A particular APHINITY.

Top Line: In a breast cancer era marked most by deintensification efforts, when is HER2-targeted therapy too much?

The Study: Dual trastuzumab + pertuzumab along with chemo is the standard of care for the neoadjuvant treatment of advanced HER2+ breast cancer. The phase 3 APHINITY trial was designed to answer if the addition of pertuzumab to chemo + trastuzumab is also useful in the adjuvant setting when no pre-op treatment is given. Initial reporting confirmed an overall advantage in disease-free survival (DFS), and now we have the second pre-planned analysis...where not much has changed. Among the 4805 enrollees, improvement in DFS remained at 91% and 88% at 6 years with and without pertuzumab, respectively. In a more “splitter” take, the pre-planned subgroup analysis showed this was driven almost exclusively by node-positive women (n=3006) with no benefit among node-negative women (n=1799). Fortunately, and perhaps not surprising given everyone was already getting chemo + trastuzumab, survival was so excellent across the board that no difference emerged at six years—95% (125 deaths) and 94% (147 deaths), respectively—especially when considering the p-value had to be split among various pre-planned analyses and endpoints leaving this analysis at the mercy of an ambitious threshold of p<0.0012. And this all should be remembered in the context of pertuzumab more than doubling rates of grade 3+ diarrhea (4% versus 10%, respectively) and undoubtedly compounding financial toxicity.

TBL: “APHINITY probably signals the end of treatment escalation for the node-negative [HER2+] subgroup and suggests that strategies to reduce the burden of chemotherapy experienced by these patients should be evaluated.” | Piccart, J Clin Oncol 2021