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Promising data on immunotherapy in upper GI cancer

Although immunotherapy drugs are currently not approved for the use in GI cancers, we are facing the rapid emergence of new and promising data in upper gastrointestinal malignancies, specifically in hepatocellular carcinoma, gastro-esophageal cancer and pancreatic cancer.

In hepatocellular carcinoma (HCC),

a phase 1/2 study (CheckMate 040)1 showed promising activity and a manageable safety profile in patients with advanced HCC. Updated survival and duration of response data were presented in both sorafenib-naïve and –experienced patients.2

About the study

For patients with advanced hepatocellular carcinoma, sorafenib is the only evidence-based systemic treatment option. However, outcomes remain poor (median OS 10.7 months). The presence of tumor-infiltrating lymphocytes expressing PD-1 in hepatocellular carcinoma lesions and their correlation with outcome suggest that immunotherapeutic approaches might be useful in this setting. The phase 1/2, open-label dose escalation and expansion trial CheckMate 040 included 262 patients with histologically confirmed advanced HCC with or without HCV or HBV infection. Previous sorafenib treatment was allowed. Patients received intravenous nivolumab every 2 weeks (Q2W). In the dose-escalation phase, patients were enrolled into three cohorts on the basis of hepatocellular carcinoma aetiology (without viral hepatitis, HCV-infected, and HBV-infected). Across these cohorts, sequential patient groups received nivolumab doses from 0.1 to 10 mg/kg until a confirmed complete response was achieved or until disease progression or unacceptable toxicity occurred. In the dose expansion phase patients from 4 cohorts (sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected) received 3 mg/kg nivolumab Q2W. Primary endpoints were safety/tolerability during the escalation phase and ORR in the extension phase.

Updated results

After a median follow-up of 12.9 months, ORR was 23 % in sor-naïve patients (n = 80, with 44 % of responses ongoing) and 16-19 % in sor-experienced patients (n = 182). Responses occurred regardless of etiology or tumor cell PD-L1 expression. Median duration of response was not reached in sor-naïve group and 17 months in sor-pretreated patients. The safety profile was consistent with that reported in other tumor types.

With these and similar promising results emerging we will likely see an approval for immunotherapeutic agents that could profoundly change the treatment of HCC in the near future. 


  1. El-Khoueiry AB et al., Nivolumab in Patients With Advanced Hepatocellular Carcinoma (CheckMate 040): An Open-Label, Non-Comparative, Phase 1/2 Dose Escalation and Expansion Trial. Lancet 2017; DOI: 10.1016/S0140-6736(17)31046-2
  2. Crozenci TS et al., abstract 4013: Nivolumab (nivo) in sorafenib (sor)-naive and -experienced pts with advanced hepatocellular carcinoma (HCC): CheckMate 040 study.

Gastric and esophageal junction cancers (GEJ),

represent a major global cancer burden and despite improvements in outcomes with trastuzumab and ramucirumab the prognosis for advanced disease remains poor, with a median overall survival of 1 year. Expression of the PD-1 ligands PD-L1 and PD-L2 has been reported in about 40 % of patients with E/GEJ cancer and is associated with a poor prognosis.

Adjuvant nivolumab in E/GEJ-cancer

Background: Currently, no effective adjuvant SOC is available after chemoradiotherapy (CRT) followed by resection for pts with E/GEJ cancer. In the phase 3 trial CheckMate 032 the PD-1 inhibitor nivolumab demonstrated an OS benefit vs. placebo, resulting in a 37 % reduction in the risk of death and double the OS rate at 12 months (27% vs 11%) in patients with advanced gastric (G)/GEJ cancer refractory to ≥ 2 lines of chemotherapy.1 These results indicate that nivolumab could be a new standard of care (SOC) for pts with heavily pretreated advanced G/GEJ cancer and provide a strong rationale to explore nivolumab in earlier lines of treatment for G/E/GEJ cancer.

About the study: The double-blind, phase 3 trial CheckMate 5772 will evaluate nivolumab as an adjuvant therapy for patients with resected E/GEJ cancer. An estimated 760 pts aged ≥ 18 years with stage II/III E/GEJ cancer are randomized to receive nivolumab or placebo. Prior to randomization, patients must have completed preoperative CRT followed by surgery and been diagnosed with residual pathologic disease. Primary endpoints are OS and disease-free survival. Other key endpoints include the OS rate at 1, 2, and 3 years as well as safety.

Better response via immune checkpoint up-regulation?

PD-1 inhibitors in metastatic gastroesophageal cancer have demonstrated response rates of approximately 25% while a majority of patients does not profit from treatment. A combination of immunotherapeutic agents with chemoradiation therapy (CRT) in earlier stage esophageal cancer may prevent metastatic disease in a greater proportion of patients. A study3 assessed the impact of CRT on the immune microenvironment and the expression patterns of multiple immune checkpoints to guide the design of future neoadjuvant clinical trials.

The majority of cancers displayed enhanced interferon γ and activated CD8+ T lymphocytes at the tumor stroma interface as well as enhanced upregulation of PD-L1 and multiple other immune checkpoints (TIM3, GITR, IDO1, LAG3, CD137, OX40 and KIR) post radiation. Animal model results indicated that PD-L1 upregulation is dose dependent and transiently elevated post radiation exposure.

Currently, a neoadjuvant trial assessing nivolumab and nivolumab/ipilimumab in combination with CRT in stage II/III operable esophageal cancer.



  1. Kang YK et al., ASCO-GI 2017, J Clin Oncol. 2017;35 (suppl 4S) [abstract 2]
  2. Kelly RJ et al., abstract TPS4131: CheckMate 577: A randomized, double-blind, phase 3 study of adjuvant nivolumab (nivo) or placebo in pts with resected esophageal (E) or gastroesophageal junction (GEJ) cancer
  3. Kelly RJ et al., abstract 4060: Magnitude and duration of immune checkpoint up-regulation and changes in the immune microenvironment post chemo-radiation (CRT) in esophageal cancer




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