HER2-directed TKIs (like zongertinib) and ADCs (trastuzumab-deruxtecan/TDXD) have different mechanisms, and clinical data shows they are effective when used sequentially. Zongertinib works post-TDXD, and vice-versa. However, there is no evidence to support using one HER2 TKI after another has failed.

While Trastuzumab deruxtecan (TDXD) is effective in HER2-low breast cancer, there is no evidence that it benefits patients with HER2-low or HER2-intermediate (IHC 2+/FISH negative) gastric cancer. Its use should be strictly limited to truly HER2-positive cases in this disease.

Despite both being options, experts favor the TKI zongertinib for second-line treatment of HER2-mutant NSCLC. This preference is driven by zongertinib's higher response rates (~71%) and longer progression-free survival in this setting, coupled with a better side effect profile compared to the ADC trastuzumab-deruxtecan (TDXD).

For HER2-mutant NSCLC, Zongertinib (a TKI) is now the first-line choice. While TKIs show activity after ADCs like TDXD, the effectiveness of using an ADC after TKI failure remains an unproven but critical clinical question for oncologists.

For HER2+ metastatic colorectal cancer, experts choose HER2-targeted therapies like TDXD or tucatinib/trastuzumab over standard second-line chemotherapy (FOLFIRI/BEV), despite label constraints. The rationale is the significantly higher response rate from targeting the oncogenic driver directly.

For RAS wild-type metastatic colorectal cancer, oncologists may prefer starting with a trastuzumab/tucatinib regimen over TDXD. This sequencing strategy preserves TDXD as a later option, as there is currently no data supporting tucatinib's efficacy after a patient has progressed on TDXD.

The success of both MOUNTAINEER (tucatinib/trastuzumab) and DESTINY-CRC02 (T-DXd) has introduced two effective, mechanistically different HER2-targeted therapies. This creates a new clinical challenge for oncologists: how to optimally sequence these agents, as there is no head-to-head data to guide the choice.

When managing toxicities from trastuzumab deruxtecan (TDXD) in urothelial cancer, clinicians should refer to established protocols and literature from breast cancer, where experience is more extensive. This cross-disciplinary approach is necessary for managing side effects like nausea, vomiting, and lung disease until more bladder cancer-specific data becomes available.

In HER2-positive colorectal cancer, the choice of targeted therapy depends on RAS mutation status. The tucatinib/trastuzumab combination is effective only in RAS wild-type patients. In contrast, the antibody-drug conjugate trastuzumab deruxtecan (TDXD) shows efficacy regardless of whether a RAS mutation is present.