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

doi:10.4103/JCRP.JCRP_22_21

CASE REPORT

Year : 2021 | Volume : 8 | Issue : 4 | Page : 152-158

Durable response of immune checkpoint inhibitor after failure of gemcitabine-based chemotherapy for a patient with metastatic biliary tract cancer

Chien- Huai Chuang¹, Chiun Hsu²
¹ Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
² Department of Oncology, National Taiwan University Hospital; Graduate Institutes of Oncology, National Taiwan University College of Medicine; Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan

Date of Submission	20-Jun-2021
Date of Decision	13-Aug-2021
Date of Acceptance	17-Aug-2021
Date of Web Publication	3-Dec-2021

Correspondence Address:
Dr. Chiun Hsu
Department of Medical Oncology, National Taiwan University Cancer Center, No. 57, Ln. 155, Sec. 3, Keelung Rd., Da'an Dist., Taipei City 106
Taiwan

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JCRP.JCRP_22_21

Abstract

Patients with advanced or metastatic biliary tract cancer (BTC) have poor survival and limited options of systemic anticancer therapy besides the combination of gemcitabine plus cisplatin. Recent advances in molecular screening have identified that a minor proportion of BTC patients may benefit from specific targeted agents, e.g., fibroblast growth factor receptor or isocitrate dehydrogenase 1 inhibitors. The role of immune checkpoint inhibitor therapy in advanced BTC remains unclear. In this report, we describe a patient with intrahepatic cholangiocarcinoma who suffered from rapid progression of extrahepatic metastases after surgery and progression of the tumors after chemotherapy. Pembrolizumab was given, and the patient remained in partial response at the time of writing this report, after 1½ years of pembrolizumab therapy, without evident adverse events. We also review and discuss the current landscape of systemic therapy for advanced BTC and the possible role of immune checkpoint inhibitor therapy.

Keywords: Biliary tract cancer, chemotherapy, immune checkpoint inhibitor, program cell death-1 expression

How to cite this article:
Chuang CH, Hsu C. Durable response of immune checkpoint inhibitor after failure of gemcitabine-based chemotherapy for a patient with metastatic biliary tract cancer. J Cancer Res Pract 2021;8:152-8

How to cite this URL:
Chuang CH, Hsu C. Durable response of immune checkpoint inhibitor after failure of gemcitabine-based chemotherapy for a patient with metastatic biliary tract cancer. J Cancer Res Pract [serial online] 2021 [cited 2023 Jun 5];8:152-8. Available from: https://www.ejcrp.org/text.asp?2021/8/4/152/331652

Introduction

Advanced or metastatic biliary tract cancer (BTC) has a poor prognosis with limited treatment options, and the incidence and mortality rates have increased in the past decades worldwide.^[1] Patients usually suffer from obstructive jaundice, repeated biliary tract infections, and complications of distant metastases during progression. First-line chemotherapy with gemcitabine and cisplatin is widely used, based on the results of the landmark ABC-02 trial.^[2] Standard care of second-line chemotherapy has yet to be established, although the addition of modified FOLFOX (folinic acid, 5-FU, and oxaliplatin) to actively control symptoms as second-line chemotherapy may improve median overall survival (OS).^[3],[4] The European Society of Medical Oncology (ESMO) recently recommended the routine use of next-generation sequencing (NGS) on tumor samples from patients with cholangiocarcinoma.^[5] Therapies targeting activating genetic alterations, such as isocitrate dehydrogenase 1 (IDH1) mutations,^[6] and fibroblast growth factor receptor 2 (FGFR2) rearrangements or fusions,^[7] have also provided new approaches with clinical benefits in patients with advanced BTC.

Immune checkpoint inhibitor (ICI) therapy targeting the program cell death-1 (PD-1)/program death ligand-1 (PD-L1) pathway has been approved for more than 10 cancer types. In patients with advanced BTC, anti-PD-1-based systemic therapy has also been extensively studied, however, the clinical value remains undetermined. Therefore, in this study, we reviewed the options of systemic therapy for advanced BTC, with an emphasis on the potential role of ICI therapy.

Case Report

A 53-year-old asymptomatic man who was a hepatitis B virus carrier receiving regular follow-up at a local hospital presented with an abnormal liver function test in June 2019. Findings of a physical examination were unremarkable. Abdominal sonography showed a hepatic tumor over the left lobe and cirrhosis. A contrast-enhanced computed tomography (CT) scan revealed a 6.2 cm infiltrative hepatic tumor at the lateral segment with lymphadenopathy at common hepatic, gastric, and para-aortic regions. He received laparoscopic hepatectomy and lymphadenectomy. Poorly differentiated cholangiocarcinoma was diagnosed with lymphovascular invasion and perineural invasion. The surgical margin was uninvolved.

New symptoms of progressive right low back pain with radiation to the flank occurred 2 weeks following the surgery. Magnetic resonance imaging of the lumbar spine showed a first lumbar vertebra (L1) tumor with cord compression. He was then referred to National Taiwan University Hospital for surgery.

Restaging CT scan revealed lymphadenopathy at the anterior pancreatic region, in addition to metastases in bilateral lungs and L1 vertebra with a compression fracture. He received twelfth thoracic vertebra (T12) to L1 laminectomy and L1 spondylectomy for tumor excision, followed by reconstruction and postoperative radiotherapy (3000 cGy in 10 fractions to the T12-L2 tumor bed, and 3500 cGy in 10 fractions to suspicious residual tumors). The pathology confirmed the diagnosis of metastatic cholangiocarcinoma.

Systemic treatment with gemcitabine and cisplatin was administered on October 2019 (gemcitabine 1000 mg/m² and cisplatin 25 mg/m² on days 1 and 8 every 3 weeks). After three cycles of chemotherapy, he developed progressive nonproductive cough and exertional dyspnea. A CT scan showed progressive disease with multiple lung nodules and clustered enlarged mediastinal and left pulmonary hilar lymph nodes. He was admitted under the impression of obstructive pneumonitis. He suffered from persistent shortness of breath even at rest and required continuous supplemental oxygen. His performance status declined to dependence on constant medical care (Eastern Cooperative Oncology Group [ECOG] 3). Blood tests showed only hypoalbuminemia (3.0 g per deciliter), and biochemistry tests of renal and kidney function were within normal limits.

We sent a surgical specimen for molecular screening by NGS (Foundation One^®), and the results identified MET amplification and TP53 alteration (G245C), a microsatellite stable (MSS) phenotype (using genome-wide analysis of 95 microsatellite loci), and the tumor mutational burden was three mutations per megabase. Given the patient's poor functional status after first-line chemotherapy, we administered pembrolizumab (100 mg every 3 weeks) on January 2020, and he received palliative radiotherapy to the left upper lung and hilar tumors (5000 cGy in 20 fractions). We used a dosage of 100 mg due to his financial concerns. His performance status gradually recovered to baseline (ECOG 1). A grade 1 skin rash was detected as an immune-related adverse effect. Follow-up serial CT scans showed a persistent partial response of the lung metastases and lymphadenopathy [Figure 1]. At present, pembrolizumab monotherapy is ongoing with a durable response. We retrospectively analyzed the PL-L1 expression, and the PD-L1 tumor proportion scores (TPSs) for the primary hepatic tumor and spinal metastatic tumor were 60% and 35%, respectively (Dako IHC 22C3 PharmDx Assay) [Figure 2].

Figure 1: PD-L1 expression (Dako IHC 22C3 PharmDx assay). (a) Primary tumor cells with positive PD-L1 expression (black arrow, PD-L1 staining, ×200); the TPS was 60%. (b) Spinal metastatic tumor cells with positive PD-L1 expression (black arrow, PD-L1 staining, ×200); the TPS was 35%. TPS: Tumor proportion score, PD-L1: Program death ligand-1

Click here to view

Figure 2: Images of contrast-enhanced computed tomography. Metastatic tumors were identified, including a left middle lung tumor (radiotherapy field) causing obstructive pneumonitis (white arrowhead), a right lung fissure tumor (white arrow), and mediastinal clustered lymph nodes (asterisk). Images before starting pembrolizumab treatment (a and b). Images at the end of 3 months of pembrolizumab treatment (c and d). Images at the end of 9 months of pembrolizumab treatment (e and f). Images at the end of 18 months of pembrolizumab treatment (g and h)

Click here to view

Discussion

Patients with advanced BTC have a poor prognosis and very limited therapeutic options.^[1] Our patient had rapid tumor progression with multiple metastases after surgery, palliative radiotherapy, and conventional chemotherapy yet achieved long-term tumor control with pembrolizumab. In this report, we review the currently available therapeutic options, including the novel strategies of targeted therapy and ICI therapy. We also discuss approaches to identify patients who may benefit from ICI therapy, such as the patient reported here.

Systemic chemotherapy is the standard of care for patients with advanced BTC. First-line chemotherapy with gemcitabine and cisplatin has demonstrated clinical benefits with a median OS of 11.7 months and objective response rate (ORR) of 28%.^[2],[8] Adverse effect rates of 25% and 16% for decreased neutrophil count and abnormal liver function, respectively, have been reported. Selected clinical trials of first-line chemotherapy for advanced BTC are summarized in [Table 1]. Triplet chemotherapy has been reported to have higher response rates in selected fit patients but with more toxicities.^[9] For example, a combination of gemcitabine, cisplatin, and nab-paclitaxel was tested in a single-arm phase II trial, with a median OS of 19.2 months and progression-free survival (PFS) of 11.8 months.^[10] The ORR increased to 45%. Neutropenia was the most common grade ¾ adverse effect, occurring in 33% of patients.

Table 1: Summary of phase 3 clinical trials of first-line chemotherapy for advanced biliary tract cancer

Click here to view

There is an unmet need in the refractory setting.^[3] Patients may suffer from obstructive jaundice, repeated biliary tract infections, and complications of distant metastases if they fail to respond to first-line chemotherapy. Both gemcitabine-based and fluoropyrimidine (fluorouracil or capecitabine)-based regimens have been tested in phase 2 trials. The results of modified FOLFOX (folinic acid, 5-FU, and oxaliplatin) as a second-line chemotherapy have demonstrated marginal benefits (median OS of 6.2 vs. 5.3 months with best supportive care). The ORR was 5% and grade ¾ toxicities were 59% in the FOLFOX arm.^[4] In our patient, chemotherapy was not feasible due to his critical condition and poor performance status, considering the limited response and adverse effects.

The use of NGS to identify actionable therapeutic targets provides new opportunities. The ESMO recommends the routine use of NGS on tumor samples in patients with cholangiocarcinoma, based on the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) ranking and clinical trial results.^[5] For patients who progressed on previous therapy with IDH1-mutant cholangiocarcinoma, ivosidenib significantly improved the PFS (median 2.7 vs. 1.4 months; hazard ratio 0.37) in the ClarIDHy trial 7 compared with placebo, providing ESCAT level IA evidence of screening for IDH1 mutations. For patients with a FGFR2 fusion or other rearrangement, the FGFR inhibitor pemigatinib resulted in an ORR of 36% and a median duration of response of 9.1 months in the FIGHT-202 single-arm trial,^[7] providing ESCAT level IB evidence of screening for FGFR2 aberrations. However, IDH1 and FGFR2 aberrations are more common in BTC not associated with infection or chronic inflammation of the liver, which is relatively rare in the Asia-Pacific region.^[11],[12]

Other potentially actionable targets recommended by the ESMO for screening include NTRK (ESCAT level IC), BRAF V600E, ERBB2, PIK3CA, BRCA ½, and MET (all ESCAT level III, indicating clinical trial evidence of efficacy in other tumor type(s) with similar molecular alterations).^[5] Our patient had no druggable alterations according to the NGS results. Moreover, both analytic and clinical validation must be considered when interpreting the results reported by specific NGS panels. In the era of precision medicine, clinical trials based on targets found through genomic sequencing have been designed, such as the ASCO TAPUR and NCI-MATCH trials. However, many identified genetic alterations of BTC were not druggable.

Novel targeted antibodies may provide a therapeutic strategy for advanced BTC patients. Bemarituzumab (anti-FGFR2b) is an investigational targeted antibody that was designed to block fibroblast growth factors (FGFs) from binding and activating FGFR2b. The FIGHT trial evaluated bemarituzumab plus chemotherapy (modified FOLFOX6) vs. chemotherapy in patients with FGFR2b-positive, HER2-negative advanced gastric or gastroesophageal cancer. Treatment with bemarituzumab plus chemotherapy demonstrated clinically significant improvements in PFS and OS in the patient with at least 10% of tumor cells overexpressing FGFR2b.^[16] FGFR2b is also over-expressed in intrahepatic cholangiocarcinoma.^[11],[12] This represents additional potential areas for the use of bemarituzumab.

ICIs including anti-PD1/anti-PD-L1 and anti-CTLA 4 agents have become the standard of care for various cancers. Anti-PD1 therapy has been extensively studied in patients with advanced or metastatic BTC [Table 2]. In general, anti-PD1 monotherapy has been reported to provide modest clinical benefits in unselected advanced BTC patients with a response rate around 5.8%–23%. The predictive values of biomarkers, including PD-L1 expression, MSI status, and tumor mutation burden, have also been explored, and a trend of a higher response rate has been observed in patients whose tumors express PD-L1.^[17],[18]

Table 2: Outcomes for immune checkpoint inhibitor monotherapy/combination in advanced biliary tract cancer

Click here to view

PD-L1 expression in BTC has also been associated with a high expression of other immune checkpoint molecules, hyper-mutated status, and poor prognosis. The reported incidence of PD-L1 expression in BTC varies widely (9.1%–72.2%) because of different thresholds of positivity and analysis methods.^[17] A high tumor mutation burden or MMR-deficient phenotypes have been associated with a high ORR (40%–50%) to anti-PD1 monotherapy,^[19] however, the proportion of these subgroups is low in BTC. Therefore, the predicted value of tumor mutation burden and MMR-deficient phenotypes in BTC remains minor. Our patient with MSS status and positive PD-L1 expression was responsive to pembrolizumab even in a critical status.

Our patient received radiotherapy to the left upper lung and hilar metastatic tumors to relieve symptoms of obstructive pneumonitis before receiving ICI. Palliative radiotherapy may not only improve obstructive pneumonitis but also provide a synergistic effect. It is thus reasonable to hypothesize that radiotherapy, which may help release tumor-associated antigens and induce “immunogenic cell death,”^[20] may promote the priming and activation of cytotoxic T cells, thus contributing to the excellent response to subsequent pembrolizumab therapy. The tumor microenvironment may also change due to radiation-induced modulation.^[27],[28] The synergy between radiation and immunotherapy remains to be explored. A recent phase III randomized trial (PACIFIC) on patients with stage III NSCLC reported the results of durvalumab versus placebo as consolidation therapy after chemoradiation and demonstrated a substantial improvement in PFS (16.8 vs. 5.6 months with placebo).^[29] However, challenges remain for the future development of this combination strategy, including trial design and the sequence of radiotherapy and immunotherapy.

The combination of anti-PD1/anti-PD-L1 with chemotherapy, targeted agents, or other ICIs is actively being pursued for BTC. In a phase 1 study, chemotherapy-naive patients with unresectable or recurrent BTC received nivolumab with gemcitabine and cisplatin. The median OS was 15.4 months, median PFS was 4.2 months, and 11 of 30 (37%) patients had an objective response.^[22]

Another phase 2 study, combining nivolumab and ipilimumab demonstrated favorable results with an ORR of 23% and a disease control rate of 44% in patients with MSS.^[24] In addition, the combination of chemotherapy, durvalumab, and tremelimumab was reported to have a promising response rate of 73.3%.^[26] Increased response rates with ICI-based combination therapy, compared with the current standard of care, have also been seen in other cancer types, however, survival benefits have not always been demonstrated in randomized controlled trials. Ongoing trials with ICIs in combination with different modalities in advanced BTC are summarized in [Table 3].

Table 3: Selected ongoing phase II/III trials of immune checkpoint inhibitor combination therapy

Click here to view

In conclusion, patients with advanced BTC who fail to respond to first-line chemotherapy urgently need an effective treatment option. Although precision medicine has progressed tremendously, only a minority of BTC patients may benefit from the currently available molecular targeted therapy or ICI therapy. The modest efficacy of ICI monotherapy has led to numerous clinical trials using combination strategies with chemotherapy, targeted therapy, and other novel treatments. More data on ICI-based combination trials may change the landscape of advanced BTC treatment.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgments

We thank the patient for consenting to this publication.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Xie C, McGrath NA, Monge Bonilla C, Fu J. Systemic treatment options for advanced biliary tract carcinoma. J Gastroenterol 2020;55:944-57.
2.	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.
3.	Tella SH, Kommalapati A, Borad MJ, Mahipal A. Second-line therapies in advanced biliary tract cancers. Lancet Oncol 2020;21:e29-41.
4.	Lamarca A, Palmer DH, Wasan HS, Ross PJ, Ma YT, Arora A, et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): A phase 3, open-label, randomised, controlled trial. Lancet Oncol 2021;22:690-701.
5.	Mosele F, Remon J, Mateo J, Westphalen CB, Barlesi F, Lolkema MP, et al. Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: A report from the ESMO Precision Medicine Working Group. Ann Oncol 2020;31:1491-505.
6.	Abou-Alfa GK, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): A multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 2020;21:796-807.
7.	Abou-Alfa GK, Sahai V, Hollebecque A, Vaccaro G, Melisi D, Al-Rajabi R, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: A multicentre, open-label, phase 2 study. Lancet Oncol 2020;21:671-84.
8.	Okusaka T, Nakachi K, Fukutomi A, Mizuno N, Ohkawa S, Funakoshi A, et al. Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: A comparative multicentre study in Japan. Br J Cancer 2010;103:469-74.
9.	Rao S, Cunningham D, Hawkins RE, Hill ME, Smith D, Daniel F, et al. Phase III study of 5FU, etoposide and leucovorin (FELV) compared to epirubicin, cisplatin and 5FU (ECF) in previously untreated patients with advanced biliary cancer. Br J Cancer 2005;92:1650-4.
10.	Shroff RT, Javle MM, Xiao L, Kaseb AO, Varadhachary GR, Wolff RA, et al. Gemcitabine, cisplatin, and nab-Paclitaxel for the treatment of advanced biliary tract cancers: A phase 2 clinical trial. JAMA Oncol 2019;5:824-30.
11.	Chong DQ, Zhu AX. The landscape of targeted therapies for cholangiocarcinoma: Current status and emerging targets. Oncotarget 2016;7:46750-67.
12.	Boscoe AN, Rolland C, Kelley RK. Frequency and prognostic significance of isocitrate dehydrogenase 1 mutations in cholangiocarcinoma: A systematic literature review. J Gastrointest Oncol 2019;10:751-65.
13.	Kim ST, Kang JH, Lee J, Lee HW, Oh SY, Jang JS, et al. Capecitabine plus oxaliplatin versus gemcitabine plus oxaliplatin as first-line therapy for advanced biliary tract cancers: A multicenter, open-label, randomized, phase III, noninferiority trial. Ann Oncol 2019;30:788-95.
14.	Morizane C, Okusaka T, Mizusawa J, Katayama H, Ueno M, Ikeda M, et al. Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: The FUGA-BT (JCOG1113) randomized phase III clinical trial. Ann Oncol 2019;30:1950-8.
15.	Sakai D, Kanai M, Kobayashi S, Eguchi H, Baba H, Seo S, et al. 615ORandomized phase III study of gemcitabine, cisplatin plus S-1 (GCS) versus gemcitabine, cisplatin (GC) for advanced biliary tract cancer (KHBO1401-MITSUBA). Ann Oncol 2018;29:viii205-70.
16.	Catenacci DV, Kang YK, Saeed A, Yamaguchi K, Qin S, Lee KW, et al. FIGHT: A randomized, double-blind, placebo-controlled, phase II study of bemarituzumab (bema) combined with modified FOLFOX6 in 1L FGFR2b+ advanced gastric/gastroesophageal junction adenocarcinoma (GC). JCO 2021;39 15 Suppl:4010.
17.	Ahn S, Lee JC, Shin DW, Kim J, Hwang JH. High PD-L1 expression is associated with therapeutic response to pembrolizumab in patients with advanced biliary tract cancer. Sci Rep 2020;10:12348.
18.	Kang J, Jeong JH, Hwang HS, Lee SS, Park DH, Oh DW, et al. 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;52:594-603.
19.	Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: Results from the phase II KEYNOTE-158 study. J Clin Oncol 2020;38:1-10.
20.	Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G. Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol 2017;17:97-111.
21.	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. JCO 2019;37:4079.
22.	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, open-label, phase 1 study. Lancet Gastroenterol Hepatol 2019;4:611-21.
23.	Kim RD, Chung V, Alese OB, El-Rayes BF, Li D, Al-Toubah TE, et al. A phase 2 multi-institutional study of nivolumab for patients with advanced refractory biliary tract cancer. JAMA Oncol 2020;6:888-94.
24.	Klein O, Kee D, Nagrial A, Markman B, Underhill C, Michael M, et al. Evaluation of combination nivolumab and ipilimumab immunotherapy in patients with advanced biliary tract cancers: Subgroup analysis of a phase 2 nonrandomized clinical trial. JAMA Oncol 2020;6:1405-9.
25.	Lwin Z, Gomez-Roca C, Saada-Bouzid E, Yanez E, Muñoz FL, Im S, et al. LBA41 LEAP-005: Phase II study of lenvatinib (len) plus pembrolizumab (pembro) in patients (pts) with previously treated advanced solid tumours. Ann Oncol 2020;31:S1170.
26.	Oh DY, Lee KH, Lee DW, Kim TY, Bang JH, Nam AR, et al. Phase II study assessing tolerability, efficacy, and biomarkers for durvalumab (D) ± tremelimumab (T) and gemcitabine/cisplatin (GemCis) in chemo-naïve advanced biliary tract cancer (aBTC). JCO 2020;38:4520.
27.	Weichselbaum RR, Liang H, Deng L, Fu YX. Radiotherapy and immunotherapy: A beneficial liaison? Nat Rev Clin Oncol 2017;14:365-79.
28.	Murciano-Goroff YR, Warner AB, Wolchok JD. The future of cancer immunotherapy: Microenvironment-targeting combinations. Cell Res 2020;30:507-19.
29.	Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 2017;377:1919-29.