Complete and Durable Response to Nivolumab in Recurrent Poorly Differentiated Pancreatic Neuroendocrine Carcinoma with High Tumor Mutational Burden

Poorly differentiated pancreatic neuroendocrine carcinomas (NECs) are rare and aggressive malignancies with rapid disease progression and early widespread metastasis. Given histology similarity, they are commonly treated with platinum-based chemotherapy as small cell lung cancer (SCLC). However, no standard treatment has been established for recurrent or progressive disease. We present an Asian patient with recurrent poorly differentiated pancreatic NEC after curative surgery and adjuvant chemotherapy with cisplatin and etoposide. The tumor mutational burden (TMB) was high. The patient received chemotherapy combined with maintenance immunotherapy with nivolumab and achieved promising and durable response, suggesting TMB could be a biomarker to identify NEC patients for immune checkpoint inhibitor (ICI) treatment.

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Prevalence of PD-L1 expression in first-line (1L) locally advanced/unresectable or metastatic urothelial carcinoma (UC).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.8_suppl.tps67 ◽

2019 ◽

Vol 37 (8_suppl) ◽

pp. TPS67-TPS67

Author(s):

Petros Grivas ◽

Alicia K. Morgans ◽

Yair Lotan ◽

Jeffrey P. Gregg ◽

Daniel M. Geynisman ◽

...

Keyword(s):

Clinical Trial ◽

Tumor Tissue ◽

Performance Status ◽

Locally Advanced ◽

Circulating Tumor Dna ◽

Mutational Burden ◽

Platinum Based Chemotherapy ◽

Tumor Mutational Burden ◽

Pre Treatment ◽

And Performance

TPS67 Background: Treatments for 1L advanced/metastatic UC include platinum-based chemotherapy, an immune checkpoint inhibitor (ICI) or clinical trial enrollment. Not all patients benefit from, or are eligible for, specific therapies due to comorbidities and performance status. There is an urgent need for biomarker-directed strategies to enable patient selection and improve outcomes. Currently the only clinically used molecular biomarker is PD-L1 protein expression in tumor tissue. Although inconsistent and variable among assays, higher PD-L1 expression generally correlates with increased ICI response rate. Improved understanding of the prevalence and potential prognostic and/or predictive role of PD-L1 can further enhance its clinical utility and guide novel clinical trial designs. Methods: This observational study will enroll 250 patients with advanced UC prior to starting or during 1L therapy, as initiated at the discretion of participating clinicians, from 60 US community sites. The primary endpoint is prevalence of PD-L1 expression by VENTANA SP263 Assay (exact [Clopper-Pearson] 95% CI) on pre-treatment tumor tissue. Secondary endpoints include the association of pre-treatment PD-L1 expression with pre-treatment tumor tissue mutational burden (tTMB), descriptions of treatment response and outcomes (ORR based on RECIST 1.1, PFS, OS) and assessment of their correlations with PD-L1 expression. Exploratory endpoints include the association of pre-treatment tumor tissue PD-L1 with pre-treatment blood-based tumor mutational burden (bTMB), changes in circulating tumor DNA (ctDNA) levels at various timepoints, the correlation between tTMB and bTMB values, and the association of those biomarkers for outcomes of PFS and OS. Enrollment will take place over 24 months with follow-up to 30 months from study enrollment. With 250 patients, the 95% CI for 30%, 45%, and 60% observed prevalence of PD-L1 high are (24.4%, 36.1%), (38.9%, 51.2%), and (53.6%, 66.1%), respectively; the various secondary and exploratory analyses will be descriptive.

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Treatment Outcome of Different Chemotherapy in Patients With Relapsed or Metastatic Malignant Urachal Tumor

Frontiers in Oncology ◽

10.3389/fonc.2021.739134 ◽

2021 ◽

Vol 11 ◽

Author(s):

Meiting Chen ◽

Cong Xue ◽

Ri-qing Huang ◽

Meng-qian Ni ◽

Lu Li ◽

...

Keyword(s):

Tp53 Mutation ◽

Progression Free Survival ◽

Cancer Center ◽

First Line ◽

Urachal Carcinoma ◽

Free Survival ◽

Mutational Burden ◽

Platinum Based Chemotherapy ◽

Significant Difference ◽

Tumor Mutational Burden

BackgroundMalignant urachal tumor is a rare subtype of genitourinary cancer. Our aim was to explore the optimal chemotherapy regimens for relapsed or metastatic urachal carcinoma.Materials and MethodsWe retrospectively enrolled 24 adult patients with relapsed or metastatic urachal carcinoma from January 2014 to September 2020 at Sun Yat-sen University Cancer Center. We summarized the chemotherapy regimens and classified them as fluorouracil based, platinum based, and paclitaxel based. Nine patients received XELOX (capecitabine and oxaliplatin) regimens, seven patients received TX (paclitaxel and capecitabine) regimens, and eight of them received chemotherapy including GP (gemcitabine and cisplatin), TP (paclitaxel and cisplatin), TN (paclitaxel and nedaplatin), and tislelizumab.ResultsThe disease control rate was 75%. Among all patients, one patient treated with XELOX achieved partial remission (PR), while 17 patients showed stable disease. The median progression-free survival (PFS) and overall survival (OS) in all treated patients was 7.43 and 29.7 months, respectively. The patients receiving first-line platinum-based chemotherapy presented better PFS than those without platinum (median PFS 8.23 vs. 3.80 months, p = 0.032), but not significant for OS between two groups. There is no significant difference in PFS and OS for fluorouracil-based and paclitaxel-based groups as first-line regimen. Next-generation gene sequencing revealed TP53 mutation and low tumor mutational burden in five out of seven cases.ConclusionThe platinum-based chemotherapy regimen is effective for relapsed or metastatic urachal carcinoma.

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IFNγ mRNA signature (IFNγ sig), circulating tumor DNA (ctDNA), and survival in NSCLC or urothelial cancer (UC) treated with durvalumab (D).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.5_suppl.51 ◽

2018 ◽

Vol 36 (5_suppl) ◽

pp. 51-51 ◽

Cited By ~ 1

Author(s):

Brandon W. Higgs ◽

Chris Morehouse ◽

Michael Kuziora ◽

Philip Z. Brohawn ◽

Sriram Sridhar ◽

...

Keyword(s):

Liver Metastases ◽

Urothelial Cancer ◽

Progressive Disease ◽

Phase 1 ◽

Circulating Tumor Dna ◽

Mutational Burden ◽

Dna Variants ◽

Tumor Mutational Burden ◽

Tumor Dna ◽

Clinical Trial Information

51 Background: Associations between early reduction in plasma ctDNA, pretreatment tumoral IFNγ sig, liver metastases and outcomes, and between tumor mutational burden (TMB) and CD274 (PD-L1) mRNA or IFNγ sig in TCGA were evaluated in NSCLC and UC pts treated with D. Methods: Pts received 10 mg/kg Q2W of D in a Phase 1/2 study in advanced solid tumors. RNAseq measured a 4-gene IFNγ sig; top tertile was IFNγ sig+. Pts with PD-L1 expression (Ventana SP263) ≥ 25% tumor cells in NSCLC or ≥ 25% tumor or immune cells in UC were PD-L1+. 70 genes were assayed for DNA variants (Guardant360) in plasma ctDNA pre/posttreatment. TCGA was used to calculate TMB; ≥ median TMB was high. Results: IFNγ sig+ NSCLC or UC pts had higher response and longer median PFS and OS compared with PD-L1+, PD-L1- and IFNγ sig- pts (Table). Responders showed significant decreases in ctDNA mean variant allele frequency (VAF) posttreatment with D; pts with progressive disease showed increased VAF. Pts with decreased VAF at week 6 had longer median PFS and OS compared with those with VAF increases. VAF changes were not associated with IFNγ sig. NSCLC without liver metastases had higher IFNγ sig (P < 0.001) than pts with liver metastases. In TCGA NSCLC and UC, IFNγ sig+ correlated with high TMB; CD274 mRNA did not. Conclusions: IFNγ sig correlated with outcomes and with TMB in NSCLC and UC. CtDNA VAFs were reduced in NSCLC or UC responders after treatment and correlated with longer survival, suggesting utility as an early indicator of clinical benefit. Clinical trial information: NCT01693562. [Table: see text]

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631 Deep, durable response to PD-1 inhibitor monotherapy in microsatellite-stable, tumor mutational burden-high colorectal cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.631 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A661-A661

Author(s):

Samuel Schellenberg ◽

Leeseul Kim ◽

Young Kwang Chae

Keyword(s):

Colorectal Cancer ◽

Carcinoembryonic Antigen ◽

Immune Checkpoint ◽

Treatment Initiation ◽

The United States ◽

Genomic Profiling ◽

Durable Response ◽

Mutational Burden ◽

Comprehensive Genomic Profiling ◽

Tumor Mutational Burden

BackgroundImmune checkpoint inhibitors have revolutionized care for a number of different cancer types. For colorectal cancer (CRC), a leading cause of cancer-related death in the United States, programmed cell death protein 1 (PD-1) inhibition is a treatment option for certain subsets of patients. High microsatellite instability (MSI-H) tumors are immunogenic, and thus PD-1 inhibition is first-line treatment. Anti-PD-1 therapy is generally not utilized for microsatellite stable (MSS) patients. Tumor mutational burden (TMB) is another predictive biomarker for immunotherapy response in all solid tumors. Here we present the case of a patient with MSS, TMB-H CRC resistant to multiple lines of chemotherapy, who responded to anti-PD-1 monotherapy.MethodsCase presentation.ResultsA 64-year-old man with a family history significant for colon cancer was diagnosed with colorectal cancer, revealed to be moderately differentiated mucinous adenocarcinoma (stage IIIC) on biopsy. A tissue-based comprehensive genomic profiling of the cancer showed KRASG12D and ERBB2 amplification, microsatellite-stable, and TMB of 11mut/mB (FoundationOne). The patient progressed on multiple lines of therapy with multiple metastatic sites, and was briefly put under home hospice with diffuse abdominal pain and weight loss. The patient was started on pembrolizumab monotherapy, around 3.5 years after initial presentation. After five months on pembrolizumab, imaging showed significant improvement in pulmonary, hepatic, adrenal, and retroperitoneal metastases and the patient demonstrated partial response to treatment according to RECIST 1.1 criteria. The patient's carcinoembryonic antigen (CEA) levels had decreased from 45 ng/mL at treatment initiation to 2.8 ng/mL, and ctDNA analysis showed a blood TMB decrease from 31.58 mut/mB at treatment initiation to .96 mut/mB (figure 1), accompanied by decreases in the variant allele frequencies of the five most prevalent variants at the time of treatment initiation (Guardant 360). The patient's pain had nearly resolved by this point and pain medications were tapered off.ConclusionsThis case demonstrates the existence of a subset of CRC patients who are MSS but TMB-H and may respond to immune checkpoint blockade. Comprehensive genomic profiling must be utilized in order to not miss this subset of patients. The mechanism of response in this subset of patients is unknown but warrants further exploration. Further studies should clarify the mechanism and likelihood of response to immunotherapy in MSS, TMB-H CRC patients, as this is critical to providing effective treatment for this subset.ConsentWritten informed consent was obtained from the patient 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.Abstract 631 Figure 1Carcinoembryonic antigen (CEA) and blood tumor mutational burden (TMB) levels through six cycles of treatment with pembrolizumab

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Immunotherapy in Ovarian Cancer: Thinking Beyond PD-1/PD-L1

Frontiers in Oncology ◽

10.3389/fonc.2021.795547 ◽

2021 ◽

Vol 11 ◽

Author(s):

Laure Chardin ◽

Alexandra Leary

Keyword(s):

Ovarian Cancer ◽

Tumor Infiltrating Lymphocytes ◽

Gynecologic Malignancy ◽

Current Management ◽

Mutational Burden ◽

Platinum Based Chemotherapy ◽

Tumor Mutational Burden ◽

Optimal Debulking ◽

Novel Therapeutic Strategies ◽

Infiltrating Lymphocytes

Ovarian cancer (OC) is the most lethal gynecologic malignancy, affecting approximately 1 in 70 women with only 45% surviving 5 years after diagnosis. This disease typically presents at an advanced stage, and optimal debulking with platinum-based chemotherapy remains the cornerstone of management. Although most ovarian cancer patients will respond effectively to current management, 70% of them will eventually develop recurrence and novel therapeutic strategies are needed. There is a rationale for immune-oncological treatments (IO) in the managements of patients with OC. Many OC tumors demonstrate tumor infiltrating lymphocytes (TILs) and the degree of TIL infiltration is strongly and reproducibly correlated with survival. Unfortunately, results to date have been disappointing in relapsed OC. Trials have reported very modest single activity with various antibodies targeting PD-1 or PD-L1 resulting in response rate ranging from 4% to 15%. This may be due to the highly immunosuppressive TME of the disease, a low tumor mutational burden and low PD-L1 expression. There is an urgent need to improve our understanding of the immune microenvironment in OC in order to develop effective therapies. This review will discuss immune subpopulations in OC microenvironment, current immunotherapy modalities targeting these immune subsets and data from clinical trials testing IO treatments in OC and its combination with other therapeutic agents.

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Complete response to anti-PD-L1 antibody in a metastatic bladder cancer associated with novel MSH4 mutation and microsatellite instability

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2019-000128 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000128

Author(s):

Yuanquan Yang ◽

Rohit K Jain ◽

Sean T Glenn ◽

Bo Xu ◽

Prashant K Singh ◽

...

Keyword(s):

Bladder Cancer ◽

Microsatellite Instability ◽

Complete Response ◽

Loss Of Function ◽

Mutational Burden ◽

Metastatic Bladder Cancer ◽

Platinum Based Chemotherapy ◽

Tumor Mutational Burden ◽

Mixed Histology ◽

Muscle Invasive

BackgroundMicrosatellite instability (MSI) occurs in 3% of urothelial carcinomas as a result of germline or somatic loss of function mutation in mismatch repair (MMR) proteins.1 Although MSH4 is a member of the DNA MMR mutS family, the association of MSH4 mutation with MSI has not been described. We report a complete responder to PD-L1 blockade who had MSH4 mutated metastatic bladder cancer with mixed histology and MSI. The genomics of urothelial, plasmacytoid and squamous histology was characterized individually through microdissection.Case presentationAn 81-year-old man was diagnosed with metastatic urothelial carcinoma 8 months after a cystectomy for muscle invasive bladder cancer. His disease was primary refractory to first-line platinum-based chemotherapy but attained complete response to second-line atezolizumab. PCR-based assay revealed MSI high. The tumor mutational burden was elevated to 36.7 mut/Mb. However, immunohistochemistry of MLH1, MSH2, MSH6 and PMS2 was intact. Whole exome sequencing confirmed that the above mentioned four classic MMR genes were wild type but revealed a deleterious MSH4 L359I mutation with variant allele fraction of 30% and Polyphen2 score of 0.873. The association of MSH4 alterations and MSI-H was independently verified in two publicly available MSI-H colorectal cancer datasets.ConclusionsThe novel MSH4 L359I mutation is associated with MSI and high mutational burden leading to remarkable response to PD-L1 blockade. More studies are warranted to establish the causality relationship between MSH4 and MSI.

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A Comprehensive Review of Poorly Differentiated Neuroendocrine Carcinomas (pdNECs): a Niche to Find Novel Opportunities

Current Pharmaceutical Design ◽

10.2174/1381612820666140826154033 ◽

2014 ◽

Vol 20 (42) ◽

pp. 6644-6651 ◽

Cited By ~ 1

Author(s):

Pablo Reguera ◽

Ainhoa Madariaga ◽

Enrique Grande

Keyword(s):

Comprehensive Review ◽

Poorly Differentiated ◽

Neuroendocrine Carcinomas

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NCMP-17. MISMATCH REPAIR MUTATIONS AND THE CENTRAL NERVOUS SYSTEM: A CASE SERIES OF GERMLINE MUTATIONS AND CNS MALIGNANCY

Neuro-Oncology ◽

10.1093/neuonc/noaa215.528 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii126-ii126

Author(s):

Amber Ruiz ◽

Jerome Graber

Keyword(s):

Treatment Response ◽

Mismatch Repair ◽

Case Series ◽

Germline Mutations ◽

Molecular Characteristics ◽

Loss Of Function ◽

Dna Mismatch ◽

Mutational Burden ◽

Increased Risk ◽

Tumor Mutational Burden

Abstract Our understanding of genetic predispositions for malignancy is continually evolving. One family of germline mutations well described in the literature is that of the DNA mismatch repair mechanism (MMR). Lynch syndrome (LS) is due to a loss of function mutation of several MMR genes- MSH2, MLH1, MSH6, and PMS2. Germline MMR mutations lead to microsatellite instability and loss of genomic integrity resulting in an increased risk for various cancers (colorectal, genitourinary, etc). LS may be as common as 1 in 400 people and some MMR mutations have been associated with gliomas. There is a paucity of information regarding frequency of glioma subtypes as well as tumor genetic and molecular characteristics which have important clinical implications. We describe a case series of 6 individuals with germline MMR mutations and brain tumors. Those with MSH2 and PMS2 mutations (n=3) developed glioblastomas at a mean age at diagnosis of 48 years. These tumors expressed MGMT hyper-methylation and high tumor mutational burden. Only one had IDH-1 mutation. Those with MLH1 mutations (n=3), did not develop gliomas. This raises the question of differential glioma subtype development based on MMR gene. It also highlights the possibility of Lynch-associated gliomas having more favorable treatment response due to MGMT methylation and potential response to immunotherapy based on high tumor mutational burden. Though the sample size is small, there appears to be a preponderance of women compared to men (5:1 respectively). Larger studies are needed to verify CNS involvement in germline MMR mutations. In doing so, we hope to identify factors that may influence clinical management and lead to a better understanding of treatment response and disease prognosis.

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