very focussed this time that things would not slip. It was an excellent display."