PD-1 Inhibitor Therapy Research Articles

P1.09-21 Tumor Responses Based on Tumor Growth Rate During PD-1 Inhibitor Therapy in Advanced Non-Small-Cell Lung Cancer Patients

P1.09-21 Tumor Responses Based on Tumor Growth Rate During PD-1 Inhibitor Therapy in Advanced Non-Small-Cell Lung Cancer Patients

IBS09.02 Immunotherapy for Small Cell and Neuroendocrine Tumors

A subset of patients with small cell lung cancer (SCLC) will achieve significant benefit from immunotherapy. Both nivolumab and pembrolizumab have demonstrated responses in patients with advanced SCLC, and atezolizumab in combination with chemotherapy results in an improvement in overall survival (OS) compared to chemotherapy alone. However, the ability to translate findings from the laboratory into patient care has been limited by several challenges. Though some patients will have durable response to PD-1 or PD-L1 agents, the majority of patients will not benefit. Combination strategies have been proposed and subsequently tested to potentially improve outcomes. Although ipilimumab was not effective as a single-agent for patients with SCLC, it has been combined with nivolumab in a phase I trial. The combination appears to be promising with response rates and OS that numerically exceeds that of single-agent PD-1 inhibitor therapy, although a randomized comparison trial has not yet been performed. Still, the majority of patients will not respond to the combination of PD-1 and CTLA-4 inhibition. Other immunotherapy targets have been explored pre-clinically though none have proven to be effective in patients to date. Another challenge in improving outcomes for patients with SCLC is that predictive biomarkers have been elusive. In contrast to non-small cell lung cancer, SCLCs rarely express PD-L1 on tumor cells and its presence has limited predictive value. However, immune cells in the tumor microenvironment more commonly express PD-L1 and may be predictive of benefit from immunotherapy. High tumor mutation burden (TMB) is also found in the majority of patients with SCLC likely due to the heavy smoking history in most patients with the disease. Patients with SCLC with a high TMB have been shown to have better outcomes with PD-1 inhibitors that those with lower TMB, however even those with the highest TMB have a fairly low chance of response or prolonged survival. Despite PD-L1 expression on immune cells and high TMB in most tumors, frequency of tumor infiltrating lymphocytes (TILs) is typically low in SCLC, possibly explaining the lack of response to immunotherapy in most patients with this disease. The benefit of immunotherapy for a subset of patients with SCLC has been proven, yet we are still faced with several challenges to optimize this treatment, including finding effective combination strategies that benefit more patients and developing predictive biomarkers to select those who are most likely to benefit. SCLC, immunotherapy

Development of an Adrenocortical Cancer Humanized Mouse Model to Characterize Anti-PD1 Effects on Tumor Microenvironment.

Although the development of immune checkpoint inhibitors has transformed treatment strategies of several human malignancies, research models to study immunotherapy in adrenocortical carcinoma (ACC) are lacking. To explore the effect of anti-PD1 immunotherapy on the alteration of the immune milieu in ACC in a newly generated preclinical model and correlate with the response of the matched patient. To characterize the CU-ACC2-M2B patient-derived xenograft in a humanized mouse model, evaluate the effect of a PD-1 inhibitor therapy, and compare it with the CU-ACC2 patient with metastatic disease. Characterization of the CU-ACC2-humanized cord blood-BALB/c-Rag2nullIl2rγnullSirpaNOD model confirmed ACC origin and match with the original human tumor. Treatment of the mice with pembrolizumab demonstrated significant tumor growth inhibition (60%) compared with controls, which correlated with increased tumor infiltrating lymphocyte activity, with an increase of human CD8+ T cells (P < 0.05), HLA-DR+ T cells (P < 0.05) as well as Granzyme B+ CD8+ T cells (<0.001). In parallel, treatment of the CU-ACC2 patient, who had progressive disease, demonstrated a partial response with 79% to 100% reduction in the size of target lesions, and no new sites of metastasis. Pretreatment analysis of the patient's metastatic liver lesion demonstrated abundant intratumoral CD8+ T cells by immunohistochemistry. Our study reports the first humanized ACC patient-derived xenograft mouse model, which may be useful to define mechanisms and biomarkers of response and resistance to immune-based therapies, to ultimately provide more personalized care for patients with ACC.

Successful combination therapy of systemic checkpoint inhibitors and intralesional interleukin-2 in patients with metastatic melanoma with primary therapeutic resistance to checkpoint inhibitors alone.

Systemic immunotherapy with PD-1 inhibitors is established in the treatment of metastatic melanoma. However, up to 60% of patients do not show long-term benefit from a PD-1 inhibitor monotherapy. Intralesional treatments with immunomodulatory agents such as the oncolytic herpes virus Talimogene Laherparepvec and interleukin-2 (IL-2) have been successfully used in patients with injectable metastases. Combination therapy of systemic and local immunotherapies is a promising treatment option in melanoma patients. We describe a case series of nine patients with metastatic melanoma and injectable lesions who developed progressive disease under a PD-1 inhibitor monotherapy. At the time of progressive disease, patients received intratumoral IL-2 treatment in addition to PD-1 inhibitor therapy. Three patients showed complete, three patients partial response and three patients progressive disease upon this combination therapy. IHC stainings were performed from metastases available at baseline (start of PD-1 inhibitor) and under combination therapy with IL-2. IHC results revealed a significant increase of CD4+ and CD8+ T cells and a higher PD-1 expression in the inflammatory infiltrate of the tumor microenvironment in metastases from patients with subsequent treatment response. All responding patients further showed a profound increase of the absolute eosinophil count (AEC) in the blood. Our case series supports the concept that patients with initial resistance to PD-1 inhibitor therapy and injectable lesions can profit from an additional intralesional IL-2 therapy which was well tolerated. Response to this therapy is accompanied by increase in AEC and a strong T cell-based inflammatory infiltrate.

Abstract 3776: Spatially resolved immunogenomic analyses reveal diverse sub tumoral microenvironments in the context of melanoma immunotherapy

Abstract Sustained periods of apparent clinical benefit despite lack of objective response are well known in a subpopulation of advanced melanoma patients. Inter-individual heterogeneity in response of separate tumors is common, characterizing complex overall response patterns. The molecular and cellular dynamics facilitating such long-term survival and heterogeneous response is poorly understood, particularly in the era of exposure to multiple potentially active therapies. We studied an exceptional case of long-term survival in a patient with non-responding metastatic melanoma in order to characterize the clonal and microenvironmental factors active across 3 time points. We performed immunogenomic analyses of 3 metachronous tumors, including a systemic therapy-naïve mass, 67 intratumor sub-regions of a non-responding mass during PD-1 inhibitor therapy, and a post-PD-1 inhibitor mass. We profiled samples using whole exome sequencing, RNA-sequencing (RNA-seq), immunohistochemistry (IHC), and T cell receptor sequencing. Longitudinal, spatial, and cross-modal analyses were performed. Longitudinal analyses identified mutations in several genes known to be associated with targeted or immune therapy resistance affecting distinct metastases. Genomic intratumoral heterogeneity (ITH) was primarily driven by subclonal copy number alterations that showed evidence of spatially-distinct evolution which may be in response to selective pressures at the tumor margin. RNA-seq revealed an unexpectedly high degree of ITH characterized by limited group-level gene or pathway associations with physical or immune characteristics of each site. Spatially-distinct pockets of immune activation and suppression were observed throughout the PD-1 inhibitor resistant metastasis despite a largely immune-excluded phenotype seen on IHC. A specific T cell Vβ CDR3 rearrangement was identified as dominant and recurrent not only across multiple spatial points within a single tumor mass, but also across metachronous tumors spanning the patient’s disease course. Immunophenotyping of the T cell population with single-cell RNA-seq suggested repeated T-cell priming events leading to the persistence of both activated and exhausted T cells bearing the same TCR-β at any given time. Our findings highlight an unexpected level of genomic and immune heterogeneity in metastatic melanoma tumors of a long-term surviving patient. The observed degree of ITH across local tumor microenvironments reiterates the inherent limitations to identifying robust and reproducible predictive biomarkers of therapy response based on limited physical sampling of tumors. Further spatiotemporal analysis of metastatic lesions in the context of immune checkpoint blockade will be required to determine how the mechanisms driving convergent microenvironmental phenotypes may be harnessed for therapeutic gain. Citation Format: Akash Mitra, Miles C. Andrews, Whijae Roh, Mariana P. de Macedo, Alexandre Reuben, Fernando Carapeto, Feng Wang, Sangeetha M. Reddy, Khalida Wani, Christine Spencer, John Miller, Aislyn Schalck, Latasha D. Little, Donald A. Sakellariou-Thompson, Curtis Gumbs, Wen-Jen Hwu, Chantale Bernatchez, Jianhua Zhang, Patrick Hwu, Nicholas Navin, Padmanee Sharma, James P. Allison, Jennifer Wargo, Alexander J. Lazar, Philip A. Futreal. Spatially resolved immunogenomic analyses reveal diverse sub tumoral microenvironments in the context of melanoma immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3776.

Increased CMTM6 can predict the clinical response to PD-1 inhibitors in non-small cell lung cancer patients

ABSTRACTCKLF-like MARVEL transmembrane domain containing 6 (CMTM6) plays a crucial role in the stability of the programmed death-ligand 1 (PD-L1). However, there has been no previous study of CMTM6 in non-small cell lung cancer (NSCLC) and its association with PD-L1 has not been confirmed. The aim of this study was to investigate the expression of CMTM6 and PD-L1 and to confirm their predictive roles for anti-PD-1 therapy in non-small cell lung cancer. CMTM6 and PD-L1 immunohistochemical expressions were evaluated in 35 advanced, treatment-refractory NSCLC patients who received PD-1 inhibitor therapy. The correlation between CMTM6 and PD-L1 expression was also determined based on immunohistochemistry and RNA-sequencing data obtained from The Cancer Genome Atlas (TCGA) database. CMTM6 expression was positively correlated with PD-L1 expression in immunohistochemical data (Pearson’s r = 0.342 and p = .044). A positive correlation was also identified in the mRNA expression data. Using receiver operating characteristic curves, the levels of CMTM6 and PD-L1 expression which provided the best distinguishing point between responder versus non-responder to PD-1 inhibitors were 70 and 75 H-scores, respectively. The patients in the PD-1 inhibitor responder group had higher CMTM6 expressions in univariate logistic regression analysis (odds ratio (OR) = 5.333, p = .037). However, PD-L1 expression was not associated with response to PD-1 inhibitor (p = .288). In multivariate analysis, CMTM6 was also found to be an independent predictor of the response to PD-1 inhibitors (OR = 6.226, p = .032). CMTM6 expression can be a promising predictor useful for therapeutic decision-making regarding PD-1 inhibitors.

Real-world data on PD-1 inhibitor therapy in metastatic melanoma

Introduction: Phase III studies of PD-1 inhibitors have demonstrated remarkable improvements in the survival of patients with metastatic melanoma (MM). If these results are generalizable to an unselected patient population treated in clinical routine is unknown. This study aimed to investigate and describe clinical efficacy and safety of PD-1 inhibitors in patients with MM treated in routine clinical practice.Material and methods: A retrospective descriptive study of patients with metastatic or inoperable cutaneous melanoma treated with PD-1 inhibitors at a single institution (Department of Oncology, Sahlgrenska University Hospital) from 1 September 2015 to 31 August 2017. Data were obtained from medical records.Results: A total of 116 patients were included in the analyses. The overall survival (OS) at 12-month follow-up was 70.2% and the median OS was 27.9 months. Patients with BRAF mutated tumors had increased OS, whereas ECOG PS ≥2, LDH > ULN and presence or history of brain metastases (stage M1d) were associated with impaired survival. Immune-related AEs of any grade occurred in 64 (55.2%) patients and 15 (12.9%) patients experienced immune-related AEs of grades 3 and 4. Notably, rheumatic adverse events occurred at a higher rate (15.5%) than previously reported. The occurrence of immune-related AEs was associated with a benefit in OS, while the severity of immune-related AEs did not affect survival, nor did the use of systemic corticosteroids.Conclusions: The efficacy and safety of PD1 inhibitors in routine clinical practice appear comparable to that described in clinical trials.

Dynamic change of PD-L1 expression on circulating tumor cells in advanced breast cancer undergoing PD-1 blockade therapy.

e14558 Background: PD-1/PD-L1 checkpoint blockade immunotherapy is revolution- izing the therapeutic strategy of malignancies. Tumor PD-L1 levels have predictive value in PD-1/PD-L1 checkpoint blockade therapies. Whether PD-L1 expression on circulating tumor cells (CTCs) could serve as an alternative biomarker is of great interest, especially in breast cancer. Methods: We established an immunofluorescence assay for semi-quantitative assessment of the PD-L1 expression levels on CTCs with four categories (PD-L1negative, PD-L1low, PD-L1medium and PD-L1high). 20patients with advanced breast cancerwere enrolled who took PD-1 inhibitortherapy. The CTC numeration and the PD-L1 expression levels were analyzedat the begining and ending of treatment . Results: 20 patients were enrolled, 85%(17/20) were triple-negative breast cancer. 65% of patients had visceral metastases, 60% of patients had ≥3 lines of treatment. Prior the treatment of PD-1 inhibitor, 95% (19/20) patients had CTCs, ranging from1 to 53(median 5). 90% (18/20) had PD-L1positive CTCs, and 75% (15/20) had at least one PD-L1high CTCs. The clinical benefit rate(CBR) rate in PD-L1high patients (26.7%) is much higher than the others (0%). we examined the proportion of PD-L1high CTCs relative to total CTCs. The median proportion of PD-L1high CTCs was 33.3%. Patients with ≥33% PD-L1high CTCs had a significantly longer PFS (median 2.6 vs. 1.4 months( P = 0.027). 100% patients with CBR had PD-L1highCTCs decreased and 46.7% of patients without CBR decreased. Further analysis showed that the mean proportion of PD-L1highCTCs at baseline and after treatment was 56.8±20.7%, 19.0±23.7%, p = 0.005. There was no significant difference in the mean proportion of PD-L1highCTCs before and after treatment in the non-CBR group (28.0±26.2%, 30.3±31.5%, p = 0.846). Conclusions: We revealed that the abundance of PD-L1high CTCs at baseline might serve as a predictor to screen patients for PD-1/PD-L1 blockade therapies and measuring the dynamic changes of PD-L1high CTCscould indicate the therapeutic response at early time.

Changes in skeletal muscle mass during PD-1 and PD-L1 checkpoint inhibitor therapy in advanced-stage non-small cell lung cancer patients.

e14061 Background: Severe skeletal muscle loss (sarcopenia) is a principle property of cancer cachexia and is found to be a hallmark of poor prognosis in patients with advanced non-small cell lung cancer (NSCLC). With the latest advancements of PD-1 and PD-L1 checkpoint immunotherapy, we aim to examine changes in sarcopenia before and after treatment with these agents. Methods: : In this study, patients with stage IIIB/IV NSCLC receiving PD-1 and PD-L1 immune checkpoint inhibitors were evaluated. CT images obtained before and after treatment were used for skeletal muscle analyses with the SliceOmatic software (Tomovision) at the level of the first lumbar vertebra. Skeletal muscle index (SMI) was assessed by measuring the cross-sectional muscle area, normalized to patient height. Height, weight, disease progression status, and overall survival (OS) was extracted from EPIC under an IRB-approved protocol. Data was then compared with baseline and clinical outcome was used for survival analysis. Results: In 100 pre-treatment subjects (48% women, mean age of 68), patients with &lt; 32 cm2/m2 SMI had a significantly lower OS (median OS = 1.41 mo, n = 16) compared to those with SMI &gt; 32 cm2/m2 (median OS = 9.44 mo, n = 84, p = 0.024). In 74 patients with pre- and post-treatment data, (avg 2.66 mo interval) an increase of &gt; 5% SMI from baseline occurred in 17 (23%) patients, while a decrease of &gt; 5% SMI from baseline occurred in 26 (35%) patients. Mean reduction in SMI from pre- to post-immunotherapy was 0.921 cm2/m2 while median reduction in SMI was 1.087 cm2/m2. Conclusions: Patients with high pretreatment SMI had a significantly greater overall survival when compared to those with low pretreatment SMI. Two-thirds of patients experienced stability or increase in SMI during immunotherapy. These results suggest that immune checkpoint inhibitors may dampen mechanisms of cancer cachexia in some patients.

A clinical prognosis model for Asian advanced melanoma patients receiving immunotherapy.

e14081 Background: Immunotherapy PD-1 inhibitor therapy shows relative lower efficacy in Asia especially in acral and mucosal subtypes. The identification of predictive factors of immunotherapy remains a crucial but unmet clinical need. The objective of this study was to evaluate advanced melanoma patients treated with anti-PD-1 in order to identify risk factors for PFS, OS and develop a prognostic scoring system for immunotherapy. Methods: Patients with unresectable melanoma treated with PD-1 inhibitor enrolled on trials between 2015 and 2017 at Peking University Cancer Center were included. A nomogram to predict survival was developed based on a multivariable Cox model. The predictive performance of the model was assessed according to the C-statistic, Kaplan–Meier curve and calibration plots. Results: The discovery cohort comprised 133 patients with unresectable melanoma. 38.3% acral and 21.8% mucosal melanomas were included, 26.3% with liver metastases, 31.6% with an elevated serum LDH, 20.3% harbored BRAF mutations. The median PFS was 4.8 months, based on the Cox model, four factors were selected for the nomogram and assigned specific scores: tumor metastases number≥3, 1; tumor size≥80 mm,1; LDH level, 1 (higher limit of normal range); liver metastases,1. The model achieved relatively good discrimination and calibration, with a C-statistic of 0⋅804 (Table). BRAF mutations were associated with shorter PFS in univariate analysis but not in multivariate analysis. Subtypes were also not related to PFS in this cohort. The median OS was 22.8 months. Univariate analysis identified eight factors were associated with significantly worse OS among 21 factors ( BRAF and subtype included, which not found as risk factors). Based on the Cox model, five factors were selected for the nomogram and assigned specific scores: ECOG &gt; 1, 0.6; Hemoglobin &lt; 120g/ml,0.6; tumor size≥80 mm,1.4; LDH level, 0.5; liver metastases, 1. C-statistic was 0⋅85, with extremely strong predictability (Table). The overall survival rate for patients with a higher score was significantly worse than lower cohort (Score: &lt; 0.6 vs. 1-2 vs. 2-4.1; OS: not reached vs. not reached vs. 8.3m; P &lt; 0⋅001). Conclusions: The nomogram facilitates personalized assessment of prognosis for Asian patients with advanced melanoma with PD-1 inhibitor. [Table: see text]

A pilot study of pembrolizumab in combination with decitabine and hypofractionated index lesion radiation in pediatric and young adult patients with relapsed and refractory solid tumors or lymphoma.

TPS25 Background: A potential limitation to the use of immune checkpoint inhibitors in younger patients with immune-resistant histologies is related to low tumor associated antigen expression and an immunosuppressive microenvironment. Low dose decitabine, as an inhibitor of DNA methyltransferase, can unrepress immunogenic cancer testes antigen expression, while hypofractionated radiation promotes infiltration of immune effector cells, stimulation of toll-like receptors on dendritic cells, and induction of type I interferons and other cytokines. As induced PD-L1 expression may also result, we hypothesize that decitabine, radiation, and the PD-1 inhibitor, pembrolizumab, will be synergistic. Here, we aim to verify the safety and preliminary activity of the combination. Correlative studies include an investigation of changes in antigen expression, the kinetics of immune effector and regulatory cell phenotype and function, and microbiome. Methods: Treatment program: Every 28 day cycle, patients receive 10 mg/m2 IV decitabine on days 1-5 and 2 mg/m2 (max dose 200 mg) IV pembrolizumab on day 8. Hypofractionated radiation (8 Gy x 3) to one or more lesion(s) is given on days 5-7 of the second cycle only. Adult patients may consent to optional biopsy of an irradiated lesion. Beyond cycle 3, patients may undergo elective surgery of one or more lesions. Patients remain on therapy for 27 cycles, absent progression by irRECIST or unacceptable toxicity. Patient eligibility: Patients 12 months to 40 years with available archived tissue may be considered, and must have adequate organ function including an absolute neutrophil count ≥ 750/mm3 and platelet count ≥ 75,000/mm3. Patients may have stable central nervous system metastases. Patients previously treated with radiotherapy may be eligible. Patients previously treated with PD-1 inhibitor therapy may be eligible, unless treated for an immune related adverse event. Current enrollment: This trial has been open to enrollment since February of 2018. No dose limiting toxicities have been observed in 2 patients evaluable for toxicity. Clinical trial information: NCT03445858.

Smoking history and PD-1/PDL-1 pathway blockade: Predicting response to treatment in metastatic cancer.

95 Background: Identifying patients who will benefit from immune-checkpoint inhibitor therapy is a challenge as proven predicative indicators remain to be elucidated. High tumor mutational burden (TMB) represents a possible biomarker for response to PD1 blockade such as in nivolumab or pembrolizumab. Genomic analyses have shown that patients with heavy smoking history are more likely to have high TMB. However smoking status alone has not been examined independently in relation to treatment response. We sought to determine whether a relationship existed between smoking history and response to treatment in metastatic non-small cell lung cancer (NSCLC), metastatic renal cell carcinoma (mRCC) and metastatic melanoma (mMelanoma). Methods: A retrospective analysis was conducted of Ochsner Health System patients with mRCC, mMelanoma, and NSCLC receiving a minimum of two cycles of nivolumab or pembrolizumab between 12/2014 and 01/2018. Pre- and post-treatment target lesions were analyzed using RECIST criteria to calculate best response to treatment. Patient demographic information was gathered including age, sex, smoking history, and performance status pre and post treatment. Kaplan-Meier method was used to estimate progression free survival (PFS) and overall survival (OS) outcomes. Results: Heavy smokers (&gt;10 pack-years) had a higher response to immunotherapy than light (&lt; 10 years) and never smokers (p = 0.0500). Heavy smokers with NSCLC treated with immuno-therapy also had significantly improved OS compared to light smokers with NSCLC (p=0.003). mRCC immuno-therapy patients with heavy smoking history showed increased PFS compared to light/never smokers (p=0.026). Conclusions: In summary, in response to PD-1 blockade heavy smokers showed improved survival compared to light and never smokers suggesting smoking history may represent a potential predictor of treatment response to PD-1 inhibitor therapy.[Table: see text]

Circulating Cytokines Predict Immune-Related Toxicity in Melanoma Patients Receiving Anti-PD-1-Based Immunotherapy.

Combination PD-1 and CTLA-4 inhibitor therapy has dramatically improved the survival of patients with advanced melanoma but is also associated with significant immune-related toxicities. This study sought to identify circulating cytokine biomarkers of treatment response and immune-related toxicity. The expression of 65 cytokines was profiled longitudinally in 98 patients with melanoma treated with PD-1 inhibitors, alone or in combination with anti-CTLA-4, and in an independent validation cohort of 49 patients treated with combination anti-PD-1 and anti-CTLA-4. Cytokine expression was correlated with RECIST response and immune-related toxicity, defined as toxicity that warranted permanent discontinuation of treatment and administration of high-dose steroids. Eleven cytokines were significantly upregulated in patients with severe immune-related toxicities at baseline (PRE) and early during treatment (EDT). The expression of these 11 cytokines was integrated into a single toxicity score, the CYTOX (cytokine toxicity) score, and the predictive utility of this score was confirmed in the discovery and validation cohorts. The AUC for the CYTOX score in the validation cohort was 0.68 at PRE [95% confidence interval (CI), 0.51-0.84; P = 0.037] and 0.70 at EDT (95% CI, 0.55-0.85; P = 0.017) using ROC analysis. The CYTOX score is predictive of severe immune-related toxicity in patients with melanoma treated with combination anti-CTLA-4 and anti-PD-1 immunotherapy. This score, which includes proinflammatory cytokines such as IL1a, IL2, and IFNα2, may help in the early management of severe, potentially life-threatening immune-related toxicity.See related commentary by Johnson and Balko, p. 1452.

Programmed Cell Death Receptor (PD-1) Ligand (PD-L1) expression in Philadelphia chromosome-negative myeloproliferative neoplasms

Programmed Cell Death Receptor (PD-1) and its Ligand (PD-L1) pathway inhibitor therapy has been explored in the field of oncology treatment mainly for solid tumors. In hematologic malignancies, there is limited information except for Hodgkin’s lymphoma, and there is even less information regarding myeloproliferative neoplasm (MPN). Therefore, we explored this by first measuring PD-1 and PD-L1 levels (percentage of positive cells) in 63 patients with Philadelphia chromosome-negative MPN (Ph(-) MPN), including 16 MF (12 PMF, 2 post-PV-MF, 2 post-ET-MF), 29 ET, and 18 PV. We found there was no significant difference in PD-1 or PD-L1 levels between the different MPN groups but that there was a significant difference when PV, ET and MF were grouped as MPN and compared with controls, of all immune cells including CD4+, CD8+, CD14+ and CD34+ progenitor cells. We further found a higher incidence of higher expression levels (more than 50% of cells with positive expression) of PD-1 and PD-L1 (20% and 26%, respectively) in the CD34+ cells; in contrast, we found a low incidence (0.08–1.8%) in the immune cells in MPN patients. PD-1 and PD-L1 levels were also measured by MFI methods, and we obtained similar results except the measurements by percentage appeared to be more sensitive than the MFI methods. We found no correlation between PD-1 and PD-L1 expression levels and clinical features including WBC, platelet counts, hemoglobin levels, presence or absence of the JAK2, MPL, or CALR gene mutation, or splenomegaly. Since MPN represents stem cell disorders, the presence of elevated expression of PD-1 and PD-L1 in these cells suggests that the exploration of PD-1 and PD-L1 pathway inhibitor therapy may be worthwhile in Ph(-) MPN.

Safety and clinical activity of durvalumab monotherapy in patients with microsatellite instability–high (MSI-H) tumors.

670 Background: MSI-H tumors have shown to be responsive to PD-1 inhibitor therapy. We evaluated the anti-PD-L1 mAb durvalumab in patients with MSI-H tumors, in two ongoing studies: a phase 1/2, multicenter, open-label study in patients with advanced solid tumors, and a phase 2 single-center study in patients with advanced colorectal cancer (CRC). Methods: Patients with MSI-H tumors (determined locally by immunohistochemistry or sequencing) received durvalumab 10 mg/kg IV every 2 weeks for 12 months or until confirmed progressive disease, whichever was first. Objectives were to evaluate safety and antitumor activity (per investigator-assessed RECIST v1.1). Results: As of Oct 16, 2017, 62 MSI-H patients (97% with prior anti-cancer therapy) received treatment in the multicenter study; median duration of follow-up was 29 months. Treatment-related adverse events (TRAEs) occurred in 37 patients (60%), most commonly diarrhea (15%), asthenia (11%), fatigue (11%), nausea (10%), and hypothyroidism (10%). Grade 3/4 TRAEs occurred in 2 patients (3%). There were no deaths or treatment discontinuations due to TRAEs. Objective response rates (ORR) were 23% for the total population and 22% for patients with CRC; 9 of 14 responders were ongoing at data cutoff. As of Sep 13, 2018, 11 patients with MSI-H CRC were treated in the single-center study; median duration of follow-up was 30 months. One patient discontinued treatment due to treatment-related aseptic meningitis (resolved with steroids); response rate and survival were similar to the multicenter study (Table). Conclusions: Durvalumab had a tolerable safety profile, and showed promising antitumor activity and overall survival in patients with MSI-H tumors. Clinical trial information: NCT01693562 and NCT02227667. [Table: see text]

Expression of PD-L1/PD-1 in lymphoepithelioma-like carcinoma of the thymus

Poorly differentiated non-keratinizing squamous cell carcinoma of the thymus, also known as lymphoepithelioma-like carcinoma, is a rare primary malignant neoplasm of thymic origin. The mainstay of treatment for these tumors is surgical and they tend to respond poorly to chemotherapy. The checkpoint programmed cell death ligand-1 protein (PD-L1) bound to its receptor (PD-1) has been demonstrated to be an important therapeutic target for many different tumors. Expression of PD-L1/PD-1 in lymphoepithelioma-like carcinoma of the thymus may indicate that these tumors are potential targets for inhibitor therapy. Twenty-one cases of lymphoepithelioma-like carcinoma of the thymus were collected and reviewed. Tissue microarrays were created using triplicate 2 mm cores for each case. PD-L1/PD-1 staining pattern (neoplastic cells versus tumor infiltrating lymphocytes) was documented for each case. Out of 21 cases, 15 (71.4%) showed various degrees of membranous PD-L1 staining. Of the positive cases, 48% showed high expression of PD-L1 (>50% of tumor cells) and 24% showed low expression (<50%). PD-1 staining showed focal positivity in 12/20 (60%) cases among tumor infiltrating lymphocytes. PD-L1/PD-1 inhibitor therapy has been applied successfully in other solid malignant tumors with high expression of PD-L1/PD-1. The high level of PD-L1 expression in our cases indicates that PD-L1 may play a role in the pathogenesis of these tumors and that PD-L1/PD-1 blockade may be a viable therapeutic option for patients with lymphoepithelioma-like carcinoma of the thymus who have failed other first-line therapies.

A Phase II Study of Sequential Pembrolizumab (PEM) Followed By AVD for Frontline Treatment of Classical Hodgkin Lymphoma (CHL): Quantifying Response Following PEM Monotherapy with FDG-PET-Derived Metabolic Tumor Volume and Total Lesion Glycolysis

Background:Pembrolizumab (PEM), a PD-1 inhibitor, is US FDA approved for the treatment of relapsed/refractory cHL based on results of a pivotal trial demonstrating an overall response rate of 69% and complete response (CR) rate of 22%. We hypothesized that PEM monotherapy would result in a higher CR rate (50%) in previously untreated patients owing to greater immunocompetence. Consequently, we initiated a phase 2 clinical trial of upfront sequential PEM and AVD (Adriamycin, Vinblastine, Dacarbazine) chemotherapy. While several of the initial patients had dramatic responses to PEM x's 3 on PET2, they only met Lugano criteria for partial responses. In an attempt to better reflect and quantify the response to checkpoint inhibition, we amended our protocol to include additional analysis of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) which have been investigated as predictors of response in cHL and DLBCL. Herein, we report an interim analysis of toxicity and efficacy, measured by Deauville score, MTV and TLG in the first 13 patients to complete PEM monotherapy.Methods:Patients ≥ 18 years of age with newly diagnosed cHL stages I-IV, including unfavorable early stage disease with at least one risk factor according to the NCCN criteria, were eligible. Patients had a pre-therapy PET-CT, followed by 3 cycles of PEM at 200 mg every 3 weeks and interim PET-CT (PET2) after single agent PEM for primary analysis. Subsequently, patients received 4-6 cycles of AVD chemotherapy based on initial stage. MTV representing the total volume of the metabolically active tumor in a volume of interest (VOI) was calculated using the fixed 41% SUVmax threshold corresponding to the dimensions of the tumor. TLG, combining the volumetric and metabolic information of FDG-PET, was calculated by multiplying the SUVmean of the segmented VOI and the MTV. These measurements were performed using SyngoVia software, Multi-foci segmentation tool (Siemens). Blinded central review of the visually assessed Deauville score was performed, and if different from the report by one of four nuclear medicine radiologists, a second central review was performed to adjudicate. Correlative studies include serum and biopsy samples pre/post PEM to assess immune biomarkers of response.Results:Fifteen patients were enrolled from September 2017, through a data cut off of July 10, 2018, at Northwestern University. Thirteen patients have completed lead-in PEM monotherapy and have undergone PET2. Median age was 30 years (range, 23-77). Eight patients had unfavorable early stage disease and 7 had advanced stage. Early stage risk factors included bulky disease (n=8), B-symptoms (n=5), and elevated ESR (n=5). Overall, therapy was well tolerated. Grade 3 events included lymphopenia (n=1) and diarrhea (n=1). Only one grade 4 immune-related adverse event (transaminitis) occurred, which resolved with steroid therapy and a delay in therapy. PET2 was scored as Deauville 2 or 3 in six cases including three with large mediastinal masses, and as D 4 or 5 in 7 cases with residual activity (Figure 1). PET2 MTV and TLG could be calculated for 12 of 13 cases, (MTV: 42 - 774 cm2, median 134 cm2; TLG: 257 - 5924; median 814). All 12 patients who completed a subsequent scan (PET3) after 2 cycles of AVD are now in a metabolic CR (Deauville 1-3), including all 7 cases with residual activity after PET2.Conclusion: These interim data suggest that upfront PEM x's 3 is highly active in previously untreated cHL. PEM monotherapy resulted in complete metabolic responses in some patients including those with large mediastinal masses, and near complete responses, best represented by the decline in MTV and TLG compared with Deauville scores or Lugano criteria. Our preliminary data suggest that MTV and TLG are useful additional interim indicators of biologic activity when assessing response after PD-1 inhibitor therapy. [Display omitted] DisclosuresAllen:Merck: Research Funding; Bayer: Consultancy. Evens:Bayer: Consultancy; Janssen: Consultancy; Affimed: Consultancy; Novartis: Consultancy; Tesaro: Research Funding; Abbvie: Consultancy; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees. Pro:kiowa: Honoraria; Takeda Pharmaceuticals: Honoraria, Other: Travel expenses; portola: Honoraria; Seattle Genetics: Consultancy, Other: Travel expenses, Research Funding. Advani:Millenium: Other: Institutional Research Support; Merck: Other: Institutional Research Support; Kura: Other: Institutional Research Support; Agensys: Other: Institutional Research Support; Takeda: Other: Consultancy/Advisory Role; Roche/Genentech: Other: Consultancy/Advisory Role, Institutional Research Support; Pharmacyclics: Other: Institutional Research Support; Cell Medica: Other: Consultancy/Advisory Role; Kyowa: Other: Consulting/Advisory Role; Janssen Pharmaceutical: Other: Institutional Research Support; Autolus: Other: Consultancy/Advisory Role; Regeneron Pharmaceuticals, Inc.: Other: Institutional Research Support; Seattle Genetics: Other: Consultancy/Advisory role, Institutional Research Support; Bayer Healthcare Pharmaceuticals: Other: Consultancy/Advisory Role; AstraZeneca: Other: Consultancy/Advisory Role; Bristol Myers Squibb: Other: Consultancy/Advisory role and Institutional Research Support; Forty Seven, Inc: Other: Institutional Research Support; Celgene: Other: Institutional Research Support; Gilead/Kite: Other: Consultancy/Advisory Role; Infinity: Other: Institutional Research Support. Winter:Merck: Honoraria, Research Funding.

Programmed Cell Death Receptor (PD-1), PD-1 Ligand (PD-L1) Expression in Philadelphia Chromosome Negative Myeloid Neoplasms

Introduction : PD-1 and PD-L1 pathway inhibitor therapy has been extensively explored in the field of oncology treatment recently, however there is no information so far about its usefulness in myeloid neoplasms (MPN). We have previously reported on PD-1 and PD-L1 expression in Philadelphia chromosome negative myeloid neoplasm (MPN), but now that we have accumulated more cases , we wish to report the final results.Materials and Methods: 63 patients with Philadelphia chromosome negative MPN in total were studied which included 16 MF (14 PMF, 2 post-PV-MF, 2 post-ET-MF), 29 ET, 18 PV, and 25 normal volunteer controls.Flow CytometryStudies: Leukocytes were obtained from whole blood after RBC lysis using RBC lysis buffer (Qiagen). To quantify surface bound PD-1 and PDL-1, the leukocytes were incubated with CD279-APC and CD274-PE, as well as CD4-FITC, CD8-FITC, CD14-PCP, or CD34-FITC (BD Biosciences) and were subjected to flow cytometric analysis.Results: PD-1 and PD-L1 positive cells were expressed as a percentage in gated CD4bright, CD8+, CD14+, or CD34+ cells. We found that 1) there was no difference in PD-1 or PD-L1 levels among different groups of MPN, but there was a significant difference when they were grouped of PV, ET and MF as MPN and compared with controls in all the immune cells including CD4+, CD8+, CD14 + and,CD34+ cells.(Representative of CD4+ shown inFig(1a). 2) High expression levels (more than 50% cell positivity) was found on the CD34+ cells with PD-1 and PD-L1 expression of 20% and 26% in MPN patients respectively ( Fig 1b,1c) . 3) We also found that there was no correlation between of the PD-1 or , PD-L1 expression levels with clinical features including such as WBC counts , platelet counts, and hemoglobin levels, , or presence or absence of the JAK2 , MPL, or CALR gene mutations or splenomegalyConclusion: We have shown elevated increased expression levels of PD1 and PDL-1 on the immune cells and high expression ( more than 50%) in the CD34+ cells , suggest that PD-1 or , PD-L1 pathway inhibitor therapy maybe worthwhile in Philadelphia chromosome negative Ph(-) MPN .. [Display omitted] DisclosuresWang:celgene: Other: clinical trial.

Association of good oncological response to therapy with the development of rheumatic immune-related adverse events following PD-1 inhibitor therapy.

To investigate whether any patient or treatment characteristics are associated with the development of rheumatic immune-related adverse events (irAEs) following programmed cell death protein 1 (PD-1) inhibitor therapy for cancer. This was a retrospective chart review of all patients who were dispensed nivolumab or pembrolizumab at a single center before 1 January, 2017, with follow-up until 1 July, 2017. Patients with any diagnosis of a non-cutaneous irAE were identified, regardless of severity, and rheumatic irAEs were characterized. Of 244 episodes of therapy, a non-cutaneous irAE occurred in 72 (29.5%). Rheumatic irAEs were diagnosed in 19 episodes of therapy (7.8%), with 12 de novo diagnoses (5.1% of episodes without a pre-existing autoimmune rheumatic disease) and 7 exacerbations of existing disease. Review by a rheumatologist occurred in only 11 of these. Rheumatic irAEs were more common in patients with a good oncological response to therapy (relative risk [RR] 11.16), those being treated for melanoma (RR 2.94) and those who developed another non-cutaneous irAE (RR 2.64). Rheumatic irAEs are relatively common with PD-1 inhibitor therapy, and appear to be associated with a good oncological response to therapy. Many rheumatic irAEs were not referred to rheumatological services. Prospective systematic investigation would be of benefit to explore these characteristics.

Association between soluble immune mediators and tumor responses in patients with nonsmall cell lung cancer treated with anti-PD-1 inhibitor.

Although programmed death (PD)-1 immune checkpoint therapies target the immune system, the relationship between inflammatory factors and the clinical outcome of anti-PD-1 therapy for nonsmall cell lung cancer (NSCLC) is not fully understood. Here we examined the association between soluble immune mediators and the outcome of treatment with PD-1 inhibitors in patients with advanced/recurrent NSCLC. In two independent cohorts, we assessed the levels of 88 different soluble immune mediators in peripheral blood before and after anti-PD-1 treatment, and evaluated their associations with clinical outcomes. In the training cohort, the plasma levels of chitinase 3-like-1 and GM-CSF before treatment (p = 0.006 and p = 0.005, respectively) and changes in the plasma levels of CXCL2, VEGF, IFNα2, and MMP2 after treatment (p < 0.001, p = 0.019, p = 0.019, and p = 0.012, respectively) were significantly correlated with PFS. The change in the plasma CXCL2 level was also significantly associated with treatment-related AEs (p = 0.017). In the validation cohort, however, only the changes in the plasma levels of CXCL2 and MMP2 after treatment were associated with PFS (p = 0.003 and p = 0.006, respectively), and these changes were maintained during the course of anti-PD-1 therapy in patients who showed better clinical outcomes, even in those with tumor pseudoprogression. Since CXCL2 and MMP2 can be easily measured by minimally invasive blood sampling, they could be useful for monitoring of clinical outcomes in NSCLC patients receiving PD-1 inhibitor therapy.