Clinicians are becoming more comfortable extrapolating positive adjuvant trial data from established targets like EGFR and ALK to other mutations like ROS1, even without specific Phase 3 evidence. This practice is particularly considered for patients in high-risk settings like locally advanced disease.
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.
Even with strong data supporting targeted agents, respecting a patient's decision to refuse them due to fears about side effects is a reasonable approach. Proceeding with standard chemotherapy and immunotherapy in such cases is a valid clinical choice that prioritizes shared decision-making and patient autonomy.
The list of oncogenic drivers where single-agent immunotherapy is ineffective should be expanded beyond EGFR and ALK to include HER2 mutations. Citing a study where the response rate to immunotherapy was zero percent for these patients, experts advise against using it in this specific molecular subtype.
The specific type of HER2 mutation significantly impacts TKI efficacy. YVMA exon 20 insertions show the highest response rates. Other TKD (tyrosine kinase domain) mutations perform moderately well, while non-TKD mutations respond poorly. This molecular nuance is critical for predicting treatment success and managing patient expectations.
The RET inhibitor selpercatinib can cause a rare side effect of chylous (milky) ascites or pleural effusion. This can be misread on scans as cancer progression, leading to premature discontinuation of an effective drug. Clinicians must tap the fluid before assuming treatment failure, as switching to pralsetinib may resolve the issue.
The ALENA trial, studying adjuvant alectinib for ALK-positive lung cancer, uniquely omitted platinum-based chemotherapy from its investigational arm. Its overwhelming success challenges the long-standing practice of using chemotherapy alongside targeted agents in the adjuvant setting and raises the question of whether it's necessary at all for this population.
The ALK inhibitor lorlatinib frequently causes neuropsychiatric side effects like mood and cognitive changes, often requiring medication. Patients are typically unaware of these shifts in their behavior. It is therefore crucial for clinicians to explicitly educate family members on what to watch for and to report any changes.