Combined CRAFITY score and α-fetoprotein response predicts treatment outcomes in patients with unresectable hepatocellular carcinoma receiving anti-programmed death-1 blockade-based immunotherapy

Biomarkers for predicting the treatment efficacy of immune checkpoint inhibitor (ICI)-based therapy in patients with unresectable hepatocellular carcinoma (uHCC) are crucial. Previous studies demonstrated that C-reactive protein and alpha-fetoprotein (AFP) in immunotherapy (CRAFITY) score at baseline predicted treatment outcomes and that patients with uHCC with AFP response, defined as > 15% decline in AFP level within the initial 3 months of ICI-based therapy, had favorable outcomes when receiving ICI-based therapy. However, whether the combination of CRAFITY score and AFP response could be used to predict treatment efficacy of programmed death-1 (PD-1) blockade-based therapy in uHCC patients remains unclear. We retrospectively enrolled 110 consecutive uHCC patients from May 2017 to March 2022. The median ICI treatment duration was 2.85 (1.67-6.63) months, and 87 patients received combination therapies. The objective response and disease control rates were 21.8% and 46.4%, respectively. The duration of progression-free survival (PFS) and overall survival (OS) was 2.87 (2.16-3.58) months and 8.20 (4.23-12.17) months, respectively. We categorized patients into three groups based on CRAFITY score (2 vs 0/1) and AFP response: patients with a CRAFITY score of 0/1 and AFP response (Group 1), those with a CRAFITY score of 2 and no AFP response (group 3), and those who did not belong to Group 1 and 3 (i.e., Group 2). The combination of CRAFITY score and AFP response could predict disease control and could predict PFS compared with CRAFITY score or AFP response alone. The combination of CRAFITY score and AFP response was an independent predictor of OS (Group 2 vs Group 1, HR: 4.513, 95% CI 1.990-10.234; Group 3 vs Group 1, HR: 3.551, 95% CI 1.544-8.168). Our findings indicated that the combination of CRAFITY score and AFP response could predict disease control, PFS, and OS in uHCC patients receiving PD-1 blockade-based immunotherapy.     

Correlation between sex and efficacy of immune checkpoint inhibitors (PD‐1 and CTLA‐4 inhibitors)

Immune checkpoint inhibitors (ICIs) exert the antitumor efficacy depending on immune response, which is affected by sex difference, where both biological and sociological factors are involved. The role of sex in ICI trials has been overlooked. How sex correlates with ICI efficacy is incompletely understood. Clinical trials evaluating ICI versus other therapies in male and female patients were included. The hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS) and progression‐free survival (PFS) were used. Six thousand and ninety‐six patients from 11 trials were included. More improvement of OS was observed in males (HR, 0.62; 95% CI, 0.53–0.71; p < 0.001) treated with ICI versus controls than females (HR, 0.74; 95% CI, 0.65–0.84; p < 0.001). ICIs improved PFS more in males (HR, 0.57; 95% CI, 0.43–0.71; p < 0.001) than females (HR, 0.71; 95% CI, 0.52–0.91; p < 0.001). The sex difference had more effect on the overall survival in melanoma patients versus NSCLC patients. Overall survival of patients treated with CTLA‐4 inhibitor was more influenced by sex variable compared with PD‐1 inhibitors. A significant sex‐related efficacy difference was observed between female and male melanoma patients. Although male patients had longer OS and PFS than females when treated with ICIs versus controls, the difference was not significant. Sex difference should be more considered in future clinical trials, guidelines and clinical practice.     

原发性肝癌诊疗指南(2022年版)

  目的  探索经肝动脉化疗栓塞（transcatheter arterial chemoembolization, TACE）为基础的不同方案治疗不可切除肝细胞癌（unresectable hepatocellular carcinoma,uHCC）患者的疗效和安全性,以及TACE联合酪氨酸激酶抑制剂（tyrosine kinase inhibitors,TKIs）和免疫检査点抑制剂（immune checkpoint inhibitors,ICIs）的最佳时机。  方法  回顾性分析2016年4月至2021年12月期间在南方医科大学南方医院接受基于TACE治疗的555例uHCC患者资料。根据不同治疗方案分为：TACE组(n=317)、TACE+TKIs组(n=66)、TACE+ICIs组(n=33)、TACE+TKIs+ICIs组(n=139)。在亚组分析中,根据不同的联合时间将TACE+TKIs+ICIs组分为 “TACE前”和“TACE后”组。采用单因素、多因素Cox回归分析影响OS的预后因素。  结果  TACE+TKIs+ICIs组获得最长的OS(21.9个月,95% CI: 17.2～26.6,P=0.030)和PFS(8.3个月,95% CI: 7.3～9.3,P=0.004)。在亚组分析中,“TACE后”组比“TACE前”组获得更长的OS(26.8个月vs.19.2个月,P=0.011)。 TACE组、TACE+TKIs组、TACE+ICIs组、TACE+TKIs+ICIs组的ORR分别为32.8%、41.1%、42.4%、52.5%（P=0.001）,DCR分别为59.6%、71.2%、69.7%、82.7%（P<0.001）。不良反应事件与既往研究相似。Cox回归分析提示肿瘤数量、肝外转移及治疗方案是患者OS的独立预后因素（均P<0.05）。  结论  TKIs或ICIs可以提高TACE治疗uHCC患者的OS和PFS,TKIs+ICIs联合TACE生存获益更佳。首次TACE术后3个月内联合“TKIs+ICIs”治疗方案的总生存期获益更显著。     

Impacts of probiotics on the efficacies of immune checkpoint inhibitors with or without chemotherapy for patients with advanced non-small-cell lung cancer

The relationships between the therapeutic effects of immune checkpoint inhibitors (ICIs) and the intestinal flora have attracted increasing attention. However, the effects of oral probiotics on the efficacies of ICIs used to treat non-small-cell lung cancer (NSCLC) remain unclear. We investigated the effects of probiotics on the efficacies of ICIs in patients treated with and without chemotherapy. We investigated patients with advanced NSCLC on ICI monotherapy or combination ICI and chemotherapy using the Okayama Lung Cancer Study Group Immunotherapy Database (OLCSG-ID) and the Okayama Lung Cancer Study Group Immunochemotherapy Database (OLCSG-ICD). In total, 927 patients (482 on ICI monotherapy, 445 on an ICI + chemotherapy) were enrolled. Most were male, of good performance status, smokers, and without epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) mutations. Probiotics were administered to 19% of patients on ICI monotherapies and 17% of those on ICIs + chemotherapy. Of the former patients, progression-free survival (PFS) and overall survival (OS) were significantly better in the probiotics group (PFS 7.9 vs. 2.9 months, hazard ratio [HR] 0.54, p < .001; OS not attained vs. 13.1 months, HR 0.45, p < .001). Among patients receiving ICI and chemotherapy, there were no significant differences in PFS between those on probiotics and not but OS was significantly better in the probiotics group (PFS 8.8 vs. 8.6 months, HR 0.89, p = .43; OS not attained vs. 22.6 months, HR 0.61, p = .03). Patients on probiotics experienced better outcomes following ICI treatment.     

Combination of CRAFITY score with Alpha-fetoprotein response predicts a favorable outcome of atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma

Immune checkpoint inhibitors (ICIs) with atezolizumab plus bevacizumab are promising agents for unresectable hepatocellular carcinoma (HCC). We tried to guide the treatment based on recent developed CRAFITY score combining with on-treatment AFP response. Eighty-nine patients who received atezolizumab plus bevacizumab regardless of as a first-line therapy or not for unresectable HCC were enrolled for analyses. Radiologic evaluation was based on modified Response Evaluation Criteria in Solid Tumors (mRECIST). The objective response rate (ORR) and disease control rate (DCR) were 25.0% and 65.5%, respectively. Multivariate analysis showed that low CRAFITY score (AFP<100 ng/ml or CRP<10 mg/l) and satisfactory AFP response at 6 weeks (≥75% decrease or ≤10% increase from baseline) were independent factors determining good overall survival (OS) (hazard ratio [HR]=0.143, P=0.002 & HR=0.337, P=0.031), progression-free survival (PFS) (HR=0.419, P=0.022 & HR=0.429, P=0.025) and good responder (odds ratio [OR]=1.763, P=0.044 & OR=3.881, P=0.011). Patients were further divided into three classes by combination of CRAFITY score and AFP response at 6 weeks [The CAR (CRAFITY score and AFP-Response) classification)]: low CRAFITY score with satisfactory AFP response at 6 weeks (class I), either high CRAFITY score or unsatisfactory AFP response at 6 weeks (class II) and high CRAFITY score together with unsatisfactory AFP response at 6 weeks (class III). ORR was 35.0%, 18.2%, and 0% in class I, II and III patients, respectively (overall P=0.034). Patients in the class I had the best OS and PFS, followed by class II and class III (median OS: not reached vs. 11.1 vs. 4.3 months, log-rank P<0.001; median PFS: 7.9 vs. 6.6 vs. 2.6 months, log-rank P=0.001). Combination CRAFITY score and AFP response at 6 weeks with AUROC predicts OS and tumor response to be 0.809 and 0.798, respectively, better than either CRAFITY score (0.771 & 0.750) or AFP response at 6 weeks (0.725 & 0.680) alone. In conclusions, the CAR classification which combining CRAFITY score and AFP response at 6 weeks provides a practical guidance for atezolizumab plus bevacizumab therapy in unresectable HCC patients.     

Alpha-fetoprotein response at different time-points is associated with efficacy of nivolumab monotherapy for unresectable hepatocellular carcinoma

Nivolumab monotherapy has a modest objective response rate (ORR) in hepatocellular carcinoma (HCC). To overcome the lack of biomarkers that predict delayed alpha-fetoprotein (AFP) response beyond 4 weeks, we applied a novel 50-10 rule of AFP response for unresectable HCC patients under nivolumab monotherapy and proposed an algorithm based on on-treatment AFP reduction at different time-points. Ninety unresectable HCC patients who underwent nivolumab monotherapy in 2015-2019 were retrospectively recruited and divided into four classes: rapid AFP decrease of ≥ 50% of baseline at week 4 (class I), AFP changes within ± 50% of baseline at week 4 that later decreased to ≥ 10% of baseline (class II) or not (class III) at week 12, and rapid AFP increase of ≥ 50% of baseline at week 4 (class IV). ORR was 47.4%, 36.0%, 7.7%, and 5.0% in class I-IV patients, respectively. Rapid (class I) and delayed (class II) AFP responders had significantly higher ORR, overall survival (OS) and progression-free survival (PFS) than non-responders (class III and IV) (ORR: 40.9% vs. 6.5%, P<0.001; median OS: not reached vs. 9.6 months, log-rank P<0.001; median PFS: 9.6 vs. 2.8 months, log-rank P<0.001). In multivariate analysis, AFP response was an independent factor associated with good OS (hazard ratio [HR]=0.301, P=0.001) and PFS (HR=0.332, P<0.001). Moreover, AFP responders had higher ORR and better OS as well as PFS than non-responders, regardless of nivolumab as a first- or more than a second-line therapy (all P<0.05). In conclusion, the novel 50-10 rule of AFP response provides practical guidance for nivolumab monotherapy in unresectable HCC patients. However, this algorithm remains to be verified in a large prospective cohort.     

Efficacy of Immune Checkpoint Inhibitors Alone or in Combination With Chemotherapy in NSCLC Harboring ERBB2 Mutations

IntroductionIn contrast to other driver mutations, no targeted therapies have yet been approved in ERBB2-mutated NSCLC (HER2mu NSCLC). Nevertheless, several compounds have revealed promising early efficacy data, which need to be evaluated in the context of current standard approaches. Although data on the efficacy of immune checkpoint inhibitors (ICIs) in second or subsequent lines of treatment remain limited and conflicting, there are virtually no data on patient outcome under ICI/platinum-doublet combinations in the first-line setting.MethodsWe retrospectively evaluated outcomes of patients with HER2mu NSCLC treated with ICI alone or in combination with chemotherapy within the German National Network Genomic Medicine Lung Cancer consortium by means of overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).ResultsICI either in combination with chemotherapy or as monotherapy was applied as first-line treatment in 27 patients, whereas 34 received single-agent ICI in second or subsequent lines. Patient characteristics were in line with previously published data. In treatment-naive patients receiving ICI in combination with chemotherapy, the ORR, median PFS, and OS rate at 1 year were 52%, 6 months, and 88%, respectively. In second or subsequent lines, ICI monotherapy was associated with an ORR of 16%, a median PFS of 4 months, and a median OS of 10 months.ConclusionsICIs are effective as monotherapy and in combination with platinum-doublet chemotherapy. Therefore, ICI-based treatments may be found as the current standard of care and benchmark for targeted therapies in HER2mu NSCLC.     

The clinical value of combination of immune checkpoint inhibitors in cancer patients: A meta‐analysis of efficacy and safety

The use of immune checkpoint inhibitors (ICIs) in combination therapy is an emerging trend in tumor immunology. However, the value of combination immunotherapy remains controversial, because of the toxic effects induced by combination. The added benefit of each additional drug has not been assessed against the added toxicity. We searched for clinical trials that evaluated ICI monotherapies and combination therapies in lung cancer and melanoma patients. The overall response rate (ORR), grade 3/4 treatment‐related adverse event rate, overall survival (OS), and progression‐free survival (PFS) were extracted from the most recently published studies to determine the relative risk (RR), hazard ratios (HRs), and 95% confidence intervals (CIs). Seven randomized controlled trials and one open‐label study were identified (n = 3,097). Treatments included combinations of several ICIs, a combination of an ICI and dacarbazine, two combinations of an ICI, paclitaxel and carboplatin, and a combination of an ICI and gp100 vaccine. Higher ORR (RR: 1.51, 95% CI: 1.03–2.20, p = 0.034), OS (HR: 0.86, 95% CI: 0.78–0.95, p = 0.000), and PFS (HR: 0.93, 95% CI: 0.72–1.14, p = 0.000) values were observed in combination therapy than in monotherapy. In addition, the toxicity of combination ICI immunotherapy was higher (RR: 1.50, 95% CI: 1.03–2.19, p = 0.036) than that of monotherapy. This meta‐analysis showed that the addition of nivolumab to ipilimumab better benefits PFS and ORR. Adding sargramostim was associated with better OS and safety. The efficacy and safety of a nivolumab‐ipilimumab‐sargramostim combination should be investigated further.     

Multi-target angiogenesis inhibitor combined with PD-1 inhibitors may benefit advanced non-small cell lung cancer patients in late line after failure of EGFR-TKI therapy

Treatments for NSCLC patients with EGFR-TKI resistance are limited. Given that immunotherapy and antiangiogenic agents may have synergistic antitumor effects, we aimed to analyze the effect of multi-target angiogenesis inhibitor anlotinib and immune checkpoint inhibitors (ICIs) combination therapy in NSCLC patients who failed EGFR-TKI. The medical records of lung adenocarcinoma (LUAD) patients with EGFR-TKI resistance were reviewed. After EGFR-TKI resistance, patients who simultaneously received anlotinib and ICIs were enrolled in the observation group, and those who received platinum-pemetrexed chemotherapy were included in the control group. A total of 80 LUAD patients were reviewed and allocated to the anlotinib and ICIs combination therapy (n = 38) and chemotherapy (n = 42) groups. A re-biopsy was performed in all patients in the observation group before the administration of anlotinib and ICIs. The median follow-up was 15.63 months (95% CI: 12.19-19.08). Combination therapy exhibited better PFS (median PFS: 4.33 months [95% CI: 2.62-6.05] vs 3.60 months [95% CI: 2.48-4.73], P = .005), and better OS (median OS: 14.17 months [95% CI: 10.17-18.17] vs 9.00 months [95% CI: 6.92-11.08], P = .029) than chemotherapy. Most patients (73.7%) received combination therapy as fourth and later lines of therapy, with a median PFS of 4.03 months (95% CI: 2.05-6.02) and a median OS of 13.80 months (95% CI: 8.25-19.36). The disease control rate was 92.1%. Four patients discontinued the combination therapy due to adverse events, but the other adverse reactions were manageable and reversible. The combination of anlotinib and PD-1 inhibitors is a promising regimen for the late-line treatment of LUAD patients with EGFR-TKI resistance.     

Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation

Non-small cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation shows good and rapid response to EGFR tyrosine kinase inhibitors (TKIs). We prospectively evaluated the efficacy of EGFR TKI for metastatic brain tumors in NSCLC patients harboring EGFR mutation. This was an open-label, single-institution, phase II study. Patients diagnosed with NSCLC harboring EGFR mutation and measurable metastatic brain tumors were eligible. They received either erlotinib or gefitinib once a day. Out of total 28 patients enrolled, 23 patients (83%) showed a partial response (PR) and 3 patients (11%) did stable disease (SD), giving a disease control rate of 93%. Median progression free survival (PFS) and overall survival (OS) were 6.6 months (95% CI, 3.8-9.3 months) and 15.9 months (95% CI, 7.2-24.6 months), respectively. There was no difference in PFS and OS according to EGFR TKIs used. After discontinuation of the treatment, 14 patients (50%) received local therapy for metastatic brain tumors during their disease course, either whole brain radiotherapy or radiosurgery, giving a local therapy-free interval of 12.6 months (95% CI, 7.6-17.6 months). EGFR TKI therapy might be the treatment of choice for metastatic brain tumors in NSCLC patients harboring an activating EGFR mutation.     

Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: A systematic review and meta-analysis

BackgroundImmune checkpoint inhibitors (ICIs) rely on the presence of ongoing immune response to exert their antitumor effect. Little is known whether an age-related decline in immune function negatively influences antitumor response and in so doing diminishes the efficacy of ICIs in elderly subjects. We performed a meta-analysis to compare the efficacy of ICIs between younger and older patients.Patients and methodsPubMed and the ASCO databases were searched up to September 2015. We included randomized controlled trials (RCTs) of ICIs (ipilimumab, tremelimumab, nivolumab and pembrolizumab) reporting subgroup comparison of overall survival (OS) and/or progression-free survival (PFS) based on age cutoffs. The summary hazard ratio (HR) and 95% confidence interval (CI) were calculated.ResultsA total of 5265 patients from nine RCTs of ICI were included. When patients are dichotomized into younger and older groups with an age cut-off of 65–70 years, ICIs improved OS in both younger (HR, 0.75; 95% CI, 0.68–0.82) and older (HR, 0.73; 95% CI, 0.62–0.87) groups. An improvement in PFS was observed in younger (HR, 0.58; 95% CI, 0.40–0.84) and older (HR, 0.77; 95% CI, 0.58–1.01) patients. Subgroup analyses according to ICI and tumor type showed a consistent survival benefit in both younger and older groups except for the subgroup of older patients treated in 4 trials of anti-programmed cell death protein-1 (PD-1) monoclonal antibody (HR, 0.86; 95% CI, 0.41–1.83).ConclusionsA benefit in OS with ICIs was significant in both younger and older patients with a cut-off age of 65–70 years.     

40例TKI治疗失败的晚期NSCLC再服TKI疗效分析

  目的  EGFR-TKI治疗曾经有效的NSCLC患者, 在TKI治疗失败后再次选用TKI治疗仍有部分患者可再次临床获益。本文通过回顾性研究验征再服T KI的疗效, 并力图发现与再服TKI疗效有关的临床因素, 以及两次TKI治疗的间隔期是否影响再服TKI的疗效。  方法  2003年3月~2012年3月经治的40例初始TKI治疗失败后再服TKI的NSCLC患者, 分析其临床因素与再服TKI治疗PFS的相关性。  结果  全组患者自初始TKI治疗起中位生存期为29个月(95%CI:21.67~36.33), 自再次TKI治疗起中位生存期为13个月(95%CI:8.65~17.35)全组再服TKI治疗的中位PFS为2个月(1~2个月), 疾病控制率为50%。两次TKI治疗间歇期长于1、2、3个月组再服TKI治疗的PFS相比相应的不足1、2、3个月组无统计学差异(P>0.05), 间歇期进行化疗组再服TKI的中位PFS短于未化疗组, 但差异无统计学意义(1个月vs.4个月, P=0.650)。  结论  初始TKI治疗有效的患者, 再次使用TKI类药物仍有部分患者可达到临床获益再次使用TKI治疗的疗效与两次T KI治疗间的间歇期长短无关。      

非小细胞肺癌患者免疫检查点抑制剂相关性肺炎与免疫检查点抑制剂疗效相关性分析

目的：探讨免疫检查点抑制剂（ICI）治疗非小细胞肺癌（NSCLC）患者发生免疫检查点抑制剂相关性肺炎（CIP）的发生情况和免疫治疗疗效的关系，分析接受ICI 治疗的NSCLC患者的预后相关因素。方法：回顾性分析2020 年3月至2023 年3月在新疆医科大学附属肿瘤医院接受ICI 治疗145 例NSCLC患者的临床资料，将患者分为CIP 组和非CIP 组，随后将发生CIP 的患者分为轻度（1、2级）CIP 和重度（3、4级）CIP 两个亚组，通过Kaplan-Meier 法比较生存曲线，分析CIP 的发生及严重程度对于患者PFS 及OS的影响。通过单因素及多因素COX风险比例回归模型分析与PFS 和OS相关的预后因素。结果：145 例患者中有26例患者出现CIP，发生率为17.93％，重度CIP 发生率为3.45%。CIP 组患者PFS 明显长于非CIP 组患者（12.3 vs 7.6个月，P<0.05），CIP 组与非CIP 组的OS比较差异无统计学意义（16.2 vs 15.8个月，P>0.05)。亚组分析显示，轻度CIP 和重度CIP 相比，PFS（12.2vs 12.9 个月）及OS（16.1 vs 17.8 个月）均无统计学意义（均P>0.05）。多因素COX 回归分析显示，CIP[HR=0.55，95%CI（0.33,0.90），P=0.02]、免疫疗程>6 个[HR=0.51 ，95%CI（0.31, 0.85），P=0.01]是影响患者PFS 的有利预后因素，免疫疗程>6 个[HR=0.4，95%CI（0.18, 0.88），P=0.02]是影响OS的有利预后因素。结论：CIP 的发生率为17.93％，CIP 的发生与PFS 的延长密切相关。免疫疗程>6个是影响NSCLC患者PFS、OS的有利预后因素。     

NSCLC Immunotherapy Efficacy and Antibiotic Use: A Systematic Review and Meta-Analysis

Immune checkpoint inhibitors (ICIs) have dramatically improved patient outcomes in a variety of tumor types, but with variable efficacy. Recent research has suggested that antibiotic-induced disruption of the microbiota may impact ICI efficacy. We performed a systematic review and meta-analysis of studies that assessed the impact of antibiotic use on the survival of patients diagnosed with NSCLC and treated with ICI. We systematically searched Medline, the Cochrane Library, and major oncology conferences proceedings. Eligible studies mentioned hazard ratio or Kaplan–Meier curves for progression-free survival (PFS) or overall survival (OS) based on antibiotic exposure before or during ICI treatment. We identified 23 eligible studies. The impact of antibiotics was then evaluated in 2208 patients for PFS and 5560 for OS. For both PFS and OS meta-analyses, the between-study heterogeneity was high (Higgins and Thompson I² of 69% and 80%, respectively). The pooled hazard ratio was 1.47 (95% confidence interval [CI]: 1.13–1.90) for PFS and 1.69 (95% CI: 1.25–2.29) for OS revealing a significantly reduced survival in patients with NSCLC exposed to antibiotics. The median OS was reduced on average by 6.7 months (95% CI: 5.1–8.4) in the patients exposed to antibiotics. The effect seems to depend on the time window of exposure with stronger effects reported when the patients took antibiotics [−60 days; +60 days] around ICI initiation. In patients with NSCLC, the findings of the meta-analysis indicate that antibiotic use before or during treatment with ICI leads to a median OS decreased by more than 6 months. Specifically, exposure shortly before or after ICI initiation seems to be particularly detrimental, whereas antibiotic use later during disease course does not seem to alter survival. Because PFS and OS were difficult to compare between studies owing to heterogeneity and the multiple confounding factors identified, further studies are needed to strengthen the understanding of this phenomenon.     

Prognostic model in patients with metastatic urothelial carcinoma receiving immune checkpoint inhibitors after platinum failure

Immune checkpoint inhibitors (ICIs) have become a standard treatment for metastatic urothelial carcinoma (mUC) after platinum-based chemotherapy. However, the prognostic factors for patients with mUC receiving ICIs are not well established. We retrospectively collected clinical and laboratory data and reviewed the survival outcomes of patients with mUC who were treated with ICIs after platinum-based chemotherapy. We used univariate and multivariable Cox proportional hazard models to identify independent prognostic factors, and the concordance index (C-index) to evaluate the performance of the new prognostic model. In addition, bootstrap analysis was employed for internal validation of the prognostic model. A total of 224 patients were included in the study. With a median follow-up of 10.5 months (interquartile range, 5.1-17.4 months), median overall survival (OS) was 13.6 months (95% confidence interval [CI], 9.7-17.3 months). In multivariable analysis, independent prognostic factors predicting adverse OS were the presence of liver metastasis (LM), hypoalbuminemia, and neutrophil-lymphocyte ratio (NLR) >5. When patients were categorized into 3 risk groups, median OS was not reached (NR) (95% CI, 17.3-NR), 9.5 months (6.8-NR), and 2.9 months (2.3-4.4) for patients with a score of 0, 1, and 2+, respectively. The C-index for the new model was 0.763 (95% CI, 0.739-0.787). A novel prognostic model, including LM, hypoalbuminemia, and NLR, was developed and validated to estimate OS in patients with platinum-refractory disease on second- or subsequent-line ICI therapy. Further investigations, including prospective validation, are needed.     

Systemic Therapy in Patients With Metastatic Xp11.2 Translocation Renal Cell Carcinoma

BackgroundXp11.2 translocation renal cell carcinoma (Xp11.2 tRCC) is a unique subtype with poor prognosis, its response to systemic therapy is not fully understood, we evaluated the benefit of systemic therapy in these patients.Patients and MethodsBetween May 2006 and December 2019, patients diagnosed with Xp11.2 tRCC from Peking university cancer hospital were collected. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) distributions.ResultsMetastatic Xp11.2 tRCC was found in 45 patients. The median PFS and median OS was 7.4 months (4.5-8.8) and 17.9 months (12.4-24.4), respectively. First-line treatment mainly included sunitinib (n = 14), sorafenib (n = 15), axitinib (n = 6), and pazopanib (n = 5), and the median PFS of these regimens were 7.4 months, 5.4 months, 9.4 months, 8.9 months, respectively. Two patients who received Vascular endothelial growth factor receptor - tyrosine kinase inhibitor (VEGFR-TKI) plus immune checkpoint inhibitor (ICI) as first line therapy had a PFS of more than 16.6 months and more than 25.6 months, respectively. Twenty-four patients received subsequent therapies, which included VEGFR-TKI/ICI, VEGFR-TKI and mTOR inhibitor. The ORR and median PFS was 33% and 7.1 months, 7.7% and 4.3 months, 0% and 2.1 months for these treatments, respectively. The estimated median OS was 17.3 months (95% CI, 11.2 to not reached) in patients with TKI/ICI treatment and 11.0 months (95% CI, 6.1 to not reached) without TKI/ICI treatment in subsequent therapies (P = .04). Patients with serous cavity effusion or IMDC poor risk groups had significantly shorter median PFS and median OS.ConclusionMetastatic Xp11.2 tRCC is an aggressive disease. VEGFR-TKI agents appeared to demonstrate some efficacy, VEGFR-TKI /ICI combination might be a useful tool for the treatment of metastatic Xp11.2 tRCC.     

Immunotherapy Treatment Patterns and Outcomes Among ALK-Positive Patients With Non–Small-Cell Lung Cancer

IntroductionThe treatment landscape for anaplastic lymphoma kinase (ALK)-positive non–small-cell lung cancer (NSCLC) primarily involves ALK-directed tyrosine kinase inhibitors (TKIs). Although therapy with immune checkpoint inhibitors (ICIs) is a treatment option in NSCLC, the efficacy of ICI is inconclusive in ALK-positive NSCLC as a result of limited data. This retrospective real-world study sought to describe the characteristics of ALK-positive NSCLC patients treated with ICI and to assesses treatment outcomes in US oncology practices.Patients and MethodsThis analysis used the Flatiron Health electronic health record–derived deidentified database and included adult (18 years and older) ALK-positive advanced NSCLC patients with receipt of one or more ICIs after January 1, 2015. Median time to ICI discontinuation and real-world progression-free survival (rwPFS) were estimated by Kaplan-Meier methods.ResultsOf 83 patients with ALK-positive NSCLC treated with ICIs, 50.6% (n = 42) received ICI without a prior ALK TKI. Median time to ICI discontinuation was 2.17 months (95% confidence interval, 1.41, 3.32). The median rwPFS was 2.34 months (95% confidence interval, 1.55, 3.09); in patients who received an ICI without prior ALK TKI, it was 3.9 months, and in patients who received ICI therapy after an ALK TKI, it was 1.5 months.ConclusionsReal-world effectiveness (rwPFS) of ICIs in ALK-positive NSCLC patients, whether provided before or after TKIs, was limited, underscoring the relative lack of efficacy of ICI in this patient population, particularly compared to approved ALK TKIs.     

Association of the Time to Immune Checkpoint Inhibitor (ICI) Initiation and Outcomes With Second Line ICI in Patients With Advanced Urothelial Carcinoma

BackgroundEarly progression on first-line (1L) platinum-based therapy or between therapy lines may be a surrogate of more aggressive disease and poor outcomes in advanced urothelial carcinoma (aUC), but its prognostic role regarding immune checkpoint inhibitor (ICI) response and survival is unclear. We hypothesized that shorter time until start of second-line (2L) ICI would be associated with worse outcomes in aUC.Patients and MethodsWe performed a retrospective multi-institution cohort study in patients with aUC treated with 1L platinum-based chemotherapy, who received 2L ICI. Patients receiving switch maintenance ICI were excluded. We defined time to 2L ICI therapy as the time between the start of 1L platinum-based chemotherapy to the start of 2L ICI and categorized patients a priori into 1 of 3 groups: less than 3 months versus 3-6 months versus more than 6 months. We calculated overall response rate (ORR) with 2L ICI, progression-free survival (PFS) and overall survival (OS) from the start of 2L ICI. ORR was compared among the 3 groups using multivariable logistic regression, and PFS, OS using cox regression. Multivariable models were adjusted for known prognostic factors.ResultsWe included 215, 215, and 219 patients in the ORR, PFS, and OS analyses, respectively, after exclusions. ORR difference did not reach statistical significance between patients with less than 3 months versus 3-6 months versus more than 6 months to 2L ICI. However, PFS (HR 1.64; 95% CI 1.02-2.63) and OS (HR 1.77; 95% CI 1.10-2.84) was shorter among those with time to 2L ICI less than 3 months compared to those who initiated 2L ICI more than 6 months.ConclusionAmong patients with aUC treated with 2L ICI, time to 2L ICI less than 3 months was associated with lower, but not significantly different ORR, but shorter PFS and OS compared to 2L ICI more than 6 months. This highlights potential cross resistance mechanisms between ICI and platinum-based chemotherapy.     

Multiparametric MRI for early identification of therapeutic response in recurrent glioblastoma treated with immune checkpoint inhibitors

BackgroundPhysiologic changes quantified by diffusion and perfusion MRI have shown utility in predicting treatment response in glioblastoma (GBM) patients treated with cytotoxic therapies. We aimed to investigate whether quantitative changes in diffusion and perfusion after treatment by immune checkpoint inhibitors (ICIs) would determine 6-month progression-free survival (PFS6) in patients with recurrent GBM.MethodsInclusion criteria for this retrospective study were: (i) diagnosis of recurrent GBM treated with ICIs and (ii) availability of diffusion and perfusion in pre and post ICI MRI (iii) at ≥6 months follow-up from treatment. After co-registration, mean values of the relative apparent diffusion coefficient (rADC), K^trans (volume transfer constant), Ve (extravascular extracellular space volume) and Vp (plasma volume), and relative cerebral blood volume (rCBV) were calculated from a volume-of-interest of the enhancing tumor. Final assignment of stable/improved versus progressive disease was determined on 6-month follow-up using modified Response Assessment in Neuro-Oncology criteria.ResultsOut of 19 patients who met inclusion criteria and follow-up (mean ± SD: 7.8 ± 1.4 mo), 12 were determined to have tumor progression, while 7 had treatment response after 6 months of ICI treatment. Only interval change of rADC was suggestive of treatment response. Patients with treatment response (6/7: 86%) had interval increased rADC, while 11/12 (92%) with tumor progression had decreased rADC (P = 0.001). Interval change in rCBV, K^trans, Vp, and Ve were not indicative of treatment response within 6 months.ConclusionsIn patients with recurrent GBM, interval change in rADC is promising in assessing treatment response versus progression within the first 6 months following ICI treatment.Key Points• In recurrent GBM treated with ICIs, interval change in rADC suggests early treatment response.• Interval change in rADC can be used as an imaging biomarker to determine PFS6.• Interval change in MR perfusion and permeability measures do not suggest ICI treatment response.