A practical framework categorizes TKIs into three classes to guide adjuvant use. Class 1 (e.g., osimertinib, alectinib) has high efficacy and low toxicity, making extrapolation easy. Class 2 (e.g., BRAF/MET inhibitors) has moderate efficacy and higher toxicity, requiring trials. Class 3 (e.g., KRAS inhibitors) has lower activity and needs trials.

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).

While ALK and ROS1 are similar kinases, assuming cross-activity of their respective inhibitors is a clinical pitfall. For example, the potent ALK inhibitor Alectinib is not an effective ROS1 inhibitor. This distinction is critical for selecting the correct targeted therapy and avoiding treatment errors.

The distinct side effect profiles of pan-RAS inhibitors (rash, mucositis) and G12D-specific inhibitors (GI issues) are driving separate clinical strategies. The G12D drugs' better combinability with chemotherapy contrasts with pan-RAS agents, which may be better suited for monotherapy due to toxicity from blocking normal RAS.

In ROS1-positive NSCLC, starting with older TKIs before newer agents like Repotrectinib dramatically worsens outcomes. Median overall survival has not been reached after 5 years for TKI-naive patients but drops to just 25 months for those pre-treated with another TKI. This starkly quantifies the critical importance of using the most effective treatment first.

Pirtobrutinib's reduced side effects, like atrial fibrillation, stem from its precise targeting of BTK with minimal 'binding promiscuity' to other kinases. This makes it a safer option for patients who have already been on a less-targeted BTK inhibitor.

While tarlatumab causes frequent low-grade side effects like Cytokine Release Syndrome, it results in significantly fewer Grade 3 or higher toxicities compared to standard second-line chemotherapy. This improved safety profile for severe events, particularly a reduction in hematologic toxicities, represents a major quality-of-life advantage for patients with relapsed small cell lung cancer.

Real-world data shows higher rates of cytokine release syndrome (CRS) with tarlatumab than trials reported, especially in sicker patients. Despite this, the drug's risk-benefit profile is often better than chemotherapy for poor-performance patients, sometimes leading to durable, life-changing outcomes where no other options exist.

While pan-RAS inhibitors like daraxoracib show broad efficacy irrespective of mutation, allele-specific agents may have fewer side effects and more predictable resistance patterns. This creates a clinical trade-off between immediate applicability and a more tailored, potentially better-tolerated long-term strategy.