Pan-Cancer Analysis Identifies Liver Metastases as Negative Predictive Factor for Immune Checkpoint Inhibitors Treatment Outcome.

This study aimed to investigate the predictive value of liver metastases (LM) in patients with various advanced cancers received immune-checkpoint inhibitors (ICIs). First, clinical and survival data from a published cohort of 1,661 patients who received ICIs therapy were downloaded and analyzed. Second, a retrospective review of 182 patients with advanced non-small-cell lung cancer (NSCLC) who received PD-1/PD-L1 monotherapy was identified. Third, a meta-analysis of published trials was performed to explore the impact of LM on the efficacy of anti-PD-1/PD-L1 based therapy in advanced lung cancers. Pan-cancer analysis revealed that patients with LM had significantly shorter overall survival (OS) than those without LM (10 vs. 20 months; P < 0.0001). Subgroup analysis showed that the presence of LM was associated with markedly shorter OS than those without LM in ICI monotherapy group (P < 0.0001), but it did not reach the statistical significance in ICI-based combination therapy (P = 0.0815). In NSCLC, the presence of LM was associated with significantly inferior treatment outcomes in both pan-cancer and real-world cohort. Interestingly, ICI-based monotherapy and combination therapy could simultaneously prolong progression-free survival (PFS) and OS than chemotherapy in patients without LM. However, ICI-based monotherapy could not prolong PFS than chemotherapy in patients with LM while ICI-based combination therapy could dramatically prolong both PFS and OS. Together, these findings suggested that the presence of LM was the negative predictive factor in cancer patients received ICIs monotherapy, especially in NSCLC. ICI-based combination therapy might overcome the intrinsic resistance of LM to ICIs while the optimal combinatorial strategies remain under further investigation.

Chen XJ ，Ren A ，Zheng L ，Zheng ED ，Jiang T ... -  《Frontiers in Immunology》

The effects of antibiotics on the efficacy of immune checkpoint inhibitors in patients with non-small-cell lung cancer differ based on PD-L1 expression.

Immune checkpoint inhibitors (ICIs) are essential for treatment of various malignancies, including non-small-cell lung cancer (NSCLC). Recently, several studies have shown that the gut microbiome plays an important role in ICI treatment of solid cancers, and antibiotic (ATB) use had a negative impact on the outcomes of ICI treatment via dysbiosis in the gut. However, whether this is applicable to NSCLC remains unclear. The impact of ATBs based on PD-L1 expression also remains unclear. We retrospectively reviewed the medical records of patients with NSCLC who received ICI monotherapy (anti-PD-1 or anti-PD-L1 antibody) at nine institutions from December 2015 to May 2018. Outcomes with use of ATBs during the 2 months before or a month after initiation of ICI treatment, including progression-free survival (PFS) and overall survival (OS), were investigated using the Kaplan-Meier method. Multivariate analysis was also conducted using a Cox proportional hazards model. A total of 531 patients were included in this study, among whom 98 (18.5%) received ATBs before or after ICI treatment. ATB use was significantly associated with a shorter median OS (11.7 months in the ATB group vs. 16.1 months in the non-ATB group; p = 0.028), whereas the difference in PFS was not significant (3.5 months in both the groups; p = 0.287). We next investigated the association based on PD-L1 expression in the 265 patients for whom PD-L1 expression was determined. There was no significant difference in the median OS or PFS between patients with NSCLC and PD-L1 expression <50% receiving ATBs and those not receiving ATBs (PFS: 3.3 vs. 2.8 months, p = 0.88; OS: 9.5 vs. 17.1 months, p = 0.24). Conversely, patients with NSCLC and PD-L1 expression ≥50% receiving ATBs showed significantly shorter median PFS and OS (PFS: 4.2 vs. 9.4 months, p = 0.012; OS: 11.9 vs. 28.4 months, p = 0.011). The impact of ATBs in patients with NSCLC and PD-L1 expression ≥50% was more significant than that in the entire cohort. Our results indicate that the impact of ATB use on the efficacy of ICIs differed based on PD-L1 expression in patients with advanced NSCLC. A negative impact of ATB use was found in patients with NSCLC and PD-L1 expression ≥50% but not in those with PD-L1 expression <50%.

Ochi N ，Ichihara E ，Takigawa N ，Harada D ，Inoue K ，Shibayama T ，Hosokawa S ，Kishino D ，Harita S ，Oda N ，Hara N ，Hotta K ，Maeda Y ，Kiura K ... -  《-》

Comparison of Efficacy and Safety of Single and Double Immune Checkpoint Inhibitor-Based First-Line Treatments for Advanced Driver-Gene Wild-Type Non-Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis.

Immune checkpoint inhibitors (ICIs) have improved survival for advanced wild-type non-small cell lung cancer (NSCLC) significantly, but few studies compared single ICI (SICI)-based treatments and double ICIs (DICI)-based treatments. We summarized the general efficacy of ICI-related treatments, compared the efficacy and safety of SICI-based [programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) or cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors ± chemotherapy (CT)] and DICI-based (PD-1/PD-L1 inhibitors+CTLA-4 inhibitors ± chemotherapy) treatments vs. CT in the first-line treatment. We included phase II/III randomized controlled trials (RCTs), including patients with histologically confirmed stage IIIB-IV driver-gene wild-type NSCLC who received first-line ICI-related therapy in at least one arm. PubMed, Embase, and Cochrane Library were searched from January 1, 2005, to December 31, 2020. This network meta-analysis was performed in a Bayesian framework using GEMTC and JAGS package in R.3.6.1. The research was registered with PROSPERO (CRD42020184534). Twenty RCTs were involved, including 13,032 patients and 17 treatment regimens. The results showed that ICI-based therapies could provide a pooled median overall survival (mOS) (POS) of 15.79 (95% CI: 14.85-16.73) months, and there were no significant differences in OS, progression-free survival (PFS), objective response rate (ORR), and grade 3 or higher adverse events (≥3AEs) between DICI-based treatments (POS: 14.81, 12.11-17.52 months) and SICI-based treatments (POS: 16.17, 14.59-17.74 months) in overall patients. However, DICI-based treatments had significantly prolonged the OS over SICI-based treatments in squamous and PD-L1 <1% subgroups. The ranking of OS benefit by Bayesian surface under the cumulative ranking curve (SUCRA) spectrum showed that DICI+chemotherapy ranked first for overall population and subgroups including squamous, non-squamous, any level of PD-L1 expression, smoking, male, Eastern Cooperative Oncology Group performance status (ECOG PS) = 0/1, age < 65/≥65 while SICI+CT for low tumor mutation burden (TMB), non-smoking, and female subgroups, and DICI for high TMB subgroups. In the first-line therapy for advanced wild-type NSCLC, both SICI- and DICI-based treatments could bring significant overall advantages over chemotherapy, with comparable outcomes of efficacy and ≥3AEs. DICI-based treatments were more effective than SICI-based treatments in squamous and PD-L1 <1% subgroups. For most populations, DICI+chemotherapy could be the best choice with a survival benefit, while SICI+chemotherapy has established its position actually. [PROSPERO], identifier [CRD42020184534].

Xu Q ，Zhang X ，Huang M ，Dai X ，Gao J ，Li S ，Sheng L ，Huang K ，Wang J ，Liu L ... -  《Frontiers in Immunology》

The landscape of immune checkpoint inhibitor plus chemotherapy versus immunotherapy for advanced non-small-cell lung cancer: A systematic review and meta-analysis.

Lung cancer is the leading cause of cancer-related deaths worldwide and the prognosis remains poor. The recent introduction of the immune checkpoint inhibitor (ICI), or plus chemotherapy, both resulted in the survival benefit for patients with advanced non-small-cell lung cancer (NSCLC), but it remains unanswered which is superior. The current study aimed to estimate the comparative efficacy and safety of ICI-chemotherapy versus ICI-monotherapy in advanced NSCLC. Studies were identified by searching PubMed, Embase, and Cochrane library. The randomized controlled trials (RCTs) that ICI monotherapy or ICI plus chemotherapy compared with chemotherapy in NSCLC were included with available primary endpoints of progression-free survival (PFS), overall survival (OS), objective response rate, or treatment-related adverse events. A fixed-effect or random-effects model was adopted depending on between-study heterogeneity. A total of 20 RCTs involving 12,025 patients with NSCLC were included. Both ICI-monotherapy and ICI-chemotherapy resulted in significantly prolonged survival compared to chemotherapy and the former led to significantly longer PFS. The magnitude of survival benefits appeared to be greatest among those treated with pembrolizumab plus platinum-based chemotherapy (OS, 0.56; PFS, 0.54). Additionally, OS and PFS advantages of ICI therapies were observed in patients with NSCLC with low or high programmed cell death 1 ligand 1 (PD-L1) expression level, but not in intermediate PD-L1 TPS. Pembrolizumab plus platinum-based chemotherapy was recommended as the optimal first-line therapy for advanced patients with NSCLC. Additionally, PD-L1 alone is not recommended as an adequate molecular biomarker to identify eligible patients for routine clinical practice in immunotherapy.

Wang C ，Qiao W ，Jiang Y ，Zhu M ，Shao J ，Wang T ，Liu D ，Li W ... -  《-》

Switching administration of anti-PD-1 and anti-PD-L1 antibodies as immune checkpoint inhibitor rechallenge in individuals with advanced non-small cell lung cancer: Case series and literature review.

Based on several phase III studies, immune checkpoint inhibitors (ICIs) are essential and promising drugs for the treatment of non-small cell lung cancer (NSCLC). However, in patients previously treated with ICI, the efficacy and safety of rechallenging the same or another type of ICI inhibitor remain unclear. Moreover, clinical data about the efficacy of switching the administration of anti-programmed death-1 (PD-1) antibodies (e.g. nivolumab, pembrolizumab) and anti-programmed death-ligand 1 (PD-L1) antibodies (e.g. atezolizumab) as ICI rechallenge are limited. Thus, the current study aimed to evaluate the efficacy and safety of such treatment strategy in NSCLC patients. We retrospectively reviewed the medical records of 17 patients with advanced or recurrent NSCLC who received both anti-PD-1 and anti-PD-L1 antibodies during their clinical courses. Among the 17 patients, one (5.9%) and nine (52.9%) achieved partial response and stable disease, respectively, after ICI rechallenge. The median progression-free survival of ICI rechallenge in these patients was 4.0 (range: 0.4-8.0) months, and the median overall survival from the start of the initial ICI was 31.0 (range: 7.6-46.8) months. Of the 10 patients who developed immune-related adverse events (irAEs) during the first ICI treatment, five presented with these events after the readministration of ICI. Among them, four experienced relapsed irAEs and two patients had pneumonitis, which is a grade 3 or higher irAE. Almost all irAEs during the rechallenge treatment were manageable. Switching the administration of anti-PD-1 and anti-PD-L1 antibodies as ICI rechallenge could be a treatment option for some NSCLC patients. • Significant findings of the study In this study, switching the administration of anti-PD-1 and anti-PD-L1 antibodies as ICI rechallenge could be an effective and safe treatment option for some patients with advanced or recurrent NSCLC. • What this study adds Switching the administration of ICI may increase the efficacy of readministration. However, the mechanism is unknown. Thus, further accumulation of cases is required, and extensive investigations must be conducted to elucidate the mechanism and benefits of such treatment.

Kitagawa S ，Hakozaki T ，Kitadai R ，Hosomi Y ... -  《-》