Armando Orlandi, Medical Director at the Agostino Gemelli University Hospital Foundation IRCCS, shared a post on LinkedIn:

“I have always loved Mark Haddon.

In ‘The Curious Incident of the Dog in the Night-Time’, Christopher Boone – a teenager with Asperger’s syndrome – refuses to accept comfortable answers. Armed with relentless logic, he uncovers a truth everyone around him had chosen not to see.

I thought of Christopher while reading DESTINY-Breast11 – because here too, at (DESTINY-Breast) Eleven O’Clock, something was killed: the T-DXd monotherapy arm, one of the most exciting innovations in HER2+ breast cancer of the last two decades.

The verdict: T-DXd inferior to ddAC-THP (ΔpCR –13.2%, p=0.001): the trial used a two-sided α=0.02, and with p=0.001 it formally and statistically demonstrates inferiority of T-DXd. That is a strong claim.
Case closed. Drug buried.

Which is precisely why the misclassification bias matters so much:

The arm was closed despite passing the prespecified futility boundary (ΔpCR ,<-15%).
36 patients (12.6%) who switched to local standard of care were automatically classified as non-responders – regardless of actual pathological response.
Correcting this bias produces an 8.4 pp swing – enough to make both corrective analyses statistically non-significant (CI crossing zero).

T-DXd monotherapy was not proven inferior. It was proven inconclusive. There is an enormous difference between the two.
The scientific question remains open – and rightly so. Trials such as ARIADNE, SHAMROCK, and EXTEND will provide cleaner answers.

In the meantime, I invite you to do two things:

Read (or re-read) ‘The Curious Incident of the Dog in the Night-Time’ – one of the most beautiful books of the last twenty years, and a masterclass in critical thinking and intellectual courage.
Read my letter and ask yourself the same questions Christopher would have asked. Because in science, as in detective fiction, the uncomfortable questions are often the most important ones.”