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).

Adding obinutuzumab to acalabrutinib/venetoclax (triplet therapy) deepens responses but led to higher death rates in trials, partly due to COVID-19. This makes it a high-risk, high-reward strategy that experts reserve for younger, healthier patients with high-risk disease who prioritize coming off therapy.

Subtle differences between second-generation BTK inhibitors like zanubrutinib and acalabrutinib lie in their pharmacokinetics. Zanubrutinib's ability to maintain drug concentration above the IC50 for the entire dosing interval may provide a theoretical advantage in highly proliferative disease by inhibiting newly synthesized BTK.

Despite a major trial using rituximab in its pirtobrutinib-venetoclax combination, experts note a strong clinical preference for obinutuzumab as the more effective anti-CD20 antibody in CLL. This suggests that in real-world practice, clinicians may substitute obinutuzumab, adapting the trial regimen for perceived superior efficacy.

For younger CLL patients with IGVH unmutated status, the AVO triplet (acalabrutinib, venetoclax, obinutuzumab) is a strong choice. It offers a ~15% improvement in 3-year progression-free survival over a doublet, justifying the increased complexity and infection risk in patients who can tolerate it.

Clinical trial experience shows that delaying the administration of obinutuzumab in an Acalabrutinib-Venetoclax-Obinutuzumab (AVO) triplet regimen improves patient tolerability. This sequencing strategy allows clinicians to enhance response with the antibody later, if needed, while minimizing upfront side effects.

While the continuous BTK inhibitor zanubrutinib showed longer progression-free survival, this efficacy came with a significant safety trade-off. It led to a 47% rate of serious adverse events compared to 24% for the fixed-duration acalabrutinib-venetoclax combination in the indirect analysis.

An MD Anderson study showed that delaying the addition of obinutuzumab to an acalabrutinib-venetoclax regimen achieved similar deep remission rates (uMRD) as upfront administration. This sequencing strategy significantly reduced severe neutropenia (52% vs 12%) and infections, making the potent combination safer.