Study of First-line Pembrolizumab (MK-3475) With Lenvatinib (MK-7902/E7080) in Urothelial Carcinoma Cisplatin-ineligible Participants Whose Tumors Express Programmed Cell Death-Ligand 1 and in Participants Ineligible for Platinum-containing Chemotherapy (MK-7902-011/E7080-G000-317/ LEAP-011)

Immune checkpoint inhibitors enrich the therapeutic landscape in oesophago-gastric carcinoma. With regard to oesophageal squamous cell carcinoma (ESCC), the selective PD-1 (programmed cell death receptor 1)-inhibitor nivolumab improves disease-free survival in the adjuvant therapy setting (CHECKMATE-577). In first-line treatment, ESCC patients (pts) benefit in overall survival (OS) from the PD-1-inhibitor pembrolizumab in combination with chemotherapy (KEYNOTE-590). In the second-line setting, nivolumab (ATTRACTION-03) and pembrolizumab (KEYNOTE-181) demonstrate a benefit in OS compared with chemotherapy. These data resulted in the approval of nivolumab for the second-line treatment of advanced ESCC pts regardless of PD-L1 (programmed cell death ligand 1) status in Europe, Asia, and the USA, and pembrolizumab for pts with PD-L1 CPS (combined positivity score) ≥ 10 in Asia and the USA. Further approvals can be expected. In gastro-oesophageal junction and gastric cancer, the addition of nivolumab to chemotherapy in first-line treatment improves OS in pts with advanced disease with PD-L1 CPS ≥ 5 (CHECKMATE-649). Additionally, pembrolizumab was non-inferior to chemotherapy for OS in PD-L1 CPS ≥ 1 pts (KEYNOTE-062). In third-line treatment, nivolumab shows benefits in OS regardless of PD-L1 expression (ATTRACTION-02) with approval in Asia, and pembrolizumab prolonged the duration of response in PD-L1 positive pts (KEYNOTE-059) with approval in the USA. We discuss the recent results of the completed phase II and III clinical trials.

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Durable Tumor Regression and Overall Survival in Patients With Advanced Merkel Cell Carcinoma Receiving Pembrolizumab as First-Line Therapy

Journal of Clinical Oncology ◽

10.1200/jco.18.01896 ◽

2019 ◽

Vol 37 (9) ◽

pp. 693-702 ◽

Cited By ~ 102

Author(s):

Paul Nghiem ◽

Shailender Bhatia ◽

Evan J. Lipson ◽

William H. Sharfman ◽

Ragini R. Kudchadkar ◽

...

Keyword(s):

Overall Survival ◽

Cell Death ◽

Programmed Cell Death ◽

Cell Carcinoma ◽

Merkel Cell Carcinoma ◽

Merkel Cell Polyomavirus ◽

Merkel Cell ◽

First Line ◽

Median Response ◽

Programmed Cell Death 1

PURPOSE Merkel cell carcinoma (MCC) is an aggressive skin cancer often caused by the Merkel cell polyomavirus. Clinical trials of programmed cell death-1 pathway inhibitors for advanced MCC (aMCC) demonstrate increased progression-free survival (PFS) compared with historical chemotherapy data. However, response durability and overall survival (OS) data are limited. PATIENTS AND METHODS In this multicenter phase II trial (Cancer Immunotherapy Trials Network-09/Keynote-017), 50 adults naïve to systemic therapy for aMCC received pembrolizumab (2 mg/kg every 3 weeks) for up to 2 years. Radiographic responses were assessed centrally per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. RESULTS Among 50 patients, the median age was 70.5 years, and 64% had Merkel cell polyomavirus–positive tumors. The objective response rate (ORR) to pembrolizumab was 56% (complete response [24%] plus partial response [32%]; 95% CI, 41.3% to 70.0%), with ORRs of 59% in virus-positive and 53% in virus-negative tumors. Median follow-up time was 14.9 months (range, 0.4 to 36.4+ months). Among 28 responders, median response duration was not reached (range, 5.9 to 34.5+ months). The 24-month PFS rate was 48.3%, and median PFS time was 16.8 months (95% CI, 4.6 months to not estimable). The 24-month OS rate was 68.7%, and median OS time was not reached. Although tumor viral status did not correlate with ORR, PFS, or OS, there was a trend toward improved PFS and OS in patients with programmed death ligand-1–positive tumors. Grade 3 or greater treatment-related adverse events occurred in 14 (28%) of 50 patients and led to treatment discontinuation in seven (14%) of 50 patients, including one treatment-related death. CONCLUSION Here, we present the longest observation to date of patients with aMCC receiving first-line anti–programmed cell death-1 therapy. Pembrolizumab demonstrated durable tumor control, a generally manageable safety profile, and favorable OS compared with historical data from patients treated with first-line chemotherapy.

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A metastatic intrahepatic cholangiocarcinoma treated with programmed cell death 1 inhibitor: a case report and literature review

Immunotherapy ◽

10.2217/imt-2019-0100 ◽

2020 ◽

Vol 12 (8) ◽

pp. 555-561 ◽

Cited By ~ 3

Author(s):

Jingjing Zhang ◽

Lihua Wu ◽

Jian Liu ◽

Meihua Lin

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Intrahepatic Cholangiocarcinoma ◽

Clinical Effectiveness ◽

First Line ◽

Mutational Burden ◽

Programmed Death ◽

Promising Therapeutic Approach ◽

Programmed Cell Death 1 ◽

Tumor Mutational Burden

Intrahepatic cholangiocarcinoma is a disease with grave prognosis due to limited therapeutic regimens. Programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor have shown dramatic clinical effectiveness in multiple solid tumors. Here, we report the case that a patient with metastasis intrahepatic cholangiocarcinoma, being failure of first-line chemotherapy, was enrolled into the Phase I study of a PD-1 inhibitor, sintilimab. The patient achieved complete remission after three cycles of treatment with mild adverse reaction. In addition, the tumor mutational burden and the microsatellite instability status were low in the present case. Hence, PD-1 inhibitor might be a promising therapeutic approach for patients with advanced cholangiocarcinoma.

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A Retrospective Study of Lenvatinib Monotherapy or Combined With Programmed Cell Death Protein 1 Antibody in the Treatment of Patients With Hepatocellular Carcinoma or Intrahepatic Cholangiocarcinoma in China

Frontiers in Oncology ◽

10.3389/fonc.2021.788635 ◽

2021 ◽

Vol 11 ◽

Author(s):

Sihui Zhu ◽

Chenxi Liu ◽

Yanbing Dong ◽

Jie Shao ◽

Baorui Liu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Death ◽

Liver Cancer ◽

Programmed Cell Death ◽

Intrahepatic Cholangiocarcinoma ◽

Real World ◽

Liver Tumors ◽

Chinese Patients ◽

First Line ◽

Cell Death Protein

Lenvatinib has been ratified as a first-line medication for advanced liver tumors by the American Food and Drug Administration. To assess the effectiveness and security of Lenvatinib in the Chinese population in a real-world setting, we enrolled 48 patients with unresectable liver cancer, managed from December 2018 to March 2021. Among them, 9 and 39 (83.30% men) patients had intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC), respectively. Twenty-one (43.75%) patients had progressive disease after first-line treatment, and others (56.25%) had not receiving systemic treatment. Lenvatinib was administered alone or in combination with a programmed cell death protein 1 antibody (anti-PD-1). Treatment duration, median progression-free survival (mPFS), and median overall survival (mOS) were examined. The mOS and mPFS were 22.43 and 8.93 months, respectively. Of HCC patients treated with Lenvatinib only, the mOS and mPFS were 22.43 and 11.60 months, respectively. The corresponding values for HCC cases managed with anti-PD-1 combined with Lenvatinib were 21.77 and 7.10 months, respectively. ICC patients did not reach the mOS and their mPFS was 8.63 months. The present findings support the efficacy and security of Lenvatinib in the real-world therapy of Chinese patients with unresectable liver cancer.

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Comparison of the Prognostic Value of Ki-67 and Programmed Cell Death Ligand-1 in Patients with Upper Tract Urothelial Carcinoma

Journal of Clinical Medicine ◽

10.3390/jcm10163728 ◽

2021 ◽

Vol 10 (16) ◽

pp. 3728

Author(s):

Mu-Yao Tsai ◽

Ping-Chia Chiang ◽

Chien-Hsu Chen ◽

Ming-Tse Sung ◽

Shun-Chen Huang ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Urothelial Carcinoma ◽

Prognostic Value ◽

Multivariable Analysis ◽

Upper Tract Urothelial Carcinoma ◽

Cancer Specific Survival ◽

Ki 67 ◽

Upper Tract ◽

T Stage

We retrospectively enrolled 102 patients with upper tract urothelial carcinoma (UTUC) who underwent radical nephroureterectomy to examine the prognostic value of Ki-67 and programmed cell death ligand-1 (PD-L1). Then, we performed PD-L1 and Ki-67 immunohistochemical staining on whole tissue sections. The cut-off value of PD-L1 positivity was a combined positive score (CPS) ≥10 and the Ki-67 overexpression was 20%. Among the 102 patients, 16.7% and 48.0% showed positive PD-L1 expression and Ki-67 overexpression, respectively. A CPS ≥10 was significantly associated with a higher pathological T stage (p = 0.049). In addition, Ki-67 overexpression was significantly associated with a pathological T stage ≥ 2 (p = 0.027) and tumour necrosis (p = 0.016). In the multivariable analysis, a positive PD-L1 expression was significantly correlated with worse cancer-specific survival (HR = 3.66, 95% CI =1.37−9.77, p = 0.01). However, there was no predictive value using a combination of PD-L1 expression and Ki-67 overexpression as a prognostic predictor. Compared with Ki-67 overexpression, a positive PD-L1 expression with CPS ≥ 10 was a stronger independent prognostic factor for CSS in patients with UTUC.

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Complete Clinical Response in Stage IVB Endometrioid Endometrial Carcinoma after First-Line Pembrolizumab Therapy: Report of a Case with Isolated Loss of PMS2 Protein

Case Reports in Oncology ◽

10.1159/000510000 ◽

2020 ◽

Vol 13 (3) ◽

pp. 1067-1074

Author(s):

Jesus Paula Carvalho ◽

Auro Del Giglio ◽

Maria Isabel Achatz ◽

Filomena Marino Carvalho

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Endometrial Carcinoma ◽

Early Stage ◽

Gynecological Cancer ◽

Stage Iv ◽

Protein Loss ◽

First Line ◽

Early Stage Disease ◽

Endometrioid Endometrial Carcinoma

Endometrial cancer is the only gynecological cancer that is rising in incidence and associated mortality worldwide. Although most cases are diagnosed as early stage disease, with chances of cure after primary surgical treatment, those with advanced or metastatic disease have a poor prognosis because of the quality of treatment options that are currently available. Mismatch repair (MMR)-deficient cancers are susceptible to programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 inhibitors. The US Food and Drug Administration granted accelerated approval to pembrolizumab for MMR-deficient tumors, the first tumor-agnostic approval for a drug. We present a case of stage IV endometrioid endometrial carcinoma with isolated PMS2 protein loss, in which treatment with first-line pembrolizumab therapy achieved a complete clinical and pathological response of tumor.

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Concordance among four commercially available, validated programmed cell death ligand-1 assays in urothelial carcinoma

Diagnostic Pathology ◽

10.1186/s13000-019-0873-6 ◽

2019 ◽

Vol 14 (1) ◽

Cited By ~ 7

Author(s):

Magdalena Zajac ◽

Marietta Scott ◽

Marianne Ratcliffe ◽

Paul Scorer ◽

Craig Barker ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Urothelial Carcinoma

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Prognostic role of programmed cell death protein 1 expression in surgically treated patients with upper tract urothelial carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.2_suppl.402 ◽

2016 ◽

Vol 34 (2_suppl) ◽

pp. 402-402

Author(s):

Nozomi Hayakawa ◽

Eiji Kikuchi ◽

Ryuichi Mizuno ◽

Keishiro Fukumoto ◽

Takeo Kosaka ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Protein Expression ◽

Urothelial Carcinoma ◽

Lymphovascular Invasion ◽

Upper Tract Urothelial Carcinoma ◽

Upper Tract ◽

Significant Difference ◽

Cell Death Protein

402 Background: Programmed cell death protein (PD-1) expressed on active T cells, and its ligand PD-L1 expressed on the surface of cancer cells, complementarily down-regulate T cell activation and are related to immune tolerance. A close association between PD-1 expression and poor prognosis has been reported in several cancers, however, in upper tract urothelial carcinoma (UTUC) the role of PD-1 expression on clinical outcome has not been investigated. Methods: The protein expression of PD-1 was evaluated by immunohistochemistry and the relationship with clinicopathological features was investigated in surgical specimens obtained from 100 patients who had been surgically treated for UTUC. At a magnification of 200x, PD-1 protein expression was estimated and the positive cells were graded as no (negative), moderate (1-10 cells), and strong ( > 10 cells). Results: Twenty-four patients (24.0%) had strong PD-1 staining, 32 patients (32.0%) had moderate PD-1 staining, and 44 patients (44.0%) had no PD-1 staining. PD-1 staining was associated with pathological T stage (p = 0.023), tumor grade (p = 0.005), and lymphovascular invasion (p = 0.033). Lymphovascular invasion (p < 0.001) and PD-1 staining (p = 0.02) were independent factors for predicting disease metastasis. The 5-year matastatic free survival rate in patients with strong PD-1 staining was 57.3 %, which was significantly lower than that with no PD-1 staining (87.3%, p=0.001) and that with moderate PD-1 staining (74.3%, p = 0.05). In a sub-group analysis of patients with ≥pT2 (N = 59), a significant difference in disease metastasis was observed between patients with strong PD-1 staining and no PD-1 staining (p = 0.018), but was not observed between strong and moderate PD-1 staining (p = 0.146). Conclusions: PD-1 expression may be a useful indicator for a worse prognosis in UTUC patients who undergo radical nephroureterectomy. Targeting therapy against PD-1 might be a promising therapeutic modality for UTUC.

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Prognostic rule of programmed cell death protein 1 expression in resectable upper tract urothelial carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e16090 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e16090-e16090

Author(s):

Nozomi Hayakawa ◽

Eiji Kikuchi ◽

Ryuichi Mizuno ◽

Mototsugu Oya

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Protein Expression ◽

Urothelial Carcinoma ◽

Upper Tract Urothelial Carcinoma ◽

High Grade ◽

Cox Regression Analysis ◽

Upper Tract ◽

Tumor Periphery ◽

Cell Death Protein

e16090 Background: Programmed cell death protein (PD-1) expressed on active T cells are related to immune tolerance. A close association between PD-1 expression and poor prognosis has been reported in several cancers, however, in upper tract urothelial carcinoma (UTUC) the rule of PD-1 expression on clinical outcome have not been investigated. Methods: The protein expression of PD-1 was evaluated by immunohistochemistry and the relationship with clinicopathological features was investigated in surgical specimens obtained from 155 patients who had been surgically treated for UTUC without previous history of bladder cancer. At a magnification of 400x, PD-1 protein expression was estimated and the positive cells was graded as weak and strong. The protein expression of PD-1 was evaluated in the most invasive part of the cancer with tumor periphery and inside separately. Results: The PD-1 expression was weak in 67 (43.2%) and strong in 88 (56.8%) in tumor periphery. On the other hands, the staining was weak in 117 (75.5%) and strong in 38(24.5%) in tumor insides. Regarding to pathological features, high grade (p = 0.026) and pT2≤ (p = 0.008) related to strong PD-1 expression in tumor inside, and high grade (p = 0.002), pT2≤ (p < 0.001) and positive LVI (p = 0.008) were associated with strong PD-1 expression in tumor periphery. The 5-year caner-specific survival (CSS) in patients with strong PD-1 staining in tumor periphery was 79.4%, which was significantly lower than those in their counterparts (86.0%, p = 0.044). The 5-year CSS in patients with strong PD-1 staining in tumor inside was 73.3%, which was significantly lower than those in their counterparts (85.1%, p < 0.021). Multivariate Cox regression analysis demonstrated that positive LVI (HR; 3.92, p < 0.001) and strong PD-1 expression in tumor inside (HR; 2.30, p < 0.036) were independent predictors for CSS. Conclusions: PD-1 expression, especially in tumor inside, may be a novel indicator for identifying a worse prognosis in UTUC patients with radical nephroureterectomy. Targeting therapy against PD-1 might be a promising therapeutic modality for UTUC, especially aggressive UTUC.

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