Medical Management of Patients with Advanced Cholangiocarcinoma

December 2019 Highlights from the First Annual Cholangiocarcinoma Summit

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Advances in Chemotherapy for Cholangiocarcinoma

According to several presenters at the First Annual Cholangiocarcinoma Summit, advances in systemic treatment for cholangiocarcinoma (CCA) are emerging, including cytotoxic chemotherapy. Earlier this year, the combination of gemcitabine, cisplatin, and nab-paclitaxel was investigated as first-line therapy in 60 patients with advanced CCA and gallbladder cancer with good performance status.1 Among evaluable patients, the median progression-free survival (PFS) was 11.8 months, the median overall survival (OS) was 19.2 months, and the partial response rate was 45%. Overall, 20% of the patients converted from unresectable to resectable disease and underwent curative surgery.1

The randomized, phase 3 Southwest Oncology Group: S1815 clinical trial evaluated the combination of gemcitabine, cisplatin, and nab-paclitaxel versus the gold standard of gemcitabine plus cisplatin in patients with newly diagnosed, advanced biliary tract cancers.2 Archived diagnostic tissue is being banked and serial blood is being collected, including at the time of disease progression. This study represents the largest repository of biliary cancer specimens to date, and a translational plan is being developed for biospecimens.

The randomized, multicenter, phase 3 NuTide 21 trial is comparing NUC-1031 (a nucleoside analogue similar to gemcitabine) plus cisplatin versus gemcitabine plus cisplatin) in patients with previously untreated locally advanced or metastatic biliary tract cancer.3 The primary objectives of this study are OS and objective response rate. Several other studies are assessing targeted therapies in cytotoxic combination settings.

These studies are all collaborative efforts, which will continue to be instrumental to investigate the replacement of the current chemotherapy standard of care and the utility of chemo-intensification, as well as the use of chemotherapy in combination with targeted therapies and immunotherapy, noted one presenter. Since immunotherapy and targeted agents are not suitable for all patients, new chemotherapeutic agents in both first- and second-line settings are still needed.

Multiple chemotherapy options exist when first-line chemotherapy (gemcitabine plus cisplatin) has failed. The scenario is challenging with respect to second-line chemotherapy for patients with CCA, in part because the aggressive behavior of the disease renders few patients sufficiently fit to receive second-line chemotherapy following progression on first-line therapy.

Most trials of second-line chemotherapy for CCA have been phase 2 studies (none of which were randomized) and retrospective analyses. Response rates in these trials were <10% overall, with a modest benefit in PFS and OS.4

ABC-06 was a phase 3, randomized, open-label clinical trial that assessed the role of FOLFOX (folinic acid [leucovorin], 5-fluorouracil [5-FU], and oxaliplatin) plus active symptom control (ie, control of complications related to the cancer, as well as to biliary obstruction) versus active symptom control alone in the second-line setting in patients diagnosed with biliary tract cancer, including ampullary tumors.5

FOLFOX improved OS (the primary end point) on an intent-to-treat basis after progression following gemcitabine plus cisplatin with a clinically meaningful reduction in the risk for death (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.50-0.97; P = .031). The rate of OS in the FOLFOX arm was increased by an absolute 15.1% at 6 months (50.6% vs 35.5% in the active-symptom-control-alone arm) and by 14.5% at 12 months (25.9% vs 11.4%, respectively).5

Subgroups with a poorer prognosis seemed to benefit the most from FOLFOX, including patients who were platinum resistant or refractory, those with low levels of albumin, and those with metastatic disease. Based on these data, FOLFOX plus active symptom control became the new standard of care in the second-line setting for advanced biliary tract cancer.5

In a phase 2 trial in the second-line setting, treatment with FOLFIRINOX (leucovorin, 5-FU, irinotecan, and oxaliplatin) resulted in a PFS of 6.2 months.6 Etoposide toniribate, a prodrug of etoposide, demonstrated evidence of activity compared with best supportive care in a small (N = 22) phase 2 study, with disease control rates of 55.6% versus 20.0%, respectively.7

Predictive Molecular Biomarkers in Cholangiocarcinoma

The International Cancer Genome Consortium has analyzed 500 cases of CCA from 10 countries and has identified 4 distinct clusters with different clinical features and molecular profiles.8 The clusters do not necessarily match the anatomic location, although the 2 are correlated. Among the 4 clusters, tumors in cluster 4 are associated with the best outcomes. Patients with tumors in cluster 4 present predominantly with intrahepatic CCA enriched by IDH1 mutations and FGFR alterations. In contrast, tumors in cluster 1 are associated with the worst outcomes. Patients with tumors in this cluster have TP53 mutations, BRCA1/2 mutations, and HER2 amplification.8

Comprehensive genomic profiling from >1000 patients in the FIGHT-202 trial confirm findings from The Cancer Genome Atlas (TCGA) that few CCA tumors are microsatellite instability (MSI)-high or have high tumor mutational burden.9 In the TCGA, IDH1 mutations and FGFR2 alterations were found in 10.5% and 9.4% of patients with CCA, respectively.9

FGFR alterations are associated with a unique epidemiology and, perhaps, natural history. These alterations usually present in younger patients, at an earlier stage, and have an indolent disease course. IDH1 mutations are also pursued in the treatment of CCA in the second-line setting. IDH1 remains a very rare mutation in gastrointestinal cancers and is specific to CCA. It is comutated with ARID1A, BAP1, and PBRM1.

BRAF mutation seems to be a promising targetable alteration in CCA. In the ROAR basket trial, in which 17% of the patients had hepatocholangiocarcinoma,10 combination therapy with dabrafenib plus trametinib was associated with a 42% overall response rate (ORR), a median PFS of 9.2 months, and a median OS of 11.7 months in BRAF-mutated patients with CCA.11

Tumor location seems to be a predictive biomarker for targetable mutations. When faced with a carcinoma of unknown primary origin, the diagnosis must be confirmed and attributed appropriately, ensuring that the tumors are not metastatic, stated one of the participants. Documenting the location of CCA tumors—that is, intrahepatic versus extrahepatic—is necessary. Patients with intrahepatic CCA have a high likelihood of targetable genomic alterations and should undergo tumor genetic testing in a timely fashion.

Tumors are genomically unstable, and the potential for evolution is a real phenomenon in attempting to capture molecular markers. “If you look at the primary tumor from 5 years before the patient received a couple of lines of therapy, are we looking at the tumor that now threatens the patient’s life?” asked one presenter.

The methodology selected for tissue acquisition in patients with CCA is important. Core needle biopsy is preferred, because it supplies more tissue for analysis and provides details about the stroma, lymphocytic infiltrate, and angiogenesis to assist in the patient’s diagnosis. In many cases, aspiration is preferred, to avoid tumor spread at the time the material is acquired.

The methodology for liquid biopsy is improving rapidly, with many assays now being used in the marketplace. The expectation is that as liquid biopsy assays improve and can detect more types of abnormalities, they will become more widely used. For many oncologists, liquid biopsy is the first choice for patients with disease recurrence, because the results are returned quickly and the coverage is relatively broad (ie, a large number of genes) in many of the assays that are available. The expectation among the experts at the meeting was that the use of liquid biopsy will expand rapidly, particularly at various points in the decision-making process, as the assays improve.

Chorus Discussion

The chorus members were asked how they would use gemcitabine and cisplatin off clinical trial. Nearly half (46%) indicated that they would treat until progression, 26% responded that they would treat for 6 months and then stop chemotherapy until progression, 23% said that they would treat for 6 months and then stop cisplatin while continuing gemcitabine maintenance, and 5% responded “other.”

When they were asked to characterize their current use of liquid biopsies, 32% said that they obtain a liquid biopsy only if the tissue is of insufficient quantity for next-generation sequencing (NGS), 23% responded that they do not use liquid biopsies, 19% answered that they obtain a liquid biopsy from all patients at baseline and at progression, 10% indicated that they obtain a liquid biopsy in biomarker-positive patients at baseline and at progression, and 3% noted that they obtain a liquid biopsy in all patients at baseline only.

Molecularly Targeted Therapies

FGFR inhibitors

Activation of the FGFR pathway has been shown to be a favorable prognostic factor in intrahepatic CCA. Alterations in FGFR have been associated with improved OS compared with wild-type FGFR. FGFR-specific inhibitors have been found to contribute to improved OS compared with the use of standard therapies in this setting.

The most described genetic abnormality in CCA is FGFR fusion, in which the FGFR gene fuses with another gene. In this regard, up to 50 gene fusion partners have been recognized. Several selective and nonselective FGFR inhibitors are in development.

In patients with FGFR2 fusion–positive CCA, the ORR to infigratinib is 31%, with a disease control rate of 84%.12 Across the various FGFR inhibitors, the number of lines of prior therapy seems to have an impact on response rates. The belief among presenters at the summit is that NGS will eventually be used for treatment decisions in this setting, and FGFR inhibitors may be used first line with identification of FGFR fusions.

An overrepresentation of FGFR genetic abnormalities has been observed among patients with locally advanced intrahepatic CCA who are candidates for transplantation. These patients tend to have impressive survival following transplant, so FGFR abnormalities may have implications in terms of patient selection for transplantation.

Resistance to FGFR inhibitors

Primary resistance to FGFR inhibitors can occur because of tumor heterogeneity, other tumor-related factors, or drug-related issues. Tumor-related factors include incomplete addiction to FGFR and comutated pathways or other upregulated bypass pathways for which FGFR inhibition alone is insufficient for a response. Although FGFR2 fusion appears to be an early alteration, other factors may have an impact on the sensitivity of CCA tumor cells to FGFR inhibitors, some of which may be heterogeneous across cells.

Comutations with FGFR2 fusion may affect the sensitivity of CCA to FGFR inhibitors. In a recent analysis, patients with an FGFR2 fusion and a TP53 alteration had no response to pemigatinib. Moreover, the response to pemigatinib in patients with CDKN2A/B alterations was decreased compared with that in the entire FGFR2-positive population.13

An integrative molecular analysis of cell-free (cf)DNA, primary tumors, and metastases was conducted in 3 patients with advanced FGFR2 fusion–positive intrahepatic CCA. Results of the study revealed the emergence of secondary kinase mutations that confer resistance to infigratinib at the time of progression, in addition to a striking degree of interlesional heterogeneity, with distinct FGFR2 point mutations identified in different metastases from the same patient.14

The highly selective, covalent-binding pan-FGFR inhibitor TAS-120 may overcome resistance to ATP-competitive FGFR inhibitors, as evidenced by studies in biliary tract cell lines and in patients with intrahepatic CCA. TAS-120 was found to be active against 4 FGFR2 mutations but had relatively less activity against the V565F gatekeeper mutation.15

“My practice is such that when I have a patient on an FGFR inhibitor, we do serial cfDNA analysis. We never stop the drug based just on the emergence of resistance. We always wait until we see progression on a scan,” said an audience member. The emergence of certain resistance mutations would prompt switching to an alternate FGFR inhibitor, such as Debio 1347 (a highly selective FGFR1, 2, 3 ATP competitive inhibitor) or TAS-120, because prior FGFR inhibitor treatment usually precludes enrollment in a clinical trial with these agents.

IDH1 inhibitors

IDH mutations occur in up to 23% of patients with CCA, and in contrast to other targetable mutations, they do not play a prognostic role in CCA.16,17

The phase 3 ClarIDHy study was a randomized, double-blind, international study of adults with histologically confirmed CCA and centrally confirmed mutated IDH1 by NGS who had received 1 or 2 prior lines of therapy.18 Patients were randomized in a 2:1 fashion to ivosidenib 500 mg administered once daily or placebo. Crossover was permitted at radiographic disease progression.18

Median PFS was 2.7 months in the ivosidenib group versus 1.4 months in the placebo arm (HR, 0.37; 95% CI, 0.25-0.54; P <.001).18 In the ivosidenib treatment arm, PFS was 32% at 6 months and 22% at 12 months, which is impressive when considering that the OS in this late-line setting is typically measured on the order of a few months (Figure 1).18 These values were not evaluable in the placebo arm because of crossover. Treatment with ivosidenib was associated with a greater disease control rate of 53%, including 2 confirmed partial responses, compared with placebo recipients, in whom stable disease was documented in only 28%.19

Figure 1

Median OS was numerically longer with ivosidenib than with placebo (10.8 vs 9.7 months, respectively).18 OS rates at 6 and 12 months were 67% and 48%, respectively, in the ivosidenib group, compared with 59% and 38%, respectively, in the placebo group.19

The investigators used a rank-preserving structural failure time method to reconstruct the survival curve for the placebo arm, as if they had never crossed over to ivosidenib. When used, the OS for the placebo group was 6 months, which is consistent with the survival data in the active symptom control arm from the ABC-06 study.5 The median OS became statistically significant with a P value <.001.18

These data demonstrate the clinical relevance and benefit of ivosidenib in IDH1-mutated CCA and establish the role of genomic testing in this rare cancer with a high unmet need. The consensus among the participants at the summit was that the results from ClarIDHy will mandate molecular profiling of all patients with CCA.

Other Emerging Molecular Targets

The spectrum of targets in both intrahepatic and extrahepatic CCA is large and includes drugs already in the advanced stages of clinical testing. Emerging molecular targets for CCA include the mitogen-activated protein (MAP) kinase and human epidermal growth factor receptor 2 (HER2) pathways.20,21

The rationale behind targeting MAP kinase is that mutations in BRAF are frequently associated with enhanced sensitivity to MEK inhibition and may constitute a survival mechanism for mutated cells. The MAP kinase pathway appears to be active in 75% of biliary cancers.22 In vivo and in vitro data demonstrate that MEK inhibition suppresses tumor growth in patients with CCA. Expression profiling across a panel of 7 human biliary cancer cell lines showed several RAS/MAP kinase pathway components and demonstrated sensitivity to MEK inhibitors.

Selumetinib and binimetinib are oral inhibitors of MEK1/2. A small phase 2 study of selumetinib in patients with advanced biliary tract cancer reported a 12% objective response rate, with 1 patient achieving a complete response (CR).23 Among 28 patients treated with binimetinib, 1 CR and 1 partial response (PR) were recorded. Overall, 43% (12 of 28) of the patients had stable disease.24

Mutations in BRAF have been found in about 5% of biliary tract tumors and may be enriched in intrahepatic biliary tract cancers.25 ROAR was a phase 2 open-label multicenter basket study of the combination of dabrafenib plus trametinib in patients with BRAF V600E-mutated cancers.11 In the evaluable/intent-to-treat population, median PFS was 9.2 months and median OS was 11.7 months, suggesting that this MEK/BRAF inhibitor combination is a promising treatment option for this patient population.

Aberrant activation of the RAS/RAF/MAPK pathway occurs in >60% of biliary tract cancers.26 Given the pivotal role of vascular endothelial growth factor, the RAS/RAF/MAPK pathway, and platelet-derived growth factor receptor-beta in the biology of biliary tract cancers, evaluation of tyrosine kinase inhibitors (TKIs) in the second-line setting represents a rational approach to treatment.

Regorafenib has been evaluated as second-line therapy in several studies of patients with CCA.27-29 Modest ORRs of 9% to 11% were achieved, with a disease control rate of 56% to 70%, a median PFS as high as 15.6 weeks, a median OS as high as 31.8 weeks, and an 18-month OS as high as 35%.27-29 With regorafenib plus gemcitabine/oxaliplatin combination therapy, improvements were reported with ORRs of 40%, median PFS of 11 months, and median OS of 28+ months.27-29

Abnormal HER2 activation is known to result in tumor growth. In patients with gallbladder cancer, HER2 mutation/amplification has a prevalence rate of approximately 14%, which decreases to 5% to 7% in patients with CCA.30

Unlike in breast cancer, however, HER2-directed therapy has not become a standard of care in gallbladder cancer because of the absence of clinical trials performed in this small patient population.

The effects of neratinib (a pan-HER TKI) alone or in combination with paclitaxel or trastuzumab have been evaluated in patients with a variety of HER2-mutant tumors, including a cohort of 20 patients with biliary tract cancers (9 with CCA, 9 with gallbladder cancer, and 2 with ampullary cancer).31 In this small subset of patients, 2 objective responses, both of which were PRs, were reported. The clinical benefit rate attributed to the treatment was 30%.31

“Looking at comutations, as was described with FGFR inhibitors, is equally important with targeted therapies,” noted an audience member. “To make treatment more successful, we’ll probably need combination therapies, because there is a low percentage of responses with monotherapy and the responses are not durable.”

Using tissue NGS and blood cfDNA, several simultaneous molecular alterations have been discovered with IDH1 mutations in CCA, many of which are potentially targetable for cancer therapies. These comutations may help to elucidate some of the resistance to IDH1 inhibitors.

Although alterations in DNA damage response (DDR) pathways are not highly prevalent in IDH1-mutant cancers, when they do exist, they may be targets for poly (adenosine diphosphate [ADP]-ribose) polymerase or ataxia telangiectasia and Rad3-related inhibitors. A relatively large representation of alterations involves activating the cell cycle, which may be targeted in combinations that include CDK4/6 inhibitors. In addition, PI3K activation through the PIK3CA mutation is observed with IDH1 mutations, which potentially may be targeted with the addition of the PI3K inhibitors. Activation of the MAPK pathway, either through BRAF mutation or K/NRAS mutation, is a potential target for MEK inhibition with or without BRAF inhibition.

Some chemotherapeutic agents may exhibit an effect that can be targeted. For example, FF-10502-01, which blocks DNA synthesis, is a novel pyrimidine nucleoside analogue of gemcitabine that is currently in development. The agent exerts cytotoxic activity by inhibiting DNA polymerase alpha during DNA synthesis. FF-10502-01 can be incorporated by DNA repair polymerase beta and translesional synthesis polymerases (eg, POLK), and can thus terminate DNA synthesis during DDR. Its efficacy in patients with heavily pretreated CCA, in which all participants received prior gemcitabine, was evaluated in a phase 2 expansion of a phase 1 study, with an ORR of 11%. Responses with FF-10502-01 have lasted for as long as 12 months.32

Adverse Events Associated with Targeted Therapies

Newer targeted therapies have been reported to be safe and well tolerated. The toxicity profiles of these agents are clearly less burdensome than those associated with platinum-based chemotherapy. Given the chronicity of therapy with targeted agents, however, low-grade toxicities do matter and may necessitate intervention.

FGFR inhibition

Unique toxicities associated with FGFR inhibitors as a class include hyperphosphatemia, fatigue, stomatitis, alopecia, decreased appetite, dry skin, dry mouth, and nail toxicity (Figure 2).33 Although most of the toxicities are grade 1 or 2, overall, 63.2% of the patients receiving infigratinib therapy require dose reduction and 77% require dose interruption. Nail toxicities also result in dose delay.34

Figure 2

Hyperphosphatemia can occur with the use of FGFR inhibitors, and its mechanism is not well understood. It is thought that the FGF ligand FGF23, which is secreted by the osteocytes, is responsible for phosphate and vitamin D homeostasis. Management of hyperphosphatemia requires dose adjustment or interruption in 42.6% of patients, along with additional medication and an intermittent dosing strategy.35 Diet must be modified to eliminate foods high in phosphates35 (ie, dairy, meat, nuts, processed food). With grade 3 hyperphosphatemia, the dose of FGFR inhibitor should be reduced and phosphate levels should be rechecked frequently. With grade 4 hyperphosphatemia, the dose of FGFR should be interrupted and resumed at a lower dose once the toxicity level is less than grade 2.

Although the presence of ocular toxicity with FGFR inhibition is uncommon, it is serious in nature. The rate of serous retinal detachment observed in the phase 2 study with pemigatinib was 4%.36,37 An ophthalmologic evaluation is required at baseline, again 4 to 6 weeks after initiating the FGFR inhibitor, and then as needed. For dry eye, artificial tears or lubricant at night may be necessary.

Skin toxicity is also an issue with FGFR inhibitors, with hand–foot syndrome and nail toxicity being the most bothersome. Nail toxicity can be functionally limiting and may require dose modification.

IDH inhibition

The experience with ivosidenib in clinical trials is that the agent is well tolerated, with fatigue, nausea, and other gastrointestinal side effects being the most frequently reported treatment-emergent adverse events (TEAEs). The most common TEAEs in the phase 3 study were ascites, an increase in bilirubin levels, anemia, and an increase in aspartate aminotransferase levels. TEAEs leading to treatment discontinuation were more common with placebo than with ivosidenib.38

Because ivosidenib is a cytochrome P450 (CYP450) inhibitor, hepatic impairment is a possible TEAE. If the agent is coadministered with a strong CYP3A4 inducer, the dose of ivosidenib should be reduced by 50%. A high-fat meal should not be administered with ivosidenib, as it can increase concentrations of the drug.

QTc prolongation with ivosidenib may be an issue in patients who are taking other medications that are known to cause QTc prolongation. An electrocardiogram performed weekly for the first 3 weeks after initiating ivosidenib and monthly thereafter is recommended.

Chorus Discussion

The landscape of CCA treatment will be changed permanently with the introduction of FGFR and IDH inhibitors, and molecular profiling will become standard, hopefully at diagnosis, the chorus members agreed. Consensus was also reached regarding the increased use of liquid biopsy, which will complement tissue-based testing.

According to the participants, the use of cfDNA outside of clinical trials, for the purpose of data collection and treatment decisions, should not yet be routine. Although the utilization of cfDNA as a research tool that is intended to create more effective therapies is valuable, the clinical decision would probably not be affected until further research validates this use. Additionally, the extra cost incurred with the use of cfDNA cannot be justified at this time. Some of the mutations identified are subclonal and may not be leading to treatment resistance, stated one of the participants. Because the genetic profile of a tumor changes >60% of the time in a patient receiving targeted therapy, one scenario in which the use of cfDNA might be indicated in clinical practice is the patient who is receiving targeted therapy and has a good overall prognosis, the presenter argued.

Since targeted therapies are here to stay, the management of toxicities associated with these treatments needs to move forward and involve other disciplines, such as dietitians, ophthalmologists, and dermatologists, among others, the participants agreed. The involvement of these other disciplines may be more challenging in the community or even in mid-level hospital centers, however, where many patients are treated. In the National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial,39 for example, the response rate to immunotherapy among patients with MSI-high cancers correlated with toxicities, as therapy was being discontinued in patients who were experiencing toxicity because of the lack of availability of a nephrologist or a hepatologist for referral. Even when available, community dermatologists may not be comfortable managing the symptoms associated with targeted therapies (eg, nail toxicity) and immunotherapies.

“As more targeted therapies become available, it is going to be important to educate our primary colleagues…our subspecialty colleagues…because it’s a team-based effort,” noted one of the chorus members.

“One of the things that will be critical for patients receiving FGFR inhibitors is to make sure that the side effects are managed appropriately [in phase 3 clinical trials and at large institutions involved], so that people don’t discontinue experimental therapy prematurely,” noted another participant.

Immunotherapy: The New Frontier?

The tumor microenvironment creates obstacles and opportunities for the use of immunotherapy. Hot tumors are MSI-high, containing many immune infiltrates and cytotoxic T-cells. Cold tumors have a dearth of immunosuppressive cells. Biliary tract tumors are considered cold, since they are populated with myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T-cells, with an absence of cytotoxic T-cells and natural killer cells.

Programmed death-ligand 1 (PD-L1) expression is an elusive biomarker, because no correlation has been demonstrated between PD-L1 expression and response to immunotherapy across different types of cancer. The tumor versus stromal component of PD-L1 expression is one caveat to quantifying PD-L1 expression and the stain used to identify PD-L1 positivity is another. A third caveat is the level of PD-L1 expression that is used to define a PD-L1–positive tumor.

The KEYNOTE-028 and KEYNOTE-158 trials of pembrolizumab in patients with biliary tract cancer demonstrated modest ORRs of 13.0% and 5.8%, respectively.40 Whereas KEYNOTE-028 enrolled PD-L1–positive patients, KEYNOTE-158 was a trial of patients who were not selected on the basis of PD-L1 expression. Given low response rates, single-agent checkpoint inhibition would appear to offer little advantage at a high cost in patients with biliary tract cancer.

In a phase 1 study of patients with biliary tract cancer, dual therapy with durvalumab and tremelimumab was associated with a median OS of 10.1 months.41 The rate of TEAEs with combination therapy was 82%, with grade ≥3 TEAEs reported in 23% of these patients.41 The use of chemotherapy may enhance the effect of immunotherapy by causing immunogenic presentation of antigens or tolerance through cell death, whether apoptotic, autophagic, or necrotic.

To capture patients before the end stages of their disease, 3 ongoing studies (Bilt-01, Bilt-02, and Bilt-03) are exploring the use of immunotherapy in earlier settings in biliary tract cancer. Moreover, efforts to optimize the tumor–stromal interaction include the use of a colony-stimulating factor-1 receptor antibody, which recruits myeloid cells to the tumor microenvironment, stabilizes the number of tumor-associated macrophages, and suppresses tumor immunity.

Another combination approach uses transforming growth factor (TGF)-beta bispecific inhibition combined with anti–PD-L1 antibody. M7824 is a bispecific monoclonal antibody that sequesters TGF-beta and inhibits PD-L1 expression. The initial clinical trial of this combination therapy was evaluated in 30 patients with biliary tract cancer and generated an overall response rate of 20%.42 More impressive is the fact that the median duration of response was not reached, and the median OS was 12.7 months.42

Granulocyte-macrophage colony-stimulating factor, a cytokine growth factor that may promote CD8-positive T-cell infiltration into tumors and tumor antigen-specific T-cell expansion, has been studied in combination with pembrolizumab in pretreated patients, inducing an ORR of 19% and a median OS that has not yet been reached.43

MEK inhibition in combination with an anti–PD-L1 antibody is being investigated in a trial of patients with unresectable CCA. Paired core tumor biopsies are a key component of this study, in which changes in immune cell subsets and markers of immune exhaustion will be assessed in MEK-inhibitor–treated versus non-MEK inhibitor–treated CCA patient samples.

Whereas MEK inhibition in only the tumor can stop uninhibited tumor cell growth, whole body MEK inhibition is problematic because it may have both positive and negative effects on the immune system. An MEK inhibitor may cause changes in the tumor cells that render them more visible to the immune system and thus easier to attack. MEK inhibitors may have a direct negative impact on immune cells, however, specifically impairing the activation of T-cells.

Histone deacetylase (HDAC) inhibitors and DNA methyltransferase inhibitors are epigenetic modulators with immunomodulatory potential in patients with CCA. They function with respect to posttranslational modifications of chromatin and work in concert to determine whether a given gene is expressed. Both HDAC inhibitors and DNA methyltransferase inhibitors can upregulate many features to elicit an immune response. They increase major histocompatibility complex class expression, cytotoxic T-cell infiltration, and costimulatory molecule expression, while decreasing the expression of immunosuppressive cells.


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