Spain hold sway now with a superior goal difference and are odds-on to stretch away from the visitors as they look to make a significant advantage in Madrid pay full dividends. There are three points that are equally important as those on Saturday.
Isco and Asensio played with veteran playmakers Andres Iniesta and David Silva as Spain dazzled Italy without a traditional striker, a "false 9" lineup Lopetegui recovered from the best times of Spain under Del Bosque.
"We believe and hope to go to the World Cup".
Is Spain the best team in global football?
The Real Madrid playmaker curled home a free-kick and then smashed in a second as Spain named no recognised striker. At 3-0, the fans implored Lopetegui to bring on David Villa, whose introduction was almost thwarted by the clock: it took a while for a break in the play to arrive, and the first was an Italian free-kick, leading Spain's ever-prudent coach to delay the change.
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"He opened the game up for us with his two goals".
A year ago, Antonio Conte's highly-organised Italy had outclassed Spain at the 2016 Euros to deny La Roja a chance to defend their 2012 title.
Spain and Italy comfortable lead that table on 16 points apiece, with their only failure to gain three points coming when the two sides drew earlier in the qualifiers.
"This Isco is better than the one of previous year, but we have always had confidence in him, " Lopetegui continued. This has been some display from Spain.
I wonder whether we will get quite the same excitement in terms of goals but drama is very much on the cards with time running out for both to get back in the hunt for qualification. The victor of this match is nearly certain to win the group and will be able to rest key players in the final rounds.
The fortnight-long global break has thrown up some interesting results thus far, with teams fighting hard to inch a step closer to securing qualification for next summer's World Cup.
What TV channel is Spain vs Italy on?