This was a safety update for the DESTINY-Breast03 study. The efficacy of that study was actually

presented previously and led to the expanded approval for trastuzumab deruxtecan last month in

earlier line therapies. So this was really a safety update. At the safety update the treatment duration

had lengthened from 6.9 months in the T-DM1 arm to 16.1 months in the T-DXd arm. So just a little bit

about some safety and some extra things that we’ve looked at, some specific adverse events.

What did you find?

This was a trial that was really designed to be a so-called second line trial. It was trastuzumab

deruxtecan versus T-DM1 for patients with HER2 positive breast cancers that had already seen

trastuzumab and/or a taxane in the metastatic setting or had relapsed within six months of seeing

HER2 directed therapy in the neoadjuvant or adjuvant study. We saw a 72% decrease in the risk of

progression, so quite impressive results in the breast world that led to this expanded indication.

What safety data were you recording?

The first thing we looked at was really the rates of serious treatment emergent adverse events and

treatment emergent adverse events. For those that were grade 3 or greater it was really quite similar

between the two arms – T-DXd at about 53%, T-DM1 at about 50%. The next thing we looked at was

something that was a little bit different, just overall side effects of the drugs. We found that nausea,

vomiting and alopecia, or hair loss, was more common with T-DXd and fatigue was pretty similar

between the arms.

We looked at a new fancy parameter called exposure adjusted incidence rates and exposure adjusted

incidence rates are a standardised measure of risk per patient year and it’s commonly used to

describe safety in studies where there is long-term follow-up and there may be an imbalance in follow-

up between the two treatment arms. So when we looked at these exposure adjusted incidence rates

across the board, grade 3 or greater serious treatment emergent adverse events were actually all

lower for T-DXd compared to T-DM1. The one exception was a treatment emergent adverse event

that led to discontinuation and why that was was there were about 8% of patients on T-DXd that

ended up needing discontinued drug due to ILD pneumonitis. So, overall, drug discontinuations were

14.8% in patients with T-DXd, again with the ILD pneumonitis at 8% driving that. Then dose

discontinuations for T-DM1 were 7.3%.

This really gave us reassurance that T-DXd has a favourable risk-benefit ratio compared to T-DM1 in

this new expanded setting. We found also that the time to dose reduction or time to treatment hold of

the drug, which is another way we can look at safety or how patients are doing, was longer with T-

DXd than T-DM1. So, putting all of this together, I think it really reassured us that we have a good

handle on the safety profile of trastuzumab deruxtecan. ILD pneumonitis is one thing that we’ve really

been following and overall T-DXd had a 10.9% rate of ILD pneumonitis any grades, no grade 4 or

grade 5 events, that means no fatal events, and grade 3 events are now still less than 1% at 0.8%.

So it really showed us that for the efficacy and how much better patients are doing on T-DXd that this

really makes quite a bit of sense. The one thing we have to say on top for these patients is nausea

and vomiting. Throughout the DESTINY-Breast03 trial there were no mandated antiemetics or nausea

medications for patients but now subsequently we do know that T-DXd is moderately emetogenic and

it is part of the label to start antiemetics up front for patients.