Treatment Duration With ICIs Impacts Prognosis in Patients With NSCLC

Immune checkpoint inhibitor (ICI) ± chemotherapy has been shown to prolong survival in patients with advanced non-small cell lung cancer (NSCLC). Some recent sponsor-initiated clinical trials used a fixed 24-month duration or continuous treatment until documented disease progression for investigational ICIs. Additionally, an exploratory analysis of CheckMate 153, which evaluated the impact of continuous versus 1-year fixed-duration ICI treatment protocol in previously treated patients with advanced NSCLC, showed that the continuous use of ICI beyond 1 year improves prognosis.

According to Haruki Kobayashi, MD, and colleagues, the optimum duration of ICI ± chemotherapy for this patient population remains unclear. The researchers retrospectively reviewed the medical records of 425 patients with advanced NSCLC who received ICI before August 31, 2019, at the Shizuoka Cancer Center in Japan to compare the effects of 2-year fixed or continuous ICI treatment on progression. Because patients with early discontinuation due to immune-related adverse events (AEs) were excluded, the researchers set the inclusion criteria as administration of >26 cycles of nivolumab therapy or >17 cycles of pembrolizumab or atezolizumab therapy within 2 years from treatment initiation, administration of >1 cycle of ICI treatment more than 21 months from treatment initiation, and no progressive disease (PD), excluding oligoprogression (defined for this study as progression at only one metastatic disease site after achieving stable disease following local radiation therapy or surgery). Patients with simultaneously progressing metastatic diseases were excluded. Results were reported in Clinical Oncology [2023;24(6):5498-5506].

The study end points included progression-free survival (PFS), overall survival (OS), time to treatment failure (TTF), and TTF-24, defined as TTF >24 months. PFS was calculated from the start of ICI treatment to the date of PD or death from any cause. OS was defined as the time from the start of ICI treatment to death. The Cox proportional hazards model was used to perform univariate and multivariate analyses of TTF-24.

The study included 425 patients with advanced NSCLC who were treated with ICIs during the study interval. The Dako PD-L1 immunohistochemistry (IHC) 22C3 (n=301) and 28-8 (n=2) pharmDx assays and the VENTANA PD-L1 IHC SP263 assay (n=1) were used to obtain a tumor proportion score (TPS) to measure PD-L1 expression. The most-used ICI ± chemotherapy regimen was pembrolizumab plus pemetrexed and cisplatin.

Of the 425 patients with advanced NSCLC, 41 received ICI ± chemotherapy for ³2 years (12 treated with ICI ± chemotherapy for 2 years and 29 treated for >2 years) The researchers observed that higher PD-L1 TPS in tumor cells correlated with a greater proportion of patients treated with ICI ± chemotherapy for ³2 years (3%, 9%, and 15% for PD-L1 TPS 0%, 1%-49%, and ³50%, respectively). No additional effect of adding platinum-based chemotherapy for 2 years was seen. The proportions of patients treated with ICI ± chemotherapy and ICI monotherapy were 9.3% and 9.7%, respectively.

The median PFS after ICI ± chemotherapy for the 41 patients was 50.8 months. The median OS after ICI therapy for patients treated with the ICI ± chemotherapy regimen was not reached. Of the 41 patients, the median TTF-24 was 48.3 months. In the univariate analysis, the TTF-24 was shorter for patients who underwent ICI ± chemotherapy for >2 years than those treated for a fixed 2-year duration (median TTF-24, 48.3 months vs not reached; P=.0541). The researchers suggested the causes could be increasing immune-related AEs, which led to discontinuation of ICI ± chemotherapy. The multivariate analysis detected no significant differences in TTF-24 between categorical variables, including the ICI treatment duration.

The researchers also found that no patient was administered steroids because of immune-related AEs during follow-up. Of the 12 patients administered ICI treatment for a fixed 2 years, one patient (8%) had stomatitis grade 3 as an immune-related AE following ICI readministration and discontinued ICI treatment. Two patients (17%) experienced oligoprogression recurrence less than 24 months after ICI ± chemotherapy. Of the 29 patients who received ICI treatment for more than 2 years, seven (24%) discontinued ICI ± chemotherapy because of an AE, including five patients with an immune-mediated-related AE (two with pneumonia grade 2, one with adrenal insufficiency grade 4, one with diarrhea grade 3, one with plural effusion grade 2 due to pleuritis, and three who required steroid treatment). Ten percent of patients had oligoprogression recurrence before 24 months from ICI ± chemotherapy initiation.

During the TTF-24 interval, there were no significant differences in the proportion of ICI treatment due to AEs between the two groups (P=.3984), but patients with ICI ± chemotherapy for >2 years experienced more AEs caused by ICI ± chemotherapy.

The authors acknowledged the potential bias caused by the physicians’ choice of the ICI treatment duration. However, they noted that consecutive patients were enrolled for analysis during the study, and there were no significant differences in these patients’ characteristics.

In conclusion, the researchers said, “The study results showed that ICI treatment >2 years did not significantly improve prognosis (longer TTF and/or survival) and increased the incidence of immune-related AEs. In the future, the time taken to discontinue individual ICI treatment should be assessed and ICI treatment could be decided to discontinue in 1 or 2 years after studying a biomarker using liquid biopsies.”