Efficacy Of ICI Research Articles

Novel Molecular Determinants of Response or Resistance to Immune Checkpoint Inhibitor Therapies in Melanoma.

BackgroundImmune checkpoint inhibitor (ICI) therapy dramatically prolongs melanoma survival. Currently, the identified ICI markers are sometimes ineffective. The objective of this study was to identify novel determinants of ICI efficacy.MethodsWe comprehensively curated pretreatment somatic mutational profiles and clinical information from 631 melanoma patients who received blockade therapy of immune checkpoints (i.e., CTLA-4, PD-1/PD-L1, or a combination). Significantly mutated genes (SMGs), mutational signatures, and potential molecular subtypes were determined. Their association with ICI responses was assessed simultaneously.ResultsWe identified 27 SMGs, including four novel SMGs (COL3A1, NRAS, NARS2, and DCC) that are associated with ICI efficacy and well-known driver genes. COL3A1 mutations were associated with improved ICI overall survival (hazard ratio (HR): 0.64, 95% CI: 0.45–0.91, p = 0.012), whereas immune resistance was observed in patients with NRAS mutations (HR: 1.42, 95% CI: 1.10–1.82, p = 0.006). The presence of the tobacco smoking-related signature was significantly correlated with inferior prognoses (HR: 1.42, 95% CI: 1.11–1.82, p = 0.005). In addition, the signature resembling that of alkylating agents and a newly discovered signature both exhibited extended prognoses (both HR < 1, p < 0.05). Based on the activities of the extracted 6 mutational signatures, we identified one immune subtype that was significantly associated with better ICI outcomes (HR: 0.44, 95% CI: 0.23–0.87, p = 0.017).ConclusionWe uncovered several novel SMGs and re-annotated mutational signatures that are linked to immunotherapy response or resistance. In addition, an immune subtype was found to exhibit favorable prognoses. Further studies are required to validate these findings.

Follicular Helper T-Cell-Based Classification of Endometrial Cancer Promotes Precise Checkpoint Immunotherapy and Provides Prognostic Stratification.

Despite the fact that management of EC is moving towards four TCGA-based molecular classifications, a pronounced variation in immune response among these molecular subtypes limits its clinical use. We aimed to investigate the determinant biomarker of ICI response in endometrial cancer (EC). We characterized transcriptome signatures associated with tumor immune microenvironment in EC. Two immune infiltration signatures were identified from the TCGA database (n = 520). The high- and low-infiltration clusters were compared for differences in patient clinical characteristics, genomic features, and immune cell transcription signatures for ICI prediction. A Lasso Cox regression model was applied to construct a prognostic gene signature. Time-dependent receiver operating characteristic curve, Kaplan–Meier curve, nomogram, and decision curve analyses were used to assess the prediction capacity. The efficacy of potential biomarker was validated by the Karolinska endometrial cancer cohort (n = 260). Immune signature profiling suggested that T follicular helper–like cells (Tfh) may be an important and favorable factor for EC; high Tfh infiltration showed potential for clinical use in the anti-PD-1 treatment. A Tfh Infiltration Risk Model (TIRM) established using eight genes was validated, and it outperformed the Immune Infiltration Risk Model. The TIRM had a stable prognostic value in combination with clinical risk factors and could be considered as a valuable tool in a clinical prediction model. We identified CRABP1 as an individual poor prognostic factor in EC. The Tfh-based classification distinguishes immune characteristics and predicts ICI efficacy. A nomogram based on Tfh-related risk score accurately predicted the prognosis of patients with EC, demonstrating superior performance to TCGA-based classification.

Low baseline plasma PCSK9 level is associated with good clinical outcomes of immune checkpoint inhibitors in advanced non-small cell lung cancer.

BackgroundProprotein convertase subtilisin/kexin type 9 (PCSK9) is a crucial protein involved in the metabolism of low‐density lipoprotein cholesterol. However, the role of plasma PCSK9 in predicting the efficacy of ICIs in advanced non‐small cell lung cancer (NSCLC) remains to be clarified.MethodsWe retrospectively reviewed the medical records of NSCLC patients who presented at Shanghai Pulmonary Hospital between April 2019 and June 2020. ELISA was conducted to detect the concentration of PCSK9. Clinical efficacy was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1).ResultsA total of 55 patients were enrolled in the study. The median progression‐free survival (PFS) following treatment with ICIs in all patients was 9.9 months. The optimal threshold of baseline plasma PCSK9 was 232.2 ng/ml. Patients with low baseline plasma PCSK9 had a longer PFS (NR vs. 7.37 months, p = 0.017, HR = 0.207, 95% CI: 0.086–0.498) and a better response (ORR 71.4% vs. 43.9%, p = 0.075, DCR 100% vs. 80.5%, p = 0.098) to ICIs. Younger patients (≤66 years) with a lower PCSK9 had a significantly longer PFS and higher treatment response than those with a high baseline level of PCSK9 (NR vs. 5.83 months, p = 0.021, HR = 0.134, 95% CI: 0.044–0.409; ORR 66.7% vs. 30.0%, p = 0.106, DCR 100% vs. 75%, p = 0.153). The situation was similar in patients who received first‐line therapy (NR vs. 8.97 months, p = 0.022, HR = 0.138, 95% CI: 0.047–0.400; ORR 63.6% vs. 46.4%, p = 0.480, DCR 100% vs. 89.3%, p = 0.545). Multivariate analysis showed that low PCSK9 concentration was independently associated with PFS (p = 0.032, HR = 0.201).ConclusionsLow baseline plasma PCSK9 level may predict good outcomes in patients with advanced NSCLC treated with ICIs.

Pathologic responses in oligometastatic NSCLC patients treated with neoadjuvant immune checkpoint blockade with and without chemotherapy followed by surgery

ObjectivesImmune checkpoint inhibitors (ICI) have significantly improved outcome of patients with advanced NSCLC and recently also showed benefit in early-stage disease. Patients with oligometastatic disease (OMD) harbor limited metastases, resectable primary tumors and derive benefit from treatment with multimodal locally ablative and systemic therapy approaches. Nothing is known about feasibility and efficacy of neoadjuvant ICI in this setting. Material and methodsWe here provide data from a multicenter retrospective study comprising 13 patients with NSCLC and OMD (≤3 distant metastases) from 5 university medical centers in Germany who have been treated with neoadjuvant ICI alone (n = 4) or in combination with chemotherapy (CT) (n = 9) prior to resection of the primary tumor. We analyzed complete (pCR) and major pathological remission (MPR) rates. ResultsThese data show that neoadjuvant immunotherapy applied mostly in combination with CT results in high rates of pCR and MPR (54 and 69%, respectively). Up to now, 85% of patients are free of progression with a median follow-up of 9 months (3–28 months). Single cell RNASeq analysis of tumor tissue from one patient treated with CT-ICI indicates a strong predominance of adaptive immune cell populations over a small minority of epithelial (tumor) cells. ConclusionNeoadjuvant ICI with or without CT is a promising therapeutic concept in patients with OMD.

Health-related quality of life in cancer patients treated with immune checkpoint inhibitors in randomised controlled trials: A systematic review and meta-analysis

BackgroundImmune checkpoint inhibitors (ICIs) have revolutionised clinical practice in oncology in the last years, leading to a survival benefit in several tumour types. To investigate whether these benefits are associated with improved quality of life, we conducted a systematic review and meta-analysis comparing patient-reported outcomes (PROs) between ICIs and standard chemotherapy (CT) in patients with advanced solid tumours. MethodsClinical trials comparing the efficacy of ICIs (either programmed death receptor-1 and programmed death-ligand 1 inhibitors or cytotoxic T-lymphocyte antigen 4 inhibitors, as single agent or in combination) versus CT were included. Trials evaluating treatment with ICIs plus CT versus CT alone were also included, whereas studies in which the control arm included other anticancer agents (such as targeted therapy and other ICIs) or placebo alone were excluded. The aim of our meta-analysis was to compare PROs in subjects treated with ICIs or ICIs plus CT (intervention) with those reported by patients receiving CT (control). The co-primary endpoints were time from baseline to first deterioration in PROs, defined as the time from baseline to the first clinically significant deterioration in PROs, and the changes in PROs from baseline to follow-up between ICI and CT treatment groups (PROSPERO registration number CRD42021247440). ResultsA total of 8341 patients from 17 randomised trials of ICI versus CT were included in the analysis. Treatment with ICI delayed clinical deterioration over standard CT in Global Health Status/QoL EORTC QLQ-C30 (hazard ratio [HR] 0.81; 95% confidence interval [CI], 0.74–0.89), and in both EQ-5D utility index (HR 0.65; 95% CI, 0.52–0.82) and EQ-5D visual analogue scale (VAS; HR 0.70; 95% CI, 0.61–0.80). The difference in mean change between the ICI-treated group and the CT-treated group was 5.82 (95% CI, 4.11–7.53) in favour of ICI. Similarly, in the EQ-5D, the mean change differences favoured treatment with ICIs in both Utility Index and VAS, with differences of 0.05 (95% CI, 0.03–0.07) and 5.41 (95% CI, 3.39–7.43), respectively. ConclusionsICIs are associated with higher levels of quality of life and longer time to clinical deterioration on several PROs scales compared with CT in different types of solid tumours.

Efficacy and safety of immune checkpoint inhibitors in colorectal cancer: a systematic review and meta-analysis

Background and objectiveImmune checkpoint inhibitor (ICI) therapies have shown promising prospects in colorectal cancer (CRC) immunotherapy; many clinical trials have been carried out. In this study, we sought to evaluate the efficacy and safety of ICI therapies in CRC by presenting a meta-analysis of relevant studies.MethodsDatabases including PubMed, Embase, Cochrane Library, and Web of Science were systematically searched for studies concerning the efficacy and safety of ICI in colorectal cancer. The reported odds ratio (OR) or weighted mean difference (WMD) with 95% confidence intervals (CIs) of overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), treatment-related adverse events (TRAEs), and TRAEs ≥ 3 in the included studies were analyzed by fixed effects/random effects models.ResultsThree studies involving 667 patients with colorectal cancer were included in our meta-analysis. No significant difference between the immune checkpoint inhibitor therapies and conventional therapies in OS (WMD = 0.73, 95% CI − 3.09, 4.54; p = 0.71), in ORR (OR = 1.54, 95% CI 0.98, 2.40; p = 0.06), and in DCR (OR = 0.97, 95% CI 0.36, 2.61; p = 0.95). The median PFS of the ICI therapy group was shorter than that of the conventional therapy group (WMD = − 0.10, 95% CI − 0.18, − 0.02; p = 0.02). At the same time, we also could not find a significant difference between the immune checkpoint inhibitor therapies and conventional therapies in TRAEs (OR = 1.56, 95% CI 0.11, 22.09; p = 0.74) and in TRAEs ≥ 3 (OR = 0.94, 95% CI 0.16, 5.65; p = 0.95).ConclusionImmune checkpoint inhibitor therapies could not improve all survival endpoints to advanced or metastatic colorectal cancer patients. Whether immune checkpoint inhibitors should be the first choice of therapies for colorectal cancer patients with undetermined microsatellite status or not able to determine microsatellite status needs more related studies to prove.

The role of ERBB4 mutations in the prognosis of advanced non-small cell lung cancer treated with immune checkpoint inhibitors

BackgroundImmune checkpoint inhibitors (ICIs) have witnessed the achievements of convincing clinical benefits that feature the significantly prolonged overall survival (OS) of patients suffering from advanced non-small cell lung cancer (NSCLC), according to reports recently. Sensitivity to immunotherapy is related to several biomarkers, such as PD-L1 expression, TMB level, MSI-H and MMR. However, a further investigation into the novel biomarkers of the prognosis on ICIs treatment is required. In addition, there is an urgent demand for the establishment of a systematic hazard model to assess the efficacy of ICIs therapy for advanced NSCLC patients.MethodsIn this study, the gene mutation and clinical data of NSCLC patients was obtained from the TCGA database, followed by the analysis of the detailed clinical information and mutational data relating to two advanced NSCLC cohorts receiving the ICIs treatment from the cBioPortal of Cancer Genomics. The Kaplan–Meier plot method was used to perform survival analyses, while selected variables were adopted to develop a systematic nomogram. The prognostic significance of ERBB4 in pan-cancer was analyzed by another cohort from the cBioPortal of Cancer Genomics.ResultsThe mutation frequencies of TP53 and ERBB4 were 54% and 8% in NSCLC, respectively. The mutual exclusive analysis in cBioPortal has indicated that ERBB4 does show co-occurencing mutations with TP53. Patients with ERBB4 mutations were confirmed to have better prognosis for ICIs treatment, compared to those seeing ERBB4 wild type (PFS: exact p = 0.017; OS: exact p < 0.01) and only TP53 mutations (OS: p = 0.021). The mutation status of ERBB4 and TP53 was tightly linked to DCB of ICIs treatment, PD-L1 expression, TMB value, and TIICs. Finally, a novel nomogram was built to evaluate the efficacy of ICIs therapy.ConclusionERBB4 mutations could serve as a predictive biomarker for the prognosis of ICIs treatment. The systematic nomogram was proven to have the great potential for evaluating the efficacy of ICIs therapy for advanced NSCLC patients.

FP10.01 The Efficacy of Immunotherapy in non-Small Cell Lung Cancer Patients with Uncommon Mutations: a Real World Research from Single Site

Patients with uncommon mutations such as BRAF, RET, MET, ROS1 or HER2-mutated NSCLC are usually treated with targeted therapies, and immune checkpoint inhibitors have become an important treatment option for non-small cell lung cancer (NSCLC)However, efficacy of immune checkpoint drugs (ICIs) in patients harboring uncommon mutations is limited. We aim to evaluate the efficacy of ICIs in those patients in real-world settings. Retrospective data were collected from NSCLC patients who were BRAF，RET, MET, ROS1 or HER2 mutation positive tested by next generation sequencing (NGS) and treated with immunotherapy The clinicopathological characteristics, overall response rate (ORR), disease control rate (DCR), and progression-free survival (PFS)of patients were analyzed. A total of 29 patients enrolled in the study, of which, median age was 59 years old, 34.5% were smokers and 79.3% were adenocarcinoma. 51.7% of the patients were treated with immunotherapy as the first line and 27.6% as second-line. Patients with BRAF, HER2, MET, RET, ROS1 mutation were 7 ,11 ,5 ,3 ,3 cases, respectively. Programmed cell death ligand 1(PD-L1) expression was assessed in 11 patients with 31.9% incidence rate for PD-L1 positive was and 20.7% for PD-L1≥50%. 24% of patients achieved partial responses with BRAF (n=2), HER2 (n=1), MET (n=2) and RET (n=2) and 58.6% (17/29) achieved stable disease (with total ORR 24.1%. The DCR was 82.8% and median PFS was 6.7 months (95% confidence interval,4.4-9.0). Patients with uncommon mutated NSCLC could benefit from ICIs. Since uncommon mutations are rare and efficacy would be different due to diverse mutation type, data from real word study would provide valuable evidence for clinical practice.

Viral Status and Efficacy of Immunotherapy in Hepatocellular Carcinoma: A Systematic Review With Meta-Analysis

Background and AimImmune checkpoint inhibitors (ICIs) have been widely used in hepatocellular carcinoma (HCC), while only a subset of patients experience clinical benefit. We aimed to investigate the effects of viral etiology on response to ICIs in HCC and depict the tumor immune microenvironment (TIME) of virally infected and uninfected HCC.MethodsA systematic search was conducted in PubMed, Web of Science, Embase, and the Cochrane central register of controlled trials up to August 2021. Clinical trials reporting the efficacy of ICIs in HCC were eligible. Baseline characteristics including first author, year of publication, National Clinical Trials (NCT) registry number, study region, sample sizes, interventions, line of treatment, and viral status were extracted. Meta-analysis was conducted to generate combined odds ratios (ORs) with 95% confidence intervals (CI) based on random or fixed effect model, depending on heterogeneity. Tumor immune microenvironment was depicted using ESTIMATE and CIBERSORT algorithm.ResultsEight studies involving 1,520 patients were included. Combined data suggested that there was no significant difference of objective response rate (ORR) between virally infected HCC and non-viral HCC patients [OR = 1.03 (95% CI, 0.77–1.37; I2 = 30.9%, pH = 0.152)]. Similarly, difference was not observed on ORR between HBV-HCC and HCV-HCC patients [OR = 0.74 (95% CI, 0.52–1.06; I2 = 7.4%, pH = 0.374)]. The infiltration of immune cells in the tumor microenvironment did not differ by etiology except for M0 macrophages, M2 macrophages, regulatory T cells, naive B cells, follicular helper T cells, activated dendritic cells, activated mast cells, and plasma cells. Despite differences in infiltration observed in specific cell types, the immune score and stromal score were generally comparable among etiology groups.ConclusionViral etiology may not be considered as the selection criteria for patients receiving ICIs in HCC, and viral status has little impact on TIME remodeling during HCC tumorigenesis.

1414P Helicobacter pylori infection is associated with clinical benefits of anti-PD-1/PD-L1-based therapies in advanced gastric/esophagogastric junction cancer: A real world multicenter observational study

Anti-PD-1/PD-L1-based therapy is the standard of care for patients with advanced gastric cancer or esophagogastric junction cancer. Helicobacter pylori (H. pylori, Hp) chronic infection in the stomach mucosa was the major cause of most gastric cancers, and there is a lack of data regarding the association between the efficacy of ICIs and H. pylori infection. We therefore perform a retrospective multicenter study to address this clinically relevant issue.

Comprehensive assessment of PD-L1 expression, tumor mutational burden and oncogenic driver alterations in non-small cell lung cancer patients treated with immune checkpoint inhibitors

ObjectivesImmune checkpoint inhibitors (ICIs) have proven to be effective treatment for lung cancer. However, a precise predictive immuno-oncology biomarker is still under development. We investigated the associations among PD-L1 expression, tumor mutational burden (TMB), and oncogenic driver alterations in advanced non-small cell lung cancer (NSCLC) patients treated with ICIs. Materials and methodsThis multicenter cohort study included 1017 lung cancer patients. PD-L1 expression using four IHC assays (22C3, 28-8, SP263, SP142), TMB by whole-exome sequencing and oncogenic driver alterations were analyzed comprehensively. Clinical characteristics, treatment and survival data were collected. ResultsThe results of 22C3 and 28–8 for PD-L1 expression showed acceptable concordance (k = 0.89; 95% confidence interval [CI], 0.87–0.92), and the clinical outcomes of ICIs classified according to PD-L1 expression by both assays were also approximately the same. There was slight concordance (k = 0.16; 95% CI, 0.11–0.22) between 22C3 and SP142, and high PD-L1 expression by SP142 was correspond to very high PD-L1 expressions by other assays. Patients with both high PD-L1 expression and high TMB showed a good response to ICIs with the response rate of 64% and median progression-free survival of 9.0 months despite of small population. Common EGFR or STK11 mutations showed a lower rate of high PD-L1 expression and a worse efficacy of ICIs and KRAS mutations had no negative impact on response to ICIs. ConclusionComprehensive assessment of PD-L1 expression, TMB, and oncogenic driver alterations would help to better predict the clinical outcomes of ICIs in NSCLC patients.

Abstract 1620: Efficacy and safety of ICIs in lung cancer patients with interstitial pneumonia

Abstract Background: ICIs has demonstrated efficacy against metastatic lung cancer. However, immune-related adverse events can occur, among which pneumonitis is relatively common. Lung cancer patients with interstitial pneumonia (IP) have a higher risk of pneumonitis associated with anticancer therapy. We hypothesized that the benefit of ICIs may outweigh the risks of pneumonitis in patients with lung cancer who have IP. We performed a pilot trial to evaluate the safety of ICIs in lung cancer patients with IP. Methods: Previously treated, inoperable NSCLC patients with IP were enrolled. Patients received anti-PD-1/L1 as monotherapy or in combination with other agents, respectively. Results: A total of 21 lung cancer patients were selected, including 15 (71.4%) male and 6 (28.6%) female with a median age of 62. None experienced drug related nonhematologic grade 3/4 or hematologic grade 4 adverse events in the 12 weeks following the initiation of ICIs treatment. Furthermore, none of the patients had pneumonitis of any grade. At the time of analysis, all patients were alive, and 11 had experienced a partial response. Conclusion: ICIs therapy may be feasible in lung cancer patients with IP. Citation Format: Yan Fu, Fuyu Gong. Efficacy and safety of ICIs in lung cancer patients with interstitial pneumonia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1620.

Abstract 1577: Caloric restriction mimetics as adjuvant to immune checkpoint inhibitors for treatment of melanoma

Abstract Immune checkpoint inhibitors (ICIs) have revolutionized melanoma therapy. Still, the 5-year survival for advanced melanoma is only 50%. This leads to two questions: what makes some tumors less responsive to ICIs, and what can be done to increase responsiveness? Prior research suggests that hypoxia in the tumor microenvironment (TME) decreases the efficacy of ICIs, and metformin, an antihyperglycemic and caloric restriction mimetic (CRM), is able to reverse this condition. We hypothesize that other CRMs will also increase responsiveness to ICIs through hypoxia, and potentially other mechanisms. We chose three CRMs to study alongside metformin: hydroxycitrate, resveratrol, and sulforaphane. To identify pathways and understand more about CRMs effect on tumor hypoxia, we performed a proteomics experiment on B16F10 murine melanoma cells treated with all four CRMs. Proteomics analysis was done with a tandem mass tag labeling. To determine effect of caloric restriction mimetics on immunotherapy efficacy, B16F10 cells will be injected subcutaneously in immunocompetent male and female C57BL/6J mice, separated into four groups: 1) no treatment control, 2) ICI therapy only, 3) CRM therapy only, 4) ICI + CRM combination. Our preliminary data shows that, like metformin, additional CRMs decrease oxidative phosphorylation in cancer cells. This supports the hypothesis that the other CRMs may function similarly to metformin in the TME. We started testing the effect of four CRMs on tumor growth and hypoxia in an animal model. Our ultimate goal is to improve responsiveness to immune checkpoint inhibitors in patients with metastatic melanoma. Citation Format: Lauren C. Morehead, Brian S. Koss, Katherine F. Wallis, Alan J. Tackett, Isabelle Racine Miousse. Caloric restriction mimetics as adjuvant to immune checkpoint inhibitors for treatment of melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1577.

Abstract 471: Reference materials for tumor mutational burden transcriptome profiling

Abstract Immune Checkpoint Inhibitor (ICI) therapies continue to revolutionize treatment of advanced malignancies. However, identification of individuals who respond to ICI treatment remains challenging. Along with programmed death ligand 1(PD-L1 aka CD274) expression and microsatellite instability, tumor mutational burden (TMB), defined as the number of nonsynonymous mutations per megabase of genome, has emerged as a promising biomarker for differentiating responders from non-responders, especially in non-small cell lung cancer. Although promising, TMB is not a perfect biomarker for ICI efficacy with some individuals responding conversely to expectations. The imperfection of TMB as a prognostic biomarker may result from it being a proxy measurement of potential neoantigens. Indeed, all mutations that contribute to TMB will not be expressed as neoantigens and not all neoantigens will illicit immune responses. In refining ICI response prediction, tumor abundance of nonsynonymous mutations has aided in neoantigen prediction. In order to begin development of quality reference materials for neoantigen prediction, we have characterized the transcriptomes of four tumor cell lines that were previously used to formulate TMB reference materials. Sequencing libraries were prepared with the TruSeq Stranded Total RNA with Illumina Ribo-Zero Plus rRNA Depletion Kit and Invitrogen Collibri Stranded RNA Library Prep Kit from Illumina with Collibri H/M/R rRNA Depletion Kit. The resultant transcriptome libraries were sequenced on an Illumina NextSeq2000 platform and relative transcript counts were determined. Broad ranges of expression were observed among transcripts containing nonsynonymous mutations in each of the tumor cell lines tested. These datasets will serve as benchmarks for others attempting to combine TMB and tumor abundance in predicting neoantigen potential. Citation Format: Matthew G. Butler, Yves Konigshofer, Jessica Dickens, Bharathi Anekella. Reference materials for tumor mutational burden transcriptome profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 471.

The Effect of Immune Checkpoint Inhibitors in Patients with Concomitant Advanced Melanoma and Chronic Lymphocytic Leukaemia

Immune checkpoint inhibitors (ICI's) have revolutionized the management of patients with advanced melanoma (AM). However, the data on the effectiveness of ICI's has been largely restricted to patients on clinical trials, thus excluding patients with second malignancies. Chronic Lymphocytic Leukemia (CLL) is the most prevalent adult leukemia and is associated immune dysregulation and a 3.8 fold increase in melanoma incidence. We report a multi-center, retrospective case-control study examining differences between patients who received checkpoint therapy in the context of the dual diagnoses of CLL and advanced melanoma (n = 20) compared to those with advanced melanoma alone (n = 154).Prognostic features for AM (including age, brain metastasis, visceral involvement, LDH and neutrophil count) were comparable between the two cohorts, however absolute lymphocyte count (ALC) was higher in CLL patients (p <0.0001) as anticipated. 3/20 of the CLL cohort experienced haematological autoimmune adverse events (AIHA, ITP, HLH), which necessitated cessation of ICI therapy; these events were not reported in the non-CLL cohort.There was not a significant difference between response rates to ICI's, 1-year survival or overall survival between CLL and non-CLL cohorts (Fig 1A). All recorded mortality (8/8) in the CLL cohort was attributable to AM progression or complications of ICI therapy rather than progressive CLL. The most significant predictor of survival in CLL cohort was prior exposure to fludarabine which showed a significantly shorter OS (median 2.3 vs 29.23 months, HR 7.406, p < 0.0001) than those who had not (Fig 1B).This cohort also offers a unique opportunity to observe the effects of ICI therapy on the progression of CLL. To our knowledge, this is the largest reported cohort of CLL patients treated with checkpoint inhibitors to date. The diagnosis of CLL pre-dated the diagnosis of AM in 18/20 cases. 5 cases had required prior treatment for CLL, while the remaining 15 cases were under observation alone. All 20 cases were Stage 0-1 according to the Rai classification at the time of melanoma diagnosis and no cases demonstrated a transformation to an aggressive subtype. 0/20 cases experienced a haematological response of their CLL while on ICI therapy and 6/20 cases progressed clinically either on the basis of tumour burden or absolute lymphocyte count within 12 months of ICI therapy (Fig 1C).This retrospective data demonstrates that ICI's have equivalent therapeutic efficacy in AM in patient with concurrent CLL This was unexpected as it was anticipated that the immune dysregulation associated with CLL would impair the ICI-mediated anti melanoma immunological response. The exception to this trend, was the poor efficacy of ICI's in patients with prior fludarabine exposure, presumably owing to the profound T cell depletion associated with this therapy. Additionally, ICI therapy alone appears ineffective in the management of CLL in keeping with recent phase II trial data. [Display omitted] DisclosuresGill:Janssen: Consultancy, Honoraria, Other: travel expenses.

Effectiveness and safety of immunotherapy in NSCLC patients with ECOG PS score ≥2 – Systematic review and meta-analysis

BackgroundImmune checkpoint inhibitors (ICIs) are standard of care in advanced non-small cell lung cancer (NSCLC), however their status in patients with poor performance status (PS) is poorly defined. We aimed to evaluate the efficacy and safety of ICIs in NSCLC patients with PS ≥ 2. MethodsWe conducted a systematic review and meta-analysis of interventional and observational studies, which reported efficacy and safety data on ICIs in PS ≥ 2 comparing to PS ≤ 1 NSCLC patients. Efficacy endpoints included: Objective Response Rate (ORR), Disease-Control Rate (DCR), Overall Survival (OS), Progression-Free Survival (PFS). Safety endpoint was the incidence of severe (grade≥3) Adverse Events (AE). Random-effects model was applied for meta-analysis. Heterogeneity was assessed using I2. The review is registered on PROSPERO (CRD42020162668). FindingsSixty-seven studies (n = 26,442 patients) were included. In PS ≥ 2 vs. PS ≤ 1 patients, the pooled odds ratios were: for ORR 0.46 (95 %CI: 0.39−0.54, I2:0 %); for DCR 0.39 (95 %CI: 0.33−0.48, I2:50 %) and for AEs 1.12 (95 %CI: 0.84–1.48, I2:39 %). The pooled hazard ratio for PFS was 2.17 (95 %CI: 1.96–2.39, I2:65 %) and for OS was 2.76 (95 %CI: 2.43–3.14, I2:76 %). The safety profile was comparable regardless of the PS status. InterpretationPatients with impaired PS status are, on average, twice less likely to achieve a response when exposed to ICIs when compared with representative PS ≤ 1 population. For lung cancer patients treated with ICIs, the impaired PS is not only prognostic, but also predictive for response, while the safety profile is not affected. Prospective randomized studies are indispensable to determine whether poor PS patients derive benefit from ICIs.

Association Between FSIP2 Mutation and an Improved Efficacy of Immune Checkpoint Inhibitors in Patients With Skin Cutaneous Melanoma.

BackgroundImmune checkpoint inhibitors (ICIs) have shown remarkable success in treating skin cutaneous melanoma (SKCM); however, the response to treatment varies greatly between patients. Considering that the efficacy of ICI treatment is influenced by many factors, we selected the Fibrosheath interacting protein 2 (FSIP2) gene and systematically analyzed its potential to predict the efficacy of ICI treatment.MethodsPatient data were collected from an ICI treatment cohort (n = 120) and a The Cancer Genome Atlas (TCGA)-SKCM cohort (n = 467). The data were divided into an FSIP2-mutant (MT) group and FSIP2-wild-type (WT) group according to FSIP2 mutation status. In this study, we analyzed the patients’ overall survival rate, tumor mutational burden (TMB), neoantigen load (NAL), copy number variation (CNV), cell infiltration data and immune-related genes. We used gene set enrichment analysis (GSEA) to delineate biological pathways and processes associated with the efficacy of immunotherapy.ResultsThe efficacy of ICI treatment of SKCM patients with FSIP2 mutation was significantly better than that of patients without FSIP2 mutation. The patients in the FSIP2-MT group had higher tumor immunogenicity and lower regulatory T cell (Treg) infiltration. Results of GSEA showed that pathways related to tumor progression (MAPK and FGFR), immunomodulation, and IL-2 synthesis inhibition were significantly downregulated in the FSIP2-MT group.ConclusionOur research suggests that the FSIP2 gene has the potential to predict the efficacy of ICI treatment. The high tumor immunogenicity and low Treg levels observed may be closely related to the fact that patients with FSIP2-MT can benefit from ICI treatment.

Combination of sintilimab, anlotinib and pegaspargase "sandwich" with radiotherapy in localized natural killer/T cell lymphoma: A multicenter, phase 2 study.

7537 Background: NK/T-cell lymphoma (NKTL) is a rare and distinct subtype NHL. Most newly diagnosed NKTL cases were localized-stage. For localized NKTL, RT alone is inadequate due to high systemic failure rate. Chemoradiation has been increasingly applied. However, current chemotherapy (CT) regimens have severe toxicity and infection, which reduce the completion of RT and patients’ medical compliance. Therefore, novel regimens with mild toxicity are needed. Sintilimab, a fully human anti-PD-1 monoclonal antibody, has showed encouraging antitumor efficacy in pts with r/r NKTL. Anlotinib, a multiple-targeted TKI that mainly blocks VEGF/VEGFR pathway, has been approved for several solid tumor types in china. Anti-angiogenesis therapy could improve efficacy of ICI in multiple tumor types. This multicenter, single-arm, phase 2 study aims to evaluate the efficacy and safety of sandwich chemoradiotion of sintilimab combined with anlotinib and pegaspargase (PEG-ASP) in newly diagnosed localized NKTL pts. Methods: Patients with pathologically confirmed previously untreated stage NKTL were enrolled. All enrolled patients received 3 cycles of sintilimab (200mg D1 ivdrip) combined with anlotinib (12mg po D1-14) and PEG-ASP (2500U/m2 D1) every 3 weeks followed by RT, then received additional 3 cycles of combination therapy as described above. The primary endpoint was overall response rate (ORR) by LUGANO 2014 criteria. Results: A total of 39 pts were enrolled, and 24 pts eligible for response evaluation (70.8% men; median age, 46 y [range 20-64]; 58.3% stage). According to PINK-E system, 8 pts (33.3%) were identified as intermediate risk group and 16 patients were low risk group. 23 of 24 patients completed protocol-specified therapeutic schemes, one patient discontinued the study after the second cycle due to disease progression. ORR was 95.8% (23/24, 95%CI: 76.9%-84.1%). Surprisingly, all the responded patients achieved CR, while 66.7% (16/24, 95%CI: 44.7%-83.6%) patients achieved CR after the second cycle. Median PFS and OS have not been reached. 1-year OS and PFS was 100% and 95.8%, respectively. All grade TRAEs occurred in 84.6% of all enrolled patients and 92.1% were grade 1-2. The most common TRAE was lymphocytopenia (9.9%). Of note, grade 3-4 hematological toxicity was reported in only one patient (4.2%). All AEs were resolved after symptomatic treatment, without systematic corticosteroid intervention. Conclusions: Sintilimab combined with anlotinib and PEG-ASP upfront and after radiotherapy was effective and could be well tolerated in localized NKTL, achieving promising CRR and rapid and long-term remission with mild toxicity. Further investigation of survival outcome is warranted. Clinical trial information: NCT03936452.

Retrospective world-wide registry on the efficacy of immune checkpoint inhibitors in alveolar soft part sarcoma: Updated results from sixty patients.

11564 Background: Alveolar soft-part sarcoma (ASPS) is a highly metastasizing ultra-rare sarcoma subtype, frequently affecting young adults. Conventional cytotoxic drugs are not effective in ASPS, but antiangiogenics demonstrated significant improvement in tumor burden reduction and PFS in the only ever conducted comparative trial. Immune check-point (PD-1/PD-L1) inhibitors (ICI) are emerging promising drugs in the therapy of ASPS, from small reported retrospective and prospective series. A world-wide registry has been set up with the aim of exploring the efficacy of ICI in ASPS. Methods: Data from adult patients (pts) diagnosed with ASPS and treated with PD- 1/PD-L1 inhibitors for advanced disease in expert sarcoma centers from Europe, Australia and US was retrospectively collected. IRB approval was obtained. Demographics, data related to treatments and outcome were considered. Radiologic assessment was based on RECIST 1.1. Progression-free (PFS) and overall survival (OS) were calculated with Kaplan-Meier method. An updated analysis of this series is presented here. Results: Sixty ASPS pts (27 female/33 male) with a median age at diagnosis of 25y (range 3-61) were registered. Primary tumor arose in limbs in 47 pts (78%) and 41 pts (68%) were metastatic at diagnosis. 52/60 pts (87%) had received previous systemic therapy (including chemotherapy in 19 pts and antiangiogenics in 47pts), with a median of one previous line (0-6). All pts received ICI for metastatic disease. Immunotherapy regimens consisted of monotherapy in 31 pts (52%) and combination in 29 pts (48%) (23 with an antiangiogenic agent). 29/60 pts (48%) received ICI within a clinical trial. Among the 52 evaluable pts, there was 1 complete response (CR) and 20 partial responses (PR) (ORR 40.4%). After a median follow-up of 21 months -mos- (range 4-59), 37/60 pts have progressed to ICI, with a median PFS of 13.4 mos (95% CI 10.1-16.7). Eleven pts received a subsequent line of ICI with a median PFS of 26 mos (95%CI 0-57). 16 pts have died, being the median OS from ICI initiation 38 mos (95% CI 33-43). The 12-mos and 24-mos OS rates were 94% and 70% respectively. Conclusions: This registry constitutes the largest available series of ASPS treated with immune check-point inhibitors. Our results suggest that treatment with ICI provide long-lasting disease control and prolonged OS in pts with advanced ASPS, an ultra-rare entity with limited active therapeutic options. The results on subsequent ICI lines suggest a lack of cross-resistance among different ICI therapies.

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

BackgroundImmune 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. MethodsWe 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. ResultsA 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. ConclusionsOur 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%.