Thread by @VincentRK

I urge oncologists & cancer patients to check out our paper in @TheLancet on Surrogate Endpoints - A Reality Check. thelancet.com/pdfs/journals/…

We discuss a black swan event. A sobering reminder of the limitations of surrogate endpoints @mtmdphd @Rfonsi1 @BldCancerDoc

Thread
1/

2/ The story: In a recent randomized trial, venetoclax had significantly better response rate, MRD- rate, & PFS compared to placebo. The kicker? Two times more deaths with venetoclax! A black swan event for many (like the fate of the turkey described by @nntaleb)

3/ How does a drug that significantly improves response and PFS end up with significantly worse overall survival? How is that even possible? Two ways; by acting as
1. Double edge sword, or
2. Wolf in sheep’s clothing

4/ Double edge sword: This happens when a drug does have efficacy, but also has serious toxicity and leads to many more deaths than the number of people helped. (In Venetoclax trial, serious toxicity & infections were identical in two arms)

5/ Wolf in sheep’s clothing: This happens when the drug deceives by reducing a biomarker or by shrinking a tumor but behind the scenes it is altering underlying the disease biology in such a way that when patients do relapse, the relapse is explosive and rapidly fatal.

6/ Three Lessons:
- Surrogate endpoints don’t mean real clinical benefit has occurred.
- Overall survival is an aggregate endpoint. Requires not just efficacy BUT also safety.
- RCTs are the only to be sure of true clinical benefit

7/ Recommendations: 1) For drugs already on the market: we are not in favor of regulators using surrogate endpoints for adjudicating the benefit. 2) Inform patients of the limitations & truth behind surrogate endpoints. PFS is a misnomer. It doesn’t mean survival is longer.

8/ As we investigate more complex treatment strategies for cancers including combined chemo immunotherapy beware of the double edge sword and the wolf in sheep’s clothing. We can be deceived.
@myelomaMD @MayoMyeloma @NorthTxMSG @MyelomaTeacher @Mohty_EBMT

9/ By the way, the fate of the turkey told by @nntaleb in The Black Swan: The turkey sees a guy coming in daily with food. So when Thanksgiving Day arrives, what happens is a black swan event for the turkey. For the guy it’s not. @Rfonsi1

End

Sorry about typo:
The last pint should read “RCTs are the only way to be sure of true clinical benefit"