Lyon's play-off first leg against Real Sociedad ended in a home defeat on Tuesday night.
Frenchman Antoine Griezmann put the visitors in front in the 17th minute with an acrobatic effort and the advantage was doubled in the 50th minute when Haris Seferovic's long-range volley caught out goalkeeper Anthony Lopes.
Things got even worse for Lyon in the 75th minute as Milan Bisevac was sent off having picked up a second yellow card.
Zenit St Petersburg's progression seems all but secure already at the half-way point of their tie against Pacos Ferreira after they claimed a 4-1 aggregate lead from the first leg in Portugal.
Roman Shirokov netted a hat-trick, with his second goal coming two minutes after Andre Leao's volleyed equaliser.
Zenit's third came through an own-goal by goalkeeper Matias Degra and Shirokov wrapped up his treble in the final moments.
Viktoria Plzen have the advantage in their tie against Maribor, winning the first leg 3-1 at home.
They were 1-0 up early on through Marian Cisovsky and added another goal via Vladimir Darida 13 minutes into the second half, shortly before Ales Mejac pulled back a goal for the away side with a delightful strike. Michal Duris restored the two-goal cushion with a minute of normal time to go.
AC Milan hold the advantage over PSV Eindhoven in their play-off tie after the first leg at the Philips Stadion ended in a 1-1 draw.
Milan striker Stephan El Shaarawy opened the scoring in the 15th minute, nodding in from Ignazio Abate's cross.
PSV equalised around the hour mark when Milan goalkeeper Christian Abbiati let a shot from Jeffrey Bruma spin up off him and Tim Matavz headed the ball into the net.
Shakhter Karagandy pulled off a surprise 2-0 victory over Celtic in Astana to take a significant step towards becoming the first Kazakh side in history to reach the group stages.
The hosts took the lead in the 12th minute of the qualifying play-off first leg through captain Andrei Finonchenko, who snuck in to poke the ball past goalkeeper Fraser Forster after a long throw from the left was flicked on at the front post.
The Scottish champions were then undone again with 13 minutes of normal time remaining as Finonchenko saw his effort well blocked by Steven Mouyokolo, Gediminas Vicius drove the loose ball forward and it teed up for Sergei Khizhnichenko to head beyond Forster.