Efficacy and safety analysis of immune checkpoint inhibitor rechallenge therapy in locally advanced and advanced non-small cell lung cancer: a retrospective study

Abstract

Background: Immune checkpoint inhibitors (ICIs) have dramatically changed the first-line treatment pattern of non-small cell lung cancer (NSCLC) without driver gene alterations. However, the optimal choice for second-line treatment after initial treatment with ICIs is unclear. This study aimed to clarify the efficacy and safety of ICI rechallenge therapy in locally advanced and advanced NSCLC.

Methods: We retrospectively analyzed the histories of 224 patients with locally advanced or advanced NSCLC treated with programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors alone or in combination with chemotherapy and/or antiangiogenic therapy in first-line treatment. Progression-free survival 2 (PFS2) was the time from the first defined progress disease (PD) to the second disease progression or death. Efficacy evaluation was performed directly in accordance with RECIST v1.1 criteria. Adverse events (AEs) were graded following the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Survival data were estimated using the Kaplan-Meier method or Cox survival regression model and compared using the log-rank test in overall cohort and other subgroups.

Results: There were no significant differences in objective response rate (ORR) and median PFS2 (mPFS2) between the ICI rechallenge group and non-rechallenge group (ORR: 10.3% vs. 15.3%, P=0.308; mPFS2: 5.33 vs. 4.40 months, P=0.715). And the ICI rechallenge group showed no new safety signals compared with non-rechallenge group. In ICI rechallenge group, patients resistant to first-line immunotherapy had a lower ORR and shorter PFS2 compared with those who responded to initial ICIs treatment (ORR: 7.0% vs. 17.6%, P=0.038; mPFS2: 3.68 vs. 5.91 months, P=0.014). No significant difference in mPFS2 was observed among different second-line treatment groups (P=0.362). Radiotherapy in second-line treatment and ICI rechallenge therapy were not the main factors affecting PFS2.

Conclusions: ICI rechallenge therapy beyond disease progression did not improve clinical outcomes in patients with NSCLC, but no new safety signals emerged. However, patients with favorable response to initial ICIs treatment still showed significant efficacy of subsequent ICI rechallenge therapy.

Keywords: ICI rechallenge therapy; Immune checkpoint inhibitors (ICIs); disease progression; non-small cell lung cancer (NSCLC); second-line treatment.

Figure 1

Overall clinical outcomes of the second-line treatment. (A) ORR and DCR of all patients. (B) PFS of all patients. n=224. ORR, objective response rate; DCR, disease control rate; PFS, progression-free survival; CI, confidence interval; m, months.

Figure 2

Clinical outcomes of the second-line treatment. (A) ORR of patients with or without radiotherapy and ORR of patients with different ECOG PS. (B) DCR of patients with or without radiotherapy and DCR of patients with different ECOG PS. (C) ORR of patients with or without ICI rechallenge. (D) DCR of patients with or without ICI rechallenge. (E) ORR of patients received ICI rechallenge treatment with different response to initial ICIs treatment. *, P<0.05. ORR, objective response rate; ECOG PS, Eastern Cooperative Oncology Group performance status; DCR, disease control rate; ICI, immune checkpoint inhibitor; resistant group, patients with PFS1 of less than 6 months; responder group, patients with PFS1 of longer than 6 months; PFS1, progression-free survival 1 (the time of initiation of PD-1/PD-L1 inhibitors alone or in combination with the chemotherapy and/or antiangiogenic drugs to first defined progress disease); PD-1, programmed death-1; PD-L1, programmed death-ligand 1.

Figure 3

Kaplan-Meier curves of the second-line treatment. (A) PFS of patients with different second-line treatment options. (B) PFS of patients with or without ICI rechallenge. (C) PFS of patients received ICI rechallenge treatment with different response to initial ICIs treatment. (D) PFS of patients with different ECOG PS. (E) PFS of patients with or without radiotherapy. PFS, progression-free survival; C + A, chemotherapy with antiangiogenic drugs; ICI, immune checkpoint inhibitor; ICIs + C, immune checkpoint inhibitors with chemotherapy; ICIs + C + A, immune checkpoint inhibitors with chemotherapy and antiangiogenic drugs; ICIs + A, immune checkpoint inhibitors with antiangiogenic drugs; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; resistant group, patients with PFS1 of less than 6 months; responder group, patients with PFS1 of longer than 6 months; PFS1, progression-free survival 1 (the time of initiation of PD-1/PD-L1 inhibitors alone or in combination with the chemotherapy and/or antiangiogenic drugs to first defined progress disease); PD-1, programmed death-1; PD-L1, programmed death-ligand 1.