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Role of immune checkpoint inhibitors in gastrointestinal cancer treatment

  • Jakob Michael Riedl
  • Michael Stotz
  • Armin GergerEmail author
Open Access
short review
  • 137 Downloads

Summary

In this short review we aim to summarize the role current clinical role of immunotherapy in particular of immune checkpoint inhibition in gastrointestinal malignancies and highlight the most important clinical trials.

Keywords

Immunotherapy Colorectal cancer Esophageal cancer Gastric cancer Microsatellite instability 

Abbreviations

CTLA‑4

Cytotoxic T‑lymphocyte-associated protein 4

GEJ

Gastroesophageal junction

HCC

Hepatocellular carcinoma

mCRC

Metastatic colorectal cancer

mmr

Mismatch repair

MSI

Microsatellite instability

MSI h

High microsatellite instability

PC

Pancreatic cancer

PC

Pancreatic cancer

PD-1

Programmed death

PD-L1

Programmed death ligand 1

ORR

Objective response rate

OS

Overall survival

VEGF

Vascular endothelial growth factor

Introduction

Accounting for around 4 million deaths per year worldwide, gastrointestinal malignancies are responsible for 40% of all cancer associated deaths [1]. Although major progress has been made in recent decades by optimizing cytotoxic chemotherapy and implementing targeted therapy in gastrointestinal cancer treatment there is still need for novel treatment options. The biggest breakthrough in oncology during recent years has been achieved by the Nobel Prize winning invention of cancer immunotherapy [2]. The clinical implementation of immune checkpoint inhibitors has led to remarkable progress of treatment response and disease outcome in various cancer entities such as melanoma, non-small cell lung cancer and renal cell carcinoma [3, 4, 5]. In gastrointestinal malignancies limited response rates have been observed in preliminary trials with immune checkpoint inhibitors. Still, recent trials focusing on selected subgroups of gastrointestinal cancer patients have reported promising results. Most relevant trials are listed in Table 1.

Esophageal and gastric cancer

Disease outcome and treatment response to cytotoxic chemotherapy is limited in both metastatic or locally advanced esophageal and gastric cancer. Thus, great hope lies in the implementation of immunotherapy for those highly aggressive cancer entities. The first promising results originated from the KEYNOTE-012 and KEYNOTE-028 trial, which evaluated the efficacy of the programmed death 1 (PD‑1) inhibitor pembrolizumab in programmed death ligand 1 (PD-L1) positive, pretreated, advanced solid tumor patients. KEYNOTE-012 included 36 patients with advanced adenocarcinoma of the stomach or gastroesophageal junction (GEJ). The objective response rate (ORR) was 22% and the median overall survival (OS) 11.4 months. Grade 3 or 4 treatment related adverse events were observed in 13% [6]. In the KEYNOTE-028 trial similar response rates and safety profiles could be shown for squamous cell and adenocarcinomas of the esophagus [7]. Based on the encouraging results with pembrolizumab from phase I trials several phase III trials were initiated in esophageal and gastric cancer. In the KEYNOTE-061 phase III trial pembrolizumab was compared to paclitaxel as second line treatment in a cohort of 592 patients with gastric or GEJ cancer. Pembrolizumab did not meet its primary endpoint of superior OS and progression-free survival (PFS), however showed more durable response and a better safety profile than paclitaxel. Further, subgroup analysis suggests a greater treatment benefit for pembrolizumab in patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 and in patient whose tumors have high levels of microsatellite instability (MSI high) or high levels of PD-L1 expression. (PD-L1 combined prognostic score >10) [8].

In addition to pembrolizumab valid data exist for the PD-1 inhibitor nivolumab. The CheckMate-032 trial evaluated the treatment efficacy and safety of nivolumab alone or in combination with the cytotoxic T‑lymphocyte-associated protein 4 (CTLA‑4) antibody ipilimumab in chemotherapy refractory patients with esophagogastric cancer irrespective of their PD-L1 expression status. Combination immunotherapy resulted in an ORR of 24% and a 12-month OS rate of 39% [9]. In 2017, preliminary results from the ATTRACTION-2 trial, a phase III trial which included patient with heavily pretreated advanced gastroesophageal cancer who either received nivolumab or placebo were presented. Nivolumab lead to a statistically significant prolonged median OS and higher ORR; however the survival benefit of 1.1 months was limited [10].

Colorectal cancer

In colorectal cancer only a small subgroup of patients (MSI-high) seem to benefit from immune checkpoint inhibition. Therefore, great efforts have been made to identify predictive biomarkers for treatment response. A preliminary phase II trial investigating the effect of pembrolizumab in patients with pretreated metastatic colorectal cancer (mCRC) showed high response rates in mismatch repair (MMR) deficient tumors, whereas MMR proficient cancers showed no treatment effect at all [11]. Accounting for around 5% of all CRC MMR deficient tumors come along with a high mutational burden and neoantigen load both of which have been shown to be associated with improved response rates to anti PD-1/PD-L1 blockade [12]. Based on the encouraging findings from the NCT01876511 trial several phase II and III trials with pembrolizumab in MMR deficient mCRC patients have been started. At the 2018 ASCO meeting preliminary results from the KEYNOTE-164 trial were presented. This phase II trial evaluated the efficacy of pembrolizumab in MSI high mCRC patients who had progressed on at least one line of previous chemotherapy. An ORR of 32% and a 12-month PFS rate of 41% indicates that pembrolizumab is also effective as second line therapy in this patient subgroup [13]. Another ongoing phase II trial investigates the efficacy of either nivolumab alone or in combination with the CTLA-4 inhibitor ipilimumab in MMR deficient mCRC patients. Preliminary results of the second or further line cohort of the CheckMate-142 trial demonstrated an ORR of 31% and a 12-month OS rate of 73% for single nivolumab treatment and an ORR of 55% and a 12-month OS rate of 85% for combination immunotherapy [14]. As first line treatment the ORR and disease control rate (DCR) for nivolumab plus ipilimumab were 60% and 84% respectively, indicating that this combination may represent a new treatment option for MMR deficient mCRC patients. The ongoing KEYNOTE-177 phase III trial is evaluating efficacy and safety of pembrolizumab versus standard of care as first line treatment in MMR deficient mCRC patients. First results are eagerly awaited and can be expected in 2019 [15].

In MMR proficient cancers which account for the vast majority of CRC immunotherapy has been mostly disappointing [11]. It is therefore of high scientific and clinical interest to find ways to make MMR proficient tumors more susceptible to immunotherapy. One approach is to combine immunotherapy with other immune modifying drugs such as vascular endothelial growth factor (VEGF) or MEK inhibitors, which have been shown to enhance T‑cell infiltration and upregulation of MHC in preclinical studies [16]. However, up to the present these combinations failed to result in superior disease outcome in randomized trials. In the COTEZO IMblaze-370 trial the combination of the PD-L1 inhibitor atezolizumab with the MEK inhibitor cobimetinib did not meet its primary endpoint of prolonged OS compared to regorafenib alone in chemotherapy resistant mCRC patients.

In addition, preliminary data of the MODUL trial comparing fluoropyrimidine plus bevacizumab plus atezolizumab versus fluoropyrimidine plus bevacizumab as 1st line maintenance therapy failed to show a survival benefit for the immunotherapy combination regiment [17]. Trials combining radiation therapy with immune checkpoint inhibitors to induce an abscopal effect are ongoing.

HCC

In advanced hepatocellular carcinoma (HCC) both nivolumab and pembrolizumab have demonstrated clinical efficacy and tolerable safety profiles in patients previously treated with sorafenib the current standard of care. The CheckMate-040 trial showed an ORR of 20% for patients treated with nivolumab with a 25% rate of grade 3/4 adverse events [18]. In the KEYNOTE-224 trial an ORR of 17% and a grade 3/4 adverse event rate of 25% was recorded for pembrolizumab [19]. Based on these encouraging findings several phase III trials comparing immune checkpoint inhibitors with sorafenib as first line therapy are ongoing; however results are still pending.

Pancreatic cancer

Various approaches of immunotherapy including the application of checkpoint inhibitors, cancer vaccines, oncolytic viruses and adoptive T cell therapy have been evaluated in the treatment of advanced pancreatic cancer (PC). However, as of yet the benefit of immunotherapy in PC has been very limited. The TeloVac trial was the largest phase III trial that compared gemcitabine with the telomerase peptide vaccine GV1001 versus gemcitabine alone in advanced pancreatic cancer patients. Unfortunately, chemoimmunotherapy did not result in a statistically significant survival benefit and therefore did not meet its primary endpoint [20].

Biliary tract cancer

Preliminary results of the KEYNOTE-158 study investigating the efficacy and safety profile of pembrolizumab in advanced biliary tract cancer were presented at this year’s ESMO conference. At data cut off an ORR of 5.8% could be shown indicating that immune checkpoint inhibition is effective in a small subgroup of biliary tract cancer patients [21]. Further studies are needed to verify the role of immunotherapy in this cancer entity.

Conclusion

Immunotherapy has been proved to be effective in various gastrointestinal malignancies, however careful patient selection is needed to increase treatment efficacy. In esophageal and gastric cancer patients with high PD-L1 expression and MSI high tumors seem to have the greatest benefit, which in our opinion justifies the off-label application of immune checkpoint inhibitors for this subgroup in the routine clinical setting. In 2017 the FDA approved pembrolizumab and nivolumab for MMR deficient mCRC patients after prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Based upon results from the CheckMate-142 trial with objective response rates of up to 50% ipilimumab has gained accelerated FDA approval to be used alongside nivolumab as second line treatment in MSI high or MMR deficient mCRC. Further, in September 2017 the FDA approved nivolumab for the treatment of patients with HCC who have progressed on sorafenib. The role of first-line immune checkpoint inhibition as compared with sorafenib in advanced HCC is under study for which results are expected in late 2018. In pancreatic and biliary tract cancer up to date no immunotherapy drugs have entered routine clinical practice however several promising trials are ongoing (Table 2).

Over recent years immunotherapy has constantly gained momentum in the treatment of gastrointestinal malignancies. Still, further research is needed to find ways to make immunologically cold tumors hot and to identify valid predictive biomarkers which help to match patients with the best available therapy whilst sparing others from unnecessary treatment side effects.
Table 1

Selection of relevant immunotherapy trials in GI cancers

Trial

Phase

Entity

Setting

Biomarker

Treatment

Outcome

Esophageal and gastric cancer

KEYNOTE 028

Ib

Esophageal, GEJ

Advanced stage, CTX resistant

PD-L1 +

Pembrolizumab

ORR 30%

KEYNOTE 012

Ib

Gastric, GEJ

Advanced, No line limit

PD-L1 +

Pembrolizumab

ORR 21%

CheckMate 032

I/II

Gastric, esophageal, GEJ

Advanced, CTX resistant

All comer

Nivolumab vs Nivo1/Ipi3 vs Ipi3/Nivo 1

ORR 12% vs 24% vs 8%

KEYNOTE 061

III

Gastric, GEJ

Advanced, 2nd line

PD-L1 +

Pembrolizumab vs Paclitaxel

OS 9.1 vs 8.3 (CPS >10 10.4 vs 8)

ATTRACTION 02

III

Gastric, GEJ

Advanced, ≥3rd line

All comer

Nivolumab vs placebo

OS 5.26 vs 4.14

KEYNOTE 062

III

Gastric, GEJ

Advanced, 1st line

PD-L1 +, HER −

Pembrolizumab vs Pembrolizumab + cisplatin + 5FU vs cisplatin + 5FU

Study ongoing

KEYNOTE 181

III

Esophageal, GEJ

Advanced, 2nd line

All comer

Pembrolizumab vs investigator choice

Study ongoing

CheckMate 648

III

Squamous cell esophageal

Advanced, 1st line

All comer

Nivolumab + Ipilimumab vs Nivolumab + 5FU/Cisplatin vs 5FU/Cisplatin

Study ongoing

CheckMate 577

III

Lower esophageal, GEJ

Adjuvant

All comer

Nivolumab vs placebo

Study ongoing

Colorectal cancer

NCT01876511

II

Metastatic carcinoma

Advanced, CTX resistant

dMMR, pMMR

Pembrolizumab

ORR 40% (dMMR) vs 0% (pMMR)

KEYNOTE 164

II

Colorectal

Advanced, ≥2nd line

MSI high

Pembrolizumab

ORR 32%

CheckMate 142

II

Colorectal

Advanced, ≥1st line

MSI high

Nivolumab + Ipilimumab

ORR 60% (1st line), ORR 55% (≥2nd line)

KEYNOTE 177

III

Colorectal

1st line

dMMR, MSI high

Pembrolizumab

Ongoing

COTEZO IMblaze 370

III

Colorectal

CTX resistant

All comer

Atezolizumab + cobimetinib vs atezolizumab vs regorafenib

OS 8.9 vs 7.1 vs 8.5

MODUL trial

II

Colorectal

Advanced, 1st line maintainance

BRAF wildtype

FP/bevacizumab + atezolizumab vs FP/bevacizumab

PFS 7.1 vs 7.4

COMMIT

III

Colorectal

Advanced, 1st line

dMMR

Atezolizumab vs FOLFOX/bevacizumab + atezolizumab vs FOLFOX/bevacizumab

Ongoing

ATOMIC

III

Colorectal

Adjuvant, stage III

dMMR, MSI high

FOLFOX + atezolizumab vs FOLFOX

Ongoing

NCT03104439

II

Colorectal, pancreatic

Advanced

All comer

Nivolumab + ipilimumab + radiation therapy

Ongoing

Hepatocellular carcinoma

CheckMate 40

I/II

HCC

Advanced

All comer

Nivolumab

ORR 20%

KEYNOTE 224

II

HCC

Advanced, 2nd line

All comer

Pembrolizumab

ORR 17%

CheckMate 559

III

HCC

Advanced, 1st line

All comer

Nivolumab

Ongoing

Imbrave

III

HCC

Advanced, 1st line

All comer

Atezolizumab + bevacizumab vs sorafenib

Ongoing

HIMALAYA

III

HCC

Advanced, 1st line

All comer

Durvalumab ± tremelimumab vs sorafenib

Ongoing

Pancreatic cancer

NCT00729664

I

Pancreatic

Advanced, chemotherapy resistant

All comer

Anti PD L1 antibody

ORR 0%

TELOVAC

III

Pancreatic

Advanced, 1st line

All comer

Gemcitabine/capecitabine + GV1001 (sequential or concurrent) vs Gemcitabine/capecitabine

OS 6.9, 8.4 vs 7.9

AM0010

I

Pancreatic

Advanced, ≥2nd line

All comer

AM0010 + FOLFOX

ORR 16%, DCR 79%

SEQUOIA

III

Pancreatic

Advanced, 2nd line

All comer

AM0010 + FOLFOX vs FOLFOX

Ongoing

Biliary tract cancer

KEYNOTE 28

I

Biliary tract

Advanced

PDL1 +

Pembrolizumab

ORR 17%

KEYNOTE 158

II

Biliary tract

Advanced, chemotherapy resistant

All comer

Pembrolizumab

ORR 5%

NCT03260712

II

Biliary tract

Advanced, 1st line

All comer

Pembrolizumab + gemcitabine + cisplatin

Ongoing

GI gastrointestinal, GEJ gastroesophageal junction, CTX chemotherapy, ORR objective response rate, OS overall survival, PFS progression free survival, CPS combined prognostic score, PD-L1 programmed death ligand 1, HER human growth factor receptor, dMMR mismatch repair deficient, pMMR mismatch repair proficient, MSI microstellite instability, FP fluoropyrimidine, HCC hepatocellular cancer

Table 2

Clinical practice points

Immunotherapy is effective in a subgroup of GI cancer patients

Accurate patient selection is critical

MSI H and PDL 1 positive tumors seem to be most susceptible

Nivolumab and pembrolizumab FDA approved for 2nd line MSI h mCRC

Ipilimumab FDA approved alongside nivolumab in 2nd line MSI h mCRC

Nivolumab FDA approved for 2nd line HCC

Identification of further predictive biomarkers needed

Notes

Funding

Open access funding provided by Medical University of Graz.

Compliance with ethical guidelines

Conflict of interest

J.M. Riedl, M. Stotz, and A. Gerger declare that they have no competing interests.

Ethical standards

No approval by an ethics committee was needed for this review. No informed consent was applicable since this manuscript does not contain any patient data.

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Copyright information

© The Author(s) 2019

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  • Jakob Michael Riedl
    • 1
  • Michael Stotz
    • 1
  • Armin Gerger
    • 1
    • 2
    Email author
  1. 1.Division of Clinical Oncology, Department of Medicine, Comprehensive Cancer Center GrazMedical University of GrazGrazAustria
  2. 2.Center for Biomarker Research in MedicineGrazAustria

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