It's Monday AM post-@ASCO #GU21 & clinic starts in a couple of hours! Lots to process - I'll try to tackle optimal 1L tx for #kidneycancer. I'll make a case for cabo/nivo, leaning on the beautiful (& timely) tables below from @lalaniMD, @SoaresAndrey & @brian_rini (1/15)

What about IO/IO? We have long f/u w #CM214 data w nivo/ipi, no doubt (@AlbigesL et al in @myESMO Open). And treatment-free interval discussed by McDermott @BIDMChealth is no doubt impt. But we've known data not as impressive for favorable risk (2/15)
And furthermore, as @ERPlimackMD points out in another tweet, impt to look at primary PD rates (seen in @lalaniMD's table) - nivo/ipi at 19%!!! CR rate used to be something we highlighted w nivo/ipi, but now comparable across studies (3/15)
Okay now to the really tough stuff - comparing TKI/IO regimens. Something interesting I will add to @brian_rini @uromigos table above is the HR for PFS by INVESTIGATOR review. If the diff in HR for PFS by IND review caught your eye, this is even more striking (4/15)
I think INV-assessed PFS is impt, but if you're a skeptic, forget that argument. Turn instead to #QOL with axi/pembro. Kudos to @brian_rini @tompowles1 @ERPlimackMD et al for advocating for QOL in KN-426. @crisbergerot et al have taughts us the importance of these metrics. (5/15)
Unfortunately, we're not seeing any improvement in QOL w axi/pembro. This is a bit concerning - if balanced between arms, are we prolonging PFS at the expense of the patient's overall well-being? Inc tumor regression should be accompanied by some symptomatic improvement. (6/15)
Okay, now on to one of the headliners at @ASCO #GU21 this past weekend. The CLEAR study presented by @motzermd @DrChoueiri @DrTHut @tompowles1 @CPRT65 et al. Simultaneously published in @NEJM - congrats friends! (7/15)
Just one point on the curves, which I heard @tompowles1 bring up on a @Uromigos podcast w @DrChoueiri (of note, I also saw @manuelmaiamd bring this up during @motzermd's presentation in the @ASCO #GU21 pres). Why do the OS curves merge? Not so in #CheckMate9ER! (8/15)
Regardless, some may be swayed by the 16% CR rate with len/pembro. Now HERE is where we need to dive into baseline characteristics. Nearly 10% more fav risk in CLEAR, and also, more pts with prior neph. So, the odds of getting CR (or even PR) stacked against #CheckMate9ER (9/15)
I'll next make the point that LEN IS HARD TO TOLERATE. I'm glad @SoaresAndrey highlights the rate of discontinuation in #CLEAR, which appears much higher than in #CheckMate9ER. I've seen 7al versions of the data, but no matter how you slice it, d/c rate⬆️with len/pembro. (10/15)
What's my experience with len? I ran a RP2 study w @DrDanielHeng @hipsytips @docjavip et al. We tried to lower dose from 18 to 14 mg & preserve efficacy, but with the caveat of this being a small non-inferiority study, it didn't appear feasible. 👀rates of d/c due to AEs! (11/15)
Remember, I was comparing 18 and 14 mg. The dose in #CLEAR even HIGHER at 20 mg! This is one of those settings where QOL data ESSENTIAL. Remember, our pts are thankfully doing better & will be on drug longer - we need to look out for their GLOBAL well-being! (12/15)
Now THIS is what we need to see. Improved QOL with cabo/nivo, as @DrChoueiri presented at #ESMO20. Remember, the dose of 40 mg is used in #CheckMate9ER - LOWER than the dose of 60 mg used in #METEOR, with cabo as 2L/3L tx. (13/15).
Confession: I was skeptical when @DrChoueiri @motzermd @tompowles1 @apolo_andrea & the brilliant team for #CheckMate9ER chose 40. But @neerajaiims & I have since reported data from #COSMIC021 (cabo/atezo across multiple settings). Efficacy at both doses seems quite good (14/15)
SUMMARY: In 2021, we are blessed w gr8 data from mult 1L trials in #kidneycancer. I feel that cabo/nivo is the way to go; the goalpost is shifted beyond just PFS/RR/OS, we now need QOL! Thx to the amazing data summaries that facilitated this thread. Open to all comments. (15/15)

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I'm going to do two history threads on Ethiopia, one on its ancient history, one on its modern story (1800 to today). 🇪🇹

I'll begin with the ancient history ... and it goes way back. Because modern humans - and before that, the ancestors of humans - almost certainly originated in Ethiopia. 🇪🇹 (sub-thread):


The first likely historical reference to Ethiopia is ancient Egyptian records of trade expeditions to the "Land of Punt" in search of gold, ebony, ivory, incense, and wild animals, starting in c 2500 BC 🇪🇹


Ethiopians themselves believe that the Queen of Sheba, who visited Israel's King Solomon in the Bible (c 950 BC), came from Ethiopia (not Yemen, as others believe). Here she is meeting Solomon in a stain-glassed window in Addis Ababa's Holy Trinity Church. 🇪🇹


References to the Queen of Sheba are everywhere in Ethiopia. The national airline's frequent flier miles are even called "ShebaMiles". 🇪🇹
So the cryptocurrency industry has basically two products, one which is relatively benign and doesn't have product market fit, and one which is malignant and does. The industry has a weird superposition of understanding this fact and (strategically?) not understanding it.


The benign product is sovereign programmable money, which is historically a niche interest of folks with a relatively clustered set of beliefs about the state, the literary merit of Snow Crash, and the utility of gold to the modern economy.

This product has narrow appeal and, accordingly, is worth about as much as everything else on a 486 sitting in someone's basement is worth.

The other product is investment scams, which have approximately the best product market fit of anything produced by humans. In no age, in no country, in no city, at no level of sophistication do people consistently say "Actually I would prefer not to get money for nothing."

This product needs the exchanges like they need oxygen, because the value of it is directly tied to having payment rails to move real currency into the ecosystem and some jurisdictional and regulatory legerdemain to stay one step ahead of the banhammer.