Approach to Unresectable Stage 4 Gastric Adenocarcinoma - Episode 7

Systemic Therapy in PD-L1-Positive Gastric Cancer

Daniel Catenacci, MD:After a second-line therapy, there are still options for palliative therapy. Again, with the same goals that we would apply in the first-line or second-line setting and the same criteria in order to be eligible. Meaning they have a preserved performance status and are otherwise eligible to receive therapy.

From a chemotherapy standpoint, usually a patient at the time of third-line therapy has already received the platinum-based therapy and has either received a taxane-based therapy or an irinotecan-based therapy. So, in the third-line setting, naturally the alternative, whichever one they have not received yet, could be an option for therapy.

Additionally, recently there have been some positive studies, one being with immunotherapy checkpoint blockade, and that is with pembrolizumab in the third-line setting for patients who are PD-L1—positive by immunohistochemistry. That accounts for about 50% to 60% of patients who will have a positive score, and that score is defined by immunohistochemistry greater than 1% of a combined positivity score. So, it’s really critical and important to recognize that in this tumor type, the PD-L1 testing is different than say, for example, lung cancer testing, which is TPS score, or tumor positivity score. In this tumor type, its combined positivity score. So, it’s not only tumor cells, but it’s also other infiltrating monocytes and leukocytes, and it’s an aggregate score. Anything above 1% is considered positive and eligible for pembrolizumab therapy in the third-line setting. Patients who are in the third-line setting and PD-L1–positive, that is another viable option for them to help palliate their symptoms.

If the patient was PD-L1—positive, and I mentioned that we do testing early on to help plan the course of their care, we would not treat with checkpoint blockade in the first or second-line setting.

We do not treat with immune checkpoint blockade because in the second-line setting, for example, there’s been recently a negative randomized study of pembrolizumab versus standard paclitaxel; that study was overall negative. Now, there was a subset within that study of patients which had a very high level of PD-L1, higher than 10%, which accounts for, again, about 10% to 15% of the whole. That seemed to drive a benefit, but that was not the intention-to-treat of the study. It wasn’t the primary endpoint, and therefore, that’s not an approved indication. It’s just information for future exploration and study. So, in the second-line setting, that is not the standard of care.

In the first-line setting, there are a number of studies that are ongoing, and we’re awaiting the results of those studies for various checkpoint inhibitors in combination with chemotherapy, and also there’s a third arm in the studies that are with chemotherapy-free arms. So, we await those results to see if that will change other standards of care. But at the moment, the standard is to not treat with checkpoint blockade until the third-line setting for PD-L1—positive patients for microsatellite stable disease.

The one issue is with microsatellite instability, that it occurs rarely in the stage 4 setting of this disease; approximately 3%. In that case, we have an approval in the second-line setting for any solid tumor that’s MSI-high, including gastric cancer. So, in that setting for an MSI-high patient, we could use pembrolizumab in the second-line setting.

Transcript edited for clarity.


A 61-Year-Old Woman With Stage 4 Gastric Cancer

November 2017

  • A 61-year-old Hispanic woman presents to her PCP complaining of unexplained weight loss (15 lbs over 6 months), intermittent abdominal pain, fatigue, and recent onset of vomiting
  • BMI: 23
  • PE: negative for ascites
  • Notable laboratory findings:
    • HB: 11.2 g/dL
    • LFT: WNL
    • GFR: 100
    • CEA, 18.4 ng/mL
    • AFP, CA 19-9, and CA 125: WNL
  • Upper gastric endoscopy: suspicious 7.2-cm ulcerative lesion involving the pyloric region
  • Endoscopic ultrasound: suspicious lymph node
  • Biopsy: confirmed poorly differentiated, gastric adenocarcinoma, diffuse histologic subtype; positive lymph node
  • Molecular testing: HER2(-), MSI-stable, PD-L1 expression 0%
  • CT of chest, abdomen, and pelvis: showed diffuse invasion of the gastric wall and visceral peritoneum, lymph node involvement, 1 hepatic lesion
  • Staging: stage IV gastric adenocarcinoma, unresectable
  • ECOG PS 0

January 2018

  • The patient was started on fluorouracil and oxaliplatin (FOLFOX)
  • Follow up CT at 3 months showed a response to systemic therapy

July 2018

  • Patient reports increasing nausea, fatigue, and shortness of breath
  • CT imaging at 7 months shows metastatic spread to multiple suprapyloric nodes and a new liver lesion
  • LFT: mildly elevated; GFR: WNL; HB: 10.8 g/dL
  • ECOG PS 1
  • Patient is motivated to try another systemic therapy
  • Treatment with paclitaxel/ramucirumab is planned