New Frontiers in Breast Cancer: Updates and Advances in Treatment - Episode 7

DESTINY-Breast03: T-DXd in Previously Treated HER2+ Breast Cancer


Comprehensive discussion on the DESTINY-Breast03 clinical trial evaluating trastuzumab deruxtecan in patients with previously treated HER2+ metastatic breast cancer.


Komal Jhaveri, MD, FACP: Let me just quickly walk us through the DESTINY-[Breast]03 trial [NCT03529110]; this was the very first randomized study of trastuzumab deruxtecan [T-DXd]. Before this, we had the DESTINY[Breast]-01 [NCT03248492], which led to the approval of this agent for [patients with metastatic disease]. These were patients with unresectable metastatic HER2-positive disease who have previously received trastuzumab and taxane in the advanced metastatic setting. [They] could have had stable treated brain metastases. And [they] were then randomized receiving either T-DXd or T-DM1 [trastuzumab emtansine] which is what we were utilizing for our patients in the second- and third-line [therapy settings]. Fifty percent of these patients got randomized in the second-line setting for the metastatic disease. The primary end point here was progression-free survival [PFS] and the secondary end point was overall survival.

And here are the Kaplan-Meier curves. These are these gorgeous Kaplan-Meier curves; you can see the quite separation of these curves right from early on favoring T-DXd. And you can see that the median progression-free survival was about 7 months in the T-DM1 control arm and was not reached by blinded independent central review. By independent review, it was about 25 months. And the 12-month PFS rate was about 76% in the T-DXd arm, which was more than double in the T-DM1 arm of 34%. The hazard ratio here is 0.28 and the P value is 10-22. Thus, [this was] truly unprecedented. And really, this is comparing 2 great drugs that we now used for our patients and the separation of curves is really unprecedented, I think. These are the key secondary end point results, the overall survival results, which were rather early. Although I have to say that even at this early immature point and [as] we await mature data, we're seeing some separation of the curves already in the hazard ratios heading in the right direction at 0.56. Hence, we look forward to updated results to see the overall survival benefit hopefully with this agent.

What about the safety? I think one of the things that we have learned about T-DXd is that the most common one is really GI [gastrointestinal] like nausea and some fatigue, [and] we've seen some neutropenia as well. But the one that we worry about is the interstitial lung disease or pneumonitis. And thus, updated safety results were presented by Erika Hamilton [MD, at Tennessee Oncology], at the ASCO [American Society of Clinical Oncology annual] meeting and fortunately, we did not see any new safety signals. And when we looked at these patients the median duration that the patient stayed on T-DXd arm was about 17 months. And for the T-DM1 arm, it was about 7 months. And thus, that’s why we looked at something called as exposure-adjusted incidence rates of adverse events [AEs]. And the most common treatment-emergent adverse events [TRAEs] were grade one or two. And the exposure-adjusted incidence rates of TRAEs and serious AEs were lower with T-DXd than T-DM1, which was reassuring.

Nausea, vomiting, fatigue, and alopecia risk were higher with T-DXd and they were more so in the initial treatment cycles. And the prevalence of nausea vomiting was higher also with T-DXd in initial treatment cycles but was consistent over time. But alopecia and fatigue [was] kind of telling us that we really need to continue to provide the support of medications to our patients and handle these side effects very well for them. Thankfully, there were no additional grade 3 adjudicated ILD [interstitial lung disease] pneumonitis events with T-DXd, and the overall rate here was 0.8%. And thankfully, there were no grade 4 or 5 events overall in the DESTINY-[Breast]03 trial. Perhaps suggesting that when we're trying to use them early on that we are potentially seeing less. And more importantly, I think we as a community are becoming more and more vigilant about this, and we need to be vigilant about this including for our nursing force that are really the front-line taking the phone calls from our patients, [and] educating our patients. And together, hopefully that has led to a decline in the prevalence of this ILD pneumonitis with this molecule.

Transcript edited for clarity.