DESTINY-Gastric03 is an important study, it really is the first study to explore a combination of first-line trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, in gastric cancer but bringing it to first-line setting. So T-DXd is now approved in later lines after trastuzumab failure. DESTINY-Gastric03 brought it together with T-DXd and anti-PD-1 and also using fluoropyrimidine, such as capecitabine or 5FU, so that this regimen will be tested in the first-line setting. We showed with DESTINY-Gastric03 that it’s a feasible regimen in first-line setting. Of course, as you know, DESTINY04 demonstrated that in second line it improved survival compared to Taxol ramucirumab and now, taking it forward to DESTINY-Gastric05 which is a definitive randomised phase III study in first-line setting using capecitabine plus T-DXd and pembrolizumab in first-line HER2+ patients with PD-L1 overexpression and randomising them to either that regimen, the experimental regimen, or standard of care pembrolizumab, fluoropyrimidine and oxaliplatin, which is the KEYNOTE-811 regimen.
I’m excited about that study because for patients with low or co-occurring HER2 expression, other alterations or focal HER2 positivity where we need the bystander effect and we need the ADCC together to help improve outcomes, T-DXd may be a game-changer. So only time will tell.
What was the safety profile?
The safety for trastuzumab deruxtecan is, of course, associated with chemotherapy side effects but also interstitial lung disease. When we are combining it, it’s important with the DESTINY-Gastric03 we saw that a lower dose of T-DXd at 5.4mg/kg in combination with capecitabine and pembrolizumab was much better tolerated and that’s what we’re taking into phase III. It’s important to always monitor for even asymptomatic ILD and to stop or discontinue therapy to avoid more severe grade 3 or 4 events. Otherwise this regimen is tolerated, other than the nausea that’s always expected with the chemo side effects or common side effects such as leukopenia and so forth.
What would be your take home message?
The take home is trastuzumab deruxtecan is hopeful for our patients with HER2+ disease in later line therapy and after trastuzumab failure. Now we’re bringing it closer to first-line setting and perhaps in the future even perioperative setting. The way to do it is to combine it with fluoropyrimidine and also anti-PD-1 therapy because that’s the standard in those settings and that’s what the goal is for the DESTINY-Gastric03 and 05 studies.
