Clinical Trials Of Immune Checkpoint Inhibitors Research Articles

1654P Analysis of predictive biomarkers for immune checkpoint inhibitor therapy in several subtypes of sarcomas

The significance of predictive biomarkers when using immune checkpoint inhibitors (ICI) is becoming increasingly prominent. Clinical trials of ICI have been performed in sarcomas, such as (SARC028). However, most results have been negative for the reason that few have taken biomarkers into account. We analysed and evaluated data for immunotherapy biomarkers in several sarcomas subtypes. 172 samples from patients with sarcomas have been collected in China since February 2018. Tumour mutation burden was detected and measured by next generation sequencing (NGS). MSI status was evaluated by NGS covering 500 MSI loci. Expression of PD-L1 was detected using Dako PD-L1 IHC 22C3 pharmDx. PD-L1 expression was determined using the percentage of viable tumour cells stained, termed as Tumor Proportion Score (TPS). TPS score was defined as: strong positive ≥50%, moderate positive ≥5% and <50%, weak positive ≥1% and <5%, and negative <1%. Among these patients, 59% (101/172) male and 41% (71/172) female had 18 fibrosarcomas, 50 liposarcomas, 25 rhabdomyosarcomas, 18 synovial sarcomas, 28 osteosarcomas, 21 soft tissue sarcomas (STS) and 12 Ewing sarcomas. All these patients had microsatellite-stable tumours, and all had low TMB level (median 3.2 mutants/Mb, average 3.5 Mutants/Mb). PD-L1 expression in fibrosarcoma was 66.7% negative, 16.7% weak positive, 5.6% moderate positive, and 11.1 strong positive. In Liposarcoma it was 85.7% negative, 8.6% weak positive, 2.7% moderate positive, 2.7% strong positive. In Rhabdomyosarcoma it was 96.0% negative, 4% moderate positive. In synovial sarcoma tumours were 100% negative for PD-L1 expression. In Osteosarcoma levels were 78.6% negative, 7.4% weak positive, 10.1% moderate positive, 3.6% strong positive. In STS it was 80.9% negative, and 19.0% weak positive. In Ewing sarcoma it was 91.7% negative, 8.3% weak positive. Biomarkers for ICI therapy, such as TMB level, MSS/MSI status, and PD-L1 expression, were present in a low proportion of sarcomas, suggesting other predictive biomarkers need to be explored and applied to stratify and select patients suitable for ICI therapy in this tumour type.

Abstract 4484: ScRNA-seq of patients with immune-related adverse events and checkpoint inhibitor therapy

Abstract Despite the remarkable success of immune checkpoint inhibitor (ICI) therapy, a significant number of patients develop severe and unpredictable immune-related adverse events (irAEs) affecting a wide variety of organs. Concerns over irAE have led to the exclusion of patients with autoimmune disease from ICI clinical trials. Role of host genetic and immune factors in mediating irAEs remain unclear and it is not clear if the manifestations of irAEs is associated with response to therapy. In this study, we used single cell RNA sequencing (ScRNA-seq) to study the peripheral immune repertoire at a single cell level to identify blood-based signatures predictive of irAEs and response to ICI therapy. We characterized changes in host immune system in 40 patients receiving ICI therapy by performing ScRNA-seq on peripheral blood mononuclear cells (PBMCs) at baseline and post-immunotherapy. In addition, we evaluated serum levels of 40 cytokines/chemokines, antinuclear autoantibodies (ANA) and 124 autoantibodies and performed bulk RNA sequencing on PBMCs at baseline and post immunotherapy in these patients. Our preliminary data analysis identified signatures of autoantibodies and cytokines correlating with response and toxicity. ScRNA-seq data revealed changes in distinct immune cell subsets and gene expression signatures in patient developing irAEs. In this meeting, we will present preliminary ScRNA-seq data combined with immune and genetic correlates of irAEs and response to therapy in our patient cohort. We hope that our studies can help identify blood-based biomarker signatures predictive of irAEs and/or response and reveal novel insights into the mechanisms underlying irAE. Our current genetic data suggests further expanding the genetic studies in larger patient population to identify the role of underlying genetic predisposition to autoimmunity in mediating irAEs. We hope our findings may ultimately help customize therapy, expand use of immunotherapy and prevent toxicities. Citation Format: Shaheen Khan, David E. Gerber. ScRNA-seq of patients with immune-related adverse events and checkpoint inhibitor therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4484.

Abstract 929: Transcriptomic analysis of pre-treatment tissue samples to predict clinical benefit to durvalumab in HIV-infected cancer patients

Abstract Introduction: Treatment with anti PD-1/PD-L1 antibodies has demonstrated clinical activity in different types of solid tumors, but only 20 to 30% of patients (pts) respond to these immune checkpoint inhibitors (ICIs). Therefore, predictive biomarkers of response that can assist in pt selection are urgently needed. Single biomarker expression, like PD-L1, may not provide enough information about cancer cells and the tumor microenviroment. Novel technologies, analyzing hundreds of genes at the same time, are needed to yield better predictive gene signatures of ICI response. The DURVAST trial analyzed the feasibility of durvalumab treatment in HIV-infected cancer pts, which are usually excluded from ICI clinical trials. The trial included 20 patients with different tumor types and yielded a disease control rate of 56%. Methods: Pre-ICI-treatment FFPE tumor tissue samples from 14 HIV-infected cancer pts (including 11 lung, 1 melanoma, 1 anal and 1 bladder cancer) were analyzed using the nCounter NanoString platform with the IO360 panel, including 770 genes involved in tumor biology, microenvironment and immune response. Gene expression results were correlated with clinical benefit (CB) (objective response and stable disease of more than 24 weeks by RECIST1.1 criteria), and compared to other predictive markers. Results: Exploratory analysis of pre-treatment gene expression profiles (GEPs) revealed differentially expressed genes (DEGs) between the pts with- and without CB. Panel-incorporated biological signatures related to tumor and immune activities were evaluated and some of the most DEGs (based on higher log2FC values and nominal p-values ≤0.05) were shown to be involved in cytokine and chemokine signaling. Although not significant, pts without CB tend to have lower expression of genes involved in cytokine and chemokine signaling (p = 0.097). In contrast, pts without CB tended to have a higher TGF beta signature scores (p = 0.318). When combining both signatures, we obtained an aggregated signature score that was significantly different between pts with- and without CB (p = 0.017). While the positive predictive values were the same for all tests, our signature score outperformed PD-L1 expression positivity by immunohistochemistry and PD-L1 RNA expression as predictors for clinical benefit with a two-fold higher sensitivity and negative predictive value. Conclusion: Gene expression analysis of pre-treatment tumor samples revealed distinct GEPs between HIV-infected cancer pts with- and without CB, where combined high baseline recruitment and activation of immune cells by cytokine and chemokine signaling pathways and low immunosuppressive TGF beta signaling pathways predict CB from durvalumab treatment. This predictive score outperformed other predictive markers of CB. These findings need further validation in an external and non-HIV infected pt cohort, in addition to a pt cohort treated with other ICIs. Citation Format: Jillian Wilhelmina Bracht, Maria Gonzalez-Cao, Teresa Moran, Judith Dalmau, Javier Garcia-Corbacho, Reyes Bernabe, Oscar Juan, Javier de Castro, Ana Gimenez-Capitan, Remedios Blanco, Erika Aldeguer, Sonia Rodriguez, Ana Drozdowskyj, Jordi Argilaguet, Julian Blanco, Julia Prado, Christian Brander, Jorge Carrillo, Bonaventura Clotet, Bartomeu Massuti, Mariano Provencio, Chung-Ying Huang, Clara Mayo de las Casas, Monica Garzon, Andres Felipe Cardona, Oscar Arrieta, Andreas Meyerhans, Miguel Angel Molina-Vila, Javier Martinez-Picado, Rafael Rosell. Transcriptomic analysis of pre-treatment tissue samples to predict clinical benefit to durvalumab in HIV-infected cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 929.

Abstract 1047: Combinatorial benefit without synergy in recent clinical trials of immune checkpoint inhibitors

Abstract IMPORTANCE Immune Checkpoint Inhibitors (ICIs), frequently combined with other therapies, have become the standard of care for the treatment of several cancers, and hundreds of clinical trials evaluate the efficacy of novel combinations with ICI. However, it is unclear whether combination therapies truly enhance ICI activity or simply provide multiple “shots on target” for a response to occur. OBJECTIVE To assess whether ICIs in combination with other therapies result in ‘additive' or ‘synergistic' anti-tumor activity. The null hypothesis is independent drug action, where each patient's response to a combination of therapies is equal to that patient's best single-agent response. DATA SOURCES We analyzed twelve randomized-controlled clinical trials testing combinations of ICIs with other drug classes in patients with advanced cancers, including melanoma and lung, breast, gastric, kidney, and head and neck cancers. For each analysis, the clinical activity of each constituent therapy of the combination was available in the respective study population. METHODS We digitized Progression Free Survival curves for combination therapies and their constituents, and computed PFS expected for the null hypothesis of independent action by randomly sampling single-agent PFS durations (with correlation ρ=0.3±0.2 to account for cross-resistance), and assigning each simulated patient the longer of the two sampled PFS values. For each combination therapy, simulated and clinically observed PFS distributions were compared. RESULTS None of the analyzed clinical trials of ICIs in combination therapies exhibited PFS surpassing the null hypothesis of independent drug action. This suggest that there is no additive or synergistic effect in patients receiving combination therapies with ICIs. Rather, these combinations provided benefits that are largely predictable from the response probabilities of each constituent therapy. CONCLUSIONS Combining ICIs with other cancer therapies provides predictable and clinically meaningful benefit by bet-hedging: providing patients with more chances of a response to any one therapy. This implies that similar benefits may in principle result from sequential treatments or biomarker-stratified choice of treatment. This insight may be most valuable in cases where toxicity prevents full-dose combinations. Citation Format: Adam C. Palmer, Peter K. Sorger, Benjamin Izar. Combinatorial benefit without synergy in recent clinical trials of immune checkpoint inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1047.

Patient-reported outcome instruments used in immune-checkpoint inhibitor clinical trials in oncology: a systematic review

ContextImmune-checkpoint inhibitors (ICI) have shown significant benefits for overall survival across various cancer types. Patient-reported outcomes (PROs) are assessed in clinical trials as a measure of efficacy. However, it remains unclear to what extent current PRO instruments capture symptoms specific to ICI toxicities. We conducted a systematic review to identify the use and content validity of PRO instruments in ICI clinical trials in oncology.MethodsLiterature was retrieved from PubMed, Embase, PsycINFO, Medline and CINAHL databases. Articles presenting ICI clinical trials’ PRO results, clinical trial study protocols, and conference abstracts stating the use of PRO measures were assessed. We evaluated the validity of identified instruments by comparing their symptom-related content with the adverse events reported in each ICI clinical trial.ResultsFrom database inception until January 2020, we identified 191 ICI clinical trials stating the use of PRO measures of which 26 published PRO results. The cancer-specific EORTC QLQ-C30 and the generic EQ-5D questionnaires were the most widely used instruments, often in combination with disease-specific PROs. Instruments used to report PRO symptom-related toxicities covered 45% of the most frequently reported AEs, whereas 23% of AEs were partially covered and 29% were not covered at all. Of non-covered AEs, 59% referred to the dermatologic system. Partially covered AEs related to endocrine and specific types of pain.ConclusionDespite the high frequency of symptom-related toxicities related to ICI, these events are only partially covered (or not addressed) by current PRO instruments, even when combined. Further research is needed to develop new strategies to tailor PRO instruments to specific ICI toxicities.

VCAN accumulation and proteolysis as predictors of T lymphocyte-excluded and permissive tumor microenvironments.

3127 Background: Immune checkpoint inhibitors (ICIs) represent a major advance for treating solid tumors. However, only a minority of patients (pts) benefit from these therapies and markers that predict response have been elusive. Versican (VCAN) is an immunosuppressive proteoglycan in the tumor microenvironment (TME), which releases an immunostimulatory N-terminal fragment versikine (Vkine) when cleaved by ADAMTS proteases. We have demonstrated in colorectal cancers (CRC) that a low VCAN/high Vkine (VCAN proteolytic predominant [VPP]) phenotype correlates with increased tumor-infiltrating CD8+ T lymphocytes (TILs). Here we examine the accumulation of VCAN as a marker of immune exclusion and its proteolysis as a marker of an immune-permissive TME. Methods: Immunohistochemistry for VCAN, Vkine and CD8+ was performed on samples from 1662 pts across breast (BC), CRC, endometrial cancer, pancreatic adenocarcinoma (PDAC), esophageal cancers and neuroendocrine tumors (NETs), across stages of disease (I-IV) and with diverse prior treatments. Stromal intensities of VCAN and Vkine staining quantified in collaboration with blinded surgical pathologists using a 0-3+ scale. 0/1+ were considered “low” for both VCAN and Vkine, whereas 2/3+ were considered “high”. The number of CD8+ TILs were counted using 400x magnification, the equivalent of a high power field (hpf). Results: Across the entire cohort VCAN phenotypes were diverse (VCAN high/Vkine low, 21%; VCAN high/Vkine high, 23%; VCAN low/Vkine low, 29%; VCAN low/Vkine high (VPP), 27%). Consistent with VCAN accumulation as a marker of T cell exclusion, VCAN low cancers had increased TILs compared to VCAN high (4.8 vs 18.3 TILs/hpf, p &lt; 0.001). Low VCAN was identified in 85% esophageal, 79% NET (including small cell lung cancer [SCLC]) 72% endometrial, 47% MSI-H CRCs, 28% triple-negative BC and only 22% MSS CRC, 18% PDAC, 17% ER+ BCs. The VPP subgroup had the highest TILs per hpf across tumors. VPP was identified in 47% of esophageal, 45% endometrial, 41% NETs (including SCLC), 24% MSI-H CRCs, and only 9% MSS CRC, 7% ER+ BCs, 3% triple-negative BCs, and 0% of PDAC (n = 131 PDAC pts). Conclusions: VCAN accumulation correlates with T lymphocyte exclusion, while VCAN proteolysis predicts an immune permissive phenotype. VCAN accumulation and proteolysis are now incorporated into ICI clinical trials as a potential marker of response. Future studies will clarify the role of these biomarkers in predicting benefits of immuno-oncology treatment strategies.

Real-world usage and outcomes for patients treated with immune checkpoint inhibitors across multiple treatment indications in the Veterans Affairs system.

e15063 Background: Increasingly broad patient groups are being treated with immune checkpoint inhibitors (ICIs) in clinical practice, but few studies have assessed their usage and outcomes in large, comprehensive real-world cohorts. In this study, we identified patients who received ICI therapy through April 2019 in the Veterans Affairs (VA) system. We described patient characteristics and assessed survival outcomes for patients across multiple treatment indications based on the cancer type and line of therapy. Methods: We conducted a retrospective analysis using electronic health record data captured from VA facilities nationwide. Patients treated with ICI were identified based on pharmacy and orders records. The associated cancer type and line of therapy (first line 1L or later line 2L+) was ascertained based on data on patients’ treatment history, administrative codes, and VA cancer registry records. The distribution of time from ICI treatment initiation to death was separately assessed by treatment indication using Kaplan-Meier estimates. Results: We identified 13,276 patients treated with ICI. The mean age was 69 years old. A majority of patients were male (97.2%) and white (76.9%), and a substantial minority were African-American (16.9%). Among patients treated with ICI for an identifiable cancer type, the most common cancer types included non-small lung cancer (NSCLC; 47.2%), melanoma (22.2%), renal cell carcinoma (RCC; 6.7%), squamous cell carcinoma of the head and neck (SCCHN; 10.4%), and urothelial cancer (6.4%). For major treatment indications, VA patients generally exhibited lower rates of survival than those reported in many ICI clinical trials, but the results are more comparable to those in trials among a subgroup of non-frail patients. Conclusions: This study describes ICI utilization and outcomes across multiple tumor types in a real-world population at the VA. The results offer evidence on the utilization and performance of ICIs in a real-world population. In addition, this work establishes a platform for further analyses of ICI outcomes in real-world practice at the VA. [Table: see text]

Longitudinal Immune and Genomic Monitoring Reveals Signatures of Immune-related Adverse Events in Cancer Patients Receiving Checkpoint Inhibitor Therapy

Abstract Despite the remarkable success of immune checkpoint inhibitor (ICI) therapy, a significant number of patients develop severe and unpredictable immune-related adverse events (irAEs) affecting a wide variety of organs. Concerns over irAE have led to the exclusion of patients with autoimmune disease from ICI clinical trials. Role of host genetic and immune factors in mediating irAEs remain unclear and it is not clear if the manifestations of irAEs is associated with response to therapy. Here, we use multi-faceted approach to characterize changes in host immune system in 200 patients receiving ICI therapy at baseline and post immunotherapy. In addition, we assessed genetic predisposition to autoimmunity using the Illumina SNP array and via targeted resequencing of over 150 immunoregulatory loci including the HLA region. In this meeting, we will present our initial genetic data, serum cytokine and autoantibody profiles and RNA sequencing on peripheral blood mononuclear cells (PBMCs) at baseline and post immunotherapy in patients with and without irAEs. Our preliminary findings suggest that patients who developed irAEs have lower baseline levels and greater post-treatment increases in key interferon gamma inducible cytokine/chemokine levels. Our autoantibody profiling data reveals unique sets of autoantibodies associated with specific irAEs. We will present a comprehensive analysis of immune and genetic correlates of irAEs and response to therapy. We hope our study can help gain insight in to the mechanisms underlying irAE and to identify biomarker signatures predictive of irAEs and/or response. These findings may ultimately help identify high-risk patients, customize therapy, expand use of immunotherapy and prevent toxicities.

Abstract P5-06-26: Gut microbiome profiling of patients with metastatic breast cancer undergoing immune checkpoint inhibitor therapy

Abstract Background: Collection of fecal samples is non-invasive, and DNA sequencing of microorganisms can provide a profile of the gut microbiome which may be an indicator of general health and disease, including inflammation, digestive inefficiencies, and the presence of pathogens. The gut microbiome has been associated with response to immune checkpoint inhibitors (ICI) in patients with solid tumors. We aim to study the association of gut microbiome and response to therapy in patients with metastatic breast cancer (BC) undergoing ICI therapies. Methods: 50 fecal samples from two ICI clinical trials (NCT02971761, N=22; NCT02778685, N=28) were collected at baseline, on treatment and at the end of treatment. DNA was extracted, and 16S rRNA gene libraries were generated targeting the variable region 4 (V4) region of the bacterial and archaeal rRNA gene. Libraries were sequenced on the Illumina MiSeq and sequence reads were analyzed using QIIME2. Results: A total of 22 dominant taxa (present ≥5% in any one sample) were identified in samples from 12 triple negative BC patients treated with pembrolizumab + GTx-024 (Enobosarm) and 17 dominant taxa were identified taxa 10 ER+ BC patients treated with pembrolizumab, letrozole, and palbociclib. As is true for most microbiome studies, inter-subject variation was much greater than intra-subject variation. However, in some patients there was a significant change in the composition of the microbial communities over time. In the first study, two patients had partial response (PR) to treatment and both had relatively “healthy” gut microbiota dominated by Bacteroides, Faecalibacterium prausnitzii, and other short chain fatty acid producers like Ruminococcus bromii or Roseburia faecis. Most of the patients who progressed had dysbiotic gut microbiomes and four had very high (≥20%) relative abundance of Prevotella copri, an organism associated with inflammation. In the second study, four patients had PR, and as before, these patients had “healthy” gut signatures dominated by Bacteroides and short chain fatty acid-producing Firmicutes. In one of these patients, a high level of Prevotella stercorea (57%)at baseline was replaced by Bacteroides and Lachnospira as treatment proceeded. Three additional patients had very high levels of P. copri (≥34%); one resolved during treatment, the others did not. Shannon’s diversity index was used to measure abundance and evenness in the fecal communities. Several samples in both studies had very low diversity at baseline. In most cases, the diversity increased following treatment. Conclusion: Most patients who progressed on ICI had dysbiotic gut microbiomes present at baseline and later time points, such as a high relative abundance of Prevotella (implicated in inflammatory processes); this often resolved during therapy. Our observations provide promise for future use of the gut microbiome as a predictor of response to immunotherapy for BC and the potential for modulating the gut microbiome to improve responses in patients with dysbiosis. Citation Format: Yuan Yuan, Sarah Highlander, Susan E Yost, Kim Robinson, Simran Padam, Aileen Tang, Norma Martinez, John Gillece, Lauren Reining, Mina Sedrak, Joanne Mortimer, James Waisman. Gut microbiome profiling of patients with metastatic breast cancer undergoing immune checkpoint inhibitor therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-26.

Immune Checkpoint Inhibitor Associated Rheumatic Adverse Events: a Review of Their Presentations and Treatments

Immune checkpoint inhibitors (ICI) are now the cornerstone of treatment for metastatic melanoma and are increasingly used in many other advanced stage malignancies. Immune checkpoint inhibitors enhance the endogenous anti-tumor response by inhibiting key regulatory pathways, facilitating robust anti-tumor responses, but often inducing a host of autoimmune toxicities which span multiple organ systems and are referred to as immune-related adverse events (irAEs). Here, we answer common questions rheumatologists may encounter in the management of these patients, including those with pre-existing autoimmune and rheumatic disease. Rheumatic irAEs including inflammatory arthritis, myositis, vasculitis, and sarcoidosis represent unique challenges for oncologists and rheumatologists in both the recognition and management of these entities. There are increasing numbers of case series and retrospective cohort studies describing the clinical and serological presentations and outcomes of patients who have developed rheumatic irAE. While in many ways similar to well established rheumatic diseases, the rheumatic irAE also appear to be different clinically, serologically, and in their response to treatment. There is also a growing body of literature on the use of ICI in patients with pre-existing autoimmune disease. While previously excluded from ICI clinical trials, the current literature would suggest that having a pre-existing autoimmune disease should not be an absolute contraindication to ICI therapy. Prompt diagnosis and treatment initiation is essential to improve patient outcomes and optimize cancer therapy. Guidelines have been developed to guide treating rheumatologists and oncologists; however, important questions remain unanswered with the majority of guidelines based on expert consensus.

Tumor Mutational Burden and Efficacy of Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis.

Tumor mutational burden (TMB) is a genomic biomarker that predicts favorable responses to immune checkpoint inhibitors (ICIs). Here, we set out to assess the predictive value of TMB on long-term survival outcomes in patients undergoing ICIs. We systematically searched PubMed, Embase, CENTRAL and clinicaltrials.gov from inception to 6 August 2019. We included retrospective studies or clinical trials of ICIs that reported hazard ratios (HRs) for overall survival (OS) and/or progression-free survival (PFS) according to TMB. Data on 5712 patients from 26 studies were included. Among patients who received ICIs, high TMB groups showed better OS (HR 0.53, 95% CI 0.42 to 0.67) and PFS (HR 0.52, 95% CI 0.40 to 0.67) compared to low TMB groups. In patients with high TMB, those who received ICIs had a better OS (HR 0.69, 95% CI 0.50 to 0.95) and PFS (HR = 0.66, 95% CI = 0.47 to 0.92) compared to those who received chemotherapy alone, while in patients with low TMB, such ICI benefits of OS or PFS were not statistically significant. In conclusion, TMB may be an effective biomarker to predict survival in patients undergoing ICI treatment. The role of TMB in identifying patient groups who may benefit from ICIs should be determined in future randomized controlled trials.

Immune checkpoint inhibitors may be safe for patients with preexisting autoimmune disease.

Immune checkpoint inhibitors may be safe for patients with preexisting autoimmune disease.

To treat or not to treat: Patient exclusion in immune oncology clinical trials due to preexisting autoimmune disease.

Newly developed immune checkpoint inhibitors (ICIs) demonstrate impressive clinical activity. However, they can also cause life-threatening side effects. The efficacy and toxicity associated with ICIs both derive from unregulated, enhanced immune activation. Health care providers have been hesitant to prescribe these medications to patients who have preexisting autoimmune disease (AD) because of concerns that this may exacerbate their underlying immune condition. These patients have also been excluded from ongoing ICI clinical trials. However, new data suggest that the potential benefits of ICI treatment may outweigh the potential risks for this patient group as long as physicians also provide sufficient monitoring for AD exacerbations or other side effects. Therefore, it may be appropriate to include patients with advanced malignancies and preexisting AD in ICI clinical trials when no other effective cancer treatment options exist. Overall, physicians should avoid excluding patients from ICI therapy unnecessarily when the potential benefits outweigh the potential risks.

Real-world prevalence of autoimmune disease (AD) among patients (pts) receiving immune checkpoint inhibitors (ICI) in ASCO’s CancerLinQ database.

6583 Background: Although pts with AD are routinely excluded from ICI clinical trials, evidence suggests they may be receiving ICI therapy once approved. We sought to understand the prevalence of AD among all pts receiving ICIs in real world clinical care, as well as in advanced non-small cell lung cancer (aNSCLC) alone, and to describe the characteristics of ICI pts with and without evidence of AD. Methods: We conducted a retrospective, observational cohort study using statistically de-identified data from January 2011 to November 2018 in CancerLinQ, ASCO’s real-world oncology database. Adult pts who received ≥ 1 dose of an ICI and had ≥ 2 clinical visits were eligible for inclusion. A sub-analysis examining only aNSCLC pts was also carried out. To reduce the likelihood of capturing pts who may have been on a clinical trial, pts were excluded if they received the ICI prior to its first FDA approval date. AD status was determined by the presence of select ICD-9/ICD-10 codes or a medication used to treat autoimmune disease (including steroids) prior to ICI treatment start date. Symphony claims data were linked to CLQ via tokenization to build out cohorts. Characteristics of pts with and without autoimmune disease were compared using Chi-square or Fisher’s exact tests. Results: Prevalence of AD was 23% (538/2425 pts) in the aNSCLC population and 27% (3407/12712 pts) in the all ICI patient population. Median age did not differ between AD pts and those with no evidence of AD (All ICI: 67.6 v 67.3 years; aNSCLC: 68.5 v 67.9). AD pts were more likely to be female (All ICI: 46% v 40%, p &lt; 0.001; aNSCLC: 55% v 44%, p &lt; 0.001). Among all ICI pts, AD pts were less likely to be Stage IV (62% v 65%) or to have melanoma (4.6% versus 8.7%) compared to pts with no evidence of AD. The most common ADs among all ICI and aNSCLC patients were glucocorticoid deficiency (6.3% and 3.9%), rheumatoid arthritis (4.2% and 5.8%), and sacroiliitis (2.7% and 3.9%), respectively. Conclusions: This analysis of real-world data finds that a large proportion of pts receiving ICI may have pre-existing AD. Further examination is warranted to examine how AD status may impact outcomes.

Rates of immunosuppressive treatment and hospitalization after checkpoint inhibitor therapy in melanoma and lung cancer patients with autoimmune diseases.

e14140 Background: Immune checkpoint inhibitors (ICIs) are known to cause immune-related adverse events. Patients with autoimmune diseases (AID) were excluded from most ICI clinical trials due to the potentially high risk of adverse effects. Data on the safety of ICIs in patients with a diagnosis of AID is therefore limited. Methods: A retrospective cohort study was conducted using a de-identified large oncology health care and pharmacy claims database with data from March 2010 until April 2017. Patients analyzed had a diagnosis of either melanoma or lung cancer and were treated with either of the anti-PD-1 inhibitors nivolumab or pembrolizumab. We assessed whether patients with AID compared with no AID were more likely to require medical interventions within 180 days of ICI therapy. We determined the percentage of patients receiving oral prednisone, IV methylprednisolone, or were hospitalized, which may represent responses to ICI toxicity. Results: 16.7% (16/96) of patients with either melanoma or lung cancer and AID received oral prednisone treatment within 180 days of ICI treatment, while 8.3% (131/1573) of patients without AID received oral prednisone during the same period. 8.4% (16/190) of patients with AID received IV methylprednisolone compared to 3.6% (79/2190) of patients without AID. Among melanoma patients, 24.1% (13/54) of patients with AID were hospitalized following ICI treatment, compared to 5.8% (28/480) of patients without ICI. Among lung cancer patients, 38.2% (52/136) of patients with AID were hospitalized compared to 31.6% (541/1711) of patients without AID. All comparisons are significant at p &lt; 0.05 except hospitalizations in lung cancer patients. Conclusions: Patients with AID were more likely to receive interventions after ICI treatment that may represent responses to immune-related adverse events, suggesting that patients with AID are at increased risk for toxicity when being treated with ICIs.

Characteristics and outcomes of patients with recurrent ovarian cancer undergoing early phase immune checkpoint inhibitor clinical trials

ObjectiveTo describe the clinical outcomes associated with the use of checkpoint inhibitor therapy in recurrent ovarian malignancy. MethodsWomen with recurrent ovarian cancer treated with an immune checkpoint inhibitor between 1/2012 and 8/2017 were included. RECIST criteria determined disease status, and immune related adverse events (irAE) were graded per trial protocols. Predictors of response, irAE, progression free survival (PFS) and overall survival (OS) were investigated. ResultsForty-four women were included with a median age of 53 years, median of 4 prior lines of chemotherapy, and most commonly high grade serous pathology (59.1%). 3 patients had partial response and 3 had pseudoprogression, for a response rate of 14.2%. In subset analysis of high grade serous (HGSOC) pathology, platinum sensitivity at time of checkpoint inhibitor therapy was correlated with response (p = 0.01). There were 28 grade 3/4 irAEs in 21 patients (47.7%). Combination therapy rather than monotherapy predicted irAE (OR 5.7, CI 1.6–20.9, p = 0.02). The most common severe irAE was elevation in hepatic or pancreatic enzymes in 12 total patients (13.6% each). Interestingly, the number of genes mutated was protective from hepatic/pancreatic AE (p = 0.02). ConclusionsWhile response rate was similar to prior literature, in patients with HGSOC platinum sensitivity at time of checkpoint inhibitor initiation was correlated to response. Grade 3/4 hepatic and pancreatic enzyme elevations were more common in ovarian cancer patients than has been previously reported in other tumor types. The number of genes mutated was inversely correlated to risk of this type of irAEs but not to total irAEs.

MS19.01 Drug-Induced Pneumonitis with IO: How worried should we be for our Lung Cancer Patients

MS19.01 Drug-Induced Pneumonitis with IO: How worried should we be for our Lung Cancer Patients

Roles of the RANKL-RANK axis in antitumour immunity - implications for therapy.

Recognizing that the transformative effects of immunotherapy are currently limited to a minority of patients with cancer, research efforts are increasingly focused on expanding and enhancing clinical responses by combining immunotherapies; the repurposing of existing drugs is an attractive approach, given their well-characterized safety and pharmacokinetic profiles. Receptor activator of nuclear factor-κB (RANK) and the RANK ligand (RANKL) were initially described in the context of T cell-dendritic cell interactions; however, the discovery of an obligate role of RANK signalling in osteoclastogenesis led to the development of the anti-RANKL antibody denosumab for antiresorptive indications, including bone metastases. Randomized clinical trials and post-marketing surveillance studies have established the acceptable safety profile of denosumab. More recently, several case reports involving patients with advanced-stage melanoma have described remarkable responses following concurrent treatment with denosumab and immune-checkpoint inhibitors. Randomized trials assessing similar combinations in patients with melanoma or renal cell carcinoma are now underway. Herein, we discuss the hallmark clinical trials of denosumab in light of possible immunological effects of this agent. We highlight the role of immune cells as sources of RANK and RANKL in the tumour microenvironment and review data on RANKL inhibition in mouse models of cancer. Finally, we describe hypothetical immune-related mechanisms of action, which could be assessed in clinical trials of immune-checkpoint inhibitors and denosumab in patients with cancer.

Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors

Immune checkpoint inhibitors (ICIs) are now a mainstay of cancer treatment. Although rare, fulminant and fatal toxic effects may complicate these otherwise transformative therapies; characterizing these events requires integration of global data. To determine the spectrum, timing, and clinical features of fatal ICI-associated toxic effects. We retrospectively queried a World Health Organization (WHO) pharmacovigilance database (Vigilyze) comprising more than 16 000 000 adverse drug reactions, and records from 7 academic centers. We performed a meta-analysis of published trials of anti-programmed death-1/ligand-1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) to evaluate their incidence using data from large academic medical centers, global WHO pharmacovigilance data, and all published ICI clinical trials of patients with cancer treated with ICIs internationally. Anti-CTLA-4 (ipilimumab or tremelimumab), anti-PD-1 (nivolumab, pembrolizumab), or anti-PD-L1 (atezolizumab, avelumab, durvalumab). Timing, spectrum, outcomes, and incidence of ICI-associated toxic effects. Internationally, 613 fatal ICI toxic events were reported from 2009 through January 2018 in Vigilyze. The spectrum differed widely between regimens: in a total of 193 anti-CTLA-4 deaths, most were usually from colitis (135 [70%]), whereas anti-PD-1/PD-L1-related fatalities were often from pneumonitis (333 [35%]), hepatitis (115 [22%]), and neurotoxic effects (50 [15%]). Combination PD-1/CTLA-4 deaths were frequently from colitis (32 [37%]) and myocarditis (22 [25%]). Fatal toxic effects typically occurred early after therapy initiation for combination therapy, anti-PD-1, and ipilimumab monotherapy (median 14.5, 40, and 40 days, respectively). Myocarditis had the highest fatality rate (52 [39.7%] of 131 reported cases), whereas endocrine events and colitis had only 2% to 5% reported fatalities; 10% to 17% of other organ-system toxic effects reported had fatal outcomes. Retrospective review of 3545 patients treated with ICIs from 7 academic centers revealed 0.6% fatality rates; cardiac and neurologic events were especially prominent (43%). Median time from symptom onset to death was 32 days. A meta-analysis of 112 trials involving 19 217 patients showed toxicity-related fatality rates of 0.36% (anti-PD-1), 0.38% (anti-PD-L1), 1.08% (anti-CTLA-4), and 1.23% (PD-1/PD-L1 plus CTLA-4). In the largest evaluation of fatal ICI-associated toxic effects published to date to our knowledge, we observed early onset of death with varied causes and frequencies depending on therapeutic regimen. Clinicians across disciplines should be aware of these uncommon lethal complications.

Adverse events and responses in patients with recurrent ovarian cancer undergoing early-phase immune checkpoint inhibitor clinical trials

Adverse events and responses in patients with recurrent ovarian cancer undergoing early-phase immune checkpoint inhibitor clinical trials