In the current study, we found that ICIs were efficacious for patients with uNSCLC and those with cNSCLC with comparable demographic characteristics after propensity score matching. Good ECOG-PS and high PD-L1 expression were significant predictive factors for efficacy of ICIs, regardless of tumor histology. Patients with uNSCLC are known to demonstrate insufficient response to chemotherapy. However, our data indicate that ICIs may provide therapeutic benefits even for patients with uNSCLC, especially those who have good ECOG-PS and high PD-L1 expression.
The median PFS of 4.4 months and median OS of 11.4 months after ICI monotherapy in the current study were comparable with those in previous studies of ICI monotherapy in patients who mostly had cNSCLC (PFS, 2.3–4.0 months and OS, 9.2–13.8 months) [3–6]. In a retrospective study of 21 patients with LCNEC who received ICI monotherapy, median PFS and OS were 4.2 and 11.8 months, respectively . In 49 patients with pulmonary pleomorphic carcinoma who received ICI monotherapy, median PFS and OS were 7.2 and 22.2 months, respectively . Given that conventional chemotherapies for NSCLC often provide limited survival benefits for lung cancer with uncommon histology, ICI monotherapy can be considered as a treatment option [14–16].
Tumor PD-L1 expression is a gold standard biomarker for the efficacy of ICIs in NSCLC; however, the level of tumor PD-L1 expression and its predictive ability varies among different tumor types. For example, only 13.5% of patients with gastric cancer had PD-L1 TPS ≥ 1% and the efficacy of nivolumab was not associated with PD-L1 expression . Furthermore, in renal cell carcinoma, 11% and 24% of patients had PD-L1 TPS ≥ 5% and ≥ 1%, respectively, and the efficacy of nivolumab was not associated with PD-L1 expression . Although uNSCLC has different pathological features from cNCSLC, tumor PD-L1 expression (TPS ≥ 1%) was observed in ~ 60% of the patients with uNSCLC and was also predictive for efficacy of ICIs.
Good ECOG-PS, a well-known predictive factor for the efficacy of ICIs in NSCLC, was also predictive in uNSCLC [11, 12, 25, 26]. Although precise mechanisms underlying ECOG-PS and the efficacy of ICIs are unknown, poor general condition may reflect deteriorated host immune status and lead to weakened effector T cells. When compared with cNSCLC, uNSCLC tends to progress rapidly and be resistant to standard chemotherapy [14, 15]. Therefore, it is suggested that patients with uNSCLC are predisposed toward poor general condition without adequate treatments. Approximately 20% of the patients with uNSCLC had poor ECOG-PS ≥ 2, compared with only 3% of those with unmatched cNSCLC. Our data suggest that early initiation of ICIs may be considered for patients with uNSCLC, especially if they have high PD-L1 expression and good ECOG-PS.
There were two main limitations to this study. First, differences in PD-L1 expression and the efficacy of ICIs among different histological subtypes of uNSCLC were unknown, because of the limited number of patients and 25% of the patients did not undergo PD-L1 testing. It is reported that 80% of patients with pleomorphic carcinoma had high PD-L1 expression and favorable clinical response to ICIs (median PFS 7.2 months and median OS 22.2 months) . Only 10–22% of patients with LCNEC had PD-L1 expression and had median PFS of 4.2 months and median OS of 11.8 months [21, 27, 28]. In the current study, the patients with pleomorphic carcinoma had the highest proportion of PD-L1 expression and the longest PFS, whereas those with LCNEC had the lowest PD-L1 and the worst PFS. It is possible that the clinical impact of PD-L1 expression and efficacy of ICIs differed owing to the histological subtypes of uNSCLC. Second, we only evaluated ICI monotherapy. Several single or combination therapeutic strategies for ICIs have emerged, such as cytotoxic T-lymphocyte antigen-4 antibody therapy, combination therapy with ICI and chemotherapy, and combinations of different ICI agents [17, 18, 29]. The clinical benefits of the novel ICIs for uNSCLC are unknown and should be investigated further.