Beyond overall response rates, a critical area of excitement for new ADCs in lung cancer is their potential to treat brain metastases. Early data showing hints of intracranial efficacy is a significant point of interest, as this addresses a common and difficult-to-treat site of disease progression, offering a potential advantage over other therapies.

Historically, HER2-mutated lung cancer was treated with cytotoxic chemotherapy, unlike other oncogene-driven cancers that used targeted therapies upfront. Zongertinib's approval as a first-line oral TKI marks a significant philosophical shift, aligning its treatment strategy with the biomarker-driven care standard in lung oncology.

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).

Unlike many traditional chemotherapies, new antibody-drug conjugates (ADCs) like IDXD are demonstrating high objective response rates (over 45%) within the brain. This intracranial efficacy is a major advance for small cell lung cancer (SCLC) patients, who frequently develop hard-to-treat brain metastases, potentially reducing reliance on immediate whole-brain radiation.

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.

The antibody-drug conjugate ifinatamab deruxtecan (I-O-DXd) demonstrates remarkable CNS activity. In SCLC patients with brain metastases who have not had prior radiation, the intracranial response rates are even better than the impressive systemic responses, addressing a critical unmet need for this disease.

The new treatment paradigm for HER2-positive lung cancer will likely involve sequencing a TKI like zongertinib first, followed by an antibody-drug conjugate (ADC). Early data suggests that the efficacy of TKIs is significantly reduced when used after an ADC, making the TKI-first approach critical for maximizing patient outcomes.

For EGFR-mutated NSCLC patients with brain metastases, even numerous ones (>30), potent systemic therapy like osimertinib plus chemotherapy is often initiated first. This can achieve high rates of complete intracranial response, allowing clinicians to delay or entirely avoid whole-brain radiation and its long-term toxicities.

While zongertinib demonstrates high systemic efficacy with a 77% response rate, its efficacy in the central nervous system (CNS) is significantly lower at 44%. This gap highlights a critical challenge for patients with brain metastases and underscores the need for combination therapies or next-generation drugs with better CNS penetration.