Following relapse after first-line therapy, sotorasib is employed as a second-line treatment for KRAS-mutated non–small cell lung cancer (NSCLC). However, resistance eventually emerges, potentially through activation of compensatory signaling pathways. Here, we evaluate the efficacy of combining sotorasib with EGFR, MEK, and CDK4/6 inhibitors in vivo using xenograft models of the H358 TNBC cell line. We have developed a mathematical model using ordinary differential equations to analyze and characterize drug response dynamics and resistance rates. To maintain parameter identifiability, we employ a tumor growth inhibition (TGI) modeling framework. Analysis based on the Bliss independence criterion indicates that these drug combinations exhibit synergistic interactions, suggesting that combination therapy can enhance the therapeutic potential of second-line regimens. We further extend our modeling approach to incorporate collateral resistance and collateral sensitivity under sequential drug administration. Our mathematical analysis demonstrates that treatment output is insensitive of treatment order in the absence of collateral effects. However, the presence of collateral sensitivity is associated with delayed progression and an increased likelihood of tumor extinction. Notably, we find that a less potent drug may warrant prolonged administration compared to a more potent drug if it confers a substantially higher degree of re-sensitization to the more potent drug. This theoretical finding emphasizes a counterintuitive role of a less potent yet sensitizing drug in combination therapy.