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.

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]

scholarly journals Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Markus V. Heppt ◽  
Teresa Amaral ◽  
Katharina C. Kähler ◽  
Lucie Heinzerling ◽  
Jessica C. Hassel ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Multi Center Study ◽  
Center Study

Real-world experience and molecular features of response to immune checkpoint blockade in patients with recurrent small cell lung cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8556-8556 ◽  
Author(s):  
Wei-Chu Victoria Lai ◽  
Hira Rizvi ◽  
Jacklynn V. Egger ◽  
Andrew J. Plodkowski ◽  
Michelle S. Ginsberg ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Real World ◽  
Immune Checkpoint ◽  
Objective Response ◽  
Immune Checkpoint Blockade ◽  
Small Cell ◽  
Checkpoint Blockade ◽  
Small Cell Lung

8556 Background: Immune checkpoint blockade (ICB) is now a routine component of treatment in recurrent small cell lung cancer (SCLC). We evaluated the response to ICB in patients (pts) with recurrent SCLC and genomic features of response using next-generation sequencing (NGS). Methods: Pts with recurrent SCLC treated with ICB were identified. The majority of pts were treated outside of a clinical trial to focus emphasis on the real-world experience. Tumor mutation burden (TMB) and the landscape of somatic variants were determined by targeted NGS using MSK-IMPACT. Objective response rate (ORR) to ICB was determined using RECIST v1.1. PFS and OS were measured from the start of ICB and analyzed using Kaplan-Meier. Results: Between December 2013 and October 2018, 108 pts with SCLC were treated with ICB (57 subjected to NGS). Pts received PD-1 monotherapy alone (n = 28) or in combination with CTLA-4 blockade (n = 80). Median line of therapy was 2 (range 1-6). ORR was 14% (15/108, 95% CI 8-22%). From the start of ICB, median PFS was 1.4 months in non-responders and 10.8 months in responders (HR 0.2; 95% CI 0.13-0.32). Median OS was 6.3 months in non-responders and undefined in responders (range 8-44 months) (HR 0.26, 95% CI 0.16-0.44). Four responders remain on ICB treatment. TMB in the ICB-treated cohort was similar to that of an unselected cohort (n = 233) of SCLC (median 8.8 Mt/MB vs 8.2 Mt/MB, p = 0.71). Clinical benefit was enriched among those with a higher TMB (upper vs middle/lower tertile PFS HR 0.48, 95% CI 0.28-0.84, p = 0.01 and ORR 26% [5/19] vs ORR 8% [3/38]). Rates of whole genome duplication and commonly altered genes in SCLC ( TP53, RB1, KMT2C/D, NOTCH1/2/4, PTPRD, APC) were similarly distributed across responders and non-responders. Completion of whole-exome sequencing and PD-L1 testing is in progress. Conclusions: In pts with recurrent SCLC receiving routine clinical care, the ORR to ICB is comparable to reports from clinical trials. A high TMB was associated with a longer median PFS and better response. Further investigation into the genomic landscape of recurrent SCLC is needed to identify biomarkers predictive of response to ICB.

scholarly journals Dramatic response to combination pembrolizumab and radiation in metastatic castration resistant prostate cancer

2020 ◽  
Vol 12 ◽  
pp. 175883592093608
Author(s):  
Harry J. Han ◽  
Yun Rose Li ◽  
Mack Roach ◽  
Rahul Aggarwal
Keyword(s):  
Prostate Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Response To Treatment ◽  
Small Subset ◽  
Castration Resistant Prostate Cancer ◽  
Durable Response ◽  
Castration Resistant ◽  
Previously Treated

Immune checkpoint inhibitors targeting PD-1 and PD-L1 have demonstrated anti-tumor activity in several advanced solid malignancies. In previously treated metastatic castration resistant prostate cancer (mCRPC), a small subset of patients have a therapeutic response to checkpoint inhibition. Those who do respond to anti-PD-1/PD-L1 therapy have a marked, durable response to treatment, suggesting some derive long-term benefit from immune checkpoint blockade. In other cancers, one strategy to increase the efficacy of immune checkpoint blockade is to combine it with a pro-immune stimulatory agent, such as radiation. Here we present a case of a patient with heavily treated mCRPC who had a significant tumor response to concurrent pembrolizumab and radiation therapy to the primary prostatic mass. We review the growing evidence supporting the use of this combination therapy in other cancers and its potential benefit and safety in mCRPC. Our report highlights a potential therapeutic approach that should be further investigated in previously treated mCRPC.

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.

scholarly journals Is there a role for immune checkpoint blockade in metastatic uveal melanoma?

2015 ◽  
Vol 13 (Suppl 1) ◽  
pp. K20
Author(s):  
Bastian Schilling ◽  
Tim Schneider ◽  
Inga Möller ◽  
Antje Sucker ◽  
Annette Paschen ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

Immune checkpoint blockade for unresectable or metastatic uveal melanoma: A systematic review

2017 ◽  
Vol 60 ◽  
pp. 44-52 ◽  
Author(s):  
Markus V. Heppt ◽  
Theresa Steeb ◽  
Justin Gabriel Schlager ◽  
Stefanie Rosumeck ◽  
Corinna Dressler ◽  
...  
Keyword(s):  
Systematic Review ◽  
Uveal Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

Burden of copy number alterations predicts outcomes in immune checkpoint blockade treated gastrointestinal cancer patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14068-e14068
Author(s):  
Zhihao Lu ◽  
Huan Chen ◽  
Shuang Li ◽  
Xi Jiao ◽  
Lihong Wu ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Copy Number ◽  
Objective Response ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Copy Number Alterations ◽  
Sequencing Platform ◽  
Gi Cancer ◽  
Ffpe Tumor ◽  
Gi Cancers

e14068 Background: Despite the great achievements made in immune checkpoint blockade (ICB) in cancer therapy, how to identify patients who may benefit from ICB still remains one of the central questions, especially in gastrointestinal (GI) cancer. Methods: To address this, we analyzed FFPE tumor specimens from 73 patients with metastatic GI cancers who were treated with ICB. All patients were randomly assigned into discovery (60%) and validation (40%) cohorts. Overall, tumor mutation burden (TMB) and copy number alterations (CNAs) were determined by using the whole-exome sequencing platform. FFPE samples of 65 patients were analyzed via a multiplex RNA immune oncology sequencing panel. Results: Here we show that lower burden of copy number alteration (CNA) was observed in responders to immunotherapy in both discovery and validation cohorts. More importantly, lower burden of CNA in GI cancers were associated with improved objective response, clinical benefit and overall survival. Efficacy also correlated with the higher TMB. Of note, a combinatorial biomarker of TMB and burden of CNA may better stratify responders from patients received immunotherapy. In addition, patients with lower burden of CNA revealed increased IFNγ and expanded immune signatures in our GI patient cohort and TCGA cohorts as well. Conclusions: Our results suggest that burden of CNA may expand the predictive and prognostic value of genomic determinants in identifying potential responders with GI cancer to immune checkpoint blockade therapy.

Bone metastasis as an independent prognostic factor for survival in patients with advanced melanoma treated with immune checkpoint blockade.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e22045-e22045
Author(s):  
Marcos Rezende Teixeira ◽  
Milton Jos De Barros E Silva ◽  
Natasha Carvalho Pandolfi ◽  
Vinicius Fernando Calsavara ◽  
Thiago Bueno Oliveira ◽  
...  
Keyword(s):  
Overall Survival ◽  
Bone Metastasis ◽  
Prognostic Factor ◽  
Immune Checkpoint ◽  
Cox Regression ◽  
Immune Checkpoint Blockade ◽  
Advanced Melanoma ◽  
Independent Prognostic Factor ◽  
Checkpoint Blockade ◽  
The Impact

e22045 Background: Immune checkpoint blockade (ICB) has changed the natural history advanced melanoma (AM) with response rates about 40% and overall survival in 5 years of more than 30%. Interestingly, the site of metastasis may have impact on immune response due to the quantity and quality of immune infiltrate as we have seen in patients (pts) with liver metastasis treated with ICB. We have hypothesized that bone metastasis(BM) represents an immune less responsive site of disease Methods: We conducted a retrospective observational analysis of patients with AM treated with ICB at A.C. Camargo Cancer Center (AC) in São Paulo, Brazil. We analyze the impact of BM on progression-free (PFS) and overall survival (OS) using Kaplan Meier method, log-rank test and time-dependent COX regression model. Results: We analyzed 170 pts with AM treated with anti-PD1 (79%) or anti-PD1 + anti-CTLA4 (21%) between September 2013 and December 2019. Fifty-five percent in first-line, 22.4% second-line and the remaining in third or more lines of therapy. Ninety- four were male (55.3%), median age of 60.5 years (24.8 to 88.3) and 61 (35.9%) pts had BRAF mutation. Among stage IV patients (94%), 52 (32.4%) were M1c, 36 (22.4%) M1d and 46 (27%) had elevated LDH. Forty-two (26%) pts had BM. The overall response rate was 30.9% for pts with BM compared to 57.7% for pts without BM (p:0.004). In a median follow-up of 23.6 months (95% CI: 18.0-29.1), the median PFS and OS for pts with and without BM were 3.8 x 18.8 months (p 0.005) and 19.4months x not achieved (p 0.001), respectively. The 24-month analysis shows an overall survival rate of 38% for patients with BM compared to 62% for the rest of the cohort population. In a multivariate analysis for overall survival, acral melanoma, elevated LDH, ECOG performance status of 1 or 2 and BM were independent adverse prognostic factors (bone metastasis - HR: 2.3; 95%CI: 1.18-4.1; p:0.013). Conclusions: In this analysis, the presence of bone disease seems to be a worse independent prognostic factor for survival. A hypothesis would be the unfavorable bone microenvironment for the action of the immunotherapy.

scholarly journals The Role of Immune Checkpoint Blockade in Uveal Melanoma

2020 ◽  
Vol 21 (3) ◽  
pp. 879 ◽  
Author(s):  
Anja Wessely ◽  
Theresa Steeb ◽  
Michael Erdmann ◽  
Lucie Heinzerling ◽  
Julio Vera ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Uveal Melanoma ◽  
Genetic Heterogeneity ◽  
Immune Checkpoint ◽  
Cutaneous Melanoma ◽  
Local Therapy ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Therapy Options

Uveal melanoma (UM) represents the most common intraocular malignancy in adults and accounts for about 5% of all melanomas. Primary disease can be effectively controlled by several local therapy options, but UM has a high potential for metastatic spread, especially to the liver. Despite its clinical and genetic heterogeneity, therapy of metastatic UM has largely been adopted from cutaneous melanoma (CM) with discouraging results until now. The introduction of antibodies targeting CTLA-4 and PD-1 for immune checkpoint blockade (ICB) has revolutionized the field of cancer therapy and has achieved pioneering results in metastatic CM. Thus, expectations were high that patients with metastatic UM would also benefit from these new therapy options. This review provides a comprehensive and up-to-date overview on the role of ICB in UM. We give a summary of UM biology, its clinical features, and how it differs from CM. The results of several studies that have been investigating ICB in metastatic UM are presented. We discuss possible reasons for the lack of efficacy of ICB in UM compared to CM, highlight the pitfalls of ICB in this cancer entity, and explain why other immune-modulating therapies could still be an option for future UM therapies.

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