Thread by @VincentRK

I hope we are moving away from “maximum tolerated dose” in oncology. #MedTwitter

Of the studies I’ve led, the one I am most proud of is the trial that showed that LOWER dose of steroids led to better survival & lower toxicity. @TheLancetOncol
#Myeloma thelancet.com/journals/lanon…

Maximum tolerated dose was an idea used with conventional cytotoxic agents. It’s time has passed.

We should now strive for minimum effective dose or optimal effective dose.

Even with targeted therapies and biologic therapies we have found years after drug approval that the original approved dose was too high and caused unnecessary toxicity.

Another good example in my own field is bortezomib, where we found years after approval that twice a week dosing was simply not needed and is too toxic. We routinely use once a week in clinical practice.

Another important consideration is that drugs where a fixed dose of a drug has been used instead of weight based dosing may be incorrect and adopted more for convenience than based on studies to truly determine the optimal doses.

The goal in phase I dose finding studies should be to find the optimal doses and the minimum effective dose.

Spending few more months or an extra year in determining the right dose will save a lot of troubles later, for patients, researchers, and pharmaceutical companies.

In myeloma we have drugs like panobinostat and melflufen which were approved (accelerated approval) before we knew the right dose. And later withdrawn from the market.

With both drug, clinicians had doubts about the dose, & there were significant side effects at approved doses.

More is not necessarily better. More is definitely associated with more toxicity.

Trying to maximize response rate can backfire.

Even for many established drugs we may need to repeat studies to define optimal dosing.

I must also add that the optimal dose can vary by race and ethnicity. And we cannot extrapolate doses across racial and ethnic groups without doing at least some additional studies unless the original trial had a diverse enough patient population to clarify this issue.

With the high dose versus low dose Dex trial I started the thread with, we questioned whether the dose that was routinely used was really necessary. That led to a randomized trial. The inspiration and idea came from a patient.

https://twitter.com/VincentRK/status/1359549101222875139