Virtual clinical trials: A tool for predicting patients who may benefit from treatment beyond progression with pembrolizumab in non-small cell lung cancer.

Enrolling patients in immunotherapy clinical trials is becoming increasingly competitive. Virtual clinical trials can help investigators answer key questions despite this. For example, pembrolizumab is the recommended first-line treatment for non-small cell lung cancer (NSCLC) with no driver alterations and a programmed death ligand 1 (PD-L1) Tumor Proportion Score ≥50%. Salvage therapies for relapsed/refractory patients are limited. Retrospective studies suggest that a subset of patients may benefit from pembrolizumab beyond progression; these results have not been validated in a prospective study. We constructed digital twins of patients and simulated clinical trials to predict the best salvage therapy after progressive disease (PD) on pembrolizumab. Response dynamics were evaluated at the lesion level to represent patients who experience systemic PD while individual lesions continue shrinking. With >25,000 radiographic lesion measurements from >500 patients, we simulated responses to pembrolizumab, chemotherapy, and PD on pembrolizumab followed by either pembrolizumab beyond progression or salvage chemotherapy. Switching all progressors to salvage chemotherapy was suboptimal. Virtual trials predicted progression-free survival (PFS) from pembrolizumab beyond progression to be comparable with salvage chemotherapy in patients whose PD was due to nontarget progression. A PFS-optimized regimen may improve disease control rates ≥15%. Pembrolizumab beyond progression may benefit a subset of patients with PD-L1-high, driver alteration-free NSCLC, but prospective studies are warranted.