Later Lines of Therapy in Metastatic Gastric Cancer

Salah-Eddin Al-Batran, MD: In the later-line setting in gastric cancer, when patients have received first-line and second-line treatment, we offer patients who still have good performance status cytotoxic drugs known to be efficient and non–cross-resistant to the previously used compounds. Not just docetaxel, paclitaxel, and irinotecan; it depends on the performance of the regimens that have been administered in the first- and second-line settings. Later on in the course of disease, we do use immunotherapy, which means checkpoint inhibitors. It depends on the country. In Germany, we limit the use of these drugs to patients having either MSI [microsatellite instability] or the PD-L1 overexpression. But sometimes, we use them in patients with high mutational burden. These may be the most frequent drugs used in the later-stage setting.

Kei Muro, MD: FTD/TPI [trifluridine/tipiracil or TAS-102] is one standard of care as a third-line or later-line option in advanced gastric cancer. The reason why is that trials show a strong benefit in overall survival in such lines of gastric cancer. The data are very similar to ATTRACTION-2 with nivolumab. The TAGS trial shows a hazard ratio in overall survival of 0.69. Median overall survival time of trifluridine/tipiracil is 5.7 months, quite similar to the nivolumab arm in an Asian population in ATTRACTION-2. TAGS and TAS-102, ATTRACTION-2 and nivolumab, and pembrolizumab in the United States: 3 agents are our standard of care as third-line or later-line treatment for advanced gastric cancer. TAS-102’s disease control rate is very similar to nivolumab or pembrolizumab, around 40%. However, response rate was only 4% in the TAGS trial with trifluridine/tipiracil, a little bit lower compared to ICI, or immune checkpoint inhibitors. If we hope the patient needs tumor shrinkage, we often use ICI therapy in the third-line or later-line setting.

David H. Ilson, MD, PhD: We now have defined third and fourth lines of therapy in gastric cancer, based on randomized clinical trials. Typically in the West, a patient would get up-front FOLFOX [folinic acid, fluorouracil, oxaliplatin] and second-line treatment would be paclitaxel plus ramucirumab. Third line, we could consider an irinotecan-based treatment, and now we have randomized trial data to support active treatment options in the refractory disease setting.

In the West, the most recent positive trial in the refractory disease setting was the TAGS trial, which was the randomized trial of TAS-102. This is a combination of tipiracil and a fluorinated pyrimidine in an oral preparation. Testing TAS-102 versus placebo plus best supportive care in chemotherapy-refractory gastric cancer, the TAGS trial did show a modest 2-month progression-free survival benefit for TAS-102 versus supportive care alone, and a modest 2-month survival improvement over best supportive care. Based on this study, TAS-102 is now a treatment option for patients with chemotherapy-refractory gastric cancer. Now we have an approved third- or fourth-line option for patients with advanced gastric cancer.

The other option is in patients who are PD-L1 positive. Based on the KEYNOTE-059 trial, which was a large phase 2 expansion cohort looking at pembrolizumab in esophagogastric adenocarcinoma with nearly 250 patients. A little bit more than 50% of patients did test PD-L1 positive. What this large expansion cohort showed was a meaningful response benefit for pembrolizumab in patients who were PD-L1 positive. Response rate was approaching 15%. If we took out the patients where were MSI-high, it was about a 10% to 12% response rate with a tail on the survival curve. For the patients who were PD-L1 negative, the response rate was 5% or less.

Based on this signal of activity, pembrolizumab was approved in the United States for patients with chemotherapy-refractory esophagogastric adenocarcinoma whose tumor tests PD-L1 positive. That is also an option.

How would I line up these treatments in a patient who’s progressing on first- and second-line treatment, if they’re PD-L1 positive? Third line, I would probably use pembrolizumab as the approved option. If they’re PD-L1 negative, I would probably consider use of TAS-102 as the first salvage option. The MSI-high patients also factor in here as well. We might consider earlier use of immune checkpoint inhibitors in these patients. Certainly, in an MSI-high patient who’s progressing on first- and second-line treatment, checkpoint inhibitor therapy would be the first choice because we see quite high response rates; 40%, 50%, 60% of patients are responding, and many are not even achieving a median survival. The response and survival benefits are ongoing for these patients. So in patients who are MSI-high, checkpoint inhibitors would be high on the list in terms of salvage options as well.

Transcript edited for clarity.