Sorry for the double post, but I don't think any PODs involving the Presidential Succession Act are realistic after the passage of the 25th Amendment. In other words, we are dealing with ASB territory.
This actually came up historically. Vice President Agnew got in trouble over a bribery scandal right around the time of Watergate. What actually happened is that he resigned, and Nixon selected a new Vice President in accordance with the 25th Amendment. This strongly suggests that in a circumstance where both the President and Vice President are in danger of being forced out of office, a new VP will be found first. This will probably involve some sort of deal behind the scenes.
If both the Prez and VP dig in their heels in this circumstance, and impeachment and removal moves forward, the House will make sure that the Speaker is suitable to take over the executive branch. That means removing the Speaker if there is even a whiff of scandal, or the Speaker steps aside to increase the chances of the impeachment being successful. Something like this actually happened in 1998-9, which is how Hastert became Speaker in the first place. By the way, the Speaker does not have to be an elected Congressman.
Now you could have a double assassination of the President and Vice President, but this is really, really hard to pull off. It was only attempted once in US history, and that was during the Civil War.
More likely is a scenario where a Vice President fills a presidential vacancy, and everyone takes their time over finding and confirming a new Vice President, as was the case with Ford and Rockefeller. Then something happens to the new President.
Its not also clear, just from reading the text of the 25th Amendment, whether in the event of a double vacancy with the presidency and vice presidency, that the country gets a new President or a new acting President. Its probably the latter. Congress has never clarified this because the situation is so unlikely to come up.