Syma Iqbal, MD
The second-line treatment of gastric and gastroesophageal junction (GEJ) cancers has shifted considerably in the last few years, due in part to the addition of immunotherapy for select subgroups of patients.
In a presentation during the 2018 OncLive®
State of the Science Summit™ on Gastrointestinal Cancers, Syma Iqbal, MD, associate professor in the Division of Oncology and assistant program director of the Oncology Department’s Fellowship Program, University of Southern California (USC) Norris Comprehensive Cancer Center, discussed current treatment approaches for patients with gastric cancer, highlighting recent and upcoming trials of immunotherapy.
For the frontline treatment of patients, fluoropyrimidines with platinum-based therapy are the widely accepted standard of care and are often the backbone of clinical trials. There are triplet therapies that have been approved for the treatment of metastatic disease, said Iqbal, but they generally come with increased toxicities, making doublets the favored approach. However, in the second- and third-line settings, there are multiple new treatment options. Iqbal said that the arena is now getting a little bit crowded, as both targeted agents and immunotherapies are entering the landscape.
Chemotherapy in the form of docetaxel, paclitaxel, and irinotecan has been the historically preferred regimen, but in treatment-naïve patients with metastatic gastric/GEJ cancers, the addition of ramucirumab (Cyramza) to first-line chemotherapy has shown a significant reduction in the risk of disease progression or death. Although it has not shown an improvement in overall survival (OS), it does not add any additional safety issues, Iqbal explained.
Most of the excitement in this field has been with immunotherapy, Iqbal said. The effects of immunotherapy have been observed in microsatellite instability-high (MSI-H) tumors, which is thought to be due to their tumor mutational burden (TMB).
PD-L1 and PD-L2 expression has also been observed in gastric cancer. In a 2014 Nature paper published by The Cancer Genome Atlas, findings showed that patients who had MSI-H tumors, as well as tested positive for Epstein-Barr virus, expressed PD-L1 and PD-L2.1
These are now the subsets of patients enrolled in immunotherapy clinical trials, Iqbal said.
The way in which PD-L1 expression is evaluated in gastric cancer has changed, and is now determined by combined positive score (CPS). Initially, when patients were evaluated for PD-L1, only the tumor cells were being studied. CPS consists of the tumor cells, lymphocytes, and macrophages, Iqbal explained, and a specimen is considered to have positive PD-L1 expression if CPS is ≥1.
One of the first trials of immunotherapy in gastric cancer presented was the randomized phase III study of nivolumab (Opdivo) as salvage treatment after second- or later-line chemotherapy in patients with advance gastric/GEJ cancer.2
This Asian study randomized patients to 3 mg/kg of nivolumab or placebo. The primary endpoint was OS. There was superiority in the nivolumab arm, with a median OS of 5.32 months (95% CI, 4.63-6.41) versus 4.14 months (95% CI, 3.42-4.86) in the placebo arm (HR, 0.63; P
<.0001). The 12-month OS rate was 26.6% (95% CI, 21.1-32.4) with nivolumab compared with 10.9% (95% CI, 6.2-17.0) in the placebo arm.
"The response rate was 11%, and we will see this number over and over again—in that response rates with these agents are in the 12% to 15% range," said Iqbal.
In the CheckMate-032 trial of patients with advanced or metastatic gastric/esophageal/GEJ cancer, nivolumab monotherapy and 2 arms of differing doses of nivolumab plus ipilimumab (Yervoy) were evaluated. It was not meant to be a 3-way comparison though, Iqbal noted. The data presented showed a similar progression-free survival (PFS), but numerically, there was a PFS benefit for nivolumab at 1 mg/kg plus ipilimumab 3 mg/kg.3
OS and overall response rate (ORR) was also numerically better for that dosage of the combination, Iqbal said.
KEYNOTE-012 was the first study to enrich the population for PD-L1–positive patients, which were defined by a CPS score ≥1. It was an evaluation of pembrolizumab (Keytruda) in patients with recurrent of metastatic adenocarcinoma of the stomach or GEJ. ORR by central review for the enriched population was 22.2% (95% CI, 10.1-39.2).4
The phase II KEYNOTE-059 study evaluated pembrolizumab for advanced gastric/GEJ adenocarcinoma. This was a multicohort study that enrolled 259 patients with 2 or more prior lines of treatment. Of those enrolled, 143 had PD-L1–positive tumors with a CPS of ≥1. For these patients, ORR was 13.3% (95% CI, 8.2%-20.0%), including a complete response rate of 1.4% and a partial response rate of 11.9%.5