Navigating Immunotherapy Resistance: The Role of Cross-Line Strategies in Cancer Treatment

Background/Objectives: Cancer is the second leading cause of death globally, and resistance to immunotherapy requires new strategies. One promising approach is cross-line immunotherapy, defined as retreatment with the same or different immune checkpoint inhibitors after progression on prior immunotherapy. Understanding the efficacy and safety of this innovative treatment modality is critical for advancing cancer care. Methods: In this study, we evaluated outcomes of cross-line immunotherapy in a cohort of 105 patients with various malignant tumors at Beijing Friendship Hospital. The primary endpoints of the study included progression-free survival (PFS2) and overall survival (OS), measured from the initiation of cross-line immunotherapy. All patients received treatment regimens determined by their physicians. The study aimed to evaluate the efficacy of cross-line immunotherapy, with or without other therapies. Results: The study reported a median PFS2 of 6.9 months (95% CI: 4.7-8.1) and a median OS of 12.9 months (95% CI: 11.7-NA). The objective response rate (ORR) was 11%, while the disease control rate (DCR) was 77%. Although 35.2% of patients experienced grade 3 or higher immune-related adverse events, primarily hematological toxicities, no specific immune treatment-related hematological events were noted. Additionally, elevated D-dimer levels and hyponatremia emerged as prognostic factors associated with poorer outcomes, whereas hypertriglyceridemia correlated with enhanced survival. A nomogram developed for predicting PFS2 and OS demonstrated high discriminative capacity. Conclusions: These findings show that cross-line immunotherapy is safe and effective for patients with malignant tumors. It offers a viable option for patients who are progressing after initial treatments, which highlights the need for personalized strategies.