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Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis; as described in the ASCO Guidelines Methodology Manual . ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines . Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating provider and do not account for individual variation among patients. See appendix for disclaimers and other important information ( Appendix 1 and Appendix 2 ). Updates are published regularly and can be found at https://ascopubs.org/nsclc-non-da-living-guideline .

Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual . ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines . Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating provider and do not account for individual variation among patients. See appendix for disclaimers and other important information ( Appendix 1 and Appendix 2 ). Updates are published regularly and can be found at https://ascopubs.org/nsclc-non-da-living-guideline .

Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual . ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines . Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating provider and do not account for individual variation among patients. See Appendix 1 (online only) for disclaimers and other important information. Updates are published regularly and can be found at https://ascopubs.org/nsclc-da-living-guideline .

Purpose:Treatment options are limited in patients with metastatic neuroendocrine neoplasms (NEN). We present the results for a phase II trial of combination nivolumab and temozolomide in patients with advanced NEN along with results of immune changes in peripheral blood.Patients and Methods:NCT03728361 is a nonrandomized, phase II study of nivolumab and temozolomide in patients with NEN. The primary endpoint was response rate using RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Immune profiling was performed by mass cytometry to evaluate the effect on peripheral blood immune cell subsets.Results:Among all 28 patients with NEN, the confirmed response rate was 9/28 [32.1%, 95% confidence interval (CI): 15.9–52.4]. Of 11 patients with lung NEN, the response rate was 64% (n = 7); there was a significant difference in responses by primary tumor location (lung vs. others, P = 0.020). The median PFS was 8.8 months (95% CI: 3.9–11.1 months), and median OS was 32.3 months (95% CI: 20.7—not reached months). Exploratory blood immune cell profiling revealed an increase in circulating CD8+ T cells (27.9% ± 13.4% vs. 31.7% ± 14.6%, P = 0.03) and a decrease in CD4+ T cells (59.6% ± 13.1% vs. 56.5% ± 13.0%, P = 0.001) after 2 weeks of treatment. LAG-3–expressing total T cells were lower in patients experiencing a partial response (0.18% ± 0.24% vs. 0.83% ± 0.55%, P = 0.028). Myeloid-derived suppressor cell levels increased during the study and did not correlate with response.Conclusions:Combination nivolumab and temozolomide demonstrated promising activity in NEN.See related commentary by Velez and Garon, p. 691

Immune checkpoint inhibitors (ICIs) are associated with a unique set of immune-related adverse events (irAEs). Few studies have evaluated the risk factors and outcomes of patients who develop ICI-induced hepatitis (ICIH).We utilized an institutional database of patients with advanced cancers treated with ICI to identify patients with ICIH. irAEs were graded using the Common Terminology Criteria for Adverse Events v4. Overall survival (OS) was calculated from the date of ICI to death from any cause or the date of the last follow-up. OS with 95% confidence intervals were estimated using the Kaplan-Meier method and stratified by the occurrence of ICIH.We identified 1096 patients treated with ICI. The most common ICIs were PD1/L1 (n = 774) and CTLA-4 inhibitors (n = 195). ICIH occurred among 64 (6%) patients: severity was grade 3 in 30 and ≥ grade 3 in 24 patients (3.1% overall). Median time to ICIH was 63 days. ICIH was more frequent in women (p = 0.038), in patients treated with combination ICIs (p 0.001), and when given as first-line therapy (p = 0.018). Occurrence of ICIH was associated with significantly longer OS, median 37.0 months (95% CI 21.4, NR) compared to 11.3 months (95% CI 10, 13, p 0.001); there was no difference in OS between patients with ≥ grade 3 ICIH vs grade 1-2.Female sex, combination immunotherapy, and the first line of immunotherapy were associated with ICIH. Patients with ICIH had improved clinical survival compared to those that did not develop ICIH. There is a need for prospective further studies to confirm our findings.

The prevalence of obesity, defined as the body mass index (BMI) ≥ 30 kg/m2, has reached epidemic levels. Obesity is associated with an increased risk of various cancers, including gastrointestinal ones. Recent evidence has suggested that obesity disproportionately impacts males and females with cancer, resulting in varied transcriptional and metabolic dysregulation. This study aimed to elucidate the differences in the metabolic milieu of adenocarcinomas of the gastrointestinal (GI) tract both related and unrelated to sex in obesity. To demonstrate these obesity and sex-related effects, we utilized three primary data sources: serum metabolomics from obese and non-obese patients assessed via the Biocrates MxP Quant 500 mass spectrometry-based kit, the ORIEN tumor RNA-sequencing data for all adenocarcinoma cases to assess the impacts of obesity, and publicly available TCGA transcriptional analysis to assess GI cancers and sex-related differences in GI cancers specifically. We applied and integrated our unique transcriptional metabolic pipeline in combination with our metabolomics data to reveal how obesity and sex can dictate differential metabolism in patients. Differentially expressed genes (DEG) analysis of ORIEN obese adenocarcinoma as compared to normal-weight adenocarcinoma patients resulted in large-scale transcriptional reprogramming (4029 DEGs, adj. p < 0.05 and |logFC| > 0.58). Gene Set Enrichment and metabolic pipeline analysis showed genes enriched for pathways relating to immunity (inflammation, and CD40 signaling, among others) and metabolism. Specifically, we found alterations to steroid metabolism and tryptophan/kynurenine metabolism in obese patients, both of which are highly associated with disease severity and immune cell dysfunction. These findings were further confirmed using the TCGA colorectal adenocarcinoma (CRC) and esophageal adenocarcinoma (ESCA) data, which showed similar patterns of increased tryptophan catabolism for kynurenine production in obese patients. These patients further showed disparate alterations between males and females when comparing obese to non-obese patient populations. Alterations to immune and metabolic pathways were validated in six patients (two obese and four normal weight) via CD8+/CD4+ peripheral blood mononuclear cell RNA-sequencing and paired serum metabolomics, which showed differential kynurenine and lipid metabolism, which corresponded with altered T-cell transcriptome in obese populations. Overall, obesity is associated with differential transcriptional and metabolic programs in various disease sites. Further, these alterations, such as kynurenine and tryptophan metabolism, which impact both metabolism and immune phenotype, vary with sex and obesity together. This study warrants further in-depth investigation into obesity and sex-related alterations in cancers that may better define biomarkers of response to immunotherapy.

Background: The prevalence of obesity, defined as body mass index (BMI) ≥ 30 kg/m2, has reached epidemic levels. Obesity is associated with an increased risk of various cancers, including gastrointestinal ones. Recent evidence has suggested that obesity disproportionately impacts males and females with cancer, resulting in varied transcriptional and metabolic dysregulation. Methods: This study aimed to elucidate the differences in the metabolic milieu of adenocarcinomas of the gastrointestinal (GI) track both related and unrelated to sex in obesity. To demonstrate these obesity and sex-related effects, we utilized three primary data sources: serum metabolomics from obese and non-obese patients assessed via the Biocrates MxP Quant 500 mass spectrometry-based kit, the ORIEN tumor RNA-sequencing data for all adenocarcinoma cases to assess the impacts of obesity, and publicly available TCGA transcriptional analysis to assess GI cancers and sex-related differences in GI cancers specifically. We applied and integrated our unique transcriptional metabolic pipeline in combination with our metabolomics data to reveal how obesity and sex can dictate differential metabolism in patients. Results: Differentially expressed genes (DEG) analysis of ORIEN obese adenocarcinoma as compared to normal-weight adenocarcinoma patients resulted in large-scale transcriptional reprogramming (4029 DEGs, adj. p < 0.05 and |logFC|>0.58). Gene Set Enrichment and metabolic pipeline analysis showed genes enriched for pathways relating to immunity (inflammation, and CD40 signaling, among others) and metabolism. Specifically, we found alterations to steroid metabolism and tryptophan/kynurenine metabolism in obese patients, both of which are highly associated with disease severity and immune cell dysfunction. These findings were further confirmed using the TCGA colorectal adenocarcinoma (CRC) and esophageal adenocarcinoma (ESCA) data, which showed similar patterns of increased tryptophan catabolism for kynurenine production in obese patients. These patients further showed disparate alterations between males and females when comparing obese to non-obese patient populations. Alterations to immune and metabolic pathways were validated in 6 patients (2 obese and 4 normal weight) via CD8+/CD4+ peripheral blood mononuclear cell RNA-sequencing and paired serum metabolomics, which showed differential kynurenine and lipid metabolism, which corresponded with altered T-cell transcriptome in obese populations. Conclusions: Overall, obesity is associated with differential transcriptional and metabolic program in various disease sites. Further, these alterations, like kynurenine and tryptophan metabolism, which impact both metabolism and immune phenotype, vary with sex and obesity together. This study warrants further in-depth investigation into obesity and sex-related alterations in cancers that may better define biomarkers of response to immunotherapy.

Background We investigated the role of A2B-adenosine receptor (A2BAR) in regulating immunosuppressive metabolic stress in the tumor microenvironment (TME). Novel A2BAR antagonist PBF-1129 was tested for anti-tumor activity in animals and evaluated for safety and immunological efficacy in a phase-I clinical trial in non-small-cell lung cancer (NSCLC) patients. Methods Anti-tumor efficacy of A2BAR antagonists and impact on metabolic and immune TME was evaluated in lung, melanoma, colon, breast and EGFR-inducible transgenic cancer models. Employing Electron Paramagnetic Resonance, we assessed changes in TME metabolic parameters including pO2, pH, and inorganic phosphate (Pi) during tumor growth and evaluated the immunological effects of PBF-1129, including its pharmacokinetics, safety, and toxicity in NSCLC patients. Results Levels of metabolic stress correlated with tumor growth, metastasis, and immunosuppression. Tumor interstitial Pi emerged as a correlative and cumulative measure of TME stress and immunosuppression. A2BAR inhibition alleviated metabolic stress, downregulated expression of adenosine-generating ecto-nucleotidases, increased expression of adenosine deaminase (ADA), decreased tumor growth and metastasis, increased IFN-γ-production and enhanced the efficacy of anti-tumor therapies following combination regimens in animal models (anti-PD-1 vs. anti-PD-1 plus PBF-1129 treatment hazard ratio [HR] = 11.74, 95% CI = 3.35 to 41.13, n = 10, P Conclusions Data identify A2BAR as a valuable therapeutic target to modify metabolic and immune TME to reduce immunosuppression, enhance the efficacy of immunotherapies, and support clinical application of PBF-1129 in combination therapies.

PURPOSE Compared with people living without HIV (PWOH), people living with HIV (PWH) and cancer have traditionally been excluded from immune checkpoint inhibitor (ICI) trials. Furthermore, there is a paucity of real-world data on the use of ICIs in PWH and cancer. METHODS This retrospective study included PWH treated with anti–PD-1- or anti–PD-L1-based therapies for advanced cancers. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates (ORRs) were measured per RECIST 1.1 or other tumor-specific criteria, whenever feasible. Restricted mean survival time (RMST) was used to compare OS and PFS between matched PWH and PWOH with metastatic NSCLC (mNSCLC). RESULTS Among 390 PWH, median age was 58 years, 85% (n = 331) were males, 36% (n = 138) were Black; 70% (n = 274) received anti–PD-1/anti–PD-L1 monotherapy. Most common cancers were NSCLC (28%, n = 111), hepatocellular carcinoma ([HCC]; 11%, n = 44), and head and neck squamous cell carcinoma (HNSCC; 10%, n = 39). Seventy percent (152/216) had CD4+ T cell counts ≥200 cells/µL, and 94% (179/190) had HIV viral load CONCLUSION Among PWH, ICIs demonstrated differential activity across cancer types with no excess toxicity. Safety and activity of ICIs were similar between matched cohorts of PWH and PWOH with mNSCLC.

Objectives Immune checkpoint inhibitor immunotherapy (IO) is revolutionizing cancer care but can lead to significant toxicity. This study seeks to describe potential risk factors for immune-related adverse events (irAEs) specifically among older adults. Materials and Methods This was a retrospective study at a single academic comprehensive cancer center based on chart review data abstracted by physicians. For patients aged ≥70 years, frequency, type, and grade of irAEs and their association with baseline patient demographics, comorbidities, mobility, and functional status were characterized using bivariate analysis. Based on those results, multivariable logistic regressions were constructed to model the association between these characteristics with any grade and grade 3 or higher irAEs. Results Data were analyzed for 238 patients aged ≥70 years who received IO for mostly (≥90%) advanced cancer between 2011 and 2018. Thirty-nine percent of older adults experienced an irAE and 13% experienced one that was grade 3 or higher. In the multivariable analysis, depression was associated with an increased incidence of any grade irAE, while decreased life-space mobility was associated with an increased incidence of grade ≥3 irAEs. Conclusion Most characteristics of special interest among older adults, include fall risk, weight loss, cognitive limitations, and hearing loss, were not associated with irAEs in our study. However, decreased life-space mobility and depression are potential risk factors for IO toxicity among older adults with advanced cancer. Interventions designed to evaluate and mitigate modifiable risk factors for treatment-related toxicity are needed, and the results of this study may be useful for guiding those efforts.

Molecular modifiers of KRAS G12C inhibitor (KRAS G12Ci) efficacy in advanced KRAS G12C-mutant NSCLC are poorly defined. In a large unbiased clinico-genomic analysis of 424 NSCLC patients, we identified and validated co-alterations in KEAP1, SMARCA4 and CDKN2A as major independent determinants of inferior clinical outcomes with KRAS G12Ci monotherapy. Collectively, co-mutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ~50% of those with early disease progression (PFS≤3 months) with KRAS G12Ci. Pathway-level integration of less prevalent co-alterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRAS G12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRAS G12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRAS G12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies.

Water plot of best response in lung NEN.

Evaluation of circulating CD8+ cell subsets. (A) Changes in levels of circulating CD8+ naïve (CD45RA+ CCR7+), central memory (CM; CD45RA- CCR7+), effector memory (EM; CD45RA- CCR7-), and terminal effector memory (TE; CD45RA+ CCR7-) subsets at screening and cycle 1, day 15 (C1D15) of nivolumab and temozolomide treatment in the entire study cohort. (B) Levels of co-inhibitory molecules PD-1, LAG3, TIM3, and KLRG1 on circulating CD8+ T cells on study treatment compared to screening. Each symbol represents one patient (n = 9). Line indicates mean, *p

Evaluation of circulating MDSC. (A) Changes in total MDSC and (B) monocytic (M-MDSC) and granulocytic (G-MDSC) subsets at cycle 1, day 15 (C1D15) compared to screening in the entire patient cohort. (C) Levels of circulating MDSC at screening by clinical response and changes during study treatment compared to screening in partial response (PR, orange) and stable disease (SD, green) patients. Each symbol represents one patient (n = 9). Line indicates mean.

Evaluation of co-inhibitory molecules by patient response. Total T cells at screening and C1D15 were identified as being CD4+ or CD8+ and patients were grouped by best clinical response as partial response (PR) or non-PR. The percentage of each T cell subset expressing (A) PD-1, (B) LAG3, (C) TIM3, and (D) KLRG3 at screening and C1D15 are shown. * p < 0.05.

Evaluation of circulating CD4+ T cell subsets. (A) Changes in regulatory T cells (Tregs) during treatment compared to screening in the entire patient cohort. (B) Changes in levels of circulating CD4+ naïve (CD45RA+ CCR7+), central memory (CM; CD45RA- CCR7+), effector memory (EM; CD45RA- CCR7-), and terminal effector memory (TE; CD45RA+ CCR7-) subsets at screening and cycle 1, day 15 (C1D15) of nivolumab and temozolomide treatment in the entire study cohort. (C) Levels of co-inhibitory molecules PD-1, LAG3, TIM3, and KLRG1 on circulating CD4+ T cells on study treatment compared to screening. Each symbol represents one patient (n = 9). Line indicates mean, *p

Purpose:Treatment options are limited in patients with metastatic neuroendocrine neoplasms (NEN). We present the results for a phase II trial of combination nivolumab and temozolomide in patients with advanced NEN along with results of immune changes in peripheral blood.Patients and Methods:NCT03728361 is a nonrandomized, phase II study of nivolumab and temozolomide in patients with NEN. The primary endpoint was response rate using RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Immune profiling was performed by mass cytometry to evaluate the effect on peripheral blood immune cell subsets.Results:Among all 28 patients with NEN, the confirmed response rate was 9/28 [32.1%, 95% confidence interval (CI): 15.9–52.4]. Of 11 patients with lung NEN, the response rate was 64% (n = 7); there was a significant difference in responses by primary tumor location (lung vs. others, P = 0.020). The median PFS was 8.8 months (95% CI: 3.9–11.1 months), and median OS was 32.3 months (95% CI: 20.7—not reached months). Exploratory blood immune cell profiling revealed an increase in circulating CD8+ T cells (27.9% ± 13.4% vs. 31.7% ± 14.6%, P = 0.03) and a decrease in CD4+ T cells (59.6% ± 13.1% vs. 56.5% ± 13.0%, P = 0.001) after 2 weeks of treatment. LAG-3–expressing total T cells were lower in patients experiencing a partial response (0.18% ± 0.24% vs. 0.83% ± 0.55%, P = 0.028). Myeloid-derived suppressor cell levels increased during the study and did not correlate with response.Conclusions:Combination nivolumab and temozolomide demonstrated promising activity in NEN.See related commentary by Velez and Garon, p. 691

Supplementary Table 1: Most common treatment related adverse events; Supplementary Table 2: Treatment related serious adverse events; Supplementary Table 3: Mass Cytometry (CyTOF) panel; Supplementary Table 4: Mass cytometry gating of immune cell populations; Supplementary Table 5. Representativeness of Study Participants.

TEAEs and TRAEs occurring in pts with intracranial disease

LIBRETTO-001 Trial Profile

Purpose:We report the intracranial efficacy of selpercatinib, a highly potent and selective RET inhibitor, approved in the United States for RET fusion-positive non–small cell lung cancers (NSCLC).Patients and Methods:In the global phase 1/2 LIBRETTO-001 trial (NCT03157128) in advanced RET-altered solid tumors, selpercatinib was dosed orally (160 mg twice every day) in 28-day cycles. Patients with baseline intracranial metastases had MRI/CT scans every 8 weeks for 1 year (12 weeks thereafter). In this pre-planned analysis of patients with RET fusion-positive NSCLC with baseline intracranial metastases, the primary endpoint was independently assessed intracranial objective response rate (ORR) per RECIST 1.1. Secondary endpoints included intracranial disease control rate, intracranial duration of response, and intracranial progression-free survival (PFS) independently reviewed.Results:Eighty patients with NSCLC had brain metastases at baseline. Patients were heavily pretreated (median = 2 systemic therapies, range = 0–10); 56% of patients received ≥1 course of intracranial radiation (14% whole brain radiotherapy, 45% stereotactic radiosurgery). Among 22 patients with measurable intracranial disease at baseline, intracranial ORR was 82% [95% confidence interval (CI), 60–95], including 23% with complete responses. Among all intracranial responders (measurable and nonmeasurable, n = 38), median duration of intracranial response was not reached (95% CI, 9.3–NE) at a median duration of follow-up of 9.5 months (IQR = 5.7, 12.0). At 12 months, 55% of intracranial responses were ongoing. In all 80 patients, median intracranial PFS was 13.7 months (95% CI, 10.9–NE) at a median duration of follow-up of 11.0 months (IQR = 7.4, 16.5). No new safety signals were revealed in patients with brain metastases compared with the full NSCLC trial population.Conclusions:Selpercatinib has robust and durable intracranial efficacy in patients with RET fusion-positive NSCLC.

LIBRETTO-001 Investigators List

Treatment options are limited in patients with metastatic neuroendocrine neoplasms (NENs). We present the results for a phase 2 trial of combination nivolumab and temozolomide in patients with advanced NEN along with results of immune changes in peripheral blood.NCT03728361 is a nonrandomized, phase 2 study of nivolumab and temozolomide in patients with NEN. The primary endpoint was response rate using RECIST 1.1. Secondary endpoints included progression free survival (PFS), overall survival (OS), and safety. Immune profiling was performed by mass cytometry to evaluate the effect on peripheral blood immune cell subsets.Among all 28 patients with NEN, the confirmed response rate was 9/28 (32.1%, 95% CI: 15.9%-52.4%). Of 11 patients with lung NEN, the response rate was 64% (n=7); there was a significant difference in responses by primary tumor location (lung vs others, p=0.020). The median PFS was 8.8 months (95% CI: 3.9 - 11.1 months), and median OS was 32.3 months (95% CI: 20.7 - NR months). Exploratory blood immune cell profiling revealed an increase in circulating CD8+ T cells (27.9±13.4% vs. 31.7±14.6%, p = 0.03) and decrease in CD4+ T cells (59.6±13.1% vs. 56.5±13.0%, p = 0.001) after 2 weeks of treatment. LAG-3 expressing total T cells were lower in patients experiencing a partial response (0.18±0.24% vs 0.83±0.55%, p = 0.028). MDSC levels increased during study and did not correlate with response.Combination nivolumab and temozolomide demonstrated promising activity in NEN.

Background Monoclonal antibody (mAb) immune checkpoint inhibitor (ICI) therapies have dramatically impacted oncology this past decade. However, only about one‐third of patients respond to treatment, and biomarkers to predict responders are lacking. Recent ICI clinical pharmacology data demonstrate high baseline drug clearance (CL0) significantly associates with shorter overall survival, independent of ICI exposure, in patients receiving ICI mAb therapies. This suggests CL0 may predict outcomes from ICI therapy, and cachectic signalling may link elevated CL0 and poor response. Our aim was to determine if mouse models of cancer cachexia will be useful for studying these phenomena and their underlying mechanisms. Methods We evaluated pembrolizumab CL in the C26 and Lewis lung carcinoma mouse models of cancer cachexia. A single treatment of vehicle or pembrolizumab, at a dose of 2 or 10 mg/kg, was administered intravenously by tail vein injection. Pembrolizumab was quantified by an ELISA in serial plasma samples, and FcRn gene (Fcgrt) expression was assessed in liver using real‐time quantitative reverse transcription PCR. Non‐compartmental and mixed‐effects pharmacokinetics analyses were performed. Results We observed higher pembrolizumab CL0 and decreased Fcgrt expression in whole liver tissue from tumour‐bearing vs. tumour‐free mice. In multivariate analysis, presence of tumour, total murine IgG, muscle weight and Fcgrt expression were significant covariates on CL, and total murine IgG was a significant covariate on V1 and Q. Conclusions These data demonstrate increases in catabolic clearance of monoclonal antibodies observed in humans can be replicated in cachectic mice, in which Fcgrt expression is also reduced. Notably, FcRn activity is essential for proper antigen presentation and antitumour immunity, which may permit the study of cachexia's impact on FcRn‐mediated clearance and efficacy of ICI therapies.

Structured Abstract: Background Immune checkpoint inhibitors are now an approved treatment for patients with extensive- stage small cell lung cancer (SCLC), an aggressive and incurable malignancy. However, the median survival for patients remains around 1 year, and treatment in the second line and beyond is associated with a low likelihood of response. There currently are no data regarding the optimal treatment of patients who progress on upfront chemo-immunotherapy, and biomarkers are needed to aid patient selection. Obtaining sufficient tissue for advanced molecular testing is a challenge in SCLC due to often limited or crushed tissue specimens. Reliable blood based biomarkers may augment tissue based testing and allow for repeated assessments that is often not possible with tumor tissue, and changes in the peripheral blood may provide information regarding the tumor microenvironment. Myeloid-derived suppressor cells (MDSC) exert immunosuppressive function and have been investigated as a potential barrier to response to immune checkpoint inhibitor (ICI) therapy. Here we demonstrate that MDSC level and function can be readily assessed in the peripheral blood at multiple time points during treatment with combination immunotherapy and temozolomide. Results This report represents the first case of a patient with refractory SCLC treated with combination nivolumab and temozolomide as part of a clinical trial (NCT03728361), who sustained a deep and durable clinical response that was accompanied by an early decrease in MDSC and improved T cell function (increased CD8+ and CD4+ T cell proliferation). We review the literature regarding use of ICI in SCLC and the evidence supporting MDSC as a possible target to enhance the activity of immunotherapy, and emphasize the importance of assessing immune cell subsets as correlative studies in clinical trials. Conclusion An assessment of MDSC level and function during treatment, as well as other immune cell subsets, should be included in prospective studies to further evaluate these assays as possible blood-based biomarkers.

Background Next-generation sequencing of circulating cell-free DNA (cfDNA) can identify sensitizing and resistance mutations in non–small-cell lung cancer (NSCLC). cfDNA is helpful when tissue is insufficient for genomic testing or repeat biopsy is not feasible or poses unacceptable risk. Here we report the experience of cfDNA testing at the time of diagnosis and how this intervention can help avoid further invasive interventions, how it can be used to determine initiation of therapy, and how variation allele frequency of the somatic alteration affects response to subsequent treatment. Patients and Methods This is a single-institution retrospective study of patients with advanced NSCLC who had cfDNA from plasma tested using the Guardant360 panel, which identifies somatic genomic alterations by massive parallel sequencing of target genes. An institutional Clinical Laboratory Improvement Amendments tissue panel using fluorescence in situ hybridization (for MET, RET, ROS1, and ALK) and next-generation sequencing for selected genes was used for tissue analysis. Actionable mutations are those with US Food and Drug Administration–approved targeted therapies (EGFR, ALK, ROS, BRAF, NTRK fusions) or therapies soon to be approved (RET fusions and MET amplifications, or MET exon 14 skipping mutation). Results A total of 163 blood samples from 143 patients were evaluated, 82 at diagnosis and 81 at disease progression. A total of 94 cases had tissue and cfDNA testing performed within 12 weeks of each other. Seventy-six (81%) of 94 cases were concordant, of which 22 cases were concordantly positive and 54 concordantly negative. Eighteen (19%) of 94 cases were discordant, of which 11 had negative blood and positive tissue results, and 7 had positive blood and negative tissue results. cfDNA testing had a sensitivity of 67% (95% confidence interval [CI], 51%, 83%), specificity of 89% (95% CI, 81%, 97%), negative predictive value of 83% (95% CI, 74%, 92%), and positive predictive value of 76% (95% CI, 60%, 91%). Nineteen (21%) of 82 cfDNA samples analyzed at diagnosis had actionable mutations identified (4 EGFR exon 19 deletion, 2 EGFR exon 21 L858R, 2 EGFR L861Q, 1 L861R, 4 EML4-ALK fusion, 2 CD74-ROS1 fusion, 2 MET exon 14 skipping mutation, 2 KIF5B-RET fusion). Of the 82 patients with cfDNA testing performed at the time of diagnosis, 8 patients (10%) initiated targeted therapy on the basis of cfDNA results only, with 6 patients experiencing partial response, 1 patient complete response, and 1 patient stable disease. The response rate for patients who initiated targeted therapies on the basis of cfDNA only at diagnosis was 88%. Variant allele frequency had no impact on response. Conclusions Initiation of targeted therapy for advanced NSCLC was feasible based only on identification of actionable mutations by cfDNA testing in 9% of the cases for which tissue diagnosis could not be obtained. Actionable targets were identified by cfDNA in 20% of the samples sent at diagnosis. A substantial number of patients benefited from cfDNA testing at initial diagnosis because it identified actionable mutations that led to appropriate targeted treatments.

OBJECTIVES: Despite growing evidence that checkpoint inhibitor immunotherapy (IO) toxicity is associated with improved treatment response, the relationship between immune-related adverse events (irAEs) and overall survival (OS) among older adults [age ≥ 70 years (y)] remains unknown. The study goal was to determine differences in OS based on age and ≥ grade 3 (G3) irAEs. MATERIALS AND METHODS: This was a retrospective cohort study of 673 patients with advanced cancer. Patients who received ≥1 dose of IO at our institution from 2011–2018 were eligible. The primary outcome was OS from the start of first line of IO treatment, compared between four patient groups stratified by age and ≥G3 irAEs with adjustment for patient characteristics using a Cox proportional hazards model. RESULTS AND CONCLUSION: Among all 673 patients, 35.4% were ≥70y, 39.8% had melanoma, and 45.6% received single-agent nivolumab. Incidence and types of ≥G3 irAEs did not differ by age. Median OS was significantly longer for all patients with ≥G3 irAEs (unadjusted 21.7 vs. 11.9 months, P=0.007). There was no difference in OS among patients ≥70y with ≥G3 irAEs (HR 0.94, 95% CI 0.61–1.47, P=0.79) in the multivariable analysis. Patients

The neonatal Fc receptor (FcRn) is responsible for recycling of IgG antibodies and albumin throughout the body. This mechanism has been exploited for pharmaceutic delivery across an array of diseases to either enhance or diminish this function. Monoclonal antibodies and albumin-bound nanoparticles are examples of FcRn-dependent anti-cancer therapeutics. Despite its importance in drug delivery, little is known about FcRn expression in circulating immune cells. Through time-of-flight mass cytometry (CyTOF) we were able to characterize FcRn expression in peripheral blood mononuclear cell (PBMC) populations of pancreatic ductal adenocarcinoma (PDAC) patients and non-cancer donors. Furthermore, we were able to replicate these findings in an orthotopic murine model of PDAC. Altogether, we found that in both patients and mice with PDAC, FcRn was elevated in migratory and resident classical dendritic cell type 2 (cDC2) as well as monocytic and granulocytic myeloid-derived suppressor cell (MDSC) populations compared to tumor-free controls. Furthermore, PBMCs from PDAC patients had elevated monocyte, dendritic cells and MDSCs relative to non-cancer donor PBMCs. Future investigations into FcRn activity may further elucidate possible mechanisms of poor efficacy of antibody immunotherapies in patients with PDAC.

BackgroundImmune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer.MethodsWe collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI.ResultsICPi-AKI occurred at a median of 16 weeks (IQR 8–32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3–10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI.ConclusionsPatients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery.

The aim of this retrospective study was to demonstrate that irAEs, specifically gastrointestinal and pulmonary, examined through International Classification of Disease (ICD) data leads to underrepresentation of true irAEs and overrepresentation of false irAEs, thereby concluding that ICD claims data are a poor approach to electronic health record (EHR) data mining for irAEs in immunotherapy clinical research. This retrospective analysis was conducted in 1,063 cancer patients who received ICIs between 2011 and 2017. We identified irAEs by manual review of medical records to determine the incidence of each of our endpoints, namely colitis, hepatitis, pneumonitis, other irAE, or no irAE. We then performed a secondary analysis utilizing ICD claims data alone using a broad range of symptom and disease-specific ICD codes representative of irAEs. 16% (n = 174/1,063) of the total study population was initially found to have either pneumonitis 3% (n = 37), colitis 7% (n = 81) or hepatitis 5% (n = 56) on manual review. Of these patients, 46% (n = 80/174) did not have ICD code evidence in the EHR reflecting their irAE. Of the total patients not found to have any irAEs during manual review, 61% (n = 459/748) of patients had ICD codes suggestive of possible irAE, yet were not identified as having an irAE during manual review. Examining gastrointestinal and pulmonary irAEs through the International Classification of Disease (ICD) data leads to underrepresentation of true irAEs and overrepresentation of false irAEs.