Immune Checkpoint Inhibitors In Patients Research Articles

New Opportunities for Minimizing Toxicity in Rectal Cancer Management.

Advances in multimodal management of locally advanced rectal cancer (LARC), consisting of preoperative chemotherapy and/or radiotherapy followed by surgery with or without adjuvant chemotherapy, have improved local disease control and patient survival but are associated with significant risk for acute and long-term morbidity. Recently published trials, evaluating treatment dose intensification via the addition of preoperative induction or consolidation chemotherapy (total neoadjuvant therapy [TNT]), have demonstrated improved tumor response rates while maintaining acceptable toxicity. In addition, TNT has led to an increased number of patients achieving a clinical complete response and thus eligible to pursue a nonoperative, organ-preserving, watch and wait approach, thereby avoiding toxicities associated with surgery, such as bowel dysfunction and stoma-related complications. Ongoing trials using immune checkpoint inhibitors in patients with mismatch repair-deficient tumors suggest that this subgroup of patients with LARC could potentially be treated with immunotherapy alone, sparing them the toxicity associated with preoperative treatment and surgery. However, the majority of rectal cancers are mismatch repair-proficient and less responsive to immune checkpoint inhibitors and require multimodal management. The synergy noted in preclinical studies between immunotherapy and radiotherapy on immunogenic tumor cell death has led to the design of ongoing clinical trials that explore the benefit of combining radiotherapy, chemotherapy, and immunotherapy (mainly of immune checkpoint inhibitors) and aim to increase the number of patients eligible for organ preservation.

Efficacy of immune checkpoint inhibitors for the treatment of advanced melanoma (AM) in patients with concomitant chronic lymphocytic leukemia (CLL).

e19511 Background: CLL is the most prevalent adult leukemia and is associated with an increased risk of melanoma. CLL alters systemic immunity and can induce T-cell exhaustion, which may limit the efficacy of ICI in patients with CLL. Immune checkpoint inhibitors (ICI) have revolutionized management of AM, but data on ICI effectiveness have largely been restricted to clinical trials, thereby excluding patients with co-existing malignancies. We, therefore, sought to examine the efficacy of ICI for melanoma in patients with concomitant CLL and AM. Methods: In this international and multicentre retrospective study, review of clinical databases identified patients with concomitant CLL and AM treated with ICI from two US tertiary cancer centers (n = 39) and an Australian multi-institutional experience (AUS, n = 19). Objective response rates (ORR), defined as complete or partial response by RECIST v1.1, and survival outcomes (overall survival, OS, and progression-free survival, PFS) among patients with CLL and AM were assessed. Clinical factors associated with improved ORR and survival were explored. Results: Between 1997 and 2020, 58 patients with CLL were treated with ICI for concomitant AM. Among all patients with CLL and AM, ORR to ICI was 41% and median duration of response was 18 months. A majority were untreated for CLL (64%) at the time of ICI. Patients with prior history of treatment for CLL had significantly reduced ORRs (21% vs 51%, p = 0.04), PFS (3.6 vs. 14.6 months, p = 0.005), and OS (7.4 vs. 52.2 months, p = 0.002), compared to patients on observation for their CLL. Prior treatment with T-lymphocyte depleting chemoimmunotherapy (fludarabine, bendamustine, and alemtuzumab) was particularly associated with poor outcomes (median OS of 7.0 months, median PFS of 3.4 months). On univariate analysis, prior treatment for CLL, high risk CLL 17p deletion, and higher CLL Rai stage were associated with shorter PFS from ICI, though CLL treatment was the only factor independently associated with shorter PFS in the multivariate model (HR 6.5, [CI 2.1-20.3], p = 0.001]. Overall, 3 patients developed CLL progression while on ICI, though in two of these patients, the AM had an objective, durable clinical response to ICI. Overall, immune-related adverse events (irAE) occurred following 38% of ICI and rates of irAE were similar by CLL treatment status. Conclusions: Our case series of patients with concomitant CLL and melanoma demonstrate frequent, durable clinical responses to ICI However, those with prior chemoimmunotherapy treatment for CLL had significantly worse outcomes. We found that CLL disease course is largely unchanged by treatment with ICI.

Correlation of DNA methylation signatures with response to immune checkpoint inhibitors in metastatic melanoma.

9561 Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic melanoma with objective response rates of 40-58%. However, reliable biomarkers to predict treatment response are lacking. Tumor tissue methylation profiles were recently proposed to have predictive value in various solid organ tumor entities. Methods: Patients with metastatic melanoma, American Joint Committee on Cancer (AJCC; 8th Edition) stage IV, receiving first-line ICI-based therapy, were retrospectively identified and formalin-fixed paraffin-embedded tumor tissue samples (FFPE) prior to ICI therapy were retrieved. We analyzed DNA methylation profiles of > 850.000 CpG sites in tumor specimens by Infinium MethylationEPIC microarrays. DNA methylation profiles were then correlated with radiological response (iRECIST). Results: 71 patients with metastatic melanoma (44 (62.0%) male, 27 (38.0%) female) were investigated; median progression free survival (PFS) was 8.5 months (range: 0 – 104.1 months) and median overall survival (OS) was 30.6 months (range: 0 – 104.1 months), respectively. 29 (40.8%) patients achieved an objective response to ICIs. Microarray analyses revealed a methylation signature including mainly hypomethylation, corresponding to the response to ICIs. Based on the 500 mostly differentially methylated genes, a total of 3 clusters were identified with the majority of responders being in cluster 2 (12/12) and 3 (12/22). The predictive performance of the methylation signature was high with 80% sensitivity, 81% specificity, and an AUC of 0.853. Conclusions: Our findings suggest that tumor DNA methylation profiling may be useful to predict response to ICIs in patients with metastatic melanoma.

Nivolumab with chemotherapy in pleural mesothelioma after surgery: The NICITA trial.

TPS8601 Background: Pleural mesothelioma (PM) is a highly aggressive cancer of the pleura, predominantly caused by prior asbestos exposure. Currently, there is no approved standard therapy for the treatment of early-stage PM. In most cases a multimodal therapy is recommended consisting of locoregional treatment by surgical cytoreduction via extended pleurectomy/decortication (eP/D), which, if feasible, can be combined with hyperthermic intrathoracic chemoperfusion (HITOC), together with inductive or adjuvant chemotherapy. Considering the immunogenic effects of chemotherapy on the tumor microenvironment, synergistic effects are expected when such a treatment is combined with immune checkpoint inhibitor therapy. In addition, interactions between immune infiltrates and mesothelioma cells play a role in the advent of PM, also implying a beneficial role for immunotherapy in this entity. This is also supported by recent clinical data that demonstrated beneficial effects of immune checkpoint inhibitors in patients with advanced PM. The NICITA trial is an investigator-initiated trial, investigating the combination of adjuvant chemotherapy with immune checkpoint inhibitor compared to chemotherapy alone in radically resected patients with early stage PM. Methods: The NICITA trial is a randomized, open-label, phase II clinical trial that is conducted in 14 centers across Germany. Eligible patients have been diagnosed with PM in tumor stages I-III (UICC 8th edition) and epithelioid subtype, and must have undergone cytoreductive surgery by eP/D with or without HITOC. Patients will be randomized 1:1 to receive either a combination of 4 cycles of pemetrexed/platinum-based adjuvant chemotherapy and nivolumab (480 mg q4w) followed by nivolumab maintenance therapy (12 cycles, 480 mg q4w) or 4 cycles of adjuvant chemotherapy only. Stratification will take place according to previous HITOC treatment (yes vs. no), ECOG status (0,1 vs. 2), and achievement of macroscopic complete resection (yes vs. no). The primary endpoint of this trial is time-to-next-treatment. Secondary endpoints include additional measures of efficacy (progression-free survival, overall survival, measures of treatment-beyond-progression) and quality of life, as well as the assessment of safety. Furthermore, a comprehensive longitudinal collection of biomarker samples, including tumor tissue, blood, and stool samples, for an accompanying translational research project is implemented in this clinical trial. Sample size justification: the recruitment of 46 patients to each arm with a low drop-out rate of 13% appears feasible resulting in 40 patients to be analyzed per arm. This sample size will permit a descriptive comparison and adequately describe the tested treatment options as deduced from the precision of the median TNT confidence interval estimate. As of February 2nd 2023, 85 of planned 92 patients have been enrolled into the NICITA trial. Clinical trial information: NCT04177953 .

Efficacy and predictors of immune checkpoint inhibitors in patients with gallbladder cancer.

e16124 Background: Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) has shown promising efficacy in multiple cancers including biliary tract cancers (BTCs). However, the data focusing on the efficacy of ICIs in patients with gallbladder cancer (GBC) is still limited. This study aims to assess the efficacy of ICIs in GBC and explore the clinicopathological and molecular markers of ICI benefit. Methods: This was a single center, retrospective study, including 80 GBC patients who had received ICI (anti-PD-1 monoclonal antibody) therapy at Eastern Hepatobiliary Surgery Hospital (Shanghai, China) between January 2016 and December 2020. Tumor samples from 31 of these patients who had previously underwent surgical resection before ICI therapy were obtained and conducted for whole exome sequencing and immunohistochemical analysis. The primary outcome was progression-free survival (PFS). The secondary outcomes were overall survival (OS), objective response rate (ORR) and disease control rate (DCR). The associations between efficacy with clinicopathological factors, genetic variations and PD-L1/CD8 expression were further explored. Results: Of 80 patients with GBC, 36 were male, the median age was 61 years (range, 30-79). The median PFS and OS was 4.5 months (95% CI, 2.99-5.95) and 8.7 months (95% CI, 7.07-10.26) respectively. Multivariate analysis indicated that alcohol intake history (HR, 2.66; 95% CI, 1.31-5.40; p=0.007), extrahepatic metastasis (HR, 2.03; 95% CI, 1.15-3.59; p=0.015), carcinoma embryonic antigen (CEA) level ≥100U/mL (HR, 3.58; 95% CI, 1.65-7.74; p=0.001) and immune-related adverse events (irAEs) (HR, 0.24; 95% CI, 0.10-0.57; p=0.001) were independent prognostic factors for PFS. Extrahepatic metastasis (HR, 2.42; 95% CI, 1.37-4.31; p=0.003), CEA level ≥100U/mL (HR, 2.82; 95% CI, 1.33-5.95; p=0.007) and irAEs (HR, 0.32; 95% CI, 0.14-0.72; p=0.006) were independent prognostic factors for OS. ORR and DCR were 13.75% and 37.5%, respectively. Patients with irAEs (85.7%, OR, 16.00; 95% CI, 3.26-78.61; p<0.001), high CD8+ T-cells-infiltrated GBCs (87.5%, OR, 19.83; 95% CI, 2.00-196.38; p=0.011), immune inflamed phenotype (66.7%, OR, 5.60; 95% CI, 1.16-27.08; p=0.032) had higher DCR, while patients with high level of total bilirubin (TBIL>34.2μmol/L) (8.3%, OR, 0.12; 95% CI, 0.01-0.97; p=0.048) had lower DCR. Patients with high CD8+ T-cells-infiltrated or immune inflamed GBCs also had a notably improved PFS and OS. Conclusions: ICIs were effective in patients with GBC. Alcohol intake history, extrahepatic metastasis, CEA level ≥100U/mL, irAEs, high positivity of CD8+ T-cells and immune inflamed phenotype may be useful for predicting the efficacy of ICIs in GBC.

Immune checkpoint inhibitors therapy in advanced bladder carcinoma: A meta-analysis of phase III randomized controlled trials.

e16584 Background: Currently, platinum-based chemotherapy is the standard treatment for advanced bladder cancer. Immune checkpoint inhibitors (ICIs) have been evaluated in these patients with clinical trials. There is no meta-analysis available of phase III randomized controlled trials comparing immune checkpoint inhibitors therapy versus chemotherapy/placebo in these patients. In this article, we write about the meta-analysis of ICIs use in advanced bladder cancer. Methods: Systemic searches of PubMed, Embase, the Cochrane Library, Google scholar, and ClinicalTrials.gov were searched for relevant studies with prespecified terms. We included only phase III randomized controlled trials comparing immune checkpoint inhibitors therapy versus chemotherapy/placebo in patients with advanced bladder carcinoma. Outcomes studied were Overall survival (OS), Progression-free survival (PFS), Objective response rate (ORR), and Grade 3 or higher adverse events (AE). We used a random effects model via RevMan 5.4 software to perform the meta-analysis. Results: 8 phase III RCTs met the inclusion criteria with a total of 5041 patients (immune checkpoint inhibitors = 2481 patients, Chemotherapy/placebo = 2560 patients) and a median follow-up of 24 months. Compared to the chemotherapy/placebo group, immune checkpoint inhibitors showed higher OS [HR = 0.83 (0.73-0.93) P = 0.002]. No significant differences were observed in PFS [HR = 0.84(0.68-1.05) P = 0.13] and ORR [HR = 2.15(0.51-9.09) P = 0.30] between the two groups. Compared to the chemotherapy group, immune checkpoint inhibitors showed significantly fewer severe adverse events [HR = 0.21 (0.14-0.32) P < 0.00001]. Conclusions: The use of immune checkpoint inhibitors in patients with advanced bladder carcinoma is associated with favorable overall survival and fewer severe adverse events. The two groups observed no significant differences between progression-free survival and objective response rates.

STK11 alterations as predictive biomarkers of resistance to immune checkpoint inhibitors in multiple cancers with mismatch repair gene alterations.

2619 Background: STK11 is an important tumor suppressor gene that encodes for a serine-threonine kinase involved in a variety of metabolic functions. STK11 alterations are associated with an inert or cold tumor microenvironment in KRAS-mutant lung adenocarcinoma, and are a major driver of primary resistance to immune checkpoint inhibitors (ICIs). Here, we explored STK11 alterations as predictive biomarkers of resistance to ICIs in multiple solid tumors with mismatch repair (MMR) gene alterations. Methods: The cBioCancer Genomics Portal (cBioportal, http://www.cbioportal.org ) was used to obtain genomic data. The association between STK11 alterations and median overall survival (mOS) was explored in an ICI-treatment cohort comprising a total of 1572 evaluable patients. This cohort includes patients with cancers of the lung, colon, unknown primary, head and neck, gastroesophageal, bladder, skin (melanoma), brain, breast and kidney that had received at least one dose of ICI. These were then cross-referenced with patients who had MSK-IMPACT testing done in the context of routine clinical care. Kaplan-Meier survival curves were generated and compared using log-rank testing. Results: In the ICI-treated patients cohort (N = 1572), 96 patients (6.1%) had STK11 alterations. Patients with STK11 alterations had higher median tumor mutation burden (TMB) than patients without STK11 alterations (8.81 mut/Mb vs. 5.87 mut/Mb, p < 0.0001). Yet, they had worse mOS (7 m, 95% CI: 6-13 m vs. 20 m, 95% CI: 18-22 m, p < 0.001). MMR alterations (not including gene promoter methylation) were identified in 103 (6.6%) and co-occurrence of STK11 with MMR alterations was identified in 9 (0.6%) patients. Compared to patients without MMR or STK11 alterations (N = 1382), the mOS was better in patients with MMR alterations without STK11 alterations (N = 94) (59 m vs. 19 m, p = 0.0004) and trending for worse in patients with MMR and STK11 alterations (N = 9) (5 m vs. 19 m, p = 0.117). The mOS was better in patients with MMR alterations without STK11 alterations compared to patients with MMR and STK11 alterations (59 m vs 5 m, p = 0.016). Controlling for KRAS mutation status, a multivariable Cox regression model shows that besides MMR and STK11 alteration status (p = 0.0008), BRAF mutant status (p = 0.0001, HR 0.598; 95% CI, 0.459-0.779) was another biomarker associated with significantly better OS. Lung cancer diagnosis was associated with worse OS (p = 0.0016, HR 1.340; 95% CI, 1.117-1.607). Conclusions: In a large cohort of ICI-treated patients with multiple cancers, STK11 alterations were associated with worse mOS despite having higher TMB. MMR alterations were only predictive of response to ICIs in patients without STK11 alterations. Our findings suggest that STK11 alterations in patients with MMR alterations could potentially identify patients who are less likely to respond to ICIs but more data are needed.

A single-centre experience of immune checkpoint inhibitors in patients with cancer in the Top End of the Northern Territory, Australia from 2016 to 2021.

e18841 Background: Immune checkpoint inhibitors (ICI) have transformed the oncological landscape, but are associated with immune-related adverse events (irAE) of varying frequency and severity. This regional single-centre experiential study evaluates the real-world incidence of irAE in patients in the Top End of the Northern Territory of Australia. The Top End represents a diverse population with high proportions of Aboriginal and Torres Strait Islander (ATSI) patients and patients living in remote and very remote areas. This captured cohort is under-represented in clinical trials. Methods: We identified all patients with solid tumours who were prescribed ICI between January 2016 and December 2021. We manually reviewed electronic and paper hospital records to record patient characteristics, treatments received, irAE, irAE treatment and patient outcomes. Results: 226 patients across 11 solid tumour streams received ICI. Of these, 58% had lung cancer, 27% melanoma, 5% head & neck cancer, 4% renal cell carcinoma, and the remainder other tumour streams. 70% were male and the median age at diagnosis was 63 years [28-84 years]. 16% identified as ATSI(compared to 2.8% ATSI nation-wide and 26.3% ATSI in the Northern Territory). Of the investigational cohort, 13% were treated in the adjuvant and 87% in the palliative setting. 11% received combination versus 89% single-agent ICI. 30% of patients had concurrent chemotherapy. 122 patients (54%) experienced any grade irAE as documented by the treating oncologist in the medical records. 59 patients (26%) had a severe (grade 3, 4, or 5) irAE. The fatality rate was 0.88% (2 patients); both were treated with a PD-L1 inhibitor for non-small cell lung cancer (NSCLC) and diagnosed with immune-related pneumonitis. The most common irAE were rash (18%), colitis (16%), arthralgia/myalgia (13%), pneumonitis (12%), thyroiditis/hypothyroidism (12%), hepatitis (9%), and adrenal insufficiency (7%). 24% of irAE required hospitalisation and 32% led to discontinuation of treatment. The median number of irAE per patient was 1. Among patients with the most common tumour types (melanoma and NSCLC), rates of irAE were, in both cases, 59% any grade irAE and 20% severe irAE. When compared to published literature, real-world rates of any grade adverse event were significantly lower than reported number in trials – likely due to exclusion of common non-immune-related adverse events in our data set. Rates of severe and fatal irAE were in line with published data. Conclusions: Immune-related adverse events are common among patients in the Top End and reflect rates in the published literature. We did not identify any safety concerns in our cohort of patients – including amongst ATSI patients and those living in remote and very remote areas. Further data analysis is needed to assess frequency and severity of irAE by specific tumour type and ICI.

Immune checkpoint inhibitors use and the incidence of hepatitis B virus reactivation or immune-related hepatitis in non-small cell lung cancer patients with chronic hepatitis B.

9086 Background: The safety and efficacy of immune-checkpoint inhibitors (ICIs) has not been thoroughly investigated in non-small cell lung cancer (NSCLC) patients with chronic hepatitis B (CHB) or occult hepatitis B infection (OBI). We analyzed incidence of hepatitis B virus (HBV) reactivation, immune-related hepatitis and jaundice in NSCLC patients treated with ICIs according to HBV DNA and hepatitis B serologic markers in real-world setting. Methods: A total of 1,277, consecutive NSCLC patients treated with ICIs from January 2015 to December 2020 at the Samsung Medical Center, Seoul, Korea were analyzed. Among them, 52 patients were hepatitis B surface antigen (+) (Group A, CHB), 759 patients were HBsAg (-)/anti-HBc IgG (+) (Group B, OBI), and 466 patients were HBsAg (-)/anti-HBc IgG (-) (Group C). Among 52 patients with CHB, 38 patients (73.1%) were receiving antiviral therapy. Primary endpoint was HBV reactivation, immune-related hepatitis and jaundice. Secondary endpoints include other immune-related adverse events, objective response rate, progression free survival (PFS) and overall survival (OS). Results: HBV reactivation was observed in two patients (0.2%) which was exclusively observed in Group A (CHB). Among CHB patients who were not receiving antiviral therapy, HBV reactivation was observed for 14.3% (2/14 patients). Incidence of immune-related hepatitis were 21.2%, 30.3% and 30.5% for Group A, Group B and Group C (p > 0.05), respectively, and incidence of immune-related of jaundice was 3.8%, 4.0% and 2.8% for Group A, Group B and Group C (p > 0.05), respectively. Incidence of ≥ grade 3 other immune-related adverse events, objective response rate, PFS, and OS were comparable among three group (p > 0.05 for all comparison). Conclusions: In this large, real-world cohort study, safety and efficacy of ICIs were comparable in patients with CHB or OBI, suggesting similar outcomes can be expected with ICIs in patients with CHB or OBI. HBV reactivation was observed in patients with CHB without antiviral therapy indicating antiviral prophylaxis might be required for them. For patients with OBI, risk of HBV reactivation was null.

Predicting benefit from immune checkpoint inhibitors in patients with non-small-cell lung cancer by CT-based ensemble deep learning: a retrospective study

Only around 20-30% of patients with non-small-cell lung cancer (NCSLC) have durable benefit from immune-checkpoint inhibitors. Although tissue-based biomarkers (eg, PD-L1) are limited by suboptimal performance, tissue availability, and tumour heterogeneity, radiographic images might holistically capture the underlying cancer biology. We aimed to investigate the application of deep learning on chest CT scans to derive an imaging signature of response to immune checkpoint inhibitors and evaluate its added value in the clinical context. In this retrospective modelling study, 976 patients with metastatic, EGFR/ALK negative NSCLC treated with immune checkpoint inhibitors at MD Anderson and Stanford were enrolled from Jan 1, 2014, to Feb 29, 2020. We built and tested an ensemble deep learning model on pretreatment CTs (Deep-CT) to predict overall survival and progression-free survival after treatment with immune checkpoint inhibitors. We also evaluated the added predictive value of the Deep-CT model in the context of existing clinicopathological and radiological metrics. Our Deep-CT model demonstrated robust stratification of patient survival of the MD Anderson testing set, which was validated in the external Stanford set. The performance of the Deep-CT model remained significant on subgroup analyses stratified by PD-L1, histology, age, sex, and race. In univariate analysis, Deep-CT outperformed the conventional risk factors, including histology, smoking status, and PD-L1 expression, and remained an independent predictor after multivariate adjustment. Integrating the Deep-CT model with conventional risk factors demonstrated significantly improved prediction performance, with overall survival C-index increases from 0·70 (clinical model) to 0·75 (composite model) during testing. On the other hand, the deep learning risk scores correlated with some radiomics features, but radiomics alone could not reach the performance level of deep learning, indicating that the deep learning model effectively captured additional imaging patterns beyond known radiomics features. This proof-of-concept study shows that automated profiling of radiographic scans through deep learning can provide orthogonal information independent of existing clinicopathological biomarkers, bringing the goal of precision immunotherapy for patients with NSCLC closer. National Institutes of Health, Mark Foundation Damon Runyon Foundation Physician Scientist Award, MD Anderson Strategic Initiative Development Program, MD Anderson Lung Moon Shot Program, Andrea Mugnaini, and Edward L C Smith.

Correlation between biomarkers and treatment outcomes in diverse cancers: a systematic review and meta-analysis of phase I and II immunotherapy clinical trials

BackgroundMany immuno-oncology (IO) trials are conducted without biomarker selection. We performed a meta-analysis of phase I/II clinical trials evaluating immune checkpoint inhibitors (ICIs) to determine the association between biomarkers and clinical outcomes, if any. MethodsA PubMed search for phase I/II clinical trials with drugs approved by the Food and Drug Administration (labelled, off-label, combined with investigational ICIs or other treatment modalities) from 2018 to 2020 was performed. The objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were compared between biomarker-positive and biomarker-negative groups, using studies that explored the correlation of biomarkers with outcomes. ResultsOverall, 174 clinical studies that included 19,178 patients were identified, and 132 studies investigated>30 correlative biomarkers that included PD-L1 expression (≥1%, 111 studies), tumour mutational burden (20 studies) and microsatellite instability/mismatch repair deficiency (10 studies). Overall, 123, 46 and 30 cohorts (drugs, tumour types or biomarkers) with 11,692, 3065, and 2256 patient outcomes for ORR, PFS and OS, respectively, were analysed in correlation with biomarkers. Meta-analyses demonstrated that ICIs in patients with biomarker-positive tumours were associated with higher ORR (odds ratio 2.15 [95% CI, 1.79–2.58], p < 0.0001); and longer PFS (hazard ratio [HR] 0.55 [95% CI, 0.45–0.67], p < 0.0001), and OS (HR 0.65 [95% CI, 0.53–0.80], p < 0.0001) compared with those with biomarker-negative tumours. Significance for ORR and PFS was retained in multivariate analysis (p < 0.001) (OS, not included owing to the small number of trials reporting OS). ConclusionOur data suggest that IO biomarkers should be used in patient selection for ICIs. Prospective studies are warranted.

Neoadjuvant Immune Checkpoint Inhibition in Metastatic Conjunctival Melanoma.

The development of immune checkpoint inhibitors (ICI) has transformed the treatment of advanced-stage cutaneous melanoma; however, most trials did not include patients with conjunctival melanoma. Herein the authors describe a patient with recurrent conjunctival melanoma who developed locally advanced, b-raf and v-raf murine sarcoma viral oncogene homolog B1-negative melanoma in her nasal cavity and extensive, metabolically active, bilateral lymphadenopathy in her thorax. Her nasal mass measured 4.3 × 1.7 cm and was determined to be unresectable. She was treated with 4 cycles of combination ipilimumab and nivolumab therapy followed by maintenance nivolumab. She experienced a dramatic treatment response with a reduction in the size of her nasal mass to 3.0 × 1.1 cm and a complete resolution of her adenopathy. She then underwent complete surgical resection of her residual mass (approximately 75% of her original tumor size) and remains melanoma-free at 1 year of follow-up. Given the underlying genetic similarities of conjunctival melanoma to cutaneous melanoma, providers should consider the use of neoadjuvant immune checkpoint inhibitors for patients with locally advanced or limited metastatic disease.

Factors Predictive of Primary Resistance to Immune Checkpoint Inhibitors in Patients with Advanced Non-Small Cell Lung Cancer.

Primary resistance to immune checkpoint inhibitors (ICI) is observed in routine clinical practice. We sought to determine factors predictive of primary resistance to ICI monotherapy, defined by the Society for Immunotherapy of Cancer (SITC) as progression within 6 months of ICI treatment with patients receiving at least 6 weeks of ICI monotherapy, in patients with advanced non-small-cell lung cancer (NSCLC). Patients with stage IV NSCLC treated with at least 6 weeks of single-agent ICI at two tertiary hospitals in Singapore were included. A multivariate logistic regression model was utilised to elucidate factors predictive of primary resistance to ICI. Of the 108 eligible patients, 59 (54.6%) experienced primary resistance. The majority were male (65.7%), smokers (66.3%), Chinese (79.6%), had adenocarcinoma (76.9%), received Pembrolizumab (55.6%) and received immunotherapy treatment in the later line setting (≥2 lines) (61.1%). Female gender (aOR = 3.16, p = 0.041), a sixth-week neutrophil-to-lymphocyte ratio (NLR) of ≥3) (aOR = 3.454, p = 0.037) and a later line of immunotherapy treatment (≥2 lines) (aOR = 2.676, p = 0.040) were factors predictive of primary resistance to ICI monotherapy in patients with advanced NSCLC. Using SITC criteria, an elevated NLR (≥3) at 6 weeks, female gender and a later line of immunotherapy treatment (≥2 lines) were predictive factors of developing primary resistance to ICI monotherapy in patients with advanced NSCLC.

Physician Views on the Provision of Information on Immune Checkpoint Inhibitor Therapy to Patients with Cancer and Pre-Existing Autoimmune Disease: A Qualitative Study.

Immune checkpoint inhibitors (ICIs) have improved cancer outcomes but can cause severe immune-related adverse events (irAEs) and flares of autoimmune conditions in cancer patients with pre-existing autoimmune disease. The objective of this study was to identify the information physicians perceived as most useful for these patients when discussing treatment initiation with ICIs. Twenty physicians at a cancer institution with experience in the treatment of irAEs were interviewed. Qualitative thematic analysis was performed to organize and interpret data. The physicians were 11 medical oncologists and 9 non-oncology specialists. The following themes were identified: (1) current methods used by physicians to provide information to patients and delivery options; (2) factors to make decisions about whether or not to start ICIs in patients who have cancer and pre-existing autoimmune conditions; (3) learning points for patients to understand; (4) preferences for the delivery of ICI information; and (5) barriers to the implementation of ICI information in clinics. Regarding points to discuss with patients, physicians agreed that the benefits of ICIs, the probability of irAEs, and risks of underlying autoimmune condition flares with the use of ICIs were most important. Non-oncologists were additionally concerned about how ICIs affect the autoimmune disease (e.g., impact on disease activity, need for changes in medications for the autoimmune disease, and monitoring of autoimmune conditions).

A Novel PD-L1 Antibody Promotes Antitumor Function of Peripheral Cytotoxic Lymphocytes after Radical Nephrectomy in Patients with Renal Cell Carcinoma.

The intrinsic and acquired resistance to PD-1/PD-L1 immune checkpoint blockade is an important challenge for patients and clinicians because no reliable tool has been developed to predict individualized response to immunotherapy. In this study, we demonstrate the translational relevance of an ex vivo functional assay that measures the tumor cell killing ability of patient-derived CD8 T and NK cells (referred to as "cytotoxic lymphocytes," or CLs) isolated from the peripheral blood of patients with renal cell carcinoma. Patient-derived PBMCs were isolated before and after nephrectomy from patients with renal cell carcinoma. We compared the efficacy of U.S. Food and Drug Administration (FDA)-approved PD-1/PD-L1 inhibitors (pembrolizumab, nivolumab, atezolizumab) and a newly developed PD-L1 inhibitor (H1A Ab) in eliciting cytotoxic function. CL activity was improved at 3 mo after radical nephrectomy compared with baseline, and it was associated with higher circulating levels of tumor-reactive effector CD8 T cells (CD11ahighCX3CR1+GZMB+). Treatment of PBMCs with FDA-approved PD-1/PD-L1 inhibitors enhanced tumor cell killing activity of CLs, but a differential response was observed at the individual-patient level. H1A demonstrated superior efficacy in promoting CL activity compared with FDA-approved PD-1/PD-L1 inhibitors. PBMC immunophenotyping by mass cytometry revealed enrichment of effector CD8 T and NK cells in H1A-treated PBMCs and immunosuppressive regulatory T cells in atezolizumab-treated samples. Our study lays the ground for future investigation of the therapeutic value of H1A as a next-generation immune checkpoint inhibitor and the potential of measuring CTL activity in PBMCs as a tool to predict individual response to immune checkpoint inhibitors in patients with advanced renal cell carcinoma.

Immune checkpoint inhibitors in first-line therapies of metastatic or early triple-negative breast cancer: a systematic review and network meta-analysis.

The optimal first-line immune checkpoint inhibitor (ICI) treatment strategy for metastatic or early triple-negative breast cancer (TNBC) has not yet been determined as a result of various randomized controlled trials (RCTs). The purpose of this study was to compare the efficacy and safety of ICIs in patients with metastatic or early TNBC. RCTs comparing the efficacy and safety of ICIs in patients with TNBC were included in the studies. Based on PRISMA guidelines, we estimated pooled hazard ratios (HRs) and odds ratios (ORs) using random-effects models of Bayesian network meta-analysis. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included pathologic complete response rate (pCR), grade ≥ 3 treatment-related adverse events (trAEs), immune-related adverse events (irAEs), and grade ≥ 3 irAEs. The criteria for eligibility were met by a total of eight RCTs involving 4,589 patients with TNBC. When ICIs were used in patients without programmed death-ligand 1 (PD-L1) selection, there was a trend toward improved PFS, OS, and pCR, without significant differences. Pembrolizumab plus chemotherapy is superior to other treatment regimens in terms of survival for TNBC patients based on Bayesian ranking profiles. Subgroup analysis by PD-L1 positive population indicated similar results, and atezolizumab plus chemotherapy provided better survival outcomes. Among grade ≥ 3 trAEs and any grade irAEs, there was no statistically significant difference among different ICI agents. The combination of ICIs with chemotherapy was associated with a higher incidence of grade ≥ 3 irAEs. Based on rank probability, the ICI plus chemotherapy group was more likely to be associated with grade ≥ 3 trAEs, any grade irAEs, and grade ≥ 3 irAEs. Hypothyroidism and hyperthyroidism were the most frequent irAEs in patients receiving ICI. ICI regimens had relatively greater efficacy and safety profile. Pembrolizumab plus chemotherapy and atezolizumab plus chemotherapy seem to be superior first-line treatments for intention-to-treat and PD-L1-positive TNBC patients, respectively. It may be useful for making clinical decisions to evaluate the efficacy and safety of different ICIs based on our study. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022354643.

Outcome of immune checkpoint inhibitors in patients with extensive-stage small-cell lung cancer and brain metastases.

Brain metastases (BMs) are common in extensive-stage small-cell lung cancer (SCLC) and are underrepresented in pivotal clinical trials that demonstrate the efficacy of immune checkpoint inhibitors (ICIs). We conducted a retrospective analysis to assess the role of ICIs in BM lesions in less selected patients. Patients with histologically confirmed extensive-stage SCLC who were treated with ICIs were included in this study. Objective response rates (ORRs) were compared between the with-BM and without-BM groups. Kaplan-Meier analysis and the log-rank test were used to evaluate and compare progression-free survival (PFS). The intracranial progression rate was estimated using the Fine-Gray competing risks model. A total of 133 patients were included, 45 of whom started ICI treatment with BMs. In the whole cohort, the overall ORR was not significantly different for patients with and without BMs (p = 0.856). The median progression-free survival for patients with and without BMs was 6.43 months (95% CI: 4.70-8.17) and 4.37 months (95% CI: 3.71-5.04), respectively (p =0.054). In multivariate analysis, BM status was not associated with poorer PFS (p = 0.101). Our data showed that different failure patterns occurred between groups, with 7 patients (8.0%) without BM and 7 patients (15.6%) with BM having intracranial-only failure as the first site progression. The cumulative incidences of brain metastases at 6 and 12 months were 15.0% and 32.9% in the without-BM group and 46.2% and 59.0% in the BM group, respectively (Gray's p<0.0001). Although patients with BMs had a higher intracranial progression rate than patients without BMs, the presence of BMs was not significantly associated with a poorer ORR and PFS with ICI treatment in multivariate analysis.

Selected Articles from This Issue

Highlights| May 04 2023 Selected Articles from This Issue Author & Article Information Online ISSN: 1538-8514 Print ISSN: 1535-7163 ©2023 American Association for Cancer Research2023American Association for Cancer Research Mol Cancer Ther (2023) 22 (5): 553. https://doi.org/10.1158/1535-7163.MCT-22-5-HI Related Content A commentary has been published: Discovery of a Small-Molecule Inhibitor Targeting the Androgen Receptor N-Terminal Domain for Castration-Resistant Prostate Cancer A commentary has been published: Novel Arginase Inhibitor, AZD0011, Demonstrates Immune Cell Stimulation and Antitumor Efficacy with Diverse Combination Partners A commentary has been published: Preclinical Evaluation of ON203, A Novel Bioengineered mAb Targeting Oxidized Macrophage Migration Inhibitory Factor as an Anticancer Therapeutic Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record May 4 2023 Citation Selected Articles from This Issue. Mol Cancer Ther 1 May 2023; 22 (5): 553. https://doi.org/10.1158/1535-7163.MCT-22-5-HI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search The oxidized macrophage migration inhibitory factor (oxMIF) is an emerging therapeutic target for many cancers due to oxMIF's selective occurrence in tumor lesions. Here, Rossmueller and colleagues describe ON203, a novel anti-oxMIF antibody with optimized physicochemical characteristics, in-vitro safety, and enhanced ADCC and ADCP effector functions. ON203 significantly reduced tumor growth and tumor cell proliferation as well as tumor cell intravasation and neo-angiogenesis in xenograft models. These findings highlight the potential of ON203 as a standalone immunotherapy or for enhancing efficacy in combination with angiogenesis and immune checkpoint-inhibitors in patients with solid tumors. Current mainstay treatment for prostate cancer is to suppress the androgen receptor (AR) signaling by castration and antiandrogens that target the ligand-binding domain (LBD). However, emergence of AR variants, such as AR-V7 lacking the LBD, have conferred severe drug resistance to all LBD-targeting AR inhibitors. AR-V7 has been established as a driver for the sustained AR signaling... You do not currently have access to this content.

Endocrine side effects of immune-checkpoint inhibitors in patients with malignant melanoma

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Immune checkpoint inhibitors for patients with isolated peritoneal carcinomatosis from dMMR/MSI-H colorectal cancer, a BIG-RENAPE collaboration.

Immunotherapy with immune checkpoint inhibitors has significantly improved the survival of patients with MSI/dMMR mCRC. These tumors are associated with a specific metastatic spread, i.e. frequent peritoneal carcinomatosis (PC) that may be treated surgically when there is no other metastatic location. We aimed at evaluating the prognosis of patients treated with immune checkpoint inhibitors for MSI/dMMR mCRC with isolated PC. All consecutive patients with isolated PC from MSI/dMMR mCRC, initially considered as unresectable by multidisciplinary team meeting, treated with immune checkpoint inhibitors were included in this French multicenter cohort study. Among 45 patients included, we observed 11 complete responses and 10 partial responses for an overall response rate iRECIST of 46%. After a median follow-up of 24.4 months, the median progression-free survival (PFS) and overall survival (OS) were not reached. Seven of the eight patients who underwent cytoreductive surgery after treatment with anti-PD1 ± anti-CTLA-4 were in complete pathologic response. These results demonstrate long-term benefit of immune checkpoint inhibitors for patients with isolated PC from MSI/dMMR mCRC. Such treatment appears as the best therapeutic option for patients with isolated PC from MSI/dMMR mCRC. With a majority of pathological complete responses for patients who underwent surgery for residual lesions, the value of such therapeutic strategy remains unknown.