PD-1 blockade in tumors with mismatch repair deficiency.

2015 ◽  
Vol 33 (18_suppl) ◽  
pp. LBA100-LBA100 ◽  
Author(s):  
Dung T. Le ◽  
Jennifer N. Uram ◽  
Hao Wang ◽  
Bjarne Bartlett ◽  
Holly Kemberling ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Somatic Mutations ◽  
Objective Response ◽  
Progression Free Survival ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Clinical Activity ◽  
Primary Endpoints ◽  
Repair Deficiency

LBA100 Background: Somatic mutations have the potential to be recognized as “non-self” immunogenic antigens. Tumors with genetic defects in mismatch repair (MMR) harbor many more mutations than tumors of the same type without such repair defects. We hypothesized that tumors with mismatch repair defects would therefore be particularly susceptible to immune checkpoint blockade. Methods: We conducted a phase II study to evaluate the clinical activity of anti-PD-1, pembrolizumab, in 41 patients with previously-treated, progressive metastatic disease with and without MMR-deficiency. Pembrolizumab was administered at 10 mg/kg intravenously every 14 days to three cohorts of patients: those with MMR-deficient colorectal cancers (CRCs) (N = 11); those with MMR-proficient CRCs (N = 21), and those with MMR-deficient cancers of types other than colorectal (N = 9). The co-primary endpoints were immune-related objective response rate (irORR) and immune-related progression-free survival (irPFS) at 20 weeks. Results: The study met its primary endpoints for both MMR-deficient cohorts. The irORR and irPFS at 20 weeks for MMR-deficient CRC were 40% and 78%, respectively, and for MMR-deficient other cancers were 71% and 67%, respectively. In MMR-proficient CRC, irORR and irPFS at 20 weeks were 0% and 11%, respectively. Response rates and Disease Control Rates (CR+PR+SD) by RECIST criteria were 40% and 90% in MMR-deficient CRC, 0% and 11% in MMR-proficient CRC, and 71% and 71% in MMR-deficient other cancers, respectively. Median PFS and overall survival (OS) were not reached in the MMR-deficient CRC group but was 2.2 and 5.0 months in the MMR-proficient CRC cohort (HR for PFS = 0.103; 95% CI, 0.029 to 0.373; p < 0.001 and HR for OS = 0.216; 95% CI, 0.047 to 1.000; p = 0.05). Whole exome sequencing revealed an average of 1,782 somatic mutations per tumor in MMR-deficient compared to 73 in MMR-proficient tumors (p = 0.0015), and high total somatic mutation loads were associated with PFS (p = 0.02). Conclusions: MMR status predicts clinical benefit of immune checkpoint blockade with pembrolizumab. Clinical trial information: NCT01876511.

Efficacy of immune checkpoint blockade in patients with advanced upper tract urothelial cancer and mismatch repair deficiency or microsatellite instability (MSI).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 487-487
Author(s):  
Alexander Andreev-Drakhlin ◽  
Amishi Yogesh Shah ◽  
Ana Cecilia Adriazola ◽  
Leah Shaw ◽  
Lidia Lopez ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Response Rate ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Complete Response ◽  
Immune Checkpoint Blockade ◽  
Clinical Activity ◽  
Upper Tract

487 Background: Tumors deficient in DNA mismatch repair (dMMR) exhibit a microsatellite unstable phenotype characterized by high tumor mutational burden and an immunogenic tumor microenvironment. Despite the histology-agnostic approval of pembrolizumab for advanced dMMR/MSI cancers, responsiveness of dMMR/MSI upper tract urothelial cancers (UTUC) to immune checkpoint (IC) blockade remains largely unknown. Methods: Consecutive records of patients (pts) from a single institution with locally advanced unresectable or metastatic dMMR/MSI UTUC who received IC therapy were analyzed. The primary endpoint was assessment of objective response rate (ORR) using RECIST v1.1. Secondary endpoints were progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier technique. dMMR/MSI status was evaluated by immunohistochemistry (IHC) and/or polymerase chain reaction (PCR). Results: Ten pts were identified with locally advanced unresectable (N = 3) or metastatic (N = 7) dMMR/MSI UTUC who received therapy with IC blockade (pembrolizumab = 7, nivolumab = 2, atezolizumab = 1). Median age was 65.5 (range = 46 – 90). Six pts were male. Seven pts had germline dMMR. MSI was detected by PCR in three pts and dMMR by IHC in seven pts (PMS2/MLH1 loss = 4, MSH2 loss = 1, MLH1 loss = 1, MSH6 loss = 1). Five pts received systemic chemotherapy (2 cisplatin based, 1 carboplatin based, 2 other) prior to IC therapy with two pts (40%) achieving partial response (PR). At a median follow-up of 15.5 months (range: 2 – 43 months), all pts were alive, and none experienced disease progression. PFS and OS at 15.5 months were 100%. The observed ORR was 90% (CI, 55.5%, 99.8%), including 8 pts who achieved complete remission (CR). The median time to best response was 4 months (range: 2 – 8 months). Toxicity leading to treatment discontinuation: 1 (grade 3) pancytopenia, 1 (grade 2) pneumonitis, 1 (grade 2) SICCA-like symptoms. Conclusions: Immunotherapy with IC inhibitors demonstrates excellent clinical activity in advanced dMMR/MSI UTUC. Further studies integrating these agents earlier in the disease course are warranted in this rare but important subgroup. Given the extremely high complete response rate in this population consideration of preference to IC therapy as initial therapy should be entertained if these findings are validated.

scholarly journals Mismatch Repair Deficiency and Response to Immune Checkpoint Blockade

2016 ◽  
Vol 21 (10) ◽  
pp. 1200-1211 ◽  
Author(s):  
Valerie Lee ◽  
Adrian Murphy ◽  
Dung T. Le ◽  
Luis A. Diaz
Keyword(s):  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Mismatch Repair Deficiency ◽  
Repair Deficiency

LAG-3 expression on peripheral blood cells identifies patients with poorer outcomes after immune checkpoint blockade

2021 ◽  
Vol 13 (608) ◽  
pp. eabf5107
Author(s):  
Ronglai Shen ◽  
Michael A. Postow ◽  
Matthew Adamow ◽  
Arshi Arora ◽  
Margaret Hannum ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Peripheral Blood ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Clinical Activity ◽  
Multiparametric Flow Cytometry ◽  
Mutation Burden ◽  
Blocking Antibodies

Immune checkpoint blocking antibodies are a cornerstone in cancer treatment; however, they benefit only a subset of patients and biomarkers to guide immune checkpoint blockade (ICB) treatment choices are lacking. We designed this study to identify blood-based correlates of clinical outcome in ICB-treated patients. We performed immune profiling of 188 ICB-treated patients with melanoma using multiparametric flow cytometry to characterize immune cells in pretreatment peripheral blood. A supervised statistical learning approach was applied to a discovery cohort to classify phenotypes and determine their association with survival and treatment response. We identified three distinct immune phenotypes (immunotypes), defined in part by the presence of a LAG-3+CD8+ T cell population. Patients with melanoma with a LAG+ immunotype had poorer outcomes after ICB with a median survival of 22.2 months compared to 75.8 months for those with the LAG− immunotype (P = 0.031). An independent cohort of 94 ICB-treated patients with urothelial carcinoma was used for validation where LAG+ immunotype was significantly associated with response (P = 0.007), survival (P < 0.001), and progression-free survival (P = 0.004). Multivariate Cox regression and stratified analyses further showed that the LAG+ immunotype was an independent marker of outcome when compared to known clinical prognostic markers and previously described markers for the clinical activity of ICB, PD-L1, and tumor mutation burden. The pretreatment peripheral blood LAG+ immunotype detects patients who are less likely to benefit from ICB and suggests a strategy for identifying actionable immune targets for further investigation.

DNA damage response (DDR) gene mutations (mut), mut load, and sensitivity to chemotherapy plus immune checkpoint blockade in urothelial cancer (UC).

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 300-300 ◽  
Author(s):  
Matt D. Galsky ◽  
Andrew V. Uzilov ◽  
Russell Bailey McBride ◽  
Huan Wang ◽  
Vaibhav G. Patel ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Immune Checkpoint ◽  
Predictive Value ◽  
Objective Response ◽  
Gene Mutations ◽  
Progression Free Survival ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Response To Treatment ◽  
Cd8 Cells

300 Background: Somatic mut in DDR genes have been associated with increased sensitivity to cisplatin in UC. Higher mut load has correlated with response to immune checkpoint blockade. We hypothesized that DDR mut result in higher mut load and DDR mut UC may be particularly sensitive to both chemotherapy and immune checkpoint blockade. Methods: Three cohorts were utilized: (1) TCGA UC cohort (n = 389), (2) Mount Sinai (MS) cohort (n = 67) of UC (cystectomy) specimens subjected to targeted exome sequencing for 341 genes (MSK-IMPACT), and (3) Phase 2 trial of gemcitabine, cisplatin, plus ipilimumab (GCI) in metastatic UC from which 28/36 enrolled patients (pts) had specimens suitable for whole exome sequencing. DDR mut were defined as somatic alterations in one of 52 genes. Deleterious (del) mut were defined as nonsense, frameshift, splice site, or hotspot point mut. Results: The mut load using all genes in the TCGA cohort, and restricted to the 341 IMPACT genes, were highly correlated (rs= 0.81, p < 0.001). Associations between del DDR mut and mut load are shown (Table). In the MS cohort, CD8+cells/mm2 by IHC were higher in tumors with del DDR mut versus no DDR mut (p = 0.04). In the GCI cohort, the sensitivity, specificity, positive predictive value, and negative predictive value of a del DDR mut for objective response to treatment was 40.9% (95% CI 20.7-63.7%), 86.7% (95% CI 42.1-99.4%), 90% (55.5-99.8%), and 31.6% (95% CI 12.6-56.6%), respectively. Median progression-free survival in the GCI cohort was 308 days (95% CI 270-NR) in del DDR mut and 196 days (95% CI 185-372) in others (p = 0.24). Notably, 2/9 pts with del DDR mutations, and with the highest mut loads, achieved complete responses after GCI and are alive without evidence of disease at 2.1+ and 1.8+ years. Conclusions: DDR mut are associated with higher mut load in UC, a high likelihood of response to GCI, and may identify a subset of pts achieving durable disease control. GC plus PD-1/PD-L1 blockade should be explored in DDR mut UC. Clinical trial information: NCT01524991. [Table: see text]

23 Circulating tumor DNA (ctDNA) serial analysis during progression on PD-1 blockade and later CTLA4 rescue in patients with mismatch repair deficient metastatic colorectal cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A22-A22
Author(s):  
Pashtoon Kasi ◽  
Carlos Chan
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Circulating Tumor Dna ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Mismatch Repair Deficiency ◽  
Repair Deficiency ◽  
Tumor Dna

BackgroundPatients with mismatch repair deficient/microsatellite instability high (dMMR/MSI-High) tumors respond well to immune checkpoint blockade.1 2 Pembrolizumab was the first drug to be approved by the FDA in an agnostic fashion for any tumor type with dMMR/MSI-High for the very same reason. The responses in dMMR/MSI-High tumors tend to be brisk, dramatic and durable to the point that the word ‘cure’ is being used for patients who do respond to PD-1 blockade. This year, pembrolizumab now got approval as 1st line therapy for dMMR/MSI-High metastatic colorectal cancers as well. However, a third of patients do not respond.3 Predictive markers and data for subsequent therapy options are lacking. Here we present for the first time a series of dMMR/MSI-High patients who not only had serial circulating tumor DNA (ctDNA) monitoring during PD-1 blockade/progression, but also were able to get anti-CTLA4 in conjunction with an anti-PD1 (‘CTLA4-rescue’), with ctDNA trends predicting responses weeks ahead of standard imaging.MethodsMetastatic colorectal cancer patients enrolled in the expanded access program for tumor informed circulating tumor DNA monitoring (Signatera 16-plex bespoke mPCR NGS assay) who were noted to be dMMR/MSI-High colorectal cancers were identified. Serial monitoring results while they were receiving immune checkpoint blockade therapy is presented. This only includes patients who had progression on PD-1 blockade whereby CTLA-4 rescue was done as part of their treatment strategy.ResultsSerial monitoring and trends of progression followed by responses are depicted in the patients who had CTLA-4 rescue post PD-1 progression (figure 1). This correlated with radiographic responses in all the patients. The ctDNA decreases in patients showing responses as well as ctDNA increases earlier during progression on PD-1 blockade happened within administration of a single dose.Abstract 23 Figure 1Example of a patient with serial tumor-informed ctDNA monitoring showing initial response and subsequent progression on PD-1 blockade followed by ‘CTLA-4 rescue’.ConclusionsTo date there is only 1 case report published earlier this year showing the value of ‘immunotherapy after immunotherapy’ in patients with dMMR/MSI-High tumors. Here we not only present a series of patients but also in parallel provide a snapshot on serial ctDNA trends whereby this could serve as a dynamic predictive marker of early response or progression to therapy.4 5 Finally, ‘CTLA4-rescue’ needs to be formally included in NCCN and other respective guidelines. Even though nivolumab/ipilimumab is listed as an option for dMMR/MSI-High tumors in addition to single agent pembrolizumab or nivolumab, it is not listed as an option post-PD-1 progression. For all the patients, we have had to fight to get peer to peer approval.Ethics ApprovalThe study is approved at University of Iowa and part of IRB#201202743.ConsentWritten informed consent was obtained from the patients for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.ReferencesLe DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357:409–13. [Crossref] [PubMed]Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509–20. [Crossref] [PubMed]Andre T, Shiu KK, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: the phase 3 KEYNOTE-177 study. J Clin Oncol 2020;38:LBA4.Anagnostou V, Forde PM, White JR, et al. Dynamics of tumor and immune responses during immune checkpoint blockade in non-small cell lung cancer. Cancer Res 2019;79:1214–25. [Crossref] [PubMed]Phallen J, Leal A, Woodward BD, et al. Early noninvasive detection of response to targeted therapy in non-small cell lung cancer. Cancer Res 2019;79:1204–13.

scholarly journals Treatment with therapeutic anticoagulation is not associated with immunotherapy response in advanced cancer patients

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Paul Johannet ◽  
Amelia Sawyers ◽  
Nicholas Gulati ◽  
Douglas Donnelly ◽  
Samuel Kozloff ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Advanced Cancer ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Immune Checkpoint Blockade ◽  
Coagulation Cascade ◽  
Advanced Cancer Patients ◽  
Clinical Endpoints

Abstract Background Recent preclinical data suggest that there may be therapeutic synergy between immune checkpoint blockade and inhibition of the coagulation cascade. Here, we investigate whether patients who received immune checkpoint inhibitors (ICI) and were on concomitant anticoagulation (AC) experienced better treatment outcomes than individuals not on AC.Affiliation: Kindly confirm if corresponding authors affiliation is identified correctly.The corresponding author's affiliation is correct. Methods We studied a cohort of 728 advanced cancer patients who received 948 lines of ICI at NYU (2010–2020). Patients were classified based on whether they did (n = 120) or did not (n = 828) receive therapeutic AC at any point during their treatment with ICI. We investigated the relationship between AC status and multiple clinical endpoints including best overall response (BOR), objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), and the incidence of bleeding complications.Affiliations: Journal instruction requires a country for affiliations; however, this is missing in affiliations 1 to 5. Please verify if the provided country is correct and amend if necessary.The country is correct for all affiliations (1 - 5). Results Treatment with AC was not associated with significantly different BOR (P = 0.80), ORR (P =0.60), DCR (P =0.77), PFS (P = 0.59), or OS (P =0.64). Patients who received AC were significantly more likely to suffer a major or clinically relevant minor bleed (P = 0.05). Conclusion AC does not appear to impact the activity or efficacy of ICI in advanced cancer patients. On the basis of our findings, we caution that there is insufficient evidence to support prospectively evaluating the combination of AC and immunotherapy.

scholarly journals Immune Checkpoint Blockade for Metastatic Uveal Melanoma: Patterns of Response and Survival According to the Presence of Hepatic and Extrahepatic Metastasis

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3359
Author(s):  
Elias Koch ◽  
Anne Petzold ◽  
Anja Wessely ◽  
Edgar Dippel ◽  
Anja Gesierich ◽  
...  
Keyword(s):  
Skin Cancer ◽  
Uveal Melanoma ◽  
Hepatic Metastasis ◽  
Immune Checkpoint ◽  
Objective Response ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Response To Treatment ◽  
Extrahepatic Metastasis ◽  
The Impact

Background: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB. Methods: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan–Meier method. Log-rank tests, χ2 tests, and t-tests were performed to detect significant differences between both cohorts. Results: The median OS of the overall population was 16 months (95% CI 13.4–23.7) and the median PFS, 2.8 months (95% CI 2.5–3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; p = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%; p = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts. Conclusion: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only.

scholarly journals Biomarkers for Response to Immune Checkpoint Blockade

2020 ◽  
Vol 4 (1) ◽  
pp. 331-351
Author(s):  
Shridar Ganesan ◽  
Janice Mehnert
Keyword(s):  
Immune Checkpoint ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Clinical Activity ◽  
Host Immune System ◽  
Mutation Burden ◽  
Life Threatening ◽  
Expression Evaluation ◽  
Distinct Features

Immune checkpoint blockade (ICB) has significant clinical activity in diverse cancer classes and can induce durable remissions in even refractory advanced disease. However, only a minority of cancer patients treated with ICB have long-term benefits, and ICB treatment is associated with significant, potentially life-threatening, autoimmune side effects. There is a great need to develop biomarkers of response to guide patient selection to maximize the chance of benefit and prevent unnecessary toxicity, and current biomarkers do not have optimal positive or negative predictive value. A variety of potential biomarkers are currently being developed, including those based on assessment of checkpoint protein expression, evaluation of tumor-intrinsic features including mutation burden and viral infection, evaluation of features of the tumor immune microenvironment including nature of immune cell infiltration, and features of the host such as composition of the gut microbiome. Better understanding of the underlying fundamental mechanisms of immune response and resistance to ICB, along with the use of complementary assays that interrogate distinct features of the tumor, the tumor microenvironment, and host immune system, will allow more precise use of these therapies to optimize patient outcomes.

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