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.

In mathematical models of eco-evolutionary dynamics with a quantitative trait, two species with different strategies can coexist only if they are separated by a valley or peak of the adaptive landscape. A community is ecologically and evolutionarily stable if each species’ trait sits on global, equal fitness peaks, forming a saturated ESS community. However, the adaptive landscape may allow communities with fewer (undersaturated) or more (hypersaturated) species than the ESS. Non-ESS communities at ecological equilibrium exhibit invasion windows of strategies that can successfully invade. Hypersaturated communities can arise through mutual invasibility where each non-ESS species’ strategy lies in another’s invasion window. Hypersaturation in ESS communities with more than 1 species remains poorly understood. We use the G-function approach to model niche coevolution and Darwinian dynamics in a Lotka–Volterra competition model. We confirm that up to 2 species can coexist in a hypersaturated community with a single-species ESS if the strategy is scalar-valued, or 3 species if the strategy is bivariate. We conjecture that at most n·s+1 species can form a hypersaturated community, where n is the number of ESS species at the strategy’s dimension s. For a scalar-valued 2-species ESS, 4 species coexist by “straddling” the would-be ESS traits. When our model has a 5-species ESS, we can get 7 or 8, but not 9 or 10, species coexisting in the hypersaturated community. In a bivariate model with a single-species ESS, an infinite number of 3-species hypersaturated communities can exist. We offer conjectures and discuss their relevance to ecosystems that may be non-ESS due to invasive species, climate change, and human-altered landscapes.