What happens when a HER2(+) breast cancer stops responding to trastuzumab (aka Herceptin)? If the cancer is also hormone-receptor(+), the ALTERNATIVE trial suggests adding an aromatase inhibitor and lapatinib to trastuzumab is a good option. Now we have phase 2 data indicating that adding pembrolizumab to trastuzumab is both safe and effective in patients with PD-L1 expression >1%. The patients who most reliably benefited? Those with tumor-infiltrating lymphocytes (TIL) making up at least 5% of the tumor stroma, which really shouldn’t be a surprise. Among 40 patients with some PD-L1 expression and TIL ≥5%, 6 achieved an objective response rate compared to 0/12 patients without PD-L1 expression. Unfortunately, trastuzumab-refractory HER2(+) breast cancer was found to be very poorly immunogenic overall, with a median stromal make-up of TILs of only 1%, but pembro may still be a good option for those who are expressing PD-L1 and especially if TILs are also present.