Efficacy of immune checkpoint inhibitors in non-small cell lung cancer with uncommon histology: a propensity-score-matched analysis

Background Clinical efficacy of immune checkpoint inhibitors (ICIs) for non-small cell lung cancer (NSCLC) with uncommon histology (uNSCLC) is unknown. Methods Patients with NSCLC treated with ICI monotherapy between January 2014 and December 2018 in 10 Japanese hospitals were retrospectively evaluated. The patients were divided into: (1) NSCLC with common histology (cNSCLC), defined as adenocarcinoma and squamous cell carcinoma; and (2) uNSCLC, defined as incompatibility with morphological and immunohistochemical criteria for adenocarcinoma or squamous cell carcinoma. Propensity score matching was performed to balance the two groups. Results Among a total of 175 patients included, 44 with uNSCLC (10 pleomorphic carcinomas, 9 large cell neuroendocrine carcinomas, 2 large cell carcinomas, and 23 not otherwise specified) and 44 with matched cNSCLC (32 adenocarcinomas and 12 squamous cell carcinomas) were selected for analyses. Median progression-free survival (PFS) (4.4 months, 95% confidence interval [CI] 1.8–7.7 months) and overall survival (OS) (11.4 months, 95% CI 7.4–27.4 months) in the uNSCLC patients were not significantly different from those in matched cNSCLC patients (5.4 months, 95% CI 3.1–7.6 months, p = 0.761; and 14.1 months, 95% CI 10.6–29.6 months, p = 0.381). In multivariate analysis, Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0–1 and programmed death ligand-1 (PD-L1) expression were predictive for PFS and OS in uNSCLC. Conclusions ICIs had similar clinical efficacy for treatment of uNSCLC and cNSCLC. Good ECOG-PS and PD-L1 expression were predictive for efficacy of ICIs in uNSCLC. Supplementary Information The online version contains supplementary material available at 10.1186/s12890-021-01681-6.

Although adenocarcinoma and squamous cell carcinoma are the dominant tumor pathologies in NSCLC, 8-18% of patients have uncommon histology, such as pleomorphic carcinoma, large cell neuroendocrine carcinoma (LCNEC), large cell carcinoma and not otherwise specified (NOS) [10][11][12][13]. As well as distinct histological features, NSCLC with uncommon histology (uNSCLC) has different clinical courses and poor therapeutic responses and prognosis compared with NSCLC with common histology (cNSCLC), such as adenocarcinoma or squamous cell carcinoma. For example, pleomorphic carcinoma of the lung is reported to progress aggressively and to be refractory to chemotherapy, with an objective response rate (ORR) of 17% and progression-free survival (PFS) of 2 months [14]. Patients with NSCLC-NOS are reported to have a median PFS of 5.9 months after first-line platinum-based chemotherapy, which is shorter than 7.3 months in patients with adenocarcinoma [15]. Patients with LCNEC have better clinical benefit from small cell lung cancer (SCLC)-based chemotherapy, such as etoposide/platinum, compared with NSCLC-based chemotherapy, such as gemcitabine/platinum, pemetrexed/platinum and paclitaxel/platinum [16].
However, little is known about the therapeutic benefits of ICIs for uNSCLCs. Some clinical trials for ICIs in NSCLC have included uNSCLCs; however, the proportion of uNSCLCs in the total study populations was only 2-7% [4,5,17,18]. Given the distinct features and poor therapeutic responses to cytotoxic chemotherapy, it is unknown whether patients with uNSCLC have similar clinical benefits from ICIs as those with cNSCLC. In this multicenter retrospective study, we compared the efficacy of ICIs in patients with uNSCLC or cNSCLC using propensity-score-matched analysis. Additionally, we identified predictive factors for ICIs in patients with uNSCLC.

Study design
This was a multicenter, retrospective cohort study that was approved by the Institutional Review Board of each participating institution. Patient consent was waved because it was a retrospective study. This study was registered with the University Hospital Medical Information Network (ID: UMIN000037777).

Patients
We retrospectively reviewed medical records of patients who were diagnosed with advanced or recurrent NSCLC between January 2014 and December 2018 in 10 hospitals in Japan. Patients with pathologically diagnosed NSCLC who received ICI monotherapy were included. Any lines of treatment were allowed if ICI monotherapy was administered. The recurrent stage was defined as recurrence after radical surgery and applicable for systemic therapy, but not for local therapy. Patients who received combination therapy with platinum-based chemotherapy and ICIs or had histories of previous ICI therapy were excluded. The patients were divided into 2 groups on the basis of pathological diagnosis: (1) cNSCLC, patients with adenocarcinoma or squamous cell carcinoma; and (2) uNSCLC, those without morphological and immunohistochemical criteria for adenocarcinoma or squamous cell carcinoma, such as pleomorphic carcinoma, large cell carcinoma, LCNEC or NOS. Pathological diagnosis was performed morphologically and immunologically at each institution.

Data collection
Clinical data, including age, sex, smoking history, pathology, PD-L1 tumor proportion score (TPS), cancer staging, Eastern Cooperative Oncology Group performance status (ECOG-PS), line of treatment, and type of ICI were obtained from the patients' medical records. The responses to ICI were evaluated in accordance with the Response Evaluation Criteria in Solid Tumors (RESIST) version 1.1 [19]. Disease control rate (DCR) was defined as complete response (CR) plus partial response (PR) plus stable disease, and ORR as CR plus PR. PFS and OS were calculated from the date of first administration of ICI.

Propensity score matching
To balance the baseline of the two groups, 1:1 propensity score matching was performed. Propensity scores were calculated using a logistic regression model and included the following variables: age, sex, smoking status, cancer stage, PD-L1 TPS, line of ICI, and ECOG-PS.

Statistical analysis
Fisher's exact test and Mann-Whitney U test were used for categorical and continuous variables, respectively. Kaplan-Meier method and the log-rank tests were used for PFS and OS. Cox proportional hazards regression analysis was used to identify predictive variables for PFS and OS. Logistic regression analysis was used to identify predictive variables for ORR and DCR. Variables of p < 0.100 in univariate analyses, pathology (uNSCLC vs. cNSCLC), and PD-L1 expression were included for multivariate analyses. All values are expressed as median (range) or number (%). A p value < 0.05 was considered significant. All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria, version 2.13.0) [20].

Univariate and multivariate analyses for efficacy of ICIs
In univariate analysis, PD-L1 expression and first-line treatment were predictive for ORR, and ECOG-PS and PD-L1 expression were predictive for DCR (Additional file 1: Tables S1 and S2). In multivariate analysis, PD-L1 expression was predictive for ORR and DCR, and ECOG-PS was predictive for ORR (Additional file 1: Tables S1 and S2). In univariate Cox proportional hazard analysis, ever-smokers, ECOG-PS of 0-1, and PD-L1 expression (both TPS ≥ 50% and ≥ 1%) were significant predictive factors for PFS. In multivariate analysis, ECOG-PS of 0-1 and PD-L1 expression were independent predictive factors for PFS (Table 3). Ever-smokers and ECOG-PS of 0-1 were independent predictive factors for OS in multivariate analysis, while PD-L1 TPS ≥ 50% demonstrated a borderline predictive significance and TPS ≥ 1% did not (Table 4). Meanwhile, uNSCLC was not predictive for ORR, DCR, PFS or OS. Additionally, the presence of brain, liver, and bone metastases or line of ICI treatment was not predictive for ORR, DCR, PFS or OS. When limited to the patients with uNSCLC, ECOG-PS of 0-1 and PD-L1 expression were independent predictive factors for PFS and OS (Additional file 1: Tables S3 and S4).

Discussion
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][4][5][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 [21]. In 49 patients with pulmonary pleomorphic carcinoma who received ICI monotherapy, median PFS and OS were 7.2 and 22.2 months, respectively [22]. 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][15][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 [23]. 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 [24]. 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  [22]. 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.

Conclusions
ICIs had similar clinical efficacy for treatment of uNSCLC and cNSCLC. Additionally, good ECOG-PS and high PD-L1 expression were predictive for the efficacy of ICIs in uNSCLC.
Additional file 1. Table S1. Logistic regression analysis for objective response. Table S2. Logistic regression analysis for disease control rate. Table S3. Cox proportional hazard analysis for progression-free survival in uncommon non-small cell lung cancer. Table S4. Cox proportional hazard analysis for overall survival in uncommon non-small cell lung cancer. Table S5. Patient characteristics according to histological subtypes in uncommon non-small cell lung cancer. Table S6. Patient characteristics according to histological subtypes in matched common non-small cell lung cancer. Fig. S1. Kaplan-Meier curves for progression-free survival and overall survival by histology in uncommon non-small cell lung cancer group. Fig. S2. Kaplan-Meier curves for progression-free survival and overall survival by histology in matched common non-small cell lung cancer group.