Role of Immunotherapy May Expand in Gastric/GEJ Cancers

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

These findings led to the 2017 FDA approval of pembrolizumab for the treatment of patients with PD-L1—positive recurrent or advanced gastric/GEJ adenocarcinoma who have received 2 or more lines of chemotherapy, including fluoropyrimidine- and platinum-containing chemotherapy, and, if appropriate, HER2/neu-targeted therapy.

Nivolumab is approved in Asia for this population, while pembrolizumab is approved in the United States, noted Iqbal.

KEYNOTE-061 attempted to bring immunotherapy into the second-line setting with a randomized trial for patients who had failed first-line chemotherapy. With a primary endpoint of OS and PFS in the CPS ≥1 population, the study compared pembrolizumab with paclitaxel. Patients were stratified by PD-L1 status.

Findings showed that pembrolizumab did not reach the prespecified level of statistical significance for improving OS over paclitaxel as a second-line therapy for this population. Although, Iqbal noted that in the subgroup analysis that looked at CPS scores—patients who were not expressers versus those who had a CPS score of ≥1 versus those who had a CPS of ≥10—the curves separated significantly, and there appeared to be a greater benefit in those patients with greater expression of PD-L1.

"Clearly, pembrolizumab had activity in the MSI-H patients, but it was disappointing that there were no significant differences in terms of survival for the patients who received pembrolizumab over paclitaxel," said Iqbal. "Data support further exploration to identity patients likely to benefit from pembrolizumab monotherapy and ongoing development of pembrolizumab-based combination therapy."

Regarding immunotherapy in the third-line setting, pembrolizumab is being evaluated in combination with the Fc-optimized monoclonal antibody margetuximab in a phase Ib/II clinical trial of patients with advanced HER2-positive GEJ/gastric adenocarcinoma (NCT02689284).

Additionally, there are several ongoing clinical trials looking at first-line combinations.

"At USC, we have the [Bristol-Myers Squibb] trial looking at FOLFOX plus nivolumab versus FOLFOX," said Iqbal. "We are awaiting data in the first-line setting with pembrolizumab combinations, and then there is maintenance therapy with immunotherapy that is pending. There is a lot to come, so there is a lot banking on immunotherapy being active in these first-line or maintenance settings."

References

1. The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202-209. doi: 10.1038/nature13480.
2. Kang YK, Satoh T, Ryu MH, et al. Nivolumab (ONO-4538/BMS-936558) as salvage treatment after second or later-line chemotherapy for advanced gastric or gastroesophageal junction cancer (AGC): a double-blinded, randomized, phase III trial. J Clin Oncol. 2017;35(suppl 4S; abstr 2). doi: 10.1200/JCO.2017.35.4_suppl.2.
3. Janjigian YY, Ott PA, Calvo E, et al. Nivolumab ± ipilimumab in pts with advanced (adv)/metastatic chemotherapy-refractory (CTx-R) gastric (G), esophageal (E), or gastroesophageal junction (GEJ) cancer: CheckMate 032 study. J Clin Oncol. 2017;35(suppl; abstr 4014). doi: 10.1200/JCO.2017.35.15_suppl.4014
4. Muro K, Chung HC, Shankaran V, et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol. 2016;17(6):717-726. doi: 10.1016/S1470-2045(16)00175-3.
5. Fuchs CS, Doi T, Jang RW-J, et al. KEYNOTE-059 cohort 1: Efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer. J Clin Oncol. 2017;35 (suppl; abstr 4003). doi: 10.1200/JCO.2017.35.15_suppl.4003.