Based on personal experience with my 460" LTD I would say that a goal of 550 to 600 HP crank with a manual OD transmission, EFI and High compression / thermodynamic efficiency could easily net 18 MPG with careful tuning of both AF ratios at cruise and ignition timing.
I am getting 14+ mpg with 3.5 gears, 3000+ stall convertor and a carefully tuned HP 950 built by comp carbs for the application. Idle feed restricters and air bleeds are all tunable on the aforementioned carburetor.
Up until about 50 MPH I am cruising on the transfer slots in the carb and can easily tune the cruise A/F to a target of 14.5 to 1. Above that I am starting to pull from the main well / booster venturis and the AF ratio goes from the 14's to the high 12's low 13's A/F. This is simply a matter of the airflow needs of the engine at 2750 to 3000 rpm at highway speeds. I can lower the float level on the primary side to delay main well fuel flow however I compromise drive ability at that point. A larger engine would of course make good economy harder to attain with a carb given the additional air flow needs at cruising speeds.
If I were to use a self learning EFI system set to cruise at stoic / 14.7 to 1 with a manual OD and or a locking automatic like the E4OD I would certainly expect to be near 18 MPG with a reasonable foot.
I am running 11 to 1 static c/r, 9.3 to 1 DCR, 220+ psi cranking with .039" quench distance with the DUAL QUENCH SCJ-A castings. I mention these heads because I feel that the minimal timing requirements of these castings plus the dual quench pads offer better octane tolerance vs the other std valve location offerings. at 460 inches I do not feel that the port cross section is too large given the amount of torque these castings make even at lower rpm windows.
I dont know if the new AFR offerings have a revised chamber and valve locations with dual quench pads...
I run 30 degrees total timing in by 2600 rpm and add 20 degrees vacuum advance in conjunction with the leaner cruise A/F's while on the transfer slots...
I think carl is on the right track as is backed up by my personal experiences.
I am making close to 550 crank HP with the 3 pattern roller cam and larger carb so I again agree that the MPG criteria is plausible...
I have contemplated the new FAST wide band EFI for exactly this reason.
One last consideration here is abundant airflow with minimal cross section at modest valve lifts paired with careful camshaft design. keep duration minimal for the power expected.
I would have some doubts about a 650 Hp combination NA making the grade due to the long duration cam needed however if Static c/r is increased to keep DCR high it might just get close.