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Original Article Efficacy and Safety of Pembrolizumab in Patients with Refractory Advanced Biliary Tract Cancer: Tumor Proportion Score as a Potential Biomarker for Response
Junho Kang1, Jae Ho Jeong1, Hee-Sang Hwang2, Sang Soo Lee3, Do Hyun Park3, Dong Wook Oh3, Tae Jun Song3, Ki-Hun Kim4, Shin Hwang4, Dae Wook Hwang4, Song Cheol Kim4, Jin-hong Park5, Seung-Mo Hong2, Kyu-pyo Kim1, Baek-Yeol Ryoo1,, Changhoon Yoo1,
Cancer Research and Treatment : Official Journal of Korean Cancer Association 2020;52(2):594-603.
DOI: https://doi.org/10.4143/crt.2019.493
Published online: December 18, 2019

1Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

2Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

3Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

4Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

5Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Correspondence: Changhoon Yoo, MD, PhD Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea
Tel: 82-2-3010-1727 Fax: 82-2-3010-6961 E-mail: yooc@amc.seoul.kr
Co-correspondence: Baek-Yeol Ryoo, MD, PhD Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea
Tel: 82-2-3010-3211 Fax: 82-2-3010-6961 E-mail: ryooby@amc.seoul.kr
*Junho Kang, Jae Ho Jeong, and Hee-Sang Hwang contributed equally to this work.
• Received: August 24, 2019   • Accepted: December 17, 2019

Copyright © 2020 by the Korean Cancer Association

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Purpose
    The current standard chemotherapy for advanced biliary tract cancer (BTC) has limited benefit, and novel therapies need to be investigated.
  • Materials and Methods
    In this prospective cohort study, programmed death ligand-1 (PD-L1)–positive BTC patients who progressed on first-line gemcitabine plus cisplatin were enrolled. Pembrolizumab 200 mg was administered intravenously every 3 weeks.
  • Results
    Between May 2018 and February 2019, 40 patients were enrolled. Pembrolizumab was given as second-line (47.5%) or ≥ third-line therapy (52.5%). The objective response rate was 10% and 12.5% by Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 and immune- modified RECIST (imRECIST) and median duration of response was 6.3 months. Among patients with progressive disease as best response, one patient (1/20, 5.0%) achieved complete response subsequently. The median progression-free survival (PFS) and overall survival (OS) were 1.5 months (95% confidence interval [CI], 0.0 to 3.0) and 4.3 months (95% CI, 3.5 to 5.1), respectively, and objective response per imRECIST was significantly associated with PFS (p < 0.001) and OS (p=0.001). Tumor proportion score ≥ 50% was significantly associated with higher response rates including the response after pseudoprogression (vs. < 50%; 37.5% vs. 6.5%; p=0.049).
  • Conclusion
    Pembrolizumab showed modest anti-tumor activity in heavily pretreated PD-L1–positive BTC patients. In patients who showed objective response, durable response could be achieved.
Biliary tract cancer (BTC) is a heterogeneous group of diseases, which consists of intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA), and gallbladder cancer (GBCA) [1]. The incidence of BTC is rare in the United States and Europe, but the prevalence is higher in Asia and Latin America [2,3]. Complete surgical resection, which is the only curative treatment, is available for only a minority of patients and is hindered by a low overall 5-year survival rate and high rate of tumor recurrence [1,4]. For patients with advanced BTC, the phase III ABC-02 and ABC-06 trials showed the clinical efficacy of gemcitabine plus cisplatin (GemCis) and oxaliplatin plus fluoropyrimidine (mFOLFOX) as first-line therapy and second-line therapy, respectively [5,6]. However, the survival outcomes remain dismal with a median overall survival (OS) of < 1 year, and none of the targeted agents have been approved for treatment of BTC [7-9].
Pembrolizumab is an anti–programmed death 1 (PD-1) antibody, which has shown anti-tumor activity in various types of cancers, including non-small-cell lung cancer, melanoma, gastric cancer, and urothelial cancer [10-13]. Tumor PD-L1 expression emerged as a potential biomarker of response to pembrolizumab in several types of tumors [13-15], and cancer patients with mismatch repair (MMR) deficiency are sensitive to immune checkpoint blockade, regardless of tumor origin [16,17]. In patients with BTC, tumor PD-L1 expression and MMR deficiency have been reported, indicating that pembrolizumab may be potentially effective in the treatment of BTC [18-21].
Although pembrolizumab has shown modest efficacy in patients with advanced PD-L1–positive BTC in prior single-arm phase I/II KEYNOTE-028 and -158 studies [22], more data are needed to evaluate the clinical outcomes of pembrolizumab in unresectable or metastatic BTC, considering the heterogeneity of the disease. In this prospective cohort study, we analyzed the efficacy and safety of pembrolizumab in patients with advanced BTC after progression on first-line GemCis.
1. Patients
This study is a single-center, prospective cohort study aimed to evaluate the efficacy, safety, and biomarker of pembrolizumab in patients with advanced BTC including iCCA, eCCA, and GBCA (ClinicalTrials.gov identifier, NCT03695-952). Patients with histologically or cytologically confirmed unresectable or metastatic BTC who radiologically progressed after receiving first-line GemCis were eligible for enrolment if they had PD-L1–positive tumors (PD-L1 ≥ 1% of tumor cells graded by local pathologists), aged ≥ 19 years, and provided a written informed consent for the collection of data on baseline characteristics and clinical outcomes. Biomarker analysis using blood and tumor tissues was also required for the enrolment.
2. Histopathological analysis
All histologic data including PD-L1 and MMR status were centrally reviewed after enrolment to this study by an academic pathologist. The administration of pembrolizumab was not affected by the results of this central review of PD-L1 and MMR status. PD-L1 expression was assessed by conducting an immunohistochemistry of archived tumor tissues with PD-L1 immunohistochemistry SP263 (Ventana Benchmark Ultra, Tuscon, AZ) or 22C3 pharmDx kit (Agilent Technologies, Santa Clara, CA). The tumor cells were considered PDL1–positive if the viable tumor cells exhibited any perceptable, partial or complete, linear cell membrane staining. The immune cells were considered PD-L1–positive if the cells displayed any membranous or cytoplasmic PD-L1 staining [23]. Tumor proportion score (TPS) was defined as the percentage of viable tumor cells that showed partial or complete membrane staining of PD-L1 relative to all viable tumor cells present in the sample [24]. Combined positive score (CPS) was defined as the number of PD-L1–positive cells (tumor cells, lymphocytes, and macrophages) divided by the total number of viable tumor cells and multiplied by 100 [25]. Antibodies specific for MMR proteins included MLH1 (1:10, clone G168- 15, BD Pharmingen, San Jose, CA), MSH2 (dilution 1:100, clone FE11, Calbiochem, San Diego, CA), MSH6 (1:100, clone EP49, Novus Biologicals, Centennial, CO), and PMS2 (1:50, clone A16-4, BD Pharmingen).
3. Treatment and assessment
All patients received 200 mg pembrolizumab intravenously every 3 weeks, on day 1 of each 3-week cycle, until disease progression, occurrence of unacceptable toxicity, withdrawal of consent, or physician’s decision to stop treatment. The tumor response was assessed every 6 weeks and prospectively graded according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and immune-modified RECIST (imRECIST). At the discretion of attending physicians, continuation of pembrolizumab beyond progressive disease (PD) was allowed if there was potential clinical benefit. Pembrolizumab dose reductions were not allowed.
4. Statistical analysis
Progression-free survival (PFS) was defined as the time from the initiation of pembrolizumab until the date of documented disease progression or death from any cause, whichever occurred first. OS was defined as the time from the initiation of pembrolizumab to death from any cause. Survival probabilities were estimated using the Kaplan-Meier method and compared using the log-rank test. The safety analysis included all patients who visited the clinic at least once after the initiation of treatment. Toxicity was evaluated based on the National Cancer Institute Common Terminology Criteria for Adverse Events ver. 4.03. A p-value of < 0.05 was considered significant. SPSS ver. 23.0 (IBM Corp., Armonk, NY) was used for statistical analyses.
5. Ethical statement
The study was approved by the Institutional Review Board of Asan Medical Center (2018-0257). All patients provided a written informed consent, and the study was conducted in accordance with the Declaration of Helsinki.
1. Patient characteristics
Between May 2018 and February 2019, 40 patients were enrolled in this study. Baseline patient characteristics are summarized in Table 1. The median age was 61 years (range, 41 to 76 years), and 23 (57.5%) patients were men. iCCA was the most common type (n=20, 50%), followed by GBCA (n=12, 30%), and eCCA (n=8, 20%). Lymph nodes (n=30, 75%) and liver (n=23, 57.5%) were the most frequent metastatic sites. At the time of pembrolizumab administration, most patients had metastatic disease (n=38, 95%). More than half of the patients had an Eastern Cooperative Oncology Group performance status of 0-1 (n=21, 52.5%).
Pembrolizumab was administered as second-, third-, and fourth-line therapy or more in 19 (47.5%), 16 (40%), and five (12.5%) patients, respectively. All patients received GemCis as first-line systemic therapy; the median time to progression of the first-line GemCis was 5.9 months (95% confidence interval [CI], 4.1 to 7.8).
2. Treatment and clinical outcomes
Median three cycles (range, 1 to 12) of pembrolizumab were administered, and disease progression was the most common cause of treatment discontinuation (n=31, 77.5%). The waterfall plot for the maximal change of the target lesions among patients with measurable disease (n=38, 95%) is presented in Fig. 1. Per RECIST v1.1, 39 (97.5%) patients were assessable for response. None of the patients exhibited complete response, while four achieved partial response (PR), with an objective response rate (ORR) of 10% (Table 2). Among patients with PD as best response, one (1/20, 5%) with eCCA as primary tumor achieved complete response (CR) subsequently (i.e., pseudoprogression) with the use of pembrolizumab beyond initial PD (Fig. 2). According to imRECIST, ORR was 12.5% (5 of 40). The ORR per imRECIST according to primary tumor site were 5% (1 of 20 patients), 25% (2 of 8 patients), and 16.7% (2 of 12 patients) in patients with iCCA, eCCA, and GBCA, respectively. In patients with CR or PR per imRECIST, the median time to response was 2.1 months (95% CI, 0.4 to 3.9), and the median duration of response (DOR) was 6.3 months (95% CI, not available). At the time of analysis, three of five patients who achieved CR or PR, including a patient with pseudoprogression, continued receiving pembrolizumab (5.1+ to 9.6+ months).
With a median follow-up of 9.6 months (95% CI, 4.5 to 14.6) in surviving patients, the median PFS was 1.5 months (95% CI, 0.0 to 3.0) per RECIST v1.1 and 2.5 months (95% CI, 1.6 to 3.4) per imRECIST (Table 2, Fig. 3). The median OS was 4.3 months (95% CI, 3.5 to 5.1). The 6-month PFS rates per RECIST v1.1, and imRECIST were 13.1% (95% CI, 1.5 to 24.7) and 14.5% (95% CI, 2.0 to 27.0), respectively, and 6-month OS rates were and 27.5% (95% CI, 12.0 to 43.0).
There were significant differences in PFS and OS according to the objective response per imRECIST (p < 0.001 and p=0.001, respectively) (Fig. 4). According to imRECIST, the median PFS and OS were 8.4 months (95% CI, not available) and 9.5 months (95% CI, not available), respectively, in patients with CR or PR; 2.9 months (95% CI, 1.1 to 4.7) and 4.6 months (95% CI, 3.7 to 5.5), respectively, in those with stable disease (SD); and 1.0 months (95% CI, 0.5 to 1.5) and 2.1 months (95% CI, 1.2 to 2.9), respectively, in those with PD. In patients with CR or PR, SD, and PD, the 6-month PFS rates were 80% (95% CI, 44.9 to 100), 11.1% (95% CI, 0.0 to 25.6), and 0% (95% CI, 0.0 to 0.0), respectively, while the 6-month OS rates were 100% (95% CI, not available), 32.4% (95% CI, 10.3 to 54.5), and 0% (95% CI, 0.0 to 0.0), respectively.
PFS per imRECIST and OS did not differ according to histologic type (adenocarcinoma vs others), primary tumor site (iCCA vs. eCCA vs. GBCA), cancer antigen 19-9 level (elevated vs. normal), and number of prior systemic chemotherapy (1 vs. ≥ 2) (p > 0.05 for all).
3. Correlative biomarker analysis
Although this study included patients who had tumor PD-L1 expression ≥ 1% by local pathologists, central pathology review revealed that nine (22.5%) and two (5.0%) patients had a TPS and a CPS of < 1, respectively. The TPS and CPS of all patients were obtained, the median TPS and CPS were 4.5 (range, 0 to 100) and 20 (range, 0 to 100), respectively. Considering there was a patient with pseudoprogression and this may underestimate the efficacy of pembrolizumab when ORR and PFS were graded by RECIST v1.1, the imRECIST-based efficacy outcomes were used in the correlative biomarker analysis. In patients with TPS ≥ 1, the median PFS per imRECIST and OS were 2.4 months (95% CI, 1.0 to 3.8) and 4.3 months (95% CI, 3.2 to 5.5), respectively. According to imRECIST, ORR was significantly higher among patients with TPS ≥ 50% (37.5% [3 of 8 patients] vs. 6.5% in TPS < 50% [2 of 31 patients]; p=0.049) (Table 3) and the median PFS was significantly longer in patients with TPS ≥ 50% (2.9 months [95% CI, 0.0 to 6.7] vs. 2.4 months [95% CI, 0.8 to 4.1] in TPS < 50%; p=0.038) (Fig. 5). OS did not differ according to the cut-off values (1, 20, and 50) of TPS and CPS (p > 0.05 for all).
The MMR status of 33 patients (82.5%) were assessable, while seven patients lacked archival tissues for further immunohistochemical staining of MMR proteins. Among these patients, none showed MMR deficiency; therefore, correlative analysis between MMR status and the efficacy of pembrolizumab could not be performed.
4. Adverse events
Data on the safety of pembrolizumab were available in 39 patients. While none of the patients experienced grade 3-5 adverse events (AEs), 8 (20.5%) experienced treatmentrelated AEs: fatigue (n=4, 10.3%) and pruritis (n=4, 10.3%) were the most frequent AEs. None of the patients experienced immune-related AEs, and no AE-related treatment delays or interruptions were reported.
In this study, pembrolizumab showed a modest anti-tumor activity and manageable AEs in heavily pretreated patients with advanced BTC. None of the patients treated with pembrolizumab developed new AEs, and response was durable for patients who achieved objective response.
In this prospective cohort study including 40 BTC patients with 77.5% of PD-L1–positive (≥ 1) by central pathology review, ORR was 10% per RECIST v1.1 and 12.5% per imRECIST. The median PFS was 1.5 months per RECIST v1.1 and 2.5 months per imRECIST, and OS was 4.3 months. Considering that our study patients were heavily pretreated as more than half of the patients (52.5%) received pembrolizumab as third-line chemotherapy or greater, our efficacy results seem to be comparable with the clinical outcomes in other prospective clinical trials using pembrolizumab for pretreated patients with advanced BTC; the KEYNOTE-028 study of 24 patients with PD-L1–positive advanced BTC showed an ORR of 13% per RECIST v1.1 and median PFS and OS of 1.8 months and 5.7 months, respectively [22]. The KEYNOTE158 study of 104 patients with 58.7% PD-L1–positive rates showed an ORR of 5.8% per RECIST v1.1 and median PFS and OS of 2.0 months and 7.4 months, respectively [22]. In a recent Japanese phase 1 study of another anti–PD-1 inhibitor nivolumab, which included 30 patients with PD-L1–positive rates of 18%, also showed consistent efficacy outcomes, with ORR of 3.3% per RECIST v1.1 and median PFS and OS of 1.4 months and 5.2 months, respectively [26].
The discrepancies in efficacy outcomes among the studies that investigated the efficacy of anti–PD-1 antibody in advanced BTC may be mainly attributable to the differences in baseline patient characteristics considering that BTC is an extremely heterogeneous disease. Although the role of PD-L1 expression as a predictive biomarker in advanced BTC patients treated with PD-1 inhibitor remains unclear, the discrepancies in the proportion of patients with PD-L1 among the studies may have an impact on the efficacy outcomes. The ORRs per RECIST v1.1 were higher in KEYNOTE-028 and our current studies of pembrolizumab (13% and 10%, respectively). The PD-L1–positive rates of patients included in these studies were 100% and 77.5%, respectively, while those in KEYNOTE-158 study of pembrolizumab (ORR 5.8%) and Japanese phase 1 study of nivolumab (ORR 3.3%) were 58.7% and 17.8%, respectively. ORR was higher in PD-L1–positive patients (6.6% vs. 2.9%) in the KEYNOTE-158 study [22]. In the Japanese phase 1 study of nivolumab, PD-L1–positive patients had longer median PFS (2.8 months vs. 1.4 months) and OS (11.6 months vs. 5.2 months) than PD-L1–negative patients [26]. Our analysis also showed an increase in ORR and PFS per imRECIST in higher cut-offs of TPS. However, these findings were based on the preliminary studies with relatively small sample size. Hence, further analyses using large randomised clinical trials are needed to determine the implication of tumor PD-L1 status in BTC patients treated with anti-PD-1 inhibitors.
Cancer patients with MMR deficiency are associated with somatic hypermutation and neoepitope formation leading to microsatellite instability (MSI) [27], and PD-1 blockades showed 40%-50% of ORR in patients with solid cancers harboring deficient MMR after progression on conventional therapies [16,17]. As the frequency of MMR deficiency or MSI-high in BTC was reported to be 2%-10% [18-20], these can be a relevant biomarker for the use of PD-1 blockades in BTC patients. In the current study, MMR status was assessed by immunohistochemistry [28]. However, none of the patients showed MMR deficiency in our study, and this result is in line with those of KEYNOTE-028 and KEYNOTE-158 studies, which reported that only 1 (0.8%) of 128 patients had MSI-H [22].
In previous studies that adopted pembrolizumab as a salvage therapy for pretreated BTC patients including ours, pembrolizumab showed a modest efficacy with ORR of 6%- 13%, median PFS of 1.5-2.0 months, and median OS of 4.3- 7.3 months. Fluoropyrimidine-based chemotherapy showed median PFS of 1.9 months and OS of 6.5 months in a previous retrospective analysis [29], while mFOLFOX showed median PFS and OS of 4.0 and 6.2 months, respectively; in a recent randomized phase 3 ABC-06 trial after progression on firstline GemCis [5], current evidences with pembrolizumab are not compelling for its use as salvage therapy in overall BTC patients. However, pembrolizumab may have clinical relevance in the management of refractory BTC patients in terms of long DOR (median DOR of 6.3 months in our study, and 2-year DOR of 67% and 50% in the KEYNOTE-028 and KEYNOTE-158 studies, respectively) and better safety profile compared with mFOLFOX (grades 3-4 AEs: 14%-17% in KEYNOTE-028 and KEYNOTE-158 studies vs. 59% in the ABC-06 trial). Extensive biomarker analysis to define the patient population who would benefit most should be performed in the future.
There are several caveats in our study. Although our study prospectively evaluated the safety and efficacy of pembrolizumab, this was conducted at a single center. Our patient population is heterogeneous, and many of them previously received a variety of treatments. Additionally, the sample size was not enough to conduct a statistically robust analysis for a correlative study.
In conclusion, pembrolizumab showed a modest efficacy in heavily pretreated PD-L1–positive BTC patients. Pembrolizumab was well tolerated, and no new AEs occurred in these fragile patient population. Future studies for improving anti–PD-1 inhibitors and finding biomarkers in BTC patients are warranted.

Conflict of interest relevant to this article was not reported.

Acknowledgements
This study was funded in part by grants from the Bio and Medical Technology Development Program of the National Research Foundation (NRF) of Korea, funded by the Ministry of Science, Communications Technology, and Future Planning of the Korean government (NRF-2016M3A9E8941331), and Asan Institute for Life Sciences at Asan Medical Center in Seoul, Korea (2018-0634).
Fig. 1.
Waterfall plots of the changes in the size of target lesions.
crt-2019-493f1.jpg
Fig. 2.
Flow charts of a patient with pseudoprogression treated with pembrolizumab. Sum of target lesions and serum cancer antigen 19-9 (CA 19-9) levels are depicted with the computed tomography scan images. PD, progressive disease; CR, complete response.
crt-2019-493f2.jpg
Fig. 3.
Progression-free survival (according to Response Evaluation Criteria in Solid Tumor [RECIST] v1.1 and immune-modified RECIST [imRECIST]) and overall survival. OS, overall survival; CI, confidence interval; PFS, progression-free survival.
crt-2019-493f3.jpg
Fig. 4.
Progression-free survival (PFS) (A) and overall survival (OS) (B) according to the objective response graded based on immune-modified Response Evaluation Criteria in Solid Tumor. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; CI, confidence interval.
crt-2019-493f4.jpg
Fig. 5.
Progression-free survival (PFS) per immune-modified Response Evaluation Criteria in Solid Tumor and overall survival (OS) according to the tumor proportion score (TPS) of programmed death ligand-1. Cut-off at 1% (A, B), 20% (C, D), and 50% (E, F). CI, confidence interval.
crt-2019-493f5.jpg
Table 1.
Baseline patient characteristics
Characteristic No. (%) (n=40)
Age, median (range, yr) 61 (41-76)
 < 65 26 (65.0)
 ≥ 65 14 (35.0)
Sex
 Male 23 (57.5)
 Female 17 (42.5)
Primary tumor location
 Intrahepatic 20 (50.0)
 Extrahepatic 8 (20.0)
 Gallbladder 12 (30.0)
Disease setting at presentation
 Metastatic 38 (95.0)
 Locally advanced unresectable 2 (5.0)
Histology
 Adenocarcinoma 34 (85.0)
 Adenosquamous carcinoma 3 (7.5)
 Others 3 (7.5)
ECOG performance status
 1 21 (52.5)
 ≥ 2 19 (47.5)
Site of metastasis
 Lymph node 30 (75.0)
 Liver 23 (57.5)
 Peritoneum 17 (42.5)
 Bone 8 (20.0)
 Lung 6 (15.0)
Differentiation
 Well differentiated 2 (5.0)
 Moderately differentiated 19 (47.5)
 Poorly differentiated 9 (22.5)
 Unknown 10 (25.0)
MMR status (n=33)
 Proficient 33 (100)
 Deficient 0
Prior curative surgery 16 (40.0)
Prior systemic therapies
 1 19 (47.5)
 2 16 (40.0)
 ≥ 3 5 (12.5)

ECOG, Eastern Cooperative Oncology Group; MMR, mismatch repair.

Table 2.
Efficacy outcomes of pembrolizumab according to RECIST v1.1 and imRECIST
Variable Per RECIST v1.1 (n=40) Per imRECIST (n=40)
Objective response
 CR 0 1 (2.5)
 PR 4 (10.0) 4 (10.0)
 SD 15 (37.5) 18 (45.0)
 PD 20 (50.0)a) 16 (40.0)
 Not evaluable 1 (2.5) 1 (2.5)
ORR (CR+PR) (%) 10.0 12.5
ORR by primary tumor site
 Intrahepatic cholangiocarcinoma 1/20 (5.0) 1/20 (5.0)
 Extrahepatic cholangiocarcinoma 1/8 (12.5) 2/8 (25.0)
 Gallbladder cancer 2/12 (16.7) 2/12 (16.7)
Progression-free survival (95% CI, mo) 1.5 (0-3.0) 2.5 (1.6-3.4)
Overall survival (95% CI, mo) 4.3 (3.5-5.1) 4.3 (3.5-5.1)

Values are presented as number (%) or median (95% CI) unless otherwise indicated. RECIST, Response Evaluation Criteria in Solid Tumors; imRECIST, immune-modified RECIST; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; CI, confidence interval.

a) Among patients with PD, one achieved CR subsequently with the use of pembrolizumab beyond PD.

Table 3.
Correlative analysis between tumor proportion score, combined positive score, and tumor response according to imRECIST
Variable CR or PRa) SD or PD p-value
TPS
 ≥ 1 (n=31) 4 (12.9) 27 (87.1) > 0.99
 < 1 (n=8) 1 (12.5) 7 (87.5)
TPS
 ≥ 20 (n=12) 3 (25.0) 9 (75.0) 0.159
 < 20 (n=27) 2 (7.4) 25 (92.6)
TPS
 ≥ 50 (n=8) 3 (37.5) 5 (62.5) 0.049
 < 50 (n=31) 2 (6.5) 29 (93.5)
CPS
 ≥ 1 (n=37) 4 (10.8) 33 (89.2) 0.243
 < 1 (n=2) 1 (50.0) 1 (50.0)
CPS
 ≥ 20 (n=21) 3 (14.3) 18 (85.7) > 0.99
 < 20 (n=18) 2 (11.1) 16 (88.9)
CPS
 ≥ 50 (n=13) 3 (23.1) 10 (76.9) 0.310
 < 50 (n=26) 2 (7.7) 24 (92.3)

Values are presented as number (%). imRECIST, immune-modified Response Evaluation Criteria in Solid Tumors; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; TPS, tumor proportion score; CPS, combined positive score.

a) Include a patient who showed CR after initial PD with the use of pembrolizumab beyond PD.

  • 1. Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet. 2014;383:2168–79. ArticlePubMedPMC
  • 2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30. ArticlePubMed
  • 3. Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology. 2001;33:1353–7. ArticlePubMed
  • 4. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17:1471–4. ArticlePubMedPDF
  • 5. Lamarca A, Palmer DH, Wasan HS, Ross PJ, Ma YT, Arora A, et al. ABC-06 | A randomised phase III, multi-centre, openlabel study of active symptom control (ASC) alone or ASC with oxaliplatin / 5-FU chemotherapy (ASC+mFOLFOX) for patients (pts) with locally advanced / metastatic biliary tract cancers (ABC) previously-treated with cisplatin/gemcitabine (CisGem) chemotherapy. J Clinl Oncol. 2019;37(15 Suppl):4003.Article
  • 6. Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273–81. ArticlePubMed
  • 7. Valle JW, Borbath I, Khan SA, Huguet F, Gruenberger T, Arnold D, et al. Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27(Suppl 5):v28–37. ArticlePubMedPDF
  • 8. Hyung J, Kim B, Yoo C, Kim KP, Jeong JH, Chang HM, et al. Clinical benefit of maintenance therapy for advanced biliary tract cancer patients showing no progression after first-line gemcitabine plus cisplatin. Cancer Res Treat. 2019;51:901–9. ArticlePubMedPDF
  • 9. Kim BJ, Hyung J, Yoo C, Kim KP, Park SJ, Lee SS, et al. Prognostic factors in patients with advanced biliary tract cancer treated with first-line gemcitabine plus cisplatin: retrospective analysis of 740 patients. Cancer Chemother Pharmacol. 2017;80:209–15. ArticlePubMedPDF
  • 10. Eggermont AM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;378:1789–801. ArticlePubMed
  • 11. Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376:1015–26. ArticlePubMedPMC
  • 12. Muro K, Chung HC, Shankaran V, Geva R, Catenacci D, Gupta S, et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, openlabel, phase 1b trial. Lancet Oncol. 2016;17:717–26. ArticlePubMed
  • 13. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018–28. ArticlePubMed
  • 14. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515:563–7. ArticlePubMedPMCPDF
  • 15. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54. ArticlePubMedPMC
  • 16. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–13. ArticlePubMedPMC
  • 17. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20. ArticlePubMedPMC
  • 18. Silva VW, Askan G, Daniel TD, Lowery M, Klimstra DS, Abou-Alfa GK, et al. Biliary carcinomas: pathology and the role of DNA mismatch repair deficiency. Chin Clin Oncol. 2016;5:62.ArticlePubMed
  • 19. Salem ME, Puccini A, Grothey A, Raghavan D, Goldberg RM, Xiu J, et al. Landscape of tumor mutation load, mismatch repair deficiency, and PD-L1 expression in a large patient cohort of gastrointestinal cancers. Mol Cancer Res. 2018;16:805–12. ArticlePubMedPMC
  • 20. Goeppert B, Roessler S, Renner M, Singer S, Mehrabi A, Vogel MN, et al. Mismatch repair deficiency is a rare but putative therapeutically relevant finding in non-liver fluke associated cholangiocarcinoma. Br J Cancer. 2019;120:109–14. ArticlePubMedPDF
  • 21. Fontugne J, Augustin J, Pujals A, Compagnon P, Rousseau B, Luciani A, et al. PD-L1 expression in perihilar and intrahepatic cholangiocarcinoma. Oncotarget. 2017;8:24644–51. ArticlePubMedPMC
  • 22. Bang YJ, Ueno M, Malka D, Chung HC, Nagrial A, Kelley RK, et al. Pembrolizumab (pembro) for advanced biliary adenocarcinoma: results from the KEYNOTE-028 (KN028) and KEYNOTE-158 (KN158) basket studies. J Clin Oncol. 2019;37(15 Suppl):4079.Article
  • 23. Scheel AH, Dietel M, Heukamp LC, Johrens K, Kirchner T, Reu S, et al. Harmonized PD-L1 immunohistochemistry for pulmonary squamous-cell and adenocarcinomas. Mod Pathol. 2016;29:1165–72. ArticlePubMedPDF
  • 24. Dolled-Filhart M, Roach C, Toland G, Stanforth D, Jansson M, Lubiniecki GM, et al. Development of a companion diagnostic for pembrolizumab in non-small cell lung cancer using immunohistochemistry for programmed death ligand-1. Arch Pathol Lab Med. 2016;140:1243–9. ArticlePubMed
  • 25. Kulangara K, Zhang N, Corigliano E, Guerrero L, Waldroup S, Jaiswal D, et al. Clinical utility of the combined positive score for programmed death ligand-1 expression and the approval of pembrolizumab for treatment of gastric cancer. Arch Pathol Lab Med. 2019;143:330–7. ArticlePubMed
  • 26. Ueno M, Ikeda M, Morizane C, Kobayashi S, Ohno I, Kondo S, et al. Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: a non-randomised, multicentre, openlabel, phase 1 study. Lancet Gastroenterol Hepatol. 2019;4:611–21. ArticlePubMed
  • 27. Dudley JC, Lin MT, Le DT, Eshleman JR. Microsatellite instability as a biomarker for PD-1 blockade. Clin Cancer Res. 2016;22:813–20. ArticlePubMed
  • 28. Luchini C, Bibeau F, Ligtenberg MJ, Singh N, Nottegar A, Bosse T, et al. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann Oncol. 2019;30:1232–43. ArticlePubMedPDF
  • 29. Kim BJ, Yoo C, Kim KP, Hyung J, Park SJ, Ryoo BY, et al. Efficacy of fluoropyrimidine-based chemotherapy in patients with advanced biliary tract cancer after failure of gemcitabine plus cisplatin: retrospective analysis of 321 patients. Br J Cancer. 2017;116:561–7. ArticlePubMedPMCPDF

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REFERENCES

    Citations

    Citations to this article as recorded by  
    • Camrelizumab combined with gemcitabine and apatinib in treating advanced PD‐L1‐positive biliary tract cancers
      Yitong Tian, Changxian Li, Ke Jin, Ling Ma, Jiaguang Zhang, Xinyi Zhang, Wei You, Haoyang Shen, Yuting Ding, Hao Qian, Xiangcheng Li, Xiaofeng Chen
      Cancer Science.2025; 116(1): 204.     CrossRef
    • Ex vivo liver resection and auto-transplantation and special systemic therapy in perihilar cholangiocarcinoma treatment
      Konstantin Y Tchilikidi
      World Journal of Gastrointestinal Surgery.2024; 16(3): 635.     CrossRef
    • The predictive value of PD-L1 expression in response to anti-PD-1/PD-L1 therapy for biliary tract cancer: a systematic review and meta-analysis
      Seung Bae Yoon, Sang Myung Woo, Jung Won Chun, Dong Uk Kim, Jaihwan Kim, Joo Kyung Park, Hoonsub So, Moon Jae Chung, In Rae Cho, Jun Heo
      Frontiers in Immunology.2024;[Epub]     CrossRef
    • Unveiling the promise of PD1/PD-L1: A new dawn in immunotherapy for cholangiocarcinoma
      Fei Chen, Jian Sheng, Xiaoping Li, Zhaofeng Gao, Siqi Zhao, Lingyu Hu, Minjie Chen, Jianguo Fei, Zhengwei Song
      Biomedicine & Pharmacotherapy.2024; 175: 116659.     CrossRef
    • Clinical outcomes of immune checkpoint inhibitor combined with other targeted or immunological therapy regimens for the treatment of advanced bile tract cancer: a systematic review and meta-analysis
      Jianpeng Zhou, Jia Li, Zhongqi Fan, Guoyue Lv, Guangyi Wang
      Frontiers in Immunology.2024;[Epub]     CrossRef
    • The Immune Landscape and Its Potential for Immunotherapy in Advanced Biliary Tract Cancer
      Andry Santoso, Iris Levink, Rille Pihlak, Ian Chau
      Current Oncology.2024; 32(1): 24.     CrossRef
    • Emerging pharmaceutical therapies for targeting cholangiocarcinoma microenvironment and chemokine pathways
      ARMAND N. YAZDANI, MICHAELA PLETSCH, ABRAHAM CHORBAJIAN, DAVID ZITSER, VIKRANT RAI
      BIOCELL.2024; 48(12): 1683.     CrossRef
    • Anti-PD-1-based immunotherapy plus lenvatinib to treat advanced gallbladder cancer in the elderly: a case series and review of current literature
      Lantian Wang, Kezhong Tang, Xiawei Li, Wenjie Lu
      Journal of Cancer Research and Clinical Oncology.2023; 149(3): 941.     CrossRef
    • A prospective multicenter phase II study of FOLFIRINOX as a first-line treatment for patients with advanced and recurrent biliary tract cancer
      Naminatsu Takahara, Yousuke Nakai, Hiroyuki Isayama, Takashi Sasaki, Yuji Morine, Kazuo Watanabe, Makoto Ueno, Tatsuya Ioka, Masashi Kanai, Shunsuke Kondo, Naohiro Okano, Kazuhiko Koike
      Investigational New Drugs.2023; 41(1): 76.     CrossRef
    • Revisiting targeted therapy and immunotherapy for advanced cholangiocarcinoma
      Jiajia Du, Xing Lv, Zunyi Zhang, Zhiyong Huang, Erlei Zhang
      Frontiers in Immunology.2023;[Epub]     CrossRef
    • Clinical outcomes of immune checkpoint inhibitors in unresectable or metastatic combined hepatocellular–cholangiocarcinoma
      Yoon Jung Jang, Eo Jin Kim, Hyung-Don Kim, Kyu-Pyo Kim, Min-Hee Ryu, Sook Ryun Park, Won-Mook Choi, Danbi Lee, Jonggi Choi, Ju Hyun Shim, Kang Mo Kim, Young-Suk Lim, Han Chu Lee, Baek-Yeol Ryoo, Changhoon Yoo
      Journal of Cancer Research and Clinical Oncology.2023; 149(10): 7547.     CrossRef
    • Precision Medicine and Immunotherapy Have Arrived for Cholangiocarcinoma: An Overview of Recent Approvals and Ongoing Clinical Trials
      Thomas B. Karasic, Jennifer R. Eads, Lipika Goyal
      JCO Precision Oncology.2023;[Epub]     CrossRef
    • Moving Beyond Single-Agent Checkpoint Inhibition in Biliary Tract Cancers: What is the Next Frontier?
      Pedro Luiz Serrano Uson Junior, Tanios Bekaii-Saab
      Immunotherapy.2023; 15(7): 531.     CrossRef
    • Chemo-Free Treatment Using Anti-PD-1 Antibodies with Lenvatinib in Unresectable Gallbladder Cancer: PD-L1 May Be a Potential Biomarker for a Better Outcome
      Tiantian Wu, Changsheng Pu, Xianjia Wu, Qiang Wang, Keming Zhang
      Diagnostics.2023; 13(11): 1833.     CrossRef
    • Lacking Immunotherapy Biomarkers for Biliary Tract Cancer: A Comprehensive Systematic Literature Review and Meta-Analysis
      Giorgio Frega, Fernando P. Cossio, Jesus M. Banales, Vincenzo Cardinale, Rocio I. R. Macias, Chiara Braconi, Angela Lamarca
      Cells.2023; 12(16): 2098.     CrossRef
    • Comparison of Efficacy and Safety of Anti-Programmed Cell Death-1 Antibody Plus Lenvatinib and Chemotherapy as First-Line Therapy for Patients with Stage IV Gallbladder Cancer: A Real-World Study in a Chinese Population
      Tiantian Wu, Changsheng Pu, Qiang Wang, Keming Zhang
      Biomedicines.2023; 11(11): 2933.     CrossRef
    • The Expression of Programmed Death-Ligand 1 on Immune Cells Is Related to a Better Prognosis in Biliary Tract Cancer
      Sung Chan Kwon, Seungmin Bang, Young Nyun Park, Ji Hoon Park, So Jeong Kim, Jung Hyun Jo, Moon Jae Chung, Jeong Youp Park, Seung Woo Park, Si Young Song, Eunhyang Park, Hee Seung Lee
      Gut and Liver.2023; 17(6): 933.     CrossRef
    • Equipoise, drug development, and biliary cancer
      Tristan Y. Lee, Susan E. Bates, Ghassan K. Abou‐Alfa
      Cancer.2022; 128(5): 944.     CrossRef
    • Novel and emerging targets for cholangiocarcinoma progression: therapeutic implications
      Lionel A. Kankeu Fonkoua, Pedro Luiz Serrano Uson Junior, Kabir Mody, Amit Mahipal, Mitesh J. Borad, Lewis R. Roberts
      Expert Opinion on Therapeutic Targets.2022; 26(1): 79.     CrossRef
    • Penpulimab, an anti-PD1 IgG1 antibody in the treatment of advanced or metastatic upper gastrointestinal cancers
      Yulong Zheng, Anna Rachelle Austria Mislang, Jermaine Coward, Rasha Cosman, Adam Cooper, Craig Underhill, Jianqing Zhu, Jianping Xiong, Ou Jiang, Hong Wang, Yanru Xie, Yuefen Zhou, Xiaoping Jin, Baiyong Li, Zhongmin Maxwell Wang, Kon Yew Kwek, Dennis Xia,
      Cancer Immunology, Immunotherapy.2022; 71(10): 2371.     CrossRef
    • Efficacy and Safety of Anti-PD1/PDL1 in Advanced Biliary Tract Cancer: A Systematic Review and Meta-Analysis
      Qi Jiang, Jinsheng Huang, Bei Zhang, Xujia Li, Xiuxing Chen, Bokang Cui, Shengping Li, Guifang Guo
      Frontiers in Immunology.2022;[Epub]     CrossRef
    • Real-world outcomes of patients with advanced intrahepatic cholangiocarcinoma treated with programmed cell death protein-1-targeted immunotherapy
      Min Deng, Shaohua Li, Qiaoxuan Wang, Rongce Zhao, Jingwen Zou, Wenping Lin, Jie Mei, Wei Wei, Rongping Guo
      Annals of Medicine.2022; 54(1): 803.     CrossRef
    • Immune cell atlas of cholangiocarcinomas reveals distinct tumor microenvironments and associated prognoses
      Tao Xia, Keyu Li, Nan Niu, Yingkuan Shao, Ding Ding, Dwayne L. Thomas, Hao Jing, Kenji Fujiwara, Haijie Hu, Arsen Osipov, Chunhui Yuan, Christopher L. Wolfgang, Elizabeth D. Thompson, Robert A. Anders, Jin He, Yiping Mou, Adrian G. Murphy, Lei Zheng
      Journal of Hematology & Oncology.2022;[Epub]     CrossRef
    • Targeted Therapies for Perihilar Cholangiocarcinoma
      Simon Gray, Angela Lamarca, Julien Edeline, Heinz-Josef Klümpen, Richard A. Hubner, Mairéad G. McNamara, Juan W. Valle
      Cancers.2022; 14(7): 1789.     CrossRef
    • Novel Palliative Chemotherapy for Cholangiocarcinoma
      Jung Won Jung, Sang Myung Woo
      The Korean Journal of Pancreas and Biliary Tract.2022; 27(2): 90.     CrossRef
    • Advances in the systemic treatment of therapeutic approaches in biliary tract cancer
      O. Mirallas, D. López-Valbuena, D. García-Illescas, C. Fabregat-Franco, H. Verdaguer, J. Tabernero, T. Macarulla
      ESMO Open.2022; 7(3): 100503.     CrossRef
    • Aging and biliary tract cancers: Epidemiology, molecular biology, and clinical practice
      Xiaoling Weng, Xiaoling Song, Rong Shao, Fatao Liu, Yingbin Liu
      Aging and Cancer.2022; 3(2): 95.     CrossRef
    • Efficacy and Safety of Drug-Eluting Beads Transarterial Chemoembolization Combining Immune Checkpoint Inhibitors in Unresectable Intrahepatic Cholangiocarcinoma: A Propensity Score Matching Analysis
      Xue-Gang Yang, Yan-Yuan Sun, De-Shan Li, Guo-Hui Xu, Xiao-Qi Huang
      Frontiers in Immunology.2022;[Epub]     CrossRef
    • Lenvatinib Plus Programmed Cell Death Protein-1 Inhibitor Beyond First-Line Systemic Therapy in Refractory Advanced Biliary Tract Cancer: A Real-World Retrospective Study in China
      Changying Shi, Yulong Li, Cheng Yang, Liang Qiao, Liukang Tang, Yuting Zheng, Xue Chen, Youwen Qian, Jiamei Yang, Dong Wu, Feng Xie
      Frontiers in Immunology.2022;[Epub]     CrossRef
    • Immunotherapy in biliary tract cancers: Current evidence and future perspectives
      Pedro Luiz Serrano Uson Junior, Raphael LC Araujo
      World Journal of Gastrointestinal Oncology.2022; 14(8): 1446.     CrossRef
    • Immune Checkpoint Inhibitors for Advanced Biliary Tract Cancer
      Hossein Taghizadeh, Gerald W. Prager
      Current Cancer Drug Targets.2022; 22(8): 639.     CrossRef
    • Safety and Efficacy of Allogeneic Natural Killer Cells in Combination with Pembrolizumab in Patients with Chemotherapy-Refractory Biliary Tract Cancer: A Multicenter Open-Label Phase 1/2a Trial
      Galam Leem, Sung-Ill Jang, Jae-Hee Cho, Jung Hyun Jo, Hee Seung Lee, Moon Jae Chung, Jeong Youp Park, Seungmin Bang, Da-Kyung Yoo, Hyo-Cheon Cheon, Jae-Eun Kim, Kyeong-Pill Lim, In-Hye Jung, Jung-Min Im, Yong-Yoon Chung, Seung Woo Park
      Cancers.2022; 14(17): 4229.     CrossRef
    • Prognostic Factors in Patients Treated with Pembrolizumab as a Second-Line Treatment for Advanced Biliary Tract Cancer
      Chan Su Park, Min Je Sung, So Jeong Kim, Jung Hyun Jo, Hee Seung Lee, Moon Jae Chung, Seungmin Bang, Seung Woo Park, Si Young Song, Jeong Youp Park
      Cancers.2022; 14(17): 4323.     CrossRef
    • The Efficacy and Safety of Hepatic Arterial Infusion Chemotherapy Based on FOLFIRI for Advanced Intrahepatic Cholangiocarcinoma as Second-Line and Successive Treatment: A Real-World Study
      Peixin Huang, Xiaoyong Huang, Yingting Zhou, Guohuan Yang, Qiman Sun, Guoming Shi, Yi Chen, Quirino Lai
      Canadian Journal of Gastroenterology and Hepatology.2022; 2022: 1.     CrossRef
    • PD-1 inhibitors plus nab-paclitaxel-containing chemotherapy for advanced gallbladder cancer in a second-line setting: A retrospective analysis of a case series
      Sirui Tan, Jing Yu, Qiyue Huang, Nan Zhou, Hongfeng Gou
      Frontiers in Oncology.2022;[Epub]     CrossRef
    • Treating Biliary Tract Cancers: New Targets and Therapies
      Joseph Ho, Constance Fiocco, Kristen Spencer
      Drugs.2022; 82(17): 1629.     CrossRef
    • Immunotherapies in clinical development for biliary tract cancer
      Arndt Vogel, Melanie Bathon, Anna Saborowski
      Expert Opinion on Investigational Drugs.2021; 30(4): 351.     CrossRef
    • Spatial Distribution and Prognostic Implications of Tumor-Infiltrating FoxP3- CD4+ T Cells in Biliary Tract Cancer
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      Cancer Research and Treatment.2021; 53(1): 162.     CrossRef
    • Clinically significant genomic alterations in the Chinese and Western patients with intrahepatic cholangiocarcinoma
      Shifeng Xu, Yuan Guo, Yanwu Zeng, Zhijian Song, Xiaodan Zhu, Ning Fan, Zhilei Zhang, Guibing Ren, Yunjin Zang, Wei Rao
      BMC Cancer.2021;[Epub]     CrossRef
    • Successful pembrolizumab treatment of microsatellite instability‐high intrahepatic cholangiocarcinoma: A case report
      Yuki Ikeda, Michihiro Ono, Ginji Ohmori, Saki Ameda, Michiko Yamada, Tomoyuki Abe, Shigeyuki Fujii, Miri Fujita, Masahiro Maeda
      Clinical Case Reports.2021; 9(4): 2259.     CrossRef
    • Horizons on the Therapy of Biliary Tract Cancers: A State-of-the-art Review
      Ran Xue, Rong Li, Jianxin Wang, Weiping Tong, Jianyu Hao
      Journal of Clinical and Translational Hepatology.2021; 000(000): 000.     CrossRef
    • An Assessment of Combination of the Camrelizumab With Chemotherapy in Metastatic Biliary Tract Cancers
      Yi Yu, Shanshan Huang, Jun Chen, Feng Yu, Lin Zhang, Xiaojun Xiang, Jun Deng, Ziling Fang, Junhe Li, Jianping Xiong
      Cancer Control.2021;[Epub]     CrossRef
    • Gastrointestinal cancer treatment with immune checkpoint inhibitors
      Jin Won Kim
      Journal of the Korean Medical Association.2021; 64(5): 342.     CrossRef
    • Phase 1b study of pegylated arginine deiminase (ADI-PEG 20) plus Pembrolizumab in advanced solid cancers
      Kwang-Yu Chang, Nai-Jung Chiang, Shang-Yin Wu, Chia-Jui Yen, Shang-Hung Chen, Yu-Min Yeh, Chien-Feng Li, Xiaoxing Feng, Katherine Wu, Amanda Johnston, John S. Bomalaski, Bor-Wen Wu, Jianjun Gao, Sumit K. Subudhi, Ahmed O. Kaseb, Jorge M. Blando, Shalini S
      OncoImmunology.2021;[Epub]     CrossRef
    • A randomised phase II study of oxaliplatin/5-FU (mFOLFOX) versus irinotecan/5-FU (mFOLFIRI) chemotherapy in locally advanced or metastatic biliary tract cancer refractory to first-line gemcitabine/cisplatin chemotherapy
      In Sil Choi, Ki Hwan Kim, Ju Hyun Lee, Koung Jin Suh, Ji-Won Kim, Jin Hyun Park, Yu Jung Kim, Jin-Soo Kim, Jee Hyun Kim, Jin Won Kim
      European Journal of Cancer.2021; 154: 288.     CrossRef
    • IMbrave 151: a randomized phase II trial of atezolizumab combined with bevacizumab and chemotherapy in patients with advanced biliary tract cancer
      Stephen P. Hack, Wendy Verret, Sohail Mulla, Bo Liu, Yulei Wang, Teresa Macarulla, Zhenggang Ren, Anthony B. El-Khoueiry, Andrew X. Zhu
      Therapeutic Advances in Medical Oncology.2021;[Epub]     CrossRef
    • Case Report: Response With Immunotherapy in a Patient With Mixed Neuroendocrine Non-Neuroendocrine Neoplasms of the Gallbladder
      Chao Liu, Xiangwei Hua, Zhen Yang, Yuan Guo, Liqun Wu, Jinzhen Cai, Ling Li, Yaxuan Zhang, Ning Fan
      Frontiers in Oncology.2021;[Epub]     CrossRef
    • Durable Response of Immune Checkpoint Inhibitor after Failure of Gemcitabine-based Chemotherapy for a Patient with Metastatic Biliary Tract Cancer
      Chien-Huai Chuang, Chiun Hsu
      Journal of Cancer Research and Practice.2021; 8(4): 152.     CrossRef
    • Efficacy and Safety of Pembrolizumab for Gemcitabine/Cisplatin-Refractory Biliary Tract Cancer: A Multicenter Retrospective Study
      Sang Hoon Lee, Hee Seung Lee, Sang Hyub Lee, Sang Myung Woo, Dong Uk Kim, Seungmin Bang
      Journal of Clinical Medicine.2020; 9(6): 1769.     CrossRef
    • Systemic treatment of advanced or recurrent biliary tract cancer
      Wei Zhang, Hongyuan Zhou, Yingying Wang, Zewu Zhang, Guangtai Cao, Tianqiang Song, Ti Zhang, Qiang Li
      BioScience Trends.2020; 14(5): 328.     CrossRef
    • Overview of current targeted therapy in gallbladder cancer
      Xiaoling Song, Yunping Hu, Yongsheng Li, Rong Shao, Fatao Liu, Yingbin Liu
      Signal Transduction and Targeted Therapy.2020;[Epub]     CrossRef

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      Efficacy and Safety of Pembrolizumab in Patients with Refractory Advanced Biliary Tract Cancer: Tumor Proportion Score as a Potential Biomarker for Response
      Cancer Res Treat. 2020;52(2):594-603.   Published online December 18, 2019
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    Efficacy and Safety of Pembrolizumab in Patients with Refractory Advanced Biliary Tract Cancer: Tumor Proportion Score as a Potential Biomarker for Response
    Image Image Image Image Image
    Fig. 1. Waterfall plots of the changes in the size of target lesions.
    Fig. 2. Flow charts of a patient with pseudoprogression treated with pembrolizumab. Sum of target lesions and serum cancer antigen 19-9 (CA 19-9) levels are depicted with the computed tomography scan images. PD, progressive disease; CR, complete response.
    Fig. 3. Progression-free survival (according to Response Evaluation Criteria in Solid Tumor [RECIST] v1.1 and immune-modified RECIST [imRECIST]) and overall survival. OS, overall survival; CI, confidence interval; PFS, progression-free survival.
    Fig. 4. Progression-free survival (PFS) (A) and overall survival (OS) (B) according to the objective response graded based on immune-modified Response Evaluation Criteria in Solid Tumor. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; CI, confidence interval.
    Fig. 5. Progression-free survival (PFS) per immune-modified Response Evaluation Criteria in Solid Tumor and overall survival (OS) according to the tumor proportion score (TPS) of programmed death ligand-1. Cut-off at 1% (A, B), 20% (C, D), and 50% (E, F). CI, confidence interval.
    Efficacy and Safety of Pembrolizumab in Patients with Refractory Advanced Biliary Tract Cancer: Tumor Proportion Score as a Potential Biomarker for Response
    Characteristic No. (%) (n=40)
    Age, median (range, yr) 61 (41-76)
     < 65 26 (65.0)
     ≥ 65 14 (35.0)
    Sex
     Male 23 (57.5)
     Female 17 (42.5)
    Primary tumor location
     Intrahepatic 20 (50.0)
     Extrahepatic 8 (20.0)
     Gallbladder 12 (30.0)
    Disease setting at presentation
     Metastatic 38 (95.0)
     Locally advanced unresectable 2 (5.0)
    Histology
     Adenocarcinoma 34 (85.0)
     Adenosquamous carcinoma 3 (7.5)
     Others 3 (7.5)
    ECOG performance status
     1 21 (52.5)
     ≥ 2 19 (47.5)
    Site of metastasis
     Lymph node 30 (75.0)
     Liver 23 (57.5)
     Peritoneum 17 (42.5)
     Bone 8 (20.0)
     Lung 6 (15.0)
    Differentiation
     Well differentiated 2 (5.0)
     Moderately differentiated 19 (47.5)
     Poorly differentiated 9 (22.5)
     Unknown 10 (25.0)
    MMR status (n=33)
     Proficient 33 (100)
     Deficient 0
    Prior curative surgery 16 (40.0)
    Prior systemic therapies
     1 19 (47.5)
     2 16 (40.0)
     ≥ 3 5 (12.5)
    Variable Per RECIST v1.1 (n=40) Per imRECIST (n=40)
    Objective response
     CR 0 1 (2.5)
     PR 4 (10.0) 4 (10.0)
     SD 15 (37.5) 18 (45.0)
     PD 20 (50.0)a) 16 (40.0)
     Not evaluable 1 (2.5) 1 (2.5)
    ORR (CR+PR) (%) 10.0 12.5
    ORR by primary tumor site
     Intrahepatic cholangiocarcinoma 1/20 (5.0) 1/20 (5.0)
     Extrahepatic cholangiocarcinoma 1/8 (12.5) 2/8 (25.0)
     Gallbladder cancer 2/12 (16.7) 2/12 (16.7)
    Progression-free survival (95% CI, mo) 1.5 (0-3.0) 2.5 (1.6-3.4)
    Overall survival (95% CI, mo) 4.3 (3.5-5.1) 4.3 (3.5-5.1)
    Variable CR or PRa) SD or PD p-value
    TPS
     ≥ 1 (n=31) 4 (12.9) 27 (87.1) > 0.99
     < 1 (n=8) 1 (12.5) 7 (87.5)
    TPS
     ≥ 20 (n=12) 3 (25.0) 9 (75.0) 0.159
     < 20 (n=27) 2 (7.4) 25 (92.6)
    TPS
     ≥ 50 (n=8) 3 (37.5) 5 (62.5) 0.049
     < 50 (n=31) 2 (6.5) 29 (93.5)
    CPS
     ≥ 1 (n=37) 4 (10.8) 33 (89.2) 0.243
     < 1 (n=2) 1 (50.0) 1 (50.0)
    CPS
     ≥ 20 (n=21) 3 (14.3) 18 (85.7) > 0.99
     < 20 (n=18) 2 (11.1) 16 (88.9)
    CPS
     ≥ 50 (n=13) 3 (23.1) 10 (76.9) 0.310
     < 50 (n=26) 2 (7.7) 24 (92.3)
    Table 1. Baseline patient characteristics

    ECOG, Eastern Cooperative Oncology Group; MMR, mismatch repair.

    Table 2. Efficacy outcomes of pembrolizumab according to RECIST v1.1 and imRECIST

    Values are presented as number (%) or median (95% CI) unless otherwise indicated. RECIST, Response Evaluation Criteria in Solid Tumors; imRECIST, immune-modified RECIST; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; CI, confidence interval.

    Among patients with PD, one achieved CR subsequently with the use of pembrolizumab beyond PD.

    Table 3. Correlative analysis between tumor proportion score, combined positive score, and tumor response according to imRECIST

    Values are presented as number (%). imRECIST, immune-modified Response Evaluation Criteria in Solid Tumors; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; TPS, tumor proportion score; CPS, combined positive score.

    Include a patient who showed CR after initial PD with the use of pembrolizumab beyond PD.


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