Pembrolizumab has been shown to be effective as primary treatment in NSCLC patients with PD-L1 expression levels ≥50%. However, it is not effective in all patients. Therefore, the prediction of non-response is of crucial importance in determining the most appropriate treatment regimen.
Based on the results of this retrospective cohort study, pleural effusion, baseline CRP levels >1.0 mg/dL, and use of steroids prior to treatment tended to reduce the effectiveness of first-line monotherapy with pembrolizumab.
Firstly, we investigated the association between the use of steroids and the effectiveness of pembrolizumab. Taniguchi et al. reported that, in patients treated with nivolumab, ECOG PS score ≥2, use of steroids at baseline, and lactate dehydrogenase levels >240 IU/L were significantly associated with poor PFS [7]. Arbor et al. reported that use of corticosteroids (≥10 mg prednisone or equivalent) at baseline was associated with poorer outcome in patients with NSCLC, who were treated with PD-(L)1 blockade [8]. These studies included patients with any PD-L1 status and lines of therapy.
This study investigated only treatment-naive patients with high expression levels of PD-L1. Consistent with previous reports, treatment with the ICI tended to be less effective in patients who had received prior treatment with steroids.
Secondly, we investigated the association between CRP and response to ICI. Oya et al. reported that, among patients treated with nivolumab, the objective response rate in those with elevated CRP levels (≥1.0 mg/dL) was significantly worse than that reported in patients without elevated CRP levels (<1.0 mg/dL) [9]. In addition, Inoue et al. reported that, among patients treated with nivolumab, a CRP-to-albumin ratio >0.3 was associated with early death mainly due to PD and/or the occurrence of immune-related adverse events [10]. Although these are reports of nivolumab, in the present study, pembrolizumab (another PD-1 inhibitor) demonstrated similar findings.
Thirdly, to the best of our knowledge, few studies have assessed the therapeutic effects of ICIs in patients complicated with pleural effusion. Kang et al. reported the response rate in advanced NSCLC patients treated with PD1/PD-L1 inhibitors. The results showed that the response rate was markedly lower in patients with pleural or pericardial metastasis than that observed in those without pleural or pericardial metastasis [11]. Shibaki et al. reported that the presence of malignant pleural effusion was an independent negative predictor affecting PFS and OS, regardless of the presence of positive PD-L1 expression [12].
Furthermore, these studies showed that ICI monotherapy tended to be less effective in patients with pleural effusion. However, the mechanism responsible for the low efficacy of ICIs observed in patients with pleural effusion remains to be elucidated [11,12].
The KEYNOTE-189 study investigated patients with previously untreated metastatic non-squamous NSCLC without epidermal growth factor receptor or anaplastic lymphoma kinase mutations. In that study, the addition of pembrolizumab to standard chemotherapy (i.e., pemetrexed and a platinum-based drug) resulted in significantly longer OS and PFS versus chemotherapy alone [13].
Moreover, the KEYNOTE-407 study examined patients with previously untreated metastatic, squamous NSCLC. In that study, the addition of pembrolizumab to chemotherapy (i.e., carboplatin plus paclitaxel or nab-paclitaxel) resulted in significantly longer OS and PFS versus chemotherapy alone [14].
According to these results, the combination of platinum-based chemotherapy and pembrolizumab is recommended as first-line therapy for the treatment of NSCLC patients with ECOG PS score 0–1. However, the types of patients who may benefit the most from this combination therapy or monotherapy with pembrolizumab remain unknown.
In this study, among patients with PD-L1 >50% who received pembrolizumab as first-line therapy, PD was reported in those who received steroids and had pleural effusion at the beginning of the treatment. Therefore, increasing the response rate in these patients through the use of combination therapy may lead to favorable outcomes.
The present study was characterized by several limitations. Firstly, this was a retrospective study. Secondly, treatment effectiveness was evaluated based on the routine practice of each physician. Thirdly, pleural effusion was considered distant metastasis; however, examination of pleural effusion was not performed in all patients.