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11 Immunotherapy inGenitourinary Malignancies
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Large clinical trials of ICI immunotherapy in both CSPC and CRPC have been
generally disappointing. KEYNOTE-199 (NCT02787005) (Antonarakis et al.,
2020) and CheckMate-650 (NCT02985957) (Sharma etal., 2020) are the largest of
these trials evaluating pembrolizumab and combined nivolumab/ipilimumab,
respectively. Prostate cancers are uniquely refractory to immunotherapy and exhibit
relatively low tumor mutation burden (TMB). One proposed reason why immunotherapy may not work effectively in prostate cancer is the activity of AR that signicantly curtails innate immune signaling. Unfortunately, newer medications that
target the AR pathway (AR pathway inhibitors or ARPI) have not enhanced prostate
cancer response to immunotherapy. Similarly, chemotherapy, radiotherapy, PARP
inhibitors, and cellular immune therapies have also failed to signicantly improve
the response to ICI in prostate cancer (Yu etal., 2023; Dorff etal., 2021; McNeel
etal., 2022; Stein etal., 2022). However, it has been reported that a combination of
atezolizumab and a tyrosine kinase inhibitor, cabozantinib, has met its primary endpoint of PFS in the CONTACT-02 study (NCT044446117). At this time, ICI are
approved only for use in prostate cancers with high TMB on genetic testing. PD-L1
immunohistochemistry has no role in clinical decision-making in prostate cancer.
Beyond ICI therapy, the immune system does play a role in prostate cancer outcomes. The OPeRATIC trial (NCT02816983) showed that patients with metastatic
CRPC who experienced increases in CD8+CD11a
high
T cells enjoyed favorable longterm outcomes (Zhang et al., 2021). Notably, one non-ICI immunotherapy is
approved in refractory prostate cancer in some settings. Sipuleucel-T is an autologous cellular immunotherapy in which a patient’s white blood cells are collected
and exposed to PA2024, which is a fusion of prostatic acid phosphatase (PAP) and
immune-stimulating molecule granulocyte-macrophage colony-stimulating factor
(GM-CSF). This exposure helps activate the patient’s immune system against prostate cancer cells. The activated immune cells are then reinfused back into the patient.
In the IMPACT trial (NCT00065442), 127 patients with metastatic CRPC with
Gleason 7 or less, no visceral metastases, and an expected survival of at least 6
months were treated with either sipuleucel-T or placebo (Kantoff et al., 2010).
Although the treatment did not show a substantial effect on slowing disease progression, it did extend survival by a mean 4.1months (25.8 versus 21.7months). This
nding was particularly noteworthy considering the limited treatment options available at that time for mCRPC.This led to the approval of Sipuleucel-T in CRPC with
bone metastases. Clinical use is limited due to the stringent criteria in this study and
its approval (for instance, the exclusion of visceral metastases) and the availability
of newer therapies.
Additional immunotherapies attempted in prostate cancer include a PSAtargeting viral vector vaccine in the PROSTVAC trial (NCT01322490) and other
combination therapies. Unfortunately, the no trial has demonstrated a signicant
improvement in overall survival compared to placebo. ICI treatment in prostate cancer aside from TMB-selected patients should only be pursued in a clinical trial.
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J. Orme
Immunotherapy inTesticular Cancer
Testicular cancers, also termed germ cell tumors (GCT), may present as a painless
lump or swelling in the testicles, often accompanied by a feeling of heaviness. Other
symptoms may include testicular pain, back pain, abdominal pain, or enlargement
of the breasts due to hormonal changes. The prognosis for testicular or germ cell
tumors is generally favorable, with a high cure rate, especially when detected at an
early stage. Even when the cancer has spread beyond the testicles, it can often be
effectively treated with a combination of surgery, chemotherapy, and radiation
therapy.
Clinical trials investigating immunotherapy in testicular cancer are relatively
limited compared to other cancer types. This likely relates to their exquisite sensitivity to—and high cure rates from—chemotherapy even in late-stage disease.
Although chemotherapies carry signicant toxicities, it is considered unethical to
compare alternative potentially non-curative therapies such as immunotherapy in
this setting. Small trials of immunotherapy have been performed in the relapsed or
refractory setting. Avelumab (Mego etal., 2019), durvalumab (Necchi etal., 2018),
nivolumab (Zschäbitz etal., 2017), and pembrolizumab (Zschäbitz et al., 2017;
Adra etal., 2018) monotherapies have each failed to achieve any meaningful clinical benet. Immunotherapy with ICI for testicular cancers is not advisable outside
of a clinical trial.
Immunotherapy inPenile Cancer
Penile cancer is extremely rare. As such, clinical trials specically investigating
immunotherapy in penile cancer are limited. Urothelial cancer trials KEYNOTE-045
(NCT02256436) and JAVELIN Bladder 100 (NCT02603432) both included small
subsets of patients with penile cancer.
Given the scarcity of data in this area, further research and clinical trials are
needed to explore the potential benets and efcacy of immunotherapy in penile
cancer treatment. Immunotherapy with ICI for penile cancers is not advisable outside of a clinical trial.
References
Abu-Rustum, N., etal. (2023). Uterine neoplasms, version 1.2023, NCCN clinical practice guide-
lines in oncology. Journal of the National Comprehensive Cancer Network, 21(2), 181–209.
Adra, N., etal. (2018). Phase II trial of pembrolizumab in patients with platinum refractory germ-
cell tumors: A Hoosier cancer research network study GU14-206. Annals of Oncology, 29(1),
209–214.
Albiges, L., etal. (2023). Efcacy and safety of atezolizumab plus cabozantinib vs cabozantinib
alone after progression with prior immune checkpoint inhibitor (ICI) treatment in metastatic
11 Immunotherapy inGenitourinary Malignancies
https://t.me/med1917
renal cell carcinoma (RCC): Primary PFS analysis from the phase 3, randomized, open-label
CONTACT-03 study. Journal of Clinical Oncology, 41(17_suppl), LBA4500.
Antonarakis, E.S., etal. (2020). Pembrolizumab for treatment-refractory metastatic castration-
resistant prostate cancer: Multicohort, open-label phase II KEYNOTE-199 study. Journal of
Clinical Oncology, 38(5), 395–405.
Bajorin, D. F., etal. (2021). Adjuvant nivolumab versus placebo in muscle-invasive urothelial
carcinoma. New England Journal of Medicine, 384(22), 2102–2114.
Balar, A.V., etal. (2017). Atezolizumab as rst-line treatment in cisplatin-ineligible patients with
locally advanced and metastatic urothelial carcinoma: A single-arm, multicentre, phase 2 trial.
The Lancet, 389(10064), 67–76.
Balar, A.V., etal. (2021). Pembrolizumab monotherapy for the treatment of high-risk non-muscle-
invasive bladder cancer unresponsive to BCG (KEYNOTE-057): An open-label, single-arm,
multicentre, phase 2 study. The Lancet Oncology, 22(7), 919–930.
Bellmunt, J., etal. (2017). Pembrolizumab as second-line therapy for advanced urothelial carci-
noma. New England Journal of Medicine, 376(11), 1015–1026.
Bellmunt, J., etal. (2021). Adjuvant atezolizumab versus observation in muscle-invasive urothelial
carcinoma (IMvigor010): A multicentre, open-label, randomised, phase 3 trial. The Lancet
Oncology, 22(4), 525–537.
Choueiri, T.K., etal. (2021a). Nivolumab plus Cabozantinib versus sunitinib for advanced renal-
cell carcinoma. New England Journal of Medicine, 384(9), 829–841.
Choueiri, T.K., etal. (2021b). Adjuvant pembrolizumab after nephrectomy in renal-cell carci-
noma. New England Journal of Medicine, 385(8), 683–694.
Dorff, T., et al. (2021). Phase Ib study of patients with metastatic castrate-resistant prostate can-
cer treated with different sequencing regimens of atezolizumab and sipuleucel-T. Journal for
Immunotherapy of Cancer, 9(8), e002931.
Flaig, T.W., etal. (2022). NCCN guidelines® insights: Bladder cancer, version 2.2022. Journal of
the National Comprehensive Cancer Network, 20(8), 866–878.
Fuhrman, S.A., Lasky, L.C., & Limas, C. (1982). Prognostic signicance of morphologic param-
eters in renal cell carcinoma. The American Journal of Surgical Pathology, 6(7), 655–663.
Heng, D.Y., etal. (2009). Prognostic factors for overall survival in patients with metastatic renal
cell carcinoma treated with vascular endothelial growth factor-targeted agents: Results from a
large, multicenter study. Journal of Clinical Oncology, 27(34), 5794–5799.
Hoimes, C. J., et al. (2023). Enfortumab Vedotin plus pembrolizumab in previously untreated
advanced urothelial cancer. Journal of Clinical Oncology, 41(1), 22–31.
Kantoff, P.W., etal. (2010). Sipuleucel-T immunotherapy for castration-resistant prostate cancer.
New England Journal of Medicine, 363(5), 411–422.
McDermott, D.F., etal. (2021). Open-label, single-arm, phase II study of pembrolizumab mono-
therapy as rst-line therapy in patients with advanced non-clear cell renal cell carcinoma.
Journal of Clinical Oncology, 39(9), 1029–1039.
McNeel, D. G., et al. (2022). Phase 2 trial of T-cell activation using MVI-816 and pembroli-
zumab in patients with metastatic, castration-resistant prostate cancer (mCRPC). Journal for
Immunotherapy of Cancer, 10(3), e004198.
Mego, M., etal. (2019). Phase II study of avelumab in multiple relapsed/refractory germ cell can-
cer. Investigational New Drugs, 37(4), 748–754.
Motzer, R.J., et al. (2002). Interferon-alfa as a comparative treatment for clinical trials of new
therapies against advanced renal cell carcinoma. Journal of Clinical Oncology, 20(1), 289–296.
Motzer, R.J., et al. (2018). Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell
carcinoma. New England Journal of Medicine, 378(14), 1277–1290.
Motzer, R.J., etal. (2019). Avelumab plus Axitinib versus sunitinib for advanced renal-cell carci-
noma. New England Journal of Medicine, 380(12), 1103–1115.
Motzer, R., etal. (2021). Lenvatinib plus pembrolizumab or everolimus for advanced renal cell
carcinoma. New England Journal of Medicine, 384(14), 1289–1300.
Motzer, R.J., etal. (2022). Kidney cancer, version 3.2022, NCCN clinical practice guidelines in
oncology. Journal of the National Comprehensive Cancer Network, 20(1), 71–90.
155
156
https://t.me/med1917
Necchi, A., etal. (2018). Abstract CT102: APACHE: An open label, randomized, phase II study
of durvalumab (Durva), alone or in combination with Tremelimumab (Treme), in patients (pts)
with advanced germ cell tumors (GCT): Results at the end of rst stage. Cancer Research,
78(13_Supplement), CT102.
Pal, S.K., etal. (2021). Cabozantinib in combination with atezolizumab for advanced renal cell
carcinoma: Results from the COSMIC-021 study. Journal of Clinical Oncology, 39(33),
3725–3736.
Powles, T., etal. (2020a). Pembrolizumab plus axitinib versus sunitinib monotherapy as rst-line
treatment of advanced renal cell carcinoma (KEYNOTE-426): Extended follow-up from a ran-
domised, open-label, phase 3 trial. The Lancet Oncology, 21(12), 1563–1573.
Powles, T., et al. (2020b). Avelumab maintenance therapy for advanced or metastatic urothelial
carcinoma. New England Journal of Medicine, 383(13), 1218–1230.
Sharma, P., etal. (2017). Nivolumab in metastatic urothelial carcinoma after platinum therapy
(CheckMate-275): A multicentre, single-arm, phase 2 trial. The Lancet Oncology, 18(3),
312–322.
Sharma, P., et al. (2020). Nivolumab plus ipilimumab for metastatic castration-resistant pros-
tate cancer: Preliminary analysis of patients in the CheckMate-650 trial. Cancer Cell, 38(4),
489–499.e3.
Siegel, R. L., et al. (2023). Cancer statistics, 2023. CA: a Cancer Journal for Clinicians,
73(1), 17–48.
Stein, M.N., etal. (2022). ADXS31142 immunotherapy ± pembrolizumab treatment for meta-
static castration-resistant prostate cancer: Open-label phase I/II KEYNOTE-046 study. The
Oncologist, 27(6), 453–461.
Vuky, J., etal. (2020). Long-term outcomes in KEYNOTE-052: Phase II study investigating rst-
line pembrolizumab in cisplatin-ineligible patients with locally advanced or metastatic urothe-
lial cancer. Journal of Clinical Oncology, 38(23), 2658–2666.
Yu, E. Y., et al. (2023). Pembrolizumab plus Olaparib in patients with metastatic castration-
resistant prostate cancer: Long-term results from the phase 1b/2 KEYNOTE-365 cohort a
study. European Urology, 83(1), 15–26.
Zhang, H., et al. (2021). Phase II evaluation of stereotactic ablative radiotherapy (SABR) and
immunity in 11C-choline-PET/CT–identied oligometastatic castration-resistant prostate can-
cer. Clinical Cancer Research, 27(23), 6376–6383.
Zschäbitz, S., etal. (2017). Response to anti-programmed cell death protein-1 antibodies in men
treated for platinum refractory germ cell cancer relapsed after high-dose chemotherapy and
stem cell transplantation. European Journal of Cancer, 76, 1–7.
J. Orme
Chapter 12
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Immunotherapy forGastrointestinal
Malignancies
MojunZhu
Abstract Gastrointestinal (GI) malignancies comprise esophageal, stomach, liver,
biliary tract, pancreatic, small bowel, appendiceal, colorectal, and anal cancer. All
of them originate from the GI tract; however, their disease course and management
vary signicantly. To date, only a small number of GI cancers respond well to
immunotherapy that has been approved by the US Food and Drug Administration.
Their different sensitivity to immunotherapy may be due to the type of cancer cells
involved (e.g., adenocarcinoma versus squamous cell carcinoma), primary location
of the cancer (e.g., pancreatic versus anal cancer), potential causes of cancer (e.g.,
acid reux for esophageal cancer versus bacterial infection for stomach cancer), and
so on. Altogether, these factors shape the interactions among cancer cells, immune
cells, and adjacent normal cells, which ultimately determine the treatment response
to immunotherapy. In this chapter, we will discuss the current state of immunotherapy in the eld of GI cancers by reviewing the most pertinent concept and landmark clinical trials that guide the use of immunotherapy to treat GI cancers.
Keywords Immunotherapy · Aanti-PD-1 · Checkpoint · GI cancer · Colorectal
cancer · Anal cancer · Esophageal cancer · Stomach cancer · Liver cancer · Biliary
tract cancer · Pancreatic cancer · Clinical trial
Colorectal, Appendiceal, andSmall Bowel Cancer
Colorectal cancer (CRC) is the most common type of GI cancer worldwide. In the
USA, it is the third most commonly diagnosed cancer and the third leading cause of
cancer-related death. Localized, stage I–III CRC is primarily treated by surgical
resection. Advanced, stage IV CRC that is not amenable to surgical resection or has
metastasized to a different organ or distant lymph nodes is treated with systemic
M. Zhu (*)
Department of Oncology, Mayo Clinic, Rochester, MN, USA
e-mail: zhu.mojun@mayo.edu
H. Dong, S. N. Markovic (eds.), The Basics of Cancer Immunotherapy,
https://doi.org/10.1007/978-3-031-59475-5_12
157© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
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M. Zhu
therapy. Chemotherapy remains the preferred, rst-line systemic therapy for most
patients with advanced CRC as immunotherapy has been found efcacious only in
patients with CRC that have defective DNA mismatch repair (MMR) mechanism
(Cercek etal., 2022; Lenz etal., 2022; Diaz Jr. etal., 2022). At the time of diagnosis,
standardized tests will be performed to assess whether the tumor is MMR-decient
(dMMR), which is commonly found in patients who carry an inherited genetic condition such as Lynch syndrome predisposing its carriers to cancer development
(Moreira etal., 2012). dMMR can also occur sporadically to patients without any
known genetic conditions. Only ~15% of CRC are dMMR; sporadic acquirement of
this feature is more common than having an hereditary disorder (Kim etal., 1994;
Leclerc etal., 2021). Following evaluation of dMMR status, patients will be assessed
to make sure that they do not have any medical conditions particularly autoimmune
disorders that can be worsened by immunotherapy.
Treatment with immune checkpoint inhibitors (ICI) that targets the PD-1/PD-L1
axis (i.e., anti-PD-1 and anti-PD-L1) as discussed in previous chapters is recommended as the rst-line therapy for patients with dMMR CRC. This recommendation is based on data from phase 3 clinical trials, which demonstrated that patients
who received anti-PD-1 for dMMR CRC lived longer (i.e., longer survival) and had
higher chances of tumor shrinkage (i.e., higher response rates) compared with those
who received chemotherapy (Diaz Jr. etal., 2022; André etal., 2020). In general, all
types of dMMR cancers can be treated with ICI (Le etal., 2015). These cancers are
enriched by immune cells known as tumor-inltrating lymphocytes (TIL), which
are reinvigorated by ICI to kill cancer cells (Smyrk etal., 2001). ICI alone as a rstline therapy is only recommended for the treatment of dMMR CRC, certain types
of lung cancer, and melanoma because longer survival and higher response rates
were demonstrated by phase 3 clinical trials comparing ICI with chemotherapy in
these cancers.
In addition to dMMR, other biomarkers such as tumor mutational burden (TMB)
and PD-L1 expression scores can help to predict treatment response to anti-PD-1;
however, utility and reliability of these biomarkers are more limited than dMMR.For
instance, CRC with a high TMB (i.e., TMB≥10 mutations per megabase) did not
appear to respond well to anti-PD-1 despite FDA approval of using pembrolizumab,
an anti-PD-1 therapy, to treat solid tumors with TMB≥10 that have progressed on
prior therapy (Rousseau etal., 2021). Biomarkers that are associated with favorable
treatment response to immunotherapy indicate that one’s immune system can be
potentiated by this therapy to kill cancer cells; however, none of the exiting biomarkers are perfect due to the presence of false-positive and false-negative errors.
As a result, the search for novel biomarkers and testing algorithms that better predict efcacy of anticancer therapy including immunotherapy is an area of active
research in the era of personalized medicine.
Cancers that arise from the appendix and small bowel are rare; therefore, there
are much less experimental data and clinical trials that have investigated immunotherapy in these cancers. Their management is largely based on our clinical experience with CRC. Similarly, ICI should be considered for dMMR cancers. Anti-PD-1
was shown to be effective in dMMR small bowel cancer that was previously treated
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with rst-line chemotherapy (Pedersen etal., 2021). The best approach to incorporating immunotherapy to the treatment of appendiceal and small bowel cancer
remains to be determined.
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Anal Cancer
In contrast to colorectal, appendiceal, and small bowel cancer that is predominantly
adenocarcinoma, most anal cancers are squamous cell carcinoma (SCC). Human
papillomavirus (HPV) infection is detected in ~90% of anal SCC (Daling etal.,
2004). These two features probably make anal cancer more sensitive to
immunotherapy.
As background, localized anal cancer is primarily treated with concurrent chemotherapy and radiotherapy (i.e., chemoradiation). Surgical resection that makes
permanent colostomy construction inevitable is only considered when the cancer if
refractoryto chemoradiation.
Advanced anal cancer is treated with systemic therapy. Although dMMR is rare
in anal cancer, anal SCC seems more susceptible to ICI than CRC. HPV positivity
and increased TIL are associated with improved survival and treatment response to
chemoradiation in anal cancer, suggesting that HPV infection may trigger immune
response and enhance the efcacy of immunotherapy (Balermpas et al., 2017).
These trends were also observed in clinical trials with anti-PD-1 in SCC of the head
and neck (Ferris etal., 2016). Retifanlimab, an anti-PD-1 therapy, in combination
with chemotherapy is being actively evaluated as a rst-line therapy for advanced
anal SCC (Rao etal., 2022). Currently, two other anti-PD-1 agents (i.e., nivolumab
and pembrolizumab) have been endorsed by the National Comprehensive Cancer
Network as second-line therapy for anal SCC after disease progression on rst-line
chemotherapy (Morris etal., 2017; Marabelle etal., 2020a). Yet, none have received
FDA approval.
Esophageal andStomach Cancer
Esophageal cancer can be either SCC or adenocarcinoma while stomach cancer and
cancer arising from the gastroesophageal junction (GEJ, that is, the part of GI tract
where the esophagus connects to the stomach) are predominantly adenocarcinoma.
These upper GI cancers are more resistant to chemotherapy than CRC and are associated with a poor prognosis. Less than 10% of patients are alive ve years after
they have been diagnosed with an advanced upper GI cancer based on data provided
by the Surveillance, Epidemiology, and End Results Program.
The advent of immunotherapy has enriched our treatment options for upper GI
cancers but has only improved clinical outcomes modestly. In general, upper GI
cancers appear more sensitive to immunotherapy than CRC; esophageal SCC
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(ESCC) appears more sensitive to immunotherapy than esophageal, GEJ, and stomach adenocarcinoma. In advanced ESCC, anti-PD-1 in combination with chemotherapy is more efcacious than chemotherapy alone as a rst-line therapy regardless
of prerequisite biomarker expression (Sun etal., 2021; Doki etal., 2022).
In esophageal, GEJ, and stomach adenocarcinoma, combined positive score
(CPS) that measures the amount of PD-L1 expression by tumor and immune cells is
a critical biomarker that predicts treatment response to anti-PD-1. The higher the
CPS score, the higher the likelihood that the cancer is going to respond to antiPD- 1. In these cancers, rst-line nivolumab or pembrolizumab in combination with
chemotherapy was found more efcacious than chemotherapy alone in patients with
CPS≥5 and 10, respectively (Sun etal., 2021; Janjigian et al., 2021). In addition,
rst-line pembrolizumab in combination with chemotherapy and trastuzumab,
which is a monoclonal antibody targeting HER2 expression in tumor cells, was
found more efcacious than chemotherapy and trastuzumab in HER2-overexpressing
GEJ and stomach adenocarcinoma withCPS≥ 1(Janjigian etal., 2023).
Similar to CRC, dMMR also predicts favorable response to immunotherapy in
upper GI cancers. It is found in ~2% and ~15% of esophageal and stomach cancers,
respectively (Bonneville etal., 2017). ICI alone or in combination with chemotherapy should be considered as a rst-line therapy for these tumors (Kim etal.,
2018). Overall, these data indicate that patients with advanced upper GI cancers that
harbor dMMR or high CPS scores benet from rst-line therapy that contains
anti-PD-1.
Furthermore, ICI is found to enhance the therapy for localized upper GI cancers,
which are generally treated with multimodality therapy consisting of chemotherapy,
radiotherapy, and surgery. In the adjuvant setting (i.e., postoperative), nivolumab
was shown to improve disease-free survival of patients with esophageal and GEJ
cancer with residual disease after receiving chemoradiation and surgery and its use
has already been approved by FDA (Kelly etal., 2021). In the neoadjuvant setting
(i.e., preoperative), several studies have demonstrated the safety and potential efcacy of combining anti-PD-1 with chemoradiation and surgery (van den Ende etal.,
2021; Zhu etal., 2022). Larger, phase 3 studies are currently underway to conrm
the efcacy of perioperative use of ICI (Eads etal., 2020; Janjigian et al., 2022;
Shitara et al., 2023).
M. Zhu
Liver Cancer
Incidence and mortality rates of liver cancer, also known as hepatocellular carcinoma (HCC), have been rising (Ryerson etal., 2016). Viral hepatitis, alcoholic cirrhosis, and nonalcoholic fatty liver disease are known risk factors for HCC,
highlighting the importance of disease prevention and screening (Akinyemiju etal.,
2017). For patients with limited amount of tumor burden, partial hepatectomy and
locoregional therapies are promising (Llovet etal., 2021). Liver transplantation as a
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curative therapy is reserved for only a small group of patients with early-stage HCC
(Mazzaferro etal., 1996).
Historically, rst-line therapy with tyrosine kinase inhibitors (TKI) such as
sorafenib has limited efcacy in HCC, prolonging patients’ overall survival by
~3months compared with placebo (Llovet etal., 2008). Given the understanding
that chronic inammation can drive development of HCC (Ringelhan etal., 2018),
immunotherapy has become an area of active research. In patients with advanced
HCC,atezolizumab (anti-PD-L1) in combination with bevacizumab (monoclonal
antibody targeting vascular endothelial growth factor [VEGF]) (Finn etal., 2020a)
and durvalumab (anti-PD-1) in combination with tremelimumab (ICI targeting
CTLA-4) (Abou-Alfa etal., 2022), respectively, improvedresponse rates and overall survival compared with rst-line sorafenib. Based on these studies, both combinations have been approved by FDA as rst-line therapy for HCC. In addition,
anti-PD-1 therapy also demonstrated efcacy in HCC that was previously treated
with sorafenib (El-Khoueiry etal., 2017; Finn etal., 2020b). Currently, there is no
conclusive data to guide the sequence of systemic therapy (i.e., ICI to be followed
by TKI versus vice versa) for HCC.
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Biliary Tract Cancer
Biliary tract cancer (BTC) encompasses gallbladder cancer and cholangiocarcinoma, which can be further divided into intrahepatic and extrahepatic cholangiocarcinoma. BTC is often diagnosed at an advanced stage and is associated with a poor
prognosis (Hundal & Shaffer, 2014). Durvalumab (anti-PD-1) in combination with
chemotherapy improved overall survival compared with chemotherapy alone, and
this combination was hence approved by FDA as a rst-line therapy for advanced
BTC (Oh etal., 2022).
Although dMMR is found in less than 3% of BTC (Bonneville etal., 2017; Abrha
etal., 2020), anti-PD-1 was shown to have signicant antitumor activity in these
tumors (Marabelle etal., 2020b). As a result, it is important to perform MMR testing at diagnosis. In addition, emerging data from genetic testing have revealed other
genetic alterations that can be targeted by novel therapy, underscoring the need for
comprehensive molecular testing to guide treatment recommendations for BTC
(Valle etal., 2017).
Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of pancreatic cancer
and has a poor prognosis (Siegel et al., 2023). Chemotherapy currently remains
rst-line therapy for advanced PDAC as immunotherapy and targeted therapy have
notdemonstrated reasonable efcacy.
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PDAC appears much more resistant to immunotherapy compared with other GI
cancers. The rates of dMMR and high TMB are low in PDAC (Bonneville etal.,
2017; Abrha etal., 2020). Treatment with anti-PD-1 led to tumor shrinkage in only
18.2% of patients with previously treated dMMR PDAC (versus 45.8% of patients
with previously treated dMMR gastric cancer) (Marabelle etal., 2020b). ICI combinations also demonstrated poor antitumor activity (O’Reilly etal., 2019). The
resistance of PDAC to ICI has been attributed to a tumor microenvironment that is
devoid of TIL (O’Donnell etal., 2019; Osipov etal., 2019). In addition, targeted
therapy against common somatic mutations in PDAC including KRAS, TP53,
SMAD4, and CDKN2A showed limited efcacy (Waddell et al., 2015; Ho etal.,
2020), which may be mediated by desmoplasia consisting of dense brosis pro-
duced by pancreatic stellate cells, impairing drug penetration (Whatcott et al.,
2015). Overall, future studies should perhaps focus on strategies that reprogram
PDAC tumor microenvironment to enable the actions of ICI and small molecule
inhibitors.
M. Zhu
Neuroendocrine Tumor andCarcinoma
Neuroendocrine tumors (NET) of GI origin comprise a diverse group of malignancies. They are divided into high, intermediate, and low grade based on the rate of
cancer cell proliferation: high-grade NET grow the fastest and therefore are the
most aggressive (Nagtegaal etal., 2020). Neuroendocrine carcinomas (NEC) are
distinct from NET as NEC are poorly differentiated and much more aggressive
(Nagtegaal etal., 2020). Although dMMR is rare in this disease (0% of pancreatic
NET (Salem etal., 2018), 3.6% of NET of all origins (Vanderwalde etal., 2018),
and 12.4% of all NEC (Sahnane etal., 2015)), anti-PD-1 may be considered selectively in high-grade NET and NEC based on data from phase 2 clinical trials (Patel
etal., 2020, 2021; Yao etal., 2021).
Summary
TheFDA approval of anti-PD-1 as a therapy for dMMR cancers marks a paradigm
shift in medical oncology. In comparison to chemotherapy, immunotherapy such as
ICI appears less toxic and more efcacious in the long term. GI cancers have demonstrated varied sensitivity to immunotherapy(Table12.1), and this is mediated by
interactions among cancer cells, immune cells, and adjacent normal cells, which
constitute a distinct tumor immune microenvironment. Active research is underway
to crack the code of tumor immune microenvironment, which holds the key to successful development of immunotherapy in the near future.
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