Identification of non-small cell lung cancer (NSCLC) patients who benefit from treatment beyond progression with pembrolizumab from individual lesion response dynamics

BackgroundPembrolizumab is the recommended first-line treatment for non-small cell lung cancer (NSCLC) with no driver alterations and PD-L1 Tumor Proportion Score (TPS) [≥] 50%. Salvage therapies for patients who develop resistance in this setting are limited. Several retrospective studies have highlighted a subset of patients who benefit from pembrolizumab treatment beyond progression (TBP), but these results have yet to be validated in a rigorous prospective study. MethodsDue to the heterogeneity of within-patient responses to pembrolizumab, many patients can experience progressive disease while some of their lesions are still shrinking. We employed nonlinear mixed-effects modeling and virtual clinical trial simulations to evaluate the risk of unconditionally switching all progressors to salvage chemotherapy and to identify the subset of patients likely to benefit from pembrolizumab TBP. By using > 25,000 radiographic lesion diameter measurements from > 500 patients, we simulated individual lesion responses to pembrolizumab, chemotherapy, and pembrolizumab treatment failure followed by pembrolizumab TBP or salvage chemotherapy. We then assessed the benefit of pembrolizumab and chemotherapy in combination and explored a potential mechanism of intrapatient drug synergy called lesion-level independent action (LLIA). ResultsSwitching all progressors to salvage chemotherapy was suboptimal. Pembrolizumab TBP could extend progression-free survival (PFS) and control tumor burden more in nontarget progressors with fewer lesions prior to treatment initiation. Assuming LLIA but not patient-level independent action (PLIA) for combination therapy yielded longer PFS. ConclusionsPembrolizumab TBP may benefit a subset of patients with PD-L1-high, driver alteration-free NSCLC who experience nontarget progression, but prospective studies are warranted.