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.

Experienced oncologists are improving the tolerability of the mTOR inhibitor everolimus by starting at 5mg or 7.5mg daily, rather than the 10mg label dose, for many patients. This practical, off-label dose adjustment has made the drug a more manageable and viable option for combination therapy in the modern era.

To improve long-term tolerability of amivantamab, some experts advocate for a "marathon, not a sprint" approach. This involves aggressive dose holds or reductions at the earliest signs of toxicity, even low-grade, to prevent side effects from escalating and ensure patients can remain on effective therapy longer.

For patients with significant comorbidities like cardiovascular disease, proactively starting lenvatinib at a reduced dose (e.g., 14mg instead of 20mg) is a practical strategy to mitigate anticipated severe toxicities from the outset.

For patients intolerant to standard TKI starting doses, a "crescendo" approach can be highly effective. This involves starting at a very low dose (e.g., 200mg every other day) and slowly increasing it over several weeks. This gradual escalation allows the body to acclimate, enabling patients to eventually tolerate the full target dose without unacceptable toxicity.

Current solid TKI pills, especially capsules, make fine-tuned dose adjustments difficult. A liquid formulation would offer crucial flexibility, allowing for precise dosing (e.g., 350mg instead of 400mg) to manage the dose-response relationship. It would also be ideal for patients with feeding tubes or GI issues who cannot tolerate or swallow solid pills, preventing treatment delays.

Tyrosine kinase inhibitors (TKIs) have dramatically increased median overall survival for GIST patients from nine months to over seven years. Some patients have now been on therapy for over 20 years. This longevity transforms GIST into a chronic condition, making long-term side effect management and quality of life critical for maintaining treatment adherence and efficacy.

Clinicians recommend starting lenvatinib at the full 20mg dose rather than escalating from a lower dose. This ensures therapeutic levels are reached. They then dose-reduce aggressively as needed. Starting low risks falsely concluding the drug is ineffective if the patient tolerates a suboptimal dose without response.

Clinicians can confidently reduce the dose of Datopotamab-deruxtecan to manage toxicity. Phase 1 data demonstrates a compelling efficacy signal even at a 4 mg/kg dose level, reassuring oncologists that dose reduction is a viable strategy to maintain treatment without sacrificing benefit.