England have crushed the Azzurri every time they have faced them at Twickenham and have an average winning margin of almost 35 points from their six previous Six Nations meetings there. Another victory on Sunday will leave them one win - away to Wales next Saturday - away from their first Grand Slam since 2003.
It is a very different scenario from 12 months ago when Lancaster had just begun his rebuilding job and such is his confidence in the squad he has assembled that on Friday he felt able to make four tactical changes, plus one injury-enforced, from the team who beat France two weeks ago.
Mako Vunipola, the giant 22-year-old New Zealand-born prop, whose father Fe'ao captained Tonga and played against England in the 1999 World Cup, will make his first start as a reward for some dynamic displays off the bench having won all his previous seven caps as a replacement.
There is a new half-back combination as Toby Flood starts at fly-half in place of the injured Owen Farrell and Danny Care regains the scrum half jersey from Ben Youngs.
James Haskell returns to blindside flanker in place of Courtney Lawes and Tom Youngs comes back in at hooker for Dylan Hartley, reversing the switch made for the France game.
There is also a recall to the bench for flanker Tom Croft, who has made a remarkable recovery after almost being paralysed after breaking his neck 11 months ago.
"We were very happy with the way we finished the France game. The impact the replacements made shows that we have competition for places across the board and we have had to make some tight calls," Lancaster said in a statement.
"I am sure those starting will seize their chance and the bench will also have a significant part to play as the game goes on."
Vunipola, who comes in for Joe Marler, weighs in at 20 stone and will hope to stabilize the England scrum, which has been arguably the weakest aspect of their campaign to date.
Italy lead the way with a 91 per cent success rate in the tournament, while England are joint-last with Scotland on 74 percent.
England also trail in last in lineout success so the potential return of Croft, an athletic and effective operator, is a real, if unexpected, boost.
The Leicester flanker was told he was lucky to have escaped paralysis after breaking his neck in a club game last April shortly after completing an impressive Six Nations campaign at number six.
He returned to tentative action for Leicester in January, with a metal plate and four pins in his spine and although he has played less than five hours in five games since then, he has shown enough for Lancaster to rush him back into the mix.
As a result of his injury rehabilitation he has added several kilogrammes of muscle bulk around his neck and shoulders that give him more power in the contact but do not seem to have diminished his athletic ability.
"Tom's seven feet tall and 10 stones in terms of throwing him up in the air," said his Leicester and England colleague Geoff Parling.
"He's a quality player who can play anywhere in the line-out. You can put him anywhere and he's comfortable. He'll pick things up very quickly."
Meanwhile, Fly-half Luciano Orquera has returned in one of eight changes to the Italy side for the clash.
Orquera, who put in a man-of-the-match display during Italy's thrilling 23-18 win against France on the opening day of the tournament, comes back in for Kristopher Burton.
Sergio Parisse will return to captain Italy as expected after his suspension for insulting a referee during a French Top 14 club match last month was shortened on Wednesday.
Parisse had been suspended for the rest of the Six Nations after the sending off for Stade Francais but the number eight appealed to the French rugby federation and his ban now ends on Saturday.
Italy coach Jacques Brunel has brought in five new faces to a pack that was dominated by Wales in their 26-9 defeat a fortnight ago, with loosehead prop Alberto De Marchi replacing Andrea Lo Cicero, who will make a record-breaking 102nd appearance for Italy if brought on.
England: 15-Alex Goode, 14-Chris Ashton, 13-Manu Tuilagi, 12-Brad Barritt, 11-Mike Brown, 10-Toby Flood, 9-Danny Care; 8-Tom Wood, 7-Chris Robshaw (captain), 6-James Haskell, 5-Geoff Parling, 4-Joe Launchbury, 3-Dan Cole, 2-Tom Youngs 1-Mako Vunipola
Replacements: 16-Dylan Hartley, 17-Dave Wilson, 18-Joe Marler, 19-Courtney Lawes, 20-Tom Croft, 21-Ben Youngs, 22-Freddie Burns, 23-Billy Twelvetrees.
Italy: 15-Andrea Masi, 14-Giovanbattista Venditti, 13-Gonzalo Canale, 12-Gonzalo Garcia, 11-Luke Mclean, 10-Luciano Orquera, 9-Edoardo Gori, 8-Sergio Parisse (captain), 7-Robert Barbieri, 6-Alessandro Zanni, 5-Joshua Furno, 4-Quintin Geldenhuys, 3-Martin Castrogiovanni, 2-Leonardo Ghiraldini, 1-Alberto De Marchi
Replacements: 16-Davide Giazzon, 17-Andrea Lo Cicero, 18-Lorenzo Cittadini, 19-Antonio Pavanello, 20-Francesco Minto, 21-Simone Favaro, 22-Tobias Botes, 23-Tommaso Benvenuti