Clinical outcomes of non-small cell lung cancer patients with leptomeningeal metastases after immune checkpoint inhibitor treatments.

Leptomeningeal metastases (LM) occur in up to 5% of non-small cell lung cancer (NSCLC) patients and often develop after previous systemic treatments. In this article, we explored whether immune checkpoint inhibitors (ICIs) enhanced the dismal survival of patients with LM. Data on NSCLC patients with LM prescribed ICIs were collected at the Guangdong Lung Cancer Institute. Furthermore, relevant literature was reviewed. A total of 255 NSCLC patients diagnosed with LM were screened from January 2015 to March 2020 at our institute. Cases reported by literature were also included. Finally, 32 NSCLC patients received ICIs after LM diagnosis; their median age was 55 years. Druggable genes were detected in 37.5% of all patients. The ICI regimens included nivolumab (n = 21), pembrolizumab (n = 9), and atezolizumab (n = 2). Ultimately, 62.5% of patients evidenced neurological symptom controlled. Two patients exhibited both intracranial and extracranial complete tumour response; one patient showed both intracranial and extracranial partial response (PR), one patient indicated intracranial PR and a systemic PR, and one patient showed central nervous system PR without extracranial response reported. The median progression-free survival (PFS) in the single-agent subgroup was 2.1 months (95% confidence interval [CI]: 1.4-2.9 months), and the median overall survival (OS) was 4.0 months (95% CI: 0.1-13.3 months). In the combined subgroup, the median PFS and OS were 3.0 months (95% CI: 1.1-4.9 months) and 5.4 months (95% CI: 0.5-10.3 months), respectively. Three patients exhibited remarkable PFS of over 20 months: all patients had ICI single agent, received cranial radiotherapy before ICI prescription, and took ICIs as second-line therapy, and two patients were EGFR/ALK wild type. Multivariate analysis showed that a better Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score was associated with prolonged PFS (P = 0.04). No difference in survival was seen between monotherapy and combination therapy groups. NSCLC patients with LM may benefit from ICIs of both monotherapy and combination with other therapies, especially those with good ECOG-PS scores. Further work in this regard is required.

Zheng MM ，Tu HY ，Yang JJ ，Zhang XC ，Zhou Q ，Xu CR ，Jiang BY ，Yang XN ，Yang XR ，Deng JY ，Yang MY ，Xu BF ，Chen XM ，Li YS ，Wu YL ... -  《-》

Survival of patients with non-small cell lung cancer having leptomeningeal metastases treated with immune checkpoint inhibitors.

Patients with non-small cell lung cancer (NSCLC) experience leptomeningeal metastases (LM) in 3-9% of cases. Because overall survival (OS) and performance status are very poor, they are mostly excluded from clinical trials. Here, we evaluated survival of patients with NSCLC having LM treated with immune checkpoint inhibitors (ICIs). A prospectively collected list of patients with advanced NSCLC treated with ICIs between November 2012 and July 2018 in 7 European centres was merged. All patients with LM before ICI start were selected, data were retrospectively added and patients were classified according to the National Comprehensive Cancer Network (NCCN) LM prognostic classification (good/poor). Progression-free survival (PFS) and OS on ICIs were evaluated. Nineteen of 1288 (1.5%) patients had LM; 73.7% had synchronous brain metastases; 73.7% had neurological symptoms at the start of ICIs and 52.6% were in the NCCN LM good prognosis group. Programmed death ligand-1 (PD-L1) expression was known for 42.1% of patients (87.5% positive). Median follow-up was 13 months from the start of ICIs, and median (95% confidence interval [CI]) PFS on ICIs was 2.0 (1.8-2.2) months. Six-month PFS rate was 21.0% and was significantly higher in the NCCN good versus poor prognostic group: 40% vs 0% (p = 0.05). Twelve-month PFS rate was 0%. Median (95% CI) OS from the start of ICIs was 3.7 (0.9-6.6) months. Six-month OS rate was 36.8%, and 12-month OS rate was 21.1%; both were not statistically significantly different for the good versus poor NCCN prognostic group (p = 0.40 and p = 0.56, respectively). Some patients with NSCLC having LM do benefit from ICI treatment; specifically, those in the NCCN LM good prognosis group can obtain a long survival.

Hendriks LEL ，Bootsma G ，Mourlanette J ，Henon C ，Mezquita L ，Ferrara R ，Audigier-Valette C ，Mazieres J ，Lefebvre C ，Duchemann B ，Cousin S ，le Pechoux C ，Botticella A ，De Ruysscher D ，Dingemans AC ，Besse B ... -  《-》

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》

Clinical outcomes of leptomeningeal metastasis in patients with non-small cell lung cancer in the modern chemotherapy era.

We analyzed the patterns of treatment and clinical outcomes of leptomeningeal metastasis (LM) in patients with non-small cell lung cancer (NSCLC) in the modern chemotherapy era. We retrospectively reviewed the data of NSCLC patients who were diagnosed with LM between 2003 and 2009 at Seoul National University Bundang Hospital. Of the 50 patients with cytologically proven LM, 25 were male (50%), 14 (28%) had an ECOG performance status (PS) ≥ 3, and the median age was 62.5 years (range, 34-81 years). The patients were diagnosed with LM after a median of 10.4 months (range, 0-86.8 months) from the initial diagnosis of metastatic NSCLC. LM was present in 11 patients at the time of initial diagnosis. The median overall survival (OS) after the diagnosis of LM was 4.3 months (95% CI, 1.5-6.7 months). Forty-eight patients (96%) received intrathecal chemotherapy and the cytological response rate was 52%. The median survival was 5.5 months in cytological responders and 1.4 months in non-responders (p=0.075). The median OS in patients with an ECOG PS of 1-2 was longer than patients with an ECOG PS of 3-4 (5.5 vs. 0.7 months, p<0.001). Twenty-two patients (44%) received systemic cytotoxic chemotherapy or an EGFR tyrosine kinase inhibitor (TKI) after being diagnosed with LM. These patients had prolonged survival (11.5 vs. 1.4 months, p<0.001), and in 14 patients (28%) who received an EGFR TKI, the median OS was 19.2 months. In subgroup of patients with an ECOG PS of 1-2, those who received further systemic chemotherapy had improved survival compared to patients who did not receive further chemotherapy (11.5 vs. 2.1 months, p<0.001). NSCLC patients with LM exhibited diverse clinical outcomes rather than a uniformly poor prognosis. Systemic chemotherapy, especially EGFR TKIs in addition to intrathecal chemotherapy, might confer a survival benefit.

Park JH ，Kim YJ ，Lee JO ，Lee KW ，Kim JH ，Bang SM ，Chung JH ，Kim JS ，Lee JS ... -  《-》

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》