Evolutionary therapy (ET) applies principles of evolutionary biology to steer tumour dynamics and forestall or delay treatment resistance, typically guided by data-driven mathematical models. Our aim is to assess whether ET protocols, and specifically Zhang et al.’s protocol proposed for metastatic castrate-resistant prostate cancer, can be theoretically effective for fast-growing metastatic cancers such as stage IV non-small-cell lung cancer (NSCLC). Using longitudinal tumour-burden data from NSCLC patients treated with erlotinib, we systematically evaluate 26 two-population differential-equation models based on classical tumour-growth dynamics, with varying assumptions about density- and frequency-dependent interactions, pharmacokinetics, and treatment-induced death. Previous work by Yin et al. on the same dataset employed an exponential model that omitted density- and frequency-dependent interactions; although it provided a good fit to tumour-burden data, its structure would theoretically lead to poorer outcomes under ET protocols. In contrast, our analysis identifies the minimal model structure required to reproduce the resistance-driven regrowth observed in NSCLC, with the Gompertzian model featuring log-kill dynamics and both density- and frequency-dependent interactions providing the best fit. In this model, Zhang et al.’s protocol prolonged median time-to-progression to 42.3 months compared with 24.8 months under maximum tolerated dose. These results indicate that ET is theoretically a viable treatment strategy for NSCLC. This study offers a practical framework for assessing ET feasibility using clinical data and supports future clinical translation of ET in NSCLC.

Evolutionary cancer therapy (ECT) delays or forestalls the progression of metastatic cancer by adjusting treatment based on individual patient and disease characteristics. Clinical implementation of ECT can improve patient outcomes but faces technical and cultural challenges. To address those, we propose a systems approach incorporating systems modeling, problem structuring, and stakeholder engagement. This approach identifies and addresses barriers to implementation, ensuring the feasibility of ECT in clinical practice and enabling better metastatic cancer care.